Low-level laser treatment stimulates hair growth via upregulating Wnt10b and β-catenin expression in C3H/HeJ mice

Abstract

This study was conducted in order to evaluate the role of low-level laser treatment (LLLT) in hair growth in C3H/HeJ mice. Healthy C57BL/6 mice were randomly divided into two groups: with and without low-level laser treatment. The skin color of each mouse was observed each day. Skin samples were collected for H&E, immunofluorescence, PCR, and western blot analysis, to observe the morphology of hair follicles and detect the expression levels of Wnt10b and β-catenin. Observation of skin color demonstrated that black pigmentation started significantly earlier in the laser group than in the control group. Hair follicle number in both groups showed no difference; however, the hair follicle length presented a significant difference. Wnt10b protein was detected on the second day in hair matrix cells in the LLLT group but not in the control group. PCR and western blot results both illustrated that expression of Wnt10b and β-catenin was significantly higher in the LLLT group than in the control group. Our study illustrated that low-level laser treatment can promote hair regrowth by inducing anagen phase of hair follicles via initiating the Wnt10b/β-catenin pathway.

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Preclinical study of a cost-effective photodynamic therapy protocol for treating oral candidoses

Abstract

Photodynamic therapy (PDT) is a promising treatment for oral candidoses. Its use as an alternative to antifungals prevents several adverse effects, including microbial resistance. However, most PDT protocols do not employ devices and consumables commonly available in dental practice, thus influencing treatment affordability. This study aimed to determine the efficacy of a PDT method based on light curing units' blue LEDs combined to a plaque-disclosing composition (5% erythrosine) against C. albicans in culture and in a murine model of oral candidosis. Standard and resistant fungal strains were tested in vitro in planktonic and biofilm forms. PDT (pre-irradiation time periods: 30 and 60 s; irradiation time: 3 min) was compared to control conditions without light and/or erythrosine. Mice with induced oral candidosis (n = 40) randomly received PDT or similar control conditions with subsequent C. albicans count. These mice underwent histological analysis, as well as 12 healthy mice submitted to experimental treatments. PDT completely inactivated C. albicans planktonic cells and biofilm. Control conditions presented minor differences (ANOVA, p < 0.05), with mean values ranging from 5.2 to 6.8 log10 (UFC/mL). Infected mice presented no significant difference in C. albicans counts consequent to treatments (ANOVA, p = 0.721), although the PDT protocol was able to enhance the inflammatory infiltrate in healthy mice. It can be concluded that the tested PDT protocol can inactivate C. albicans but still needs further investigation in order to achieve efficacy and safety.

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Score of Toxic Epidermal Necrosis Predicts the Outcomes of Pediatric Epidermal Necrolysis

Abstract

Background/Objectives

Epidermal necrolysis (Stevens–Johnson syndrome and toxic epidermal necrolysis) includes immune-mediated, life-threatening inflammatory blistering disorders that can affect children. The Score of Toxic Epidermal Necrosis (SCORTEN) tool has accurately predicted the outcome of these disorders in adults but has not been tested in children.

Methods

We performed a retrospective chart review to compare the accuracy of the adult SCORTEN tool with that of two modifications tailored to children in predicting disease outcome.

Results

The longer the patient's median length of hospital stay was, the higher the adult and two proposed pediatric SCORTENs were. In addition, all patients who died had SCORTENs greater than 4.

Conclusion

The pediatric-modified tools were not superior to the adult SCORTEN, which accurately predicted outcome.

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Pasireotide in an insulin-requiring diabetic acromegalic patient without worsening of hyperglycemia

Summary

Long-acting pasireotide is an effective treatment option for acromegaly, but it is associated with hyperglycemia, which could impact its use in patients with diabetes. We present a case of a 53-year-old man with acromegaly and type 2 diabetes mellitus (glycated hemoglobin (HbA_1c): 7.5%), who refused surgery to remove a pituitary macroadenoma and enrolled in a Phase 3 clinical trial comparing long-acting pasireotide and long-acting octreotide in acromegalic patients. The patient initially received octreotide, but insulin-like growth factor 1 (IGF-1) levels remained elevated after 12 months (383.9 ng/mL; 193.0 ng/mL; reference range: 86.5–223.8 ng/mL), indicating uncontrolled acromegaly. He switched to pasireotide 40 mg and subsequently increased to 60 mg. Within 6 months, IGF-1 levels normalized (193.0 ng/mL), and they were mostly normal for the next 62 months of treatment with pasireotide (median IGF-1: 190.7 ng/mL). Additionally, HbA_1c levels remained similar to or lower than baseline levels (range, 6.7% to 7.8%) during treatment with pasireotide despite major changes to the patient's antidiabetic regimen, which included insulin and metformin. Uncontrolled acromegaly can result in hyperglycemia due to an increase in insulin resistance. Despite having insulin-requiring type 2 diabetes, the patient presented here did not experience a long-term increase in HbA_1c levels upon initiating pasireotide, likely because long-term control of acromegaly resulted in increased insulin sensitivity. This case highlights the utility of long-acting pasireotide to treat acromegaly in patients whose levels were uncontrolled after long-acting octreotide and who manage diabetes with insulin.

Learning points

Long-acting pasireotide provided adequate, long-term biochemical control of acromegaly in a patient with insulin-requiring type 2 diabetes mellitus who was unresponsive to long-acting octreotide.

Glycemic levels initially increased after starting treatment with pasireotide but quickly stabilized as acromegaly became controlled.

Long-acting pasireotide, along with an appropriate antidiabetic regimen, may be a suitable therapy for patients with acromegaly who also have insulin-requiring type 2 diabetes mellitus.

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Establishing Content Validity of the CLEFT-Q: A New Patient-reported Outcome Instrument for Cleft Lip/Palate

Background: The CLEFT-Q is a new patient-reported outcome instrument designed to measure outcomes that matter to patients. The aim of this qualitative study was to establish content validity of the CLEFT-Q in patients who differ by age and culture. Methods: Patients aged between 6 and 29 years were recruited from plastic surgery clinics in Canada, India, Ireland, the Philippines, the Netherlands and the United States. Healthcare providers and other experts participated in a focus group or provided individual feedback. Input was sought on all aspects of the CLEFT-Q (item wording, instructions, and response options), and to identify missing content. Patient interviews and expert feedback took place between September 2013 and September 2014. Results: Sixty-nine patients and 44 experts participated. The first draft of the CLEFT-Q consisted of 163 items measuring 12 constructs. The first round of feedback identified 92 items that required revision. In total, 3 rounds of interviews, and the involvement of an artist to create pictures for 17 items, were needed to establish content validity. At the conclusion of cognitive interviews, the CLEFT-Q consisted of 13 scales (total 171 items) that measure appearance, health-related quality of life, and facial function. The mean Flesch-Kincaid readability statistic for items was 1.4 (0 to 5.2). Conclusion: Cognitive interviews and expert review allowed us to identify items that required re-wording, re-conceptualizing, or to be removed, as well as any missing items. This process was useful for refining the CLEFT-Q scales for further testing.

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Survival Differences in Women with and without Autologous Breast Reconstruction after Mastectomy for Breast Cancer

Background: Breast reconstruction (BR) is an option for women who are treated with mastectomy; however, there has been concern regarding the oncologic safety of BR. In this study, we evaluated recurrences and mortality in women treated with mastectomy and compared outcomes in those treated with mastectomy alone to those with mastectomy plus transverse rectus adbominis (TRAM) flap BR. Methods: The prospective cohort study included women treated with mastectomy at Women's College Hospital from 1987 to 1997. Women with TRAM flap BR were matched to controls based on age and year of diagnosis, stage, and nodal status. Patients were followed from the date of diagnosis until death or date of last follow-up. Hazard ratios were generated to compare cases and controls for outcome variables using Cox's proportional hazards models. Results: Of 443 women with invasive breast cancer, 85 subjects had TRAM flap BR. Sixty-five of these women were matched to 115 controls. The mean follow-up was 11.2 (0.4–26.3) years. There were no significant differences between those with and without BR with weight, height, or smoking status. Women with TRAM flap were less likely to experience a distant recurrence compared to women without a TRAM flap (relative risk, 0.42; P = 0.0009) and were more likely to be alive (relative risk, 0.54; P = 0.03). Conclusions: Women who elect for TRAM flap BR after an invasive breast cancer diagnosis do have lower rates of recurrences and mortality than women treated with mastectomy alone. This cannot be explained by differences in various clinical or lifestyle factors.

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Positive clinical outcome in a patient with recalcitrant bullous pemphigoid treated with rituximab and intravenous immunoglobulin

Summary

A 41-year-old white man was treated for bullous pemphigoid (BP) for 4 years, using high-dose prednisone as well as ciclosporin and mycophenolate mofetil. Sustained clinical improvement was not observed. He suffered several serious side effects. Consequently, he was treated with a combination of rituximab (RTX) and intravenous immunoglobulin (IVIg). He received 12 infusions of RTX in 6 months and monthly IVIg until the end of the therapy. Within 5 weeks of this therapy, appearance of new lesions ceased. Within 8 weeks, all previous lesions resolved and previous medications were discontinued. No hospitalizations, relapses, infections or other serious adverse events occurred. The high levels of pathogenic autoantibody decreased and have remained undetectable. After three infusions of RTX, CD19+ B cells were undetectable and returned to normal levels within 18 months. The patient remains in complete clinical remission off all systemic therapy and free of disease for a 20-month follow-up.

http://ift.tt/2pEStMN

Positive clinical outcome in a patient with recalcitrant bullous pemphigoid treated with rituximab and intravenous immunoglobulin

Summary

A 41-year-old white man was treated for bullous pemphigoid (BP) for 4 years, using high-dose prednisone as well as ciclosporin and mycophenolate mofetil. Sustained clinical improvement was not observed. He suffered several serious side effects. Consequently, he was treated with a combination of rituximab (RTX) and intravenous immunoglobulin (IVIg). He received 12 infusions of RTX in 6 months and monthly IVIg until the end of the therapy. Within 5 weeks of this therapy, appearance of new lesions ceased. Within 8 weeks, all previous lesions resolved and previous medications were discontinued. No hospitalizations, relapses, infections or other serious adverse events occurred. The high levels of pathogenic autoantibody decreased and have remained undetectable. After three infusions of RTX, CD19+ B cells were undetectable and returned to normal levels within 18 months. The patient remains in complete clinical remission off all systemic therapy and free of disease for a 20-month follow-up.

http://ift.tt/2pEStMN

Carbon nanotubes: Culprit or witness of air pollution?

Publication date: Available online 15 May 2017
Source:Nano Today
Author(s): Jelena Kolosnjaj-Tabi, Henri Szwarc, Fathi Moussa
The notorious PM2.5 (2.5μm diameter particulate matters) that can reach human lungs, considered as responsible for most deleterious effects of air pollution, are now unmasked. Anthropogenic carbon nanotubes and other carbon nanoparticles have been unambiguously identified as the major components of PM2.5 in alveolar macrophages of Parisian children. Soot and diesel particulate matter have recognized detrimental health effects. However, information on the health effects of anthropogenic carbon nanotubes, which are the main components of PM2.5 found within human alveolar cells, is still lacking. While nanotechnologists are focused on applications with a profit, notably in the field of nano-biomedicine, the health effects of nano-particulate pollutants attract little of their attention. In an attempt to bridge the research gaps between cutting-edge nanotechnologies, environmental studies and biomedical approaches, this opinion paper attempts to inform the nanotechnology community about critical issues related to airborne anthropogenic carbon nanotubes. The question that has to be urgently addressed is whether carbon nanotubes are the main culprit or act only as nano-vectors of carcinogenic polycyclic aromatic hydrocarbons and other toxic gaseous pollutants.

Graphical abstract

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Water splitting dye-sensitized solar cells

Publication date: Available online 15 May 2017
Source:Nano Today
Author(s): Pengtao Xu, Nicholas S. McCool, Thomas E. Mallouk
Research in artificial photosynthesis is driven by the goal of creating low-cost, integrated systems for the direct conversion of solar energy to high energy density fuels. Water-splitting dye-sensitized solar cells can in principle leverage the successful architecture, spectral tunability, and high quantum efficiency of regenerative photovoltaic dye cells toward this goal. In this article, we review the current development of both dye-sensitized photoanodes and photocathodes for water splitting. A detailed discussion of the individual components of photoanodes and photocathodes – semiconductors, sensitizers, and catalysts – is presented. We review experiments on the electron transfer kinetics that control the efficiency of water splitting, and highlight recent research on electrode architectures that can improve both the efficiency and stability of water-splitting dye cells.

Graphical abstract

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A rounded opacity silhouetting the left heart border and hilum

Pericardial incidentaloma: benign pericardial cyst

από Lin, A. N., Lin, S., Lin, K., Raju, F. στο BMJ Case Reports Last 6 Issues

Μετάφραση άρθρου

Description

A 73-year-old woman with hypertension and atrial fibrillation presented with head and neck injury after mechanical fall. During workup, chest X-ray anteroposterior view (figure 1) revealed a rounded opacity silhouetting the left heart border and hilum. Subsequent contrast-enhanced CT of the chest showed single, 6.4 cm, rounded, well-defined, thin-walled, non-enhanced, low attenuated (–20 and 20 Hounsfield Unit) and homogenous cyst-like structure at the left mediastinum connected to pericardial recesses and not attached to adjacent structures (figure 2A–C). Transthoracic echocardiogram ruled out left ventricular aneurysm, aortic aneurysm, solid tumour and outflow tracts obstruction. Although bronchogenic cyst, oesophageal duplication cyst, thymic tumour and mediastinal lymphoma were considered as possible differentials, radiological features such as CT appearance, homogenous attenuation, unrelated to the underlying structures favoured pericardial cyst. Since patient was asymptomatic, patient and family member were unwilling to undergo surgical removal and pathological confirmation. Follow-up with non-enhanced CT of...

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Novel sulfonamide-containing 2-indolinones that selectively inhibit tumor-associated alpha carbonic anhydrases

Publication date: Available online 15 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Nilgün Karalı, Atilla Akdemir, Füsun Göktaş, Pınar Eraslan Elma, Andrea Angeli, Merih Kızılırmak, Claudiu T. Supuran
Human carbonic anhydrases IX and XII are upregulated in many tumors and form a novel target for new generation anticancer drugs. Here we report the synthesis of novel 2-indolinone derivatives with the sulfonamide group as a zinc binding moiety. Enzyme inhibition assays confirmed that the compounds showed selectivity against hCA IX and XII over the widely distributed off-targets hCA I and II. Molecular modelling studies were performed to suggest modes of binding for these compounds.

Graphical abstract

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Transient hemiparaesthesias and dysarthria

Mitral Stenosis

από Oehler, A. C., Sullivan, P. D., Mansoor, A. M. στο BMJ Case Reports Last 6 Issues

Μετάφραση άρθρου

Description

A previously healthy 29-year-old Mexican woman presented to an emergency department with transient hemiparaesthesias and dysarthria. There was no evidence of stroke on cross-sectional imaging of the head, and she was discharged without a clear diagnosis. Two days later, she returned with acute abdominal pain. Abdominal imaging revealed complete occlusion of the right renal artery, prompting emergency embolectomy. Following the procedure, she developed acute haemoptysis, dyspnoea and hypoxaemia. Chest imaging demonstrated evidence of pulmonary venous hypertension. Cardiac auscultation revealed an opening snap followed by a diastolic murmur with presystolic accentuation. These sounds were better appreciated in combination with phonocardiography, a technique supplanted by echocardiography in the 1970s1 that visualised heart sounds (video 1). An echocardiogram confirmed the presence of mitral stenosis (MS), unifying the syndrome of embolic phenomena, haemoptysis and pulmonary hypertension. She underwent successful mitral valve replacement and has since returned to normal...

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Assessment of perception, experience, and information-seeking behavior of the public of Ras Al-Khaimah, United Arab Emirates, toward usage and safety of complementary and alternative medicine

Sathvik Belagodu Sridhar, Atiqulla Shariff, Nour Al Halabi, Rand Sarmini, Lubab Arkan Harb

Journal of Pharmacy And Bioallied Sciences 2017 9(1):48-55

Aims and Objectives: This study was conducted to identify the different types of complementary and alternative medicine (CAM) used, reasons for the use of CAM, and the perceptions, experience, and information seeking-behavior toward usage and safety of CAM by the general public of Ras Al-Khaimah, UAE. Materials and Methods: This was a prospective cross-sectional study. A validated, self-administered, or interviewer-assisted survey questionnaire was used to collect the data. Data from 403 respondents satisfying inclusion criteria were collected and were analyzed using the Statistical Package for the Social Sciences version 24.0. Results: A majority of the respondents (218 [54.1%]) were females. The most commonly (210 [52.1%]) used CAM among the study respondents was herbal medicine. A total of 91 (22.6%) of the survey respondents mentioned that they receive conventional medications along with their CAM. Majority (213 [52.9%]) of the survey respondents opted for CAM to prevent illness. Good number (208 [51.6%]) of the survey respondents mentioned that CAM usage was beneficial in improving their health condition, and they (216 [53.6%]) do believe it as safe and effective. However, a small group (26 [6%]) of respondents reported side effects or complications with the use of CAM. Conclusion: Widespread use of CAM for different medical problems was evident in our study. Although majority of the CAM users believe it as safe and effective, CAM usage should be discussed with the health-care providers to understand the safety issues involved in the use of majority of CAM.

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Modulatory effects of Decalepis hamiltonii extract and its compounds on the antioxidant status of the aging rat brain

Ramachandregowda Sowbhagya, Siddhaghatta Kariyappa Anupama, Dundaiah Bhagyalakshmi, Santosh Anand, Tekupalli Ravikiran

Journal of Pharmacy And Bioallied Sciences 2017 9(1):8-15

Objective: The present study was aimed to investigate the neuroprotective effects of Decalepis hamiltonii (Dh) aqueous root extract and its compounds against age-related oxidative stress (OS) in the discrete regions of the rat brain. Materials and Methods: Male Wistar albino rats of 4- and 22-month-old were divided into control and six supplemented groups. The supplemented groups were orally administered with ellagic acid (EA), 4-hydroxyisophthalic acid (4-HIA), and Dh extract for 30 days. Results: Age-related decrease in antioxidant enzyme activities was noticed. The hippocampus was found to be more vulnerable to OS as seen by the elevation in the OS markers. Supplementation of the Dh extract, EA, and 4-HIA was found to be effective in up-regulating the antioxidant status. However, the extent of up-regulation was more evident in Dh supplemented animals. Conclusion: Our results suggest that Dh extract and its compounds exhibit neuroprotective effects against age-related OS and can be used as a dietary therapeutic intervention for the treatment of neurological disorders.

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Estimation of guggulsterone E and Z in the Guggul-based commercial formulations using high-performance thin-layer chromatography

Pramod Kumar Sairkar, Anjana Sharma, NP Shukla

Journal of Pharmacy And Bioallied Sciences 2017 9(1):1-7

Background: Guggulsterone (GS) is a plant steroid and bioactive compound present in gum Guggul of Commiphora wightii. An Indian herbal medicine system "Ayurveda" has a long history of use of gum Guggul and plant extract of C. wightii as medicine for the treatment of various illnesses. Complex nature, low availability, and inconsistency of phytoconstituents make its analysis of difficult tasks. Aims: In this work, six different Guggul-based herbal formulations were examined for estimation of GS and their isomers (E and Z) through high-performance thin-layer chromatography technique. Materials and Methods: For that various concentrations of standard E-GS and Z-GS (50 ng–250 ng/spot) with samples (20 μg/spot) were applied on silica gel coated aluminum plate and developed with the mobile phase of toluene: ethyl acetate: formic acid: methanol (6:2:1:0.5). The scanning was performed at 254 nm wavelength and the absorbance (scan) spectrum of E-GS and Z-GS peak was generated at 200 nm–400 nm wavelength range. Results and Conclusions: Rf value and scan spectrum pattern of the samples reveal that they contain either one form of GS (E-GS, Z-GS) or both. The quantity of E-GS and Z-GS within the samples was ranged from 0.230 ± 0.0040–0.926 ± 0.0168% to 0.537 ± 0.0026–0.723 ± 0.0177%, respectively.

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Prevalence, pattern, and correlates of alcohol misuse among male patients attending rural primary care in India

Sanghamitra Pati, Subhashisa Swain, Sandeep Mahapatra, Mohammad Akhtar Hussain, Sandipana Pati

Journal of Pharmacy And Bioallied Sciences 2017 9(1):66-72

Background: There are limited data available on how the problem of alcohol use is detected in primary care setting in India. Particularly in Odisha, it has not been investigated yet. This study was conducted to determine the prevalence of drinking, drinking patterns, and quitting behavior among the male patients visiting a primary health-care facility in a district of Odisha. Methodology: A cross-sectional study was conducted among patients attending community health center (CHC), Buguda in the state of Odisha, India, from December 1, 2014, to February 31, 2015. Patients above 18 years of age, conscious, and willing to participate in the study were included in the study, while those with cognitive impairment and critically ill were excluded from the study. All eligible consecutive patients attending outpatient department of CHC were invited to participate while they came out after physician's consultation. A pilot study was conducted prior to the study. Informed verbal consent from each patient was obtained before the interview. The study was approved by the Institutional Ethics Committee of Indian Institute of Public Health, Bhubaneswar. Results: A total of 431 patients were interviewed. Our study showed 38% (95% confidence interval [CI]: 33.5%–42.7%) of respondents were alcoholic and of those 60% (95% CI: 51.4%–66.5%) were hazardous drinkers. One in five patients had a history of alcoholics in their family, and a similar proportion of participants were heavy workers. Smokers were eight times (adjusted odds ratio [AOR] =7.56; 4.03–14.52) more likely to be alcoholics as compared to nonsmokers (P

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Moisture sorption–desorption characteristics and the corresponding thermodynamic properties of carvedilol phosphate

Ravikiran Allada, Arthanareeswari Maruthapillai, Kamaraj Palanisamy, Praveen Chappa

Journal of Pharmacy And Bioallied Sciences 2017 9(1):16-21

Aims: Carvedilol phosphate (CDP) is a nonselective beta-blocker used for the treatment of heart failures and hypertension. In this work, moisture sorption–desorption characteristics and thermodynamic properties of CDP have been investigated. Materials and Methods: The isotherms were determined using dynamic vapor sorption analyzer at different humidity conditions (0%–90% relative humidity) and three pharmaceutically relevant temperatures (20°C, 30°C, and 40°C). The experimental sorption data determined were fitted to various models, namely, Brunauer–Emmett–Teller; Guggenheim-Anderson-De Boer (GAB); Peleg; and modified GAB. Isosteric heats of sorption were evaluated through the direct use of sorption isotherms by means of the Clausius-Clapeyron equation. Statistical Analysis Used: The sorption model parameters were determined from the experimental sorption data using nonlinear regression analysis, and mean relative percentage deviation (P), correlation (Correl), root mean square error, and model efficiency were considered as the criteria to select the best fit model. Results: The sorption–desorption isotherms have sigmoidal shape – confirming to Type II isotherms. Based on the statistical data analysis, modified GAB model was found to be more adequate to explain sorption characteristics of CDP. It is noted that the rate of adsorption and desorption is specific to the temperature at which it was being studied. It is observed that isosteric heat of sorption decreased with increasing equilibrium moisture content. Conclusions: The calculation of the thermodynamic properties was further used to draw an understanding of the properties of water and energy requirements associated with the sorption behavior. The sorption–desorption data and the set of equations are useful in the simulation of processing, handling, and storage of CDP and further behavior during manufacture and storage of CDP formulations.

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Influence of milling process on efavirenz solubility

Erizal Zaini, Deni Wahyu, Maria Dona Octavia, Lili Fitriani

Journal of Pharmacy And Bioallied Sciences 2017 9(1):22-25

Introduction: The aim of this study was to investigate the influence of the milling process on the solubility of efavirenz. Materials and Methods: Milling process was done using Nanomilling for 30, 60, and 180 min. Intact and milled efavirenz were characterized by powder X-ray diffraction, scanning electron microscopy (SEM), spectroscopy infrared (IR), differential scanning calorimetry (DSC), and solubility test. Results: The X-ray diffractogram showed a decline on peak intensity of milled efavirenz compared to intact efavirenz. The SEM graph depicted the change from crystalline to amorphous habit after milling process. The IR spectrum showed there was no difference between intact and milled efavirenz. Thermal analysis which performed by DSC showed a reduction on endothermic peak after milling process which related to decreasing of crystallinity. Solubility test of intact and milled efavirenz was conducted in distilled water free CO2with 0.25% sodium lauryl sulfate media and measured using high-performance liquid chromatography method with acetonitrile: distilled water (80:20) as mobile phases. The solubility was significantly increased (P

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Prevalence of exposure to secondhand smoke among higher secondary school students in Ernakulam District, Kerala, Southern India

PS Rakesh, Jishnu Satheesh Lalu, K Leelamoni

Journal of Pharmacy And Bioallied Sciences 2017 9(1):44-47

Introduction: The association between secondhand smoke and health outcomes, such as frequent respiratory infections, ischemic heart disease, lung cancer, asthma, and stroke, has long been established. The study aimed to estimate the prevalence of secondhand smoking exposure among higher secondary school students in Ernakulam district, Kerala, Southern India. Materials and Methods: A structured questionnaire was administered to all students from four randomly selected higher secondary schools in Ernakulam district. Descriptive statistics was done using frequencies and percentages. Univariate and multivariate analyses were done for factors associated with household exposure to tobacco smoke generating odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 629 students participated in the study. The prevalence of ever smokers was 11.9% and of current smokers was 5.2%. Among the study participants, 23.2% were exposed to secondhand smoking from a family member and 18.8% from friends. Lower educational status of father was associated with the household exposure to secondhand smoke (adjusted OR 4.51 [95% CI 1.66–12.22]). More than half of the study participants (56.3%) reported that they were exposed to cigarette smoke in past 1 week in a public place and 10.2% in closed public places. Nearly one-third of the students reported that they have seen somebody smoking inside school campus in the past 30 days. Conclusion: Exposure to secondhand smoke at home, schools, and public places was higher among the late adolescent higher secondary school students in Ernakulam district. The findings underscore the urgent need for increased efforts to implement the strategies to reduce secondhand smoke exposure among adolescents.

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Chromatographic isolation and spectroscopic identification of phytoconstituents of jujuba seeds (Zizyphus jujuba Mill.)

Md Manowwar Alam, Abuzer Ali, Mohammad Ali, Showkat R Mir

Journal of Pharmacy And Bioallied Sciences 2017 9(1):26-32

Background: The seeds of Zizyphus jujuba Mill. (Rhamnaceae) are astringent, aphrodisiac, tonic; used to cure cough, asthma, vomiting, burning sensation, biliousness, leucorrhoea, and eye infections in traditional systems of medicine. Materials and Methods: The methanol extract of seeds of Z. jujuba was partitioned into petroleum ether and water soluble fractions. Isolation of compounds was performed by silica gel column chromatography. The structures of isolated compounds were established on the basis of spectral studies and chemical reactions. Results: Chromatographic separation of methanolic extract of seeds yielded three new phyto-constituents characterized as 3, 5, 7-trimethoxy-8, 3′, 4′, 5′-tetrahydroxy flavone-6-oxy hexahydrobisabolene ether (4), 1, 9-dihydroxy tetrahydrogeranyl-8-oxy-O-β-D-glucuronopyranoside (5) and terahydrogeranyl-8-oxy-O-β-D-glucuronopyranosyl (2a→1b)-O-β-D-glucofuranosyl (2b→1c)-O-β-D-glucofuranosyl (2c→1d)-O-β-D-glucopyranosyl (2d→1e)-O-β-D-glucopyranosyl (2c→f)-O-β-D-glucopyranosyl-2f-benzoate (6) along with five known compounds, palmitoyl palmitoleoyl arachidoyl glyceride (1), tetratriacontenoic acid (2), palmitoyl oleoyl linolenoyl glyceride (3), hexanyl tetraglucoside (7) and pentasaccharide (8). Conclusion: This is the first report of saturated monoterpene and sesquiterpene derivatives from jujuba seeds.

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Efficacy and tolerability of antihypertensive drugs in diabetic and nondiabetic patients

Maria Aslam, Mobasher Ahmad, Fizza Mobasher

Journal of Pharmacy And Bioallied Sciences 2017 9(1):56-65

Objectives of the Study: The aim of the study was to compare the efficacy and tolerability of different classes of antihypertensive drugs in diabetic and nondiabetic patients (NDPs) with essential hypertension. Material and Methods: The study was conducted in Mayo Hospital, Punjab Institute of Cardiology, and National Defence Hospital, Lahore, Pakistan, on 200 hypertensive patients with diabetes and 230 hypertensive patients without (Three hospitals) diabetes. Both male and female patients of age between 30 and 80 years with systolic blood pressure (SBP) above 130 mmHg and diastolic blood pressure (DBP) above 80 mmHg were enrolled in the study. Angiotensin converting enzyme inhibitors (ACEI), beta-blocker (βB), calcium-channel blocker (CCB), diuretics (D), angiotensin receptor blocker (ARB) as well as α-blocker classes of antihypertensive drugs were used. These drugs were used as monotherapy as well as combination therapy. The study was conducted for 4 months (July–October). After 4 months, patients were assessed for efficacy by monitoring blood pressure (BP) and tolerability by assessing safety profile on renal function, liver function as well as lipid profile. Results: Significant control in mean BP by all drug groups was observed in "both groups that is patients with diabetes and without diabetes." The efficacy and tolerability data revealed that in diabetic patients with hypertension, the highest decrease in SBP and DBP was observed using monotherapy with ACEI, two-drug combination therapy with ACEI plus diuretic, ARBs plus diuretic, ACEI plus CCBs, three-drug combination therapy with ACEI plus CCBs plus diuretic, and four drug combination therapy with ACEI plus CCBs plus diuretic plus βBs, ARB's plus CCBs plus diuretic plus βBs while in NDPs, monotherapy with diuretic, two-drug combination therapy with ACEI plus CCBs, ACEI plus βBs, three-drug combination therapy with βBs plus ACEI plus D was found more effective in controlling SBP as well as DBP. Adverse effects observed were dry cough, pedal edema, dizziness, muscular cramps, constipation, palpitations, sweating, vertigo, tinnitus, paresthesia, and sexual dysfunction. Conclusion: All classes of antihypertensives were found to control blood pressure significantly in both groups of patients that is diabetic patients with hypertesion and non-diabetic patients with hypertension.

http://ift.tt/2rkM4n7

Evaluation of Cassia tora Linn. against oxidative stress-induced DNA and cell membrane damage

R Sunil Kumar, Ramesh Balenahalli Narasingappa, Chandrashekar G Joshi, Talakatta K Girish, Ummiti JS Prasada Rao, Ananda Danagoudar

Journal of Pharmacy And Bioallied Sciences 2017 9(1):33-43

Objective: The present study aims to evaluate antioxidants and protective role of Cassia tora Linn. against oxidative stress-induced DNA and cell membrane damage. Materials and Methods: The total and profiles of flavonoids were identified and quantified through reversed-phase high-performance liquid chromatography. In vitro antioxidant activity was determined using standard antioxidant assays. The protective role of C. tora extracts against oxidative stress-induced DNA and cell membrane damage was examined by electrophoretic and scanning electron microscopic studies, respectively. Results: The total flavonoid content of CtEA was 106.8 ± 2.8 mg/g d.w.QE, CtME was 72.4 ± 1.12 mg/g d.w.QE, and CtWE was 30.4 ± 0.8 mg/g d.w.QE. The concentration of flavonoids present in CtEA in decreasing order: quercetin >kaempferol >epicatechin; in CtME: quercetin >rutin >kaempferol; whereas, in CtWE: quercetin >rutin >kaempferol. The CtEA inhibited free radical-induced red blood cell hemolysis and cell membrane morphology better than CtME as confirmed by a scanning electron micrograph. CtEA also showed better protection than CtME and CtWE against free radical-induced DNA damage as confirmed by electrophoresis. Conclusion: C. tora contains flavonoids and inhibits oxidative stress and can be used for many health benefits and pharmacotherapy.

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Marfan syndrome

T Sivasankari, Philips Mathew, Ravi David Austin, Sakthi Devi

Journal of Pharmacy And Bioallied Sciences 2017 9(1):73-77

Marfan syndrome (MFS) is the autosomal dominant-inherited multisystem connective-tissue disorder, with a reported incidence of 1 in 10,000 individuals and equal distribution in both genders. The main clinical manifestation of this disorder consists of an exaggerated length of the upper and lower limbs, hyperlaxity, scoliosis, alterations in the cardiovascular and pulmonary systems, and atypical bone overgrowth. Orofacial manifestations such as high-arched palate, hypodontia, long narrow teeth, bifid uvula, mandibular prognathism, and temporomandibular disorders are also common. Early diagnosis of MFS is essential to prevent the cardiovascular complications and treatment of orofacial manifestations, thus to increase the quality of life of the patient.

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Detection of HER2 Amplification in Circulating Tumor Cells of HER2-Negative Gastric Cancer Patients

Abstract

A key to the successful use of targeted cancer therapy is the ability to preselect patients who are likely to benefit from the treatment according to molecular markers. Assessment for predicting therapy response is mostly done using tumor biopsies. However, these might not truly represent all of the patient's malignant cells because of tumor heterogeneity and/or clonal evolution during disease progression. One potential strategy that can complement primary tumor biopsy is the analysis of circulating tumor cells (CTCs). In this study, we analyzed CTCs of patients with gastric cancer (GC) to find those who were likely to benefit from trastuzumab therapies. We developed an imaging-based method that enabled CTC identification simultaneously with evaluation of HER2 gene amplification (the 3D–IF-FISH method). Then we performed a study enrolling 101 GC patients in whom we analyzed CTCs by both 3D–IF-FISH and an FDA-approved CellSearch system. As compared with the CellSearch system, 3D–IF-FISH methods identified a higher number of patients whose primary tumors were HER2- but who had HER2+ CTCs, suggesting that the 3D–IF-FISH method is effective in preselecting patients for trastuzumab therapies. To demonstrate this, we performed an exploratory clinical study to evaluate the clinical benefits of trastuzumab treatment for advanced GC patients (n = 15) whose primary tumors were HER2-, but whose CTCs showed HER2 amplification. An interim evaluation after the first stage showed that these preselected patients had response rates comparable to those reported in the trastuzumab-plus-chemotherapy arm of the ToGA study. The present study offers a new, non-invasive strategy to select patients who are likely to benefit from trastuzumab-based therapies, despite their primary biopsy being HER2-negative. (UMIN ID: UMIN000008622).

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The development and use of a drug-induced immunosuppressed rat-model to screen Phela for mechanism of immune stimulation

Publication date: 12 July 2017
Source:Journal of Ethnopharmacology, Volume 206
Author(s): Makhotso Rose Lekhooa, Andrew Walubo, Jan B. du Plessis, Motlalepula Gilbert Matsabisa
Ethnopharmacology relevancyPhela, is code name for a medicinal product made from four South African traditional medicinal plants (Clerodendrum glabrum E. Mey, Polianthes tuberosa (Linn.), Rotheca myricoides (Hochst.) Steane & Mabb. and Senna occidentalis (L.) Link). All these plants have established traditional use in a wide spectrum of diseases. Phela is under development for use as an immune booster in immunocompromised patients, which includes patients with the human immunodeficiency virus (HIV). Already several studies, both pre-clinical and clinical, have shown that Phela is a safe and effective immune booster. Despite some studies on the action of Phela, the mechanism of action by Phela is still not known. Understanding the mechanism of action will enable safer and effective use of the drug for the right indications. Unfortunately, there is no well characterized test-system for screening products for immune stimulant activity. Therefore, the objective of this study was to use Phela as the test article, to develop and validate a rat-model (test system) by which to screen medicines for immune stimulant activity.Material and methodsFirst, the batch of Phela used was authenticated by high performance liquid chromatography (HPLC) techniques; analytical methods for the immunosuppressant drugs, cyclosporine A (CsA), cyclophosphamide (CP) and dexamethasone (Dex) were developed and validated; and a slide-A-Lyzer dialysis was used to test for potential interactions in rat plasma of Phela with CsA, CP and Dex. Thereafter, using Sprague Dawley (SD) rats and in separate experiments, the effective dose of Phela in the study animals was determined in a dose ranging study with levamisole, a known immune stimulant as the positive control; the appropriate doses for immunosuppression by CsA, CP and Dex were determined; the time to reach 'established immunosuppression' with each drug was determined (it was also the time for intervention with Phela); and eventually, the effect of Phela on the immune system was tested separately for each drug induced immunosuppression. The immune system was monitored by observing for changes in plasma profiles of IL-2, IL-10, IgG, IgM, CD4 and CD8 cell counts at appropriate intervals, while in addition to function tests, the kidneys, liver, spleen, thymus, were weighed and examined for any pathology.ResultsThe chromatographic fingerprint certified this batch of Phela as similar to the authentic Phela. There was no significant interaction between Phela and CsA, CP and Dex. The effective dose of Phela was determined to be 15.4mg/kg/day. Phela led to a moderate increase in the immune parameters in the normal rats. Co-administration of Phela 15mg/kg/day orally for 21 days with CsA led to stoppage and reversal of the immunosppressive effects of CsA that were exhibited as increased IL-2, IL-10, CD4 and CD8 counts, implying that Phela stimulates the cell mediate immunity (CMI). For CP, Phela led to stoppage and reversal, though moderate, of CP-induced suppression of IL-10, IgM and IgG only, implying that Phela stimulates the humoral immunity (HI) too. Phela had no effect on Dex induced immunosuppression. Stimulation of the CMI means that Phela clinical testing programme should focus on diseases or disorders that compromise the CMI, e.g., HIV and TB. The stimulation of the HI immunity means that Phela may stimulate existing memory cells to produce antibodies.ConclusionThe present study has revealed Phela's mechanism of action as mainly by stimulation of the CMI, implying that the use of Phela as immune booster in HIV patients is appropriate; and that using Phela as the test product, a rat model for screening medicinal products for immune stimulation has been successfully developed and validated, with a hope that it will lead to the testing of other related medicinal products.

Graphical abstract

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Tropical ulcer plant treatments used by Papua New Guinea's Apsokok nomads

Publication date: 9 June 2017
Source:Journal of Ethnopharmacology, Volume 205
Author(s): Thomas A.K. Prescott, Peter Homot, Fionnuala T. Lundy, Rui Fang, Sheila Patrick, Rodrigo Cámara-Leret, Robert Kiapranis
Ethnopharmacological relevanceThe tropical ulcer is a debilitating bacterial infection that is common in Papua New Guinea. Deploying healthcare infrastructure to remote and inaccessible rainforest locations is not practical, therefore local plants may be the best treatment option. Here we present an ethnobotanical survey of the tropical ulcer plant medicines used by the semi-nomadic Apsokok who roam the remote central mountains of Papua New Guinea's West New Britain Province. In vitro biological activity in assays relevant to tropical ulcer wound healing is also presented.Materials and methodsFocus groups and semi-structured interviews were used to acquire information on the uses of plants, vouchers of which were identified by comparison with authentic herbarium specimens. Antibacterial disc diffusion assays with Staphylococcus aureus and Fusobacterium ulcerans, MMP-9 enzyme inhibition and dermal fibroblast stimulation assays were carried out on plant saps and aqueous extracts of plant material. LC-MS was used to identify known plant metabolites.ResultsThe ethnobotanical survey identified sixteen species that were used to treat tropical ulcers, all of which were applied topically. A subset of twelve species were investigated further in vitro. Four species produced zones of inhibition with S. aureus, all 12 species provided low level inhibition of MMP-9 and 8 species stimulated dermal fibroblast proliferation, although cytotoxicity occurred at higher concentrations. The extract of Homalium foetidum Benth. inhibited S. aureus and MMP-9 while at lower sub-cytotoxic concentrations stimulated fibroblast proliferation. Trans-3-O-p-coumaroylquinic acid cis-3-O-p-coumaroylquinic acid were detected in the aqueous extract of H. foetidum.ConclusionsTopical application of plant saps to wounds results in very high localised concentrations of plant metabolites which is likely to result in inhibition of MMP proteases. H. foetidum is a candidate plant for tropical ulcer treatment in remote areas.

Graphical abstract

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A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed. The Oncologist 2017;22:1–6

Key Points.

To our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.

Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.

Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases.

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Real-World Data on Prognostic Factors for Overall Survival in EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Gefitinib

Background.

This study aimed to identify independent prognostic factors for overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation and receiving gefitinib as first-line treatment in real-world practice.

Materials and Methods.

We enrolled 226 patients from June 2011 to May 2013. During this period, gefitinib was the only EGFR-tyrosine kinase inhibitor reimbursed by the Bureau of National Health Insurance of Taiwan.

Results.

The median progression-free survival and median OS were 11.9 months (95% confidence interval [CI]: 9.7–14.2) and 26.9 months (21.2–32.5), respectively. The Cox proportional hazards regression model revealed that postoperative recurrence, performance status (Eastern Cooperative Oncology Grade [ECOG] ≥2), smoking index (≥20 pack-years), liver metastasis at initial diagnosis, and chronic hepatitis C virus (HCV) infection were independent prognostic factors for OS (hazard ratio [95% CI] 0.3 [0.11–0.83], p = .02; 2.69 [1.60–4.51], p < .001; 1.92 [1.24–2.97], p = .003; 2.26 [1.34–3.82], p = .002; 3.38 [1.85–7.78], p < .001, respectively). However, brain metastasis (BM) at initial diagnosis or intracranial progression during gefitinib treatment had no impact on OS (1.266 [0.83–1.93], p = .275 and 0.75 [0.48–1.19], p = .211, respectively).

Conclusion.

HCV infection, performance status (ECOG ≥2), newly diagnosed advanced NSCLC without prior operation, and liver metastasis predicted poor OS in EGFR mutation-positive advanced NSCLC patients treated with first-line gefitinib; however, neither BM at initial diagnosis nor intracranial progression during gefitinib treatment had an impact on OS. The Oncologist 2017;22:1–9

Implications for Practice.

The finding that chronic hepatitis C virus (HCV) infection might predict poor overall survival (OS) in epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (NSCLC) patients treated with first-line gefitinib may raise awareness of benefit from anti-HCV treatment in this patient population. Brain metastasis in the initial diagnosis or intracranial progression during gefitinib treatment is not a prognostic factor for OS. This study, which enrolled a real-world population of NSCLC patients, including sicker patients who were not eligible for a clinical trial, may have impact on guiding usual clinical practice.

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Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

ALK rearrangements have been observed in 0.05%–2.5% of patients with colorectal cancers (CRCs) and are predicted to be oncogenic drivers largely mutually exclusive of KRAS, NRAS, or BRAF alterations. Here we present the case of a patient with metastatic CRC who was treatment naïve at the time of molecular testing. Initial ALK immunohistochemistry (IHC) staining was negative, but parallel genomic profiling of both circulating tumor DNA (ctDNA) and tissue using similar hybrid capture-based assays each identified an identical STRN-ALK fusion. Subsequent ALK IHC staining of the same specimens was positive, suggesting that the initial result was a false negative. This report is the first instance of an ALK fusion in CRC detected using a ctDNA assay. The Oncologist 2017;22:1–6

Key Points.

Current guidelines for colorectal cancer (CRC) only recommend genomic assessment of KRAS, NRAS, BRAF, and microsatellite instability (MSI) status.

ALK rearrangements are rare in CRC, but patients with activating ALK fusions have responded to targeted therapies

ALK rearrangements can be detected by genomic profiling of ctDNA from blood or tissue, and this methodology may be informative in cases where immunohistochemistry (IHC) or other standard testing is negative.

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Immunotherapy for Head and Neck Squamous Cell Carcinoma: A Review of Current and Emerging Therapeutic Options

Advances in the field of cancer immunotherapy have occurred rapidly over the past decade. Exciting results from clinical trials have led to new treatment options and improved survival for patients with a myriad of solid tumor pathologies. However, questions remain unanswered regarding duration and timing of therapy, combination regimens, appropriate biomarkers of disease, and optimal monitoring of therapeutic response. This article reviews emerging immunotherapeutic agents and significant clinical trials that have led to advancements in the field of immuno-oncology for patients with head and neck squamous cell carcinoma. The Oncologist 2017;22:1–15

Implications for Practice: This review article summarizes recently developed agents that harness the immune system to fight head and neck squamous cell carcinoma. A brief review of the immune system and its role in cancer development is included. Recently completed and emerging therapeutic trials centering on the immune system and head and neck cancer are reviewed.

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Medroxyprogesterone acetate drives M2 macrophage differentiation toward a phenotype of decidual macrophage

Publication date: Available online 15 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Yung-Chieh Tsai, Joseph T. Tseng, Chia-Yih Wang, Mei-Tsz Su, Jyun-Yuan Huang, Pao-Lin Kuo
M1 macrophage differentiation plays a crucial role in enhanced inflammation during pregnancy, which may lead to pregnancy complications. Therefore, modulation of macrophage differentiation toward the M2 phenotype is desirable to ensure a successful pregnancy. Medroxyprogesterone acetate (MPA) is a potent progestin with an anti-inflammatory property, but its effect on macrophage differentiation is unknown. This study aimed to examine whether MPA can induce an M2 macrophage differentiation by using the human monocytes cell line THP-1 or primary monocytes. THP-1 cells were primed with phorbol-12-myristate-13 acetate (PMA) to initiate macrophage differentiation. By incubating with MPA, the cells (denoted as MPA-pTHP-1) underwent M2 macrophage differentiation with downregulations of CD11c, IL-1β and TNF-α, and upregulations of CD163 and IL-10; while cells incubated with progesterone (P4) did not show the M2 phenotype. Primary monocytes treated with MPA also had the same M2 phenotype. Moreover, M1 macrophages derived from IFN-γ/LPS-treated THP-1 cells, which had high levels of IL-1b and iNOS, and low levels of IL-10 and IDO, were reversed to the M2 phenotype by the MPA treatment. We also found that the MPA-pTHP-1 promoted the decidualization of endometrial stromal cells and the invasion of trophoblast cells. To mimic conditions of exposure to various pathogens, MPA-pTHP-1 cells were stimulated by different types of TLR ligands. We found they produced lower levels of IL-1β and TNF-α, as well as a higher level of IL-10, compared to untreated cells. Finally, we found the level of phosphorylated ERK in the MPA-pTHP-1 cells was increased, but its IL-10 production was suppressed by either the progesterone/glucocorticoid antagonist (Mifepristone) or MEK inhibitor (U0126). Taken together, MPA could drive monocyte differentiation toward an M2 phenotype that mimics decidual macrophages. This finding holds great potential to combat chronic endometrial inflammation.



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May iotaderma (#279)

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Injectable and topical neurotoxins in dermatology

The use of neuromodulators for therapeutic and cosmetic indications has proven to be remarkably safe. While aesthetic and functional adverse events are uncommon, each anatomic region has its own set of risks of which the physician and patient must be aware before treatment. The therapeutic usages of botulinum toxins now include multiple specialties and multiple indications. New aesthetic indications have also developed, and there has been an increased utilization of combination therapies to combat the effects of global aging.

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CME examination

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Answers to CME examination

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Acral lesions with an underlying internal malignancy

A 58-year-old Hispanic woman with cholangiocarcinoma of the common bile duct resected 1 year before consultation (Fig 1) presented with a 1-month history of bilateral, asymptomatic, fissured, hyperkeratotic purple-red plaques on her first and second fingers and xanthonychia and onycholysis of all fingernails (Fig 2). There was no significant irritant or allergen exposure. Clobetasol propionate 0.05% with occlusion once daily and emollients had no effect. Lesions spread toward the fifth finger and dorsal surfaces of her hands.

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Dermatology: An illustrated colour text, 6th ed

Dermatology: An illustrated colour text, 6th ed, by Elsevier is the newest edition of the illustrated introductory dermatology text. Dermatology: An illustrated colour text continues to be targeted toward medical students, general practitioners, and early resident trainees with the objective of introducing the diagnosis and management of common dermatologic diseases. It is a concise, well-organized text with significant supplemental online resources to expand the scope of the text. The authors, Drs Gawkrodger and Ardern-Jones, succeed with the newest edition in providing both a readable introductory text and covering a wide range of dermatologic topics.

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JAAD Case Reports Article List

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Answers to CME examination

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Table of Contents

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Injectable and topical neurotoxins in dermatology

Botulinum toxin is a potentially deadly anaerobic bacterial toxin that acts by inhibiting release of acetylcholine at the neuromuscular junction, thereby inhibiting contraction of the exposed striated muscle. There are currently 4 botulinum toxin preparations approved by the US Food and Drug Administration (FDA): onabotulinumtoxin, abobotulinumtoxin, incobotulinumtoxin and rimabotulinumtoxin. While significant overlap exists, each product has unique properties and specifications, including dosing, diffusion, and storage.

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Approaching skin examinations with sensitivity: Guidance in a sexual assault crisis

See related article on page 1221.

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Pink nodule on the sole

A 59-year-old white woman presented with a 5-year history of an asymptomatic 5-mm × 6-mm pink nodule with a superficial crust on the sole of her left foot (Fig 1). Dermoscopy revealed an amelanotic lesion, with a central yellowish crust, with scattered dotted vessels, surrounded by a chrysalis-like rolled border with hairpin vessels and short fine telangiectasia (Fig 2). Excision of the lesion was performed, with the histology shown in Fig 3.

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Apremilast in the treatment of moderate to severe hidradenitis suppurativa: A case series of 9 patients

To the Editor: Despite the many therapeutic approaches available for hidradenitis suppurativa, there is still a need for effective medications to treat moderate and severe forms of the disease. In this study, we assessed the efficacy of the oral phosphodiesterase 4 inhibitor apremilast (30 mg, twice a day) in the management of 9 patients with moderate to severe hidradenitis suppurativa (Hurley stage II-III) who had responded poorly to other treatments.

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CME examination

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Cover Sheet for Index

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Subungual tumor on the left index finger with light yellowish discoloration

A 37-year-old man presented with a 5-year history of nail dystrophy on his left index finger. The lesion recently developed intermittent pain and tenderness on the periungual area because of its increase in size and the consequential nail ingrowth. The patient remembered that the mass had enlarged gradually over the past 5 years. He did not recall any trauma before the onset of the nail abnormalities. Previous antifungal therapy and perilesional triamcinolone injection had not led to improvement.

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Ethical mutiny: When the captain of the ship is an outlier

This case highlights the ethical dilemma inherent in becoming an employed physician in a practice whose owner encourages unethical behavior. Dermatology guidelines are generated to specify acceptable clinical practices. What is a dermatologist's obligation upon learning that those guidelines are not being followed in their practice?

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Itch intensity in moderate-to-severe plaque psoriasis versus atopic dermatitis: A meta-analysis

To the Editor: Atopic dermatitis is commonly referred to as the "itch that rashes,"1 whereas plaque psoriasis has not traditionally been viewed as a pruritic dermatosis. More recently, the role of pruritus in psoriasis has emerged as an important symptom affecting quality of life, and clinical trials for psoriasis have begun using itch scores more consistently as an outcome measure.2,3 To date, there have been no studies directly comparing itch intensity in atopic dermatitis and plaque psoriasis.

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Loss of efficacy of secukinumab for psoriasis at 24 to 32 weeks: Update and commentary

To the Editor: After the publication of our letter,1 we received inquiries regarding our study and patient population. We appreciate the interest in our work and would like to clarify our study, report updates, and propose potential explanations for our findings.

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Yellow plaques on the hands of a 10-year-old girl

A 10-year-old Lebanese girl presented with intertriginous yellow plaques on both hands (Fig 1). The lesions were asymptomatic. On further history and examination, she had a significant family history of dyslipidemia, similar skin lesions on both knees and elbows, and a carotid bruit. A fasting lipid profile showed total cholesterol of 800 mg/dL, low-density lipoprotein of 544 mg/dL, high-density lipoprotein of 128 mg/dL, and triglycerides of 312 mg/dL. A carotid duplex ultrasonography scan revealed 50% carotid stenosis on the right side, and a 2-dimensional echocardiogram revealed mild mitral regurgitation.

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Reproductive factors, exogenous hormone use, and risk of pancreatic cancer in postmenopausal women

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Geoffrey C. Kabat, Victor Kamensky, Thomas E. Rohan
IntroductionThe epidemiologic literature on menstrual and reproductive factors associated with pancreatic cancer has yielded weak and inconsistent evidence of an association. Furthermore, few cohort studies have examined the association of exogenous hormone use, including type and duration, with this disease. The aim of this study was to assess the association of these exposures with risk of pancreatic cancer in a large cohort of postmenopausal women.MethodsWe used data from the Women's Health Initiative on 1003 cases of pancreatic cancer diagnosed among 158,298 participants over 14.3 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations of interest.ResultsBeing parous vs. nulliparous was associated with reduced risk (HR=0.84, 95% CI 0.70–1.00), and women who had 1–2 and 3–4 births were at decreased risk compared to nulliparous women, whereas women who had >5 births showed no decrease in risk. Compared to women who gave birth between the ages of 20–29, women who gave birth at age 30 or above were at increased risk (HR 1.23, 95% CI 1.00–1.53, p for trend 0.003). Other reproductive factors and exogenous hormone use were not associated with risk.ConclusionsTogether with the existing literature on this topic, our results suggest that reproductive and hormonal exposures are unlikely to play an important role in the etiology of pancreatic cancer.



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Mitral Stenosis

Description

A previously healthy 29-year-old Mexican woman presented to an emergency department with transient hemiparaesthesias and dysarthria. There was no evidence of stroke on cross-sectional imaging of the head, and she was discharged without a clear diagnosis. Two days later, she returned with acute abdominal pain. Abdominal imaging revealed complete occlusion of the right renal artery, prompting emergency embolectomy. Following the procedure, she developed acute haemoptysis, dyspnoea and hypoxaemia. Chest imaging demonstrated evidence of pulmonary venous hypertension. Cardiac auscultation revealed an opening snap followed by a diastolic murmur with presystolic accentuation. These sounds were better appreciated in combination with phonocardiography, a technique supplanted by echocardiography in the 1970s1 that visualised heart sounds (video 1). An echocardiogram confirmed the presence of mitral stenosis (MS), unifying the syndrome of embolic phenomena, haemoptysis and pulmonary hypertension. She underwent successful mitral valve replacement and has since returned to normal...

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Uncommon presentation of adult-form scimitar syndrome associated with single left pulmonary vein in a pregnant woman

Scimitar syndrome is the constellation of malformations including an abnormal venous drainage of the right lung into the inferior vena cava, associated with the right lung and systemic supply to the right lung. The anomalous vein looks like the curved, Turkish sword (scimitar), hence the name.

The adult form of scimitar syndrome is rare, and it is usually an incidental diagnosis based on the characteristic finding on radiological imaging since the patients are usually asymptomatic or with minimal symptoms.

Our patient presented with a rare presentation of scimitar syndrome, which is tachyarrhythmia (sinus tachycardia, with episodes of supraventricular tachycardia). The diagnosis of scimitar syndrome was made based on the typical radiological finding of the anomalous venous drainage on CT angiography. Our patient does not have the full spectrum of the scimitar syndrome; therefore, she did not suffer from the usual complication (pulmonary hypertension). She was treated with ablation without surgical intervention.

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Mitral valve vegetation diagnosed with oesophageal ultrasound with bronchoscope (EUS-B)

Oesophageal ultrasound with bronchoscope (EUS-B) is designed to evaluate mediastinal structures. We describe a case of a 78-year-old woman who presented with altered mental status for 2 weeks. CT head revealed a subacute infarct in the right middle cerebral artery distribution. She was also found to have a lung mass on chest imaging. EUS-B-guided fine needle aspiration demonstrated the presence of adenocarcinoma in station 7 lymph node and in the mass. Immunohistochemistry confirmed it to be a lung primary as the Thyroid Transcription Factor-1 (TTF-1) was strongly positive. During the procedure, the cardiac valves were evaluated, and a mitral valve vegetation was noted. Formal echocardiography confirmed the presence of the vegetation. During hospital stay, the patient developed fever. Her blood cultures grew oxacillin-resistant Staphylococcus aureus. She was subsequently treated for infective endocarditis. We suggest that the use of EUS-B to routinely scan adjacent structures during a procedure may help obtain additional clinical information that may be critical to patient management.

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Double hit lymphoma presenting as haemophagocytic lymphohistiocytosis

Description

A 67-year-old woman with history of severe rheumatoid arthritis and use of multiple biologics including infliximab, tocilizumab and abatacept presented with fever of 39.1°C and severe pancytopenia (white blood cell count (WBC)=1.0x10⁹/L,  absolute neutrophil count (ANC)=0.55x10⁹/L, haemoglobin=8.7 g/dL, platelets=46x10⁹/L). As part of the pancytopenia evaluation, imaging (CT of the chest, abdomen and pelvis) showed diffuse lymphadenopathy. Further evaluation revealed an elevated ferritin (8564 ng/mL), hypofibrinogenaemia (fibrinogen=95 mg/dL), elevated triglycerides (399 mg/dL) and a soluble interleukin 2 receptor level of 41 167 units/mL, satisfying diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH). A subsequent bone marrow biopsy also revealed morphological evidence of haemophagocytosis (figure 1A), in addition to a population of very large and atypical mononuclear cells with markedly irregular, folded nuclear contours, prominent nucleoli and moderate amounts of cytoplasm (figure 1B,C). A similar large cell infiltrate was identified in the left axillary lymph node, causing complete effacement of nodal architecture (figure...

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Anaemia and respiratory failure in a child: can it be idiopathic pulmonary haemosiderosis?

We present an 8-year-old male child admitted with cough and high-grade fever for 7 days and respiratory difficulty for 2 days. There was a history of blood transfusion at 2 years of age during a respiratory illness. The child was anaemic, tachycardic, tachypnoeic and hypoxic at presentation. Chest examination revealed equal air entry with fine crackles bilaterally. Blood reports were suggestive of anaemia (haemoglobin 6.5 g/dL), leucocytosis and high C reactive protein levels. Chest radiograph revealed bilateral air space opacities involving diffuse lung fields, right more than left. Relevant microbiological workup was negative. Based on the clinical scenario and investigations, a provisional diagnosis of pulmonary haemosiderosis was kept. The patient was started on intravenous pulse methylprednisolone. Fibre-optic bronchoscopy was done following recovery from the acute event. Bronchoalveolar lavage demonstrated a significant number of haemosiderin-laden macrophages confirming pulmonary haemosiderosis.

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A rare case of thrombotic microangiopathy triggered by acute pancreatitis

Thrombotic microangiopathy (TMA) occurring after acute pancreatitis is rarely described. Without prompt intervention, TMA can be, and often is, lethal, so prompt recognition is important. Here, we present a case of a 61-year-old woman with a history of alcohol misuse who presented with epigastric pain, nausea and vomiting after binge drinking. Elevated serum lipase and imaging were suggestive of acute-on-chronic pancreatitis. Although the patient's symptoms of acute pancreatitis subsided, her anaemia, thrombocytopenia and acute kidney injury worsened. A peripheral blood smear revealed schistocytes, prompting suspicion for TMA. Therapeutic plasma exchange (TPE) was promptly initiated and she completed 10 TPE sessions that improved her anaemia and serum creatinine and resolved the thrombocytopenia. Since TPE was effective and the ADAMTS13 assay revealed 55% activity in the absence of anti-ADAMTS13 IgG prior to initiation of therapy, a confident diagnosis of TMA caused by acute pancreatitis was made. There was no evidence of relapse 2 years later.

http://ift.tt/2qmtuwv

Novel use of combination of electromyography and ultrasound to guide quadratus lumborum block after open appendicectomy

The quadratus lumborum (QL) block facilitates the administration of anaesthesia to the anterior abdominal wall. The use of ultrasound (US) improves the accuracy of the QL block and reduces the risk of adverse events. Electromyography (EMG) in combination with US for muscle plane blocks has not been described previously. We postulated that the addition of EMG-guided needle positioning might assist the execution of this block. This case report describes the first use of combined needle EMG and US to carry out a QL block performed for postoperative analgesia following an open appendicectomy.

http://ift.tt/2pQKM16

Pericardial incidentaloma: benign pericardial cyst

Description

A 73-year-old woman with hypertension and atrial fibrillation presented with head and neck injury after mechanical fall. During workup, chest X-ray anteroposterior view (figure 1) revealed a rounded opacity silhouetting the left heart border and hilum. Subsequent contrast-enhanced CT of the chest showed single, 6.4 cm, rounded, well-defined, thin-walled, non-enhanced, low attenuated (–20 and 20 Hounsfield Unit) and homogenous cyst-like structure at the left mediastinum connected to pericardial recesses and not attached to adjacent structures (figure 2A–C). Transthoracic echocardiogram ruled out left ventricular aneurysm, aortic aneurysm, solid tumour and outflow tracts obstruction. Although bronchogenic cyst, oesophageal duplication cyst, thymic tumour and mediastinal lymphoma were considered as possible differentials, radiological features such as CT appearance, homogenous attenuation, unrelated to the underlying structures favoured pericardial cyst. Since patient was asymptomatic, patient and family member were unwilling to undergo surgical removal and pathological confirmation. Follow-up with non-enhanced CT of...

http://ift.tt/2qmmz6w

Anticipatory Coarticulation and the Minimal Planning Unit of Speech.

Author: Liu, Qiang; Kawamoto, Alan H.; Payne, Katherine K.; Dorsey, Genvieve N.

DOI: 10.1037/xhp0000443

Publication Date: POST AUTHOR CORRECTIONS, 11 May 2017

http://ift.tt/2qpQB7H

India and the Coronary Stent Market: Getting the Price Right.

Author: Wadhera, Priya MS; Alexander, Thomas MD; Nallamothu, Brahmajee K. MD, MPH

Page: 1879-1881

http://ift.tt/2pEnJvo

New Hope For People With Dysglycemia and Cardiovascular Disease Manifestations: Reduction of Acute Coronary Events With Pioglitazone.

Author: Ryden, Lars MD, PhD; Mellbin, Linda MD, PhD

Page: 1894-1896

http://ift.tt/2pEkrbi

The Long and Winding Road After FDA Approval: A Medical Device Industry Perspective.

Author: Stein, Kenneth M. MD

Page: 1877-1878

http://ift.tt/2pEkB2q

Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus.

Author: Young, Lawrence H. MD; Viscoli, Catherine M. PhD; Curtis, Jeptha P. MD; Inzucchi, Silvio E. MD; Schwartz, Gregory G. MD; Lovejoy, Anne M. PAC; Furie, Karen L. MD; Gorman, Mark J. MD; Conwit, Robin MD; Abbott, J. Dawn MD; Jacoby, Daniel L. MD; Kolansky, Daniel M. MD; Pfau, Steven E. MD; Ling, Frederick S. MD; Kernan, Walter N. MD; for the IRIS Investigators

Page: 1882-1893

http://ift.tt/2qpK2BY

Stress Testing in Asymptomatic Aortic Stenosis.

Author: Redfors, Bjorn MD, PhD; Pibarot, Philippe DVM, PhD; Gillam, Linda D. MD, MPH; Burkhoff, Daniel MD, PhD; Bax, Jeroen J. MD, PhD; Lindman, Brian R. MD, MSCI; Bonow, Robert O. MD, MS; O'Gara, Patrick T. MD; Leon, Martin B. MD; Genereux, Philippe MD

Page: 1956-1976

http://ift.tt/2qpI0Su

Response by Wiberg et al to Letter Regarding Article, "Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial".

Author: Wiberg, Sebastian MD; Hassager, Christian MD, DMSc; Kjaergaard, Jesper MD, PhD, DMSc

Page: e1044-e1045

http://ift.tt/2pEBE4v

A Rock and a Hard Place: Chiseling Away at the Multiple Mechanisms of Aortic Stenosis.

Author: Aikawa, Elena MD, PhD; Libby, Peter MD

Page: 1951-1955

http://ift.tt/2pElEj6

Response to Outlier Status: Lessons From Public Reporting for Percutaneous Coronary Intervention.

Author: Joynt, Karen E. MD, MPH

Page: 1908-1910

http://ift.tt/2pEFgn6

Letter by Rottenberg Regarding Article, "Conventional Versus Compression-Only Versus No Bystander Cardiopulmonary Resuscitation for Pediatric Out-of-Hospital Cardiac Arrest".

Author: Rottenberg, Eric M. AAS

Page: e1050-e1051

http://ift.tt/2qpNtbO

Response by Karam et al to Letter Regarding Article, "Identifying Patients at Risk for Prehospital Sudden Cardiac Arrest at the Early Phase of Myocardial Infarction: The e-MUST Study (Evaluation en Medecine d'Urgence des Strategies Therapeutiques des infarctus du myocarde)".

Author: Karam, Nicole MD, MPH; Bataille, Sophie MD; Marijon, Eloi MD, PhD; Tafflet, Muriel MPH; Lapostolle, Frederic MD; Spaulding, Christian MD, PhD; Jouven, Xavier MD, PhD *; Lambert, Yves MD *; For the e-MUST Study Investigators

Page: e1048-e1049

http://ift.tt/2pEcoLO

Quality of Care at Hospitals Identified as Outliers in Publicly Reported Mortality Statistics for Percutaneous Coronary Intervention.

Author: Waldo, Stephen W. MD; McCabe, James M. MD; Kennedy, Kevin F. MS; Zigler, Corwin M. PhD; Pinto, Duane S. MD; Yeh, Robert W. MD, MSc

Page: 1897-1907

http://ift.tt/2qpPlBA

Serial Measurement of High-Sensitivity Troponin I and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus in the EXAMINE Trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care).

Author: Cavender, Matthew A. MD, MPH; White, William B. MD; Jarolim, Petr MD, PhD; Bakris, George L. MD; Cushman, William C. MD; Kupfer, Stuart MD; Gao, Qi MS; Mehta, Cyrus R. PhD; Zannad, Faiez MD; Cannon, Christopher P. MD; Morrow, David A. MD, MPH

Page: 1911-1921

http://ift.tt/2qpJV9N

[beta]2-Glycoprotein I/IgA Immune Complexes: A Marker to Predict Thrombosis After Renal Transplantation in Patients With Antiphospholipid Antibodies.

Author: Serrano, Manuel MD *; Martinez-Flores, Jose A. PhD *; Perez, Dolores BS; Garcia, Florencio MD, PhD; Cabrera, Oscar MD; Pleguezuelo, Daniel MD; Paz-Artal, Estela MD, PhD; Morales, Jose M. MD, PhD; Gonzalez, Esther MD, PhD; Serrano, Antonio MD, PhD

Page: 1922-1934

http://ift.tt/2pEjUpP

Dipeptidyl Peptidase-4 Induces Aortic Valve Calcification by Inhibiting Insulin-Like Growth Factor-1 Signaling in Valvular Interstitial Cells.

Author: Choi, Bongkun PhD *; Lee, Sahmin MD, PhD *; Kim, Sang-Min MS; Lee, Eun-Jin PhD; Lee, Sun Ro BS; Kim, Dae-Hee MD, PhD; Jang, Jeong Yoon MD; Kang, Sang-Wook PhD; Lee, Ki-Up MD; Chang, Eun-Ju PhD +; Song, Jae-Kwan MD, PhD +

Page: 1935-1950

http://ift.tt/2qpMRmx

Winter Is Coming After a Cardiac Arrest.

Author: Fernandez-Vega, Ana MD; Martinez-Losas, Pedro MD; Noriega, Francisco J. MD, PhD; Fernandez-Ortiz, Antonio MD, PhD; Biagioni, Corina MD; Cruz-Utrilla, Alejandro MD; Martinez-Vives, Pablo MD; Garcia-Arribas, Daniel MD; Viana-Tejedor, Ana MD, PhD

Page: 1977-1978

http://ift.tt/2pErilb

Primary Prevention With Statin Therapy in the Elderly: New Meta-Analyses From the Contemporary JUPITER and HOPE-3 Randomized Trials.

Author: Ridker, Paul M MD; Lonn, Eva MD; Paynter, Nina P. PhD; Glynn, Robert ScD; Yusuf, Salim MD

Page: 1979-1981

http://ift.tt/2qpYr1n

Primary Stable Microvascular Angina: A Long-Term Clinical Follow-Up Study.

Author: Lanza, Gaetano Antonio MD; Filice, Monica MD; De Vita, Antonio MD; Lamendola, Priscilla MD; Villano, Angelo MD; Spera, Francesco MD; Golino, Michele MD; Rota, Elisabetta MD; Argiro, Alessia MD; Crea, Filippo MD

Page: 1982-1984

http://ift.tt/2pECy14

Letter by Ma et al Regarding Article, "Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial".

Author: Ma, Lei-Lei MD; Kong, Fei-Juan MD; Ge, Jun-Bo MD

Page: e1042-e1043

http://ift.tt/2qq2BWL

Letter by Tuncez et al Regarding Article, "Identifying Patients at Risk for Prehospital Sudden Cardiac Arrest at the Early Phase of Myocardial Infarction: The e-MUST Study (Evaluation en Medecine d'Urgence des Strategies Therapeutiques des infarctus du myocarde)".

Author: Tuncez, Abdullah MD; Ates, Muhammed Salih MD; Tezcan, Huseyin MD

Page: e1046-e1047

http://ift.tt/2qpK8JZ

p38 MAPK as an essential regulator of dorsal-ventral axis specification and skeletogenesis during sea urchin development: a re-evaluation [RESEARCH ARTICLE]

Maria Dolores Molina, Magali Quirin, Emmanuel Haillot, Felipe Jimenez, Aline Chessel, and Thierry Lepage

Dorsal-ventral axis formation in the sea urchin embryo relies on the asymmetrical expression of the TGF-beta Nodal. The p38-MAPK pathway has been proposed to be essential for dorsal-ventral axis formation by acting upstream of nodal expression. Herein, we report that, in contrast to previous studies that used pharmacological inhibitors of p38, manipulating the activity of p38 by genetic means has no obvious impact on morphogenesis. Instead, we discovered that p38 inhibitors strongly disrupt specification of all germ layers by blocking signalling from the Nodal receptor and by interfering with the ERK pathway. Strikingly, while expression of a p38 mutant resistant to SB203580 did not rescue dorsal-ventral axis formation or skeletogenesis in embryos treated with this inhibitor, expression of Nodal receptor mutants resistant to SB203580 fully restored nodal expression in SB203580 treated embryos. Taken together, these results establish that p38 activity is required neither for dorsal-ventral axis formation through nodal expression nor for skeletogenesis. Our results prompt a re-evaluation of the conclusions of several recent studies that linked p38 activity to dorsal-ventral axis formation and to patterning of the skeleton.

http://ift.tt/2qLucVF

Development of the larval lymphatic system in the zebrafish [RESEARCH ARTICLE]

Hyun Min Jung, Daniel Castranova, Matthew R. Swift, Van N. Pham, Marina Venero Galanternik, Sumio Isogai, Matthew G. Butler, Timothy S. Mulligan, and Brant M. Weinstein

The lymphatic vascular system is a hierarchically organized complex network essential for tissue fluid homeostasis, immune trafficking, and absorption of dietary fats in the human body. Despite its importance, the assembly of the lymphatic network is still not fully understood. The zebrafish is a powerful model organism that enables study of lymphatic vessel development using high-resolution imaging and sophisticated genetic and experimental manipulation. Although several studies have described early lymphatic development in the fish, lymphatic development at later stages has not been completely elucidated. In this study, we generated a new Tg(mrc1a:egfp)^y251 transgenic zebrafish using a Mannose receptor C type 1 (MRC1) promoter that drives strong EGFP expression in lymphatic vessels at all stages of development and in adult zebrafish. We used this line to describe the assembly of the major vessels of the trunk lymphatic vascular network, including the later-developing collateral cardinal lymphatics, spinal lymphatic, superficial lateral lymphatics, and superficial intersegmental lymphatics. Our results show that major trunk lymphatic vessels are conserved in the zebrafish, and provide a thorough and complete description of trunk lymphatic vessel assembly.

http://ift.tt/2rkCrVD

The cell wall-localized atypical {beta}-1,3 glucanase ZERZAUST controls tissue morphogenesis in Arabidopsis thaliana [RESEARCH ARTICLE]

Prasad Vaddepalli, Lynette Fulton, Jennifer Wieland, Katrin Wassmer, Milena Schaeffer, Stefanie Ranf, and Kay Schneitz

Orchestration of cellular behavior in plant organogenesis requires integration of intercellular communication and cell wall dynamics. The underlying signaling mechanisms are poorly understood. Tissue morphogenesis in Arabidopsis depends on the receptor-like kinase STRUBBELIG. Mutations in ZERZAUST were previously shown to result in a strubbelig-like mutant phenotype. Here we report on the molecular identification and functional characterization of ZERZAUST. We show that ZERZAUST encodes a putative GPI-anchored β-1,3 glucanase suggested to degrade the cell wall polymer callose. However, a combination of in vitro, cell biological and genetic experiments indicate that ZERZAUST is not involved in the regulation of callose accumulation. Nonetheless, Fourier-transformed infrared-spectroscopy revealed that zerzaust mutants show defects in cell wall composition. Furthermore, the results indicate that ZERZAUST represents a mobile apoplastic protein, and that its carbohydrate binding module family 43 domain is required for proper subcellular localization and function whereas its GPI anchor is dispensable. Our collective data reveal that the atypical β-1,3 glucanase ZERZAUST acts in a non-cell autonomous manner and is required for cell wall organization during tissue morphogenesis.

http://ift.tt/2rkCwst

Btbd7 is essential for region-specific epithelial cell dynamics and branching morphogenesis in vivo [RESEARCH ARTICLE]

William P. Daley, Kazue Matsumoto, Andrew D. Doyle, Shaohe Wang, Brian J. DuChez, Kenn Holmbeck, and Kenneth M. Yamada

Branching morphogenesis of developing organs requires coordinated but poorly understood changes in epithelial cell-cell adhesion and cell motility. We report that Btbd7 is a crucial regulator of branching morphogenesis in vivo. Btbd7 levels are elevated in peripheral cells of branching epithelial end buds, where it enhances cell motility and cell-cell adhesion dynamics. Genetic ablation of Btbd7 in mice disrupts branching morphogenesis of salivary gland, lung, and kidney. Btbd7 knockout results in more tightly packed outer bud cells, which display stronger E-cadherin localization, reduced cell motility, and decreased dynamics of transient cell separations associated with cleft formation; inner bud cells remain unaffected. Mechanistic analyses using in vitro MDCK cells to mimic outer bud cell behavior establish that Btbd7 promotes loss of E-cadherin from cell-cell adhesions with enhanced migration and transient cell separation. Btbd7 can enhance E-cadherin ubiquitination, internalization, and degradation in MDCK and peripheral bud cells for regulating cell dynamics. These studies show how a specific regulatory molecule, Btbd7, can function at a local region of developing organs to regulate dynamics of cell adhesion and motility during epithelial branching morphogenesis.

http://ift.tt/2qLfDBf

Fgf10-Sox9 are essential for establishment of distal progenitor cells during salivary gland development [RESEARCH ARTICLE]

Lemonia Chatzeli, Marcia Gaete, and Abigail S. Tucker

Salivary glands are formed by branching morphogenesis with epithelial progenitors forming a network of ducts and acini (secretory cells). During this process, epithelial progenitors specialise into distal (tips of the gland) and proximal (the stalk region) identities that produce the acini and higher order ducts respectively. Little is known about the factors that regulate progenitor expansion and specialisation in the different parts of the gland. Here we show that Sox9 is involved in establishing the identity of the distal compartment before the initiation of branching morphogenesis. Sox9 is expressed throughout the gland at the initiation stage before becoming restricted to the distal epithelium from the bud stage and throughout branching morphogenesis. Deletion of Sox9 in the epithelium results in loss of the distal epithelial progenitors, a reduction in proliferation and a subsequent failure in branching. We demonstrate that Sox9 is positively regulated by mesenchymal Fgf10, a process that requires active Erk signalling. These results provide new insights into the factors required for the expansion of salivary gland epithelial progenitors, which can be useful for organ regeneration therapy.

http://ift.tt/2rkJc9O

The phosphatase Pgam5 antagonizes Wnt/{beta}-Catenin signaling in embryonic anterior-posterior axis patterning [RESEARCH ARTICLE]

Verena Rauschenberger, Dominic B. Bernkopf, Sabrina Krenn, Kowcee Jalal, Jens Heller, Jürgen Behrens, Marc Gentzel, and Alexandra Schambony

The scaffold protein Dishevelled is a central intracellular component of Wnt signaling pathways. Various kinases have been described that regulate and modulate Wnt signaling through phosphorylation of Dishevelled. However, besides the general protein phosphatases 1 and 2 (PP1 and PP2), no specific protein phosphatases have been identified. Here, we report on the identification and functional characterization of the protein phosphatase Pgam5 in vitro and in vivo. Pgam5 is a novel antagonist of Wnt/β-Catenin signaling in human cells and Xenopus embryogenesis. In early development, Pgam5 is essential for head formation and establishing and maintaining the Wnt/β-Catenin signaling gradient that patterns the anterior-posterior body axis. Inhibition of Wnt/β-Catenin signaling and developmental function depend on Pgam5 phosphatase activity. We show that Pgam5 interacts with Dishevelled2 and that Dishevelled2 is a substrate of Pgam5. Pgam5 mediates a marked decrease of Dishevelled2 phosphorylation in the cytoplasm and in the nucleus as well as decreased interaction between Dishevelled2, Tcf1 and β-Catenin, indicating that Pgam5 regulates Dishevelled function upstream and downstream of β-Catenin stabilization.

http://ift.tt/2qLnUFf

RET-mediated glial cell line derived neurotrophic factor signaling inhibits mouse prostate development [RESEARCH ARTICLE]

Hyun-Jung Park and Eric C. Bolton

In humans and rodents, the prostate gland develops from the embryonic urogenital sinus (UGS). The androgen receptor (AR) is thought to control the expression of morphogenetic genes in inductive UGS mesenchyme, which promotes proliferation and cytodifferentiation of the prostatic epithelium. However, the nature of the AR-regulated morphogenetic genes and the mechanisms whereby AR controls prostate development are not understood. Glial cell line-derived neurotrophic factor (GDNF) binds GDNF family receptor-α1 (GFRα1) and signals through activation of RET tyrosine kinase. Gene disruption studies in mice have revealed essential roles for GDNF signaling in development, however its role in prostate development is unexplored. Here, we establish novel roles of GDNF signaling in mouse prostate development. Utilizing an organ culture system for prostate development and Ret mutant mice, we demonstrate that RET-mediated GDNF signaling in UGS increases proliferation of mesenchyme cells and suppresses androgen-induced proliferation and differentiation of prostate epithelial cells, inhibiting prostate development. We also identify AR as a GDNF-repressed gene and Gdnf and Gfrα1 as androgen-repressed genes in UGS, thus establishing reciprocal regulatory crosstalk between AR and GDNF signaling in prostate development.

http://ift.tt/2rkXAz5

Apical constriction is driven by a pulsatile apical myosin network in delaminating Drosophila neuroblasts [RESEARCH ARTICLE]

Yanru An, Guosheng Xue, Yang Shaobo, Deng Mingxi, Xiaowei Zhou, Weichuan Yu, Toyotaka Ishibashi, Lei Zhang, and Yan Yan

Cell delamination is a conserved morphogenetic process important for generation of cell diversity and maintenance of tissue homeostasis. Here we used Drosophila embryonic neuroblasts as a model to study the apical constriction process during cell delamination. We observe dynamic myosin signals both around the cell adherens junctions and underneath the cell apical surface in the neuroectoderm. On the cell apical cortex the non-junctional myosin forms flows and pulses, which are termed as medial myosin pulses. Quantitative differences in medial myosin pulse intensity and frequency are critical to distinguish delaminating neuroblasts from their neighbors. Inhibition of medial myosin pulses blocks delamination. The fate of neuroblasts is set apart from their neighbors by Notch signaling-mediated lateral inhibition. When we inhibit Notch signaling activity in the embryo, we observe that small clusters of cells undergo apical constriction and display an abnormal apical myosin pattern. Together, we demonstrate that a contractile actomyosin network across the apical cell surface is organized to drive apical constriction in delaminating neuroblasts.

http://ift.tt/2qLgB0b

Gain-of-function mutations of mau/DrAqp3a influence zebrafish pigment pattern formation through the tissue environment [RESEARCH ARTICLE]

Anastasia Eskova, Francois Chauvigne, Hans-Martin Maischein, Moritz Ammelburg, Joan Cerda, Christiane Nüsslein-Volhard, and Uwe Irion

The development of the pigmentation pattern in zebrafish is a tightly regulated process that depends on both the self-organizing properties of pigment cells and extrinsic cues from other tissues. Many of the known mutations that alter the pattern act cell autonomously in pigment cells, and our knowledge about external regulators is limited. Here, we describe several dominant missense mutations in Aquaporin 3a (Aqp3a/mau) that lead to broken stripes and short fins in zebrafish. A loss-of-function allele, generated by CRISPR-Cas9, has no phenotypic consequences, demonstrating that Aqp3a is dispensable for normal development. Strikingly, the pigment cells from dominant mau mutants are capable of forming a wild type pattern when developing in a wild type environment, but the surrounding tissues in the mutants influence pigment cell behaviour and interfere with the patterning process. The mutated amino acid residues in the dominant alleles line the pore surface of Aqp3a and influence pore permeability These results demonstrate an important effect of the tissue environment on pigment cell behaviour and thereby on pattern formation.

http://ift.tt/2rkLHsN

Reduced MAD2 levels dampen apoptotic response to non-exchange sex chromosomes and lead to sperm aneuploidy [RESEARCH ARTICLE]

Imrul Faisal and Liisa Kauppi

In meiosis, non-exchange homologous chromosomes are at risk for missegregation and should be monitored by the spindle assembly checkpoint (SAC) to avoid formation of aneuploid gametes. Sex chromosome missegregation is particularly common and can lead to sterility or to aneuploid offspring (e.g. individuals with Turner or Klinefelter syndrome). Despite major implications for health and reproduction, modifiers of meiotic SAC robustness and the subsequent apoptotic response in male mammals remain obscure. Levels of SAC proteins, e.g. MAD2, are critical for normal checkpoint function in many experimental systems, but surprisingly, apparently not in male meiosis, as indicated by the lack of chromosome segregation defects reported earlier in Mad2^+/- spermatocytes. To directly test whether MAD2 levels impact the meiotic response to missegregating chromosomes, we utilized Spo11β-only^mb mice that are prone to non-exchange X-Y chromosomes. We show that reduced MAD2 levels attenuate the apoptotic response to missegregating sex chromosomes and allow the formation of aneuploid sperm. These findings demonstrate that SAC protein levels are critical for the efficient elimination of aberrant spermatocytes.

http://ift.tt/2qLnSgB

MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma [RESEARCH ARTICLE]

S. Haston, S. Pozzi, G. Carreno, S. Manshaei, L. Panousopoulos, J. M. Gonzalez-Meljem, J. R. Apps, A. Virasami, S. Thavaraj, A. Gutteridge, T. Forshew, R. Marais, S. Brandner, T. S. Jacques, C. L. Andoniadou, and J. P. Martinez-Barbera

Despite the importance of the RAS-RAF-MAPK pathway in normal physiology and disease of numerous organs, its role during pituitary development and tumourigenesis remains largely unknown. Here we show that the over-activation of the MAPK pathway, through conditional expression of the gain-of-function alleles BrafV600E and KrasG12D in the developing mouse pituitary, results in severe hyperplasia and abnormal morphogenesis of the gland by the end of gestation. Cell-lineage commitment and terminal differentiation are disrupted, leading to a significant reduction in numbers of most of the hormone-producing cells before birth, with the exception of corticotrophs. Of note, Sox2+ve stem cells and clonogenic potential are drastically increased in the mutant pituitaries. Finally, we reveal that papillary craniopharyngioma (PCP), a benign human pituitary tumour harbouring BRAF p.V600E also contains Sox2+ve cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a critical function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2+ve cells and suggest that persistent proliferative capacity of Sox2+ve cells may underlie the pathogenesis of PCP.

http://ift.tt/2rkKAJK

FGF signaling refines Wnt gradients to regulate patterning of taste papillae [RESEARCH ARTICLE]

Michaela Prochazkova, Teemu J. Häkkinen, Jan Prochazka, Frantisek Spoutil, Andrew H. Jheon, Youngwook Ahn, Robb Krumlauf, Jukka Jernvall, and Ophir D. Klein

The patterning of repeated structures is a major theme in developmental biology, and the interrelationship between spacing and size of such structures is an open question. Fungiform papillae are repeated epithelial structures that house taste buds on the anterior tongue. Here, we report that FGF signaling is a critical regulator of fungiform papillae development. We found that mesenchymal FGF10 controls the size of the papillary area, while overall patterning remains unchanged. Our results show that FGF signaling negatively affects the extent of canonical Wnt signaling, which is the main activation pathway during fungiform papillae development, but this effect does not occur at the level of gene transcription. Rather, our experimental data together with computational modeling indicate that FGF10 modulates the range of Wnt effects, likely via induction of Sostdc1 expression. We suggest that modification of the reach of Wnt signaling could be due to local changes in morphogen diffusion, representing a novel mechanism in this tissue context, and we propose that this phenomenon might be involved in a broader array of mammalian developmental processes.

http://ift.tt/2qLye07

COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal CXCR4 expression [RESEARCH ARTICLE]

Josephine Parisot, Gemma Flore, Michele Bertacchi, and Michele Studer

Development of the dentate gyrus (DG), the primary gateway for hippocampal inputs, spans embryonic and postnatal stages and involves complex morphogenetic events. We have previously identified the nuclear receptor COUP-TFI as a novel transcriptional regulator in the postnatal organization and function of the hippocampus. Here, we dissect its role in DG morphogenesis by inactivating it either in granule cell progenitors or in granule neurons. Loss of COUP-TFI function in progenitors leads to decreased granule cell proliferative activity, precocious differentiation and increased apoptosis, resulting in a severe DG growth defect in adult mice. COUP-TFI-deficient cells express high levels of the chemokine receptor CXCR4 and migrate abnormally, forming heterotopic clusters of differentiated granule cells along their paths. Conversely, high COUP-TFI expression levels downregulate CXCR4 expression, whereas increased CXCR4 expression in wild-type hippocampal cells affect cell migration. Finally, loss of COUP-TFI in postmitotic cells leads only to minor and transient abnormalities, and normal CXCR4 expression. Together, our results indicate that COUP-TFI is required predominantly in DG progenitors by modulating expression of the CXCR4 receptor during granule cell neurogenesis and migration.

http://ift.tt/2rkUCKM

Sonic Hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis [RESEARCH ARTICLE]

Joshua L. Everson, Dustin M. Fink, Joon Won Yoon, Elizabeth J. Leslie, Henry W. Kietzman, Lydia J. Ansen-Wilson, Hannah M. Chung, David O. Walterhouse, Mary L. Marazita, and Robert J. Lipinski

Cleft lip is one of the most common human birth defects, yet our understanding of the mechanisms that regulate lip morphogenesis is limited. Here, we show that Sonic Hedgehog (Shh)-induced proliferation of cranial neural crest cell (cNCC) mesenchyme is required for upper lip closure. Gene expression profiling revealed a subset of Forkhead box (Fox) genes regulated by Shh signaling during lip morphogenesis. During cleft pathogenesis, reduced proliferation in the medial nasal process mesenchyme paralleled the domain of reduced Foxf2 and Gli1 expression. SHH ligand induction of Foxf2 expression was dependent upon Shh pathway effectors in cNCCs, while a functional GLI binding site was identified downstream of Foxf2. Consistent with the cellular mechanism demonstrated for cleft lip pathogenesis, we found that either SHH ligand addition or FOXF2 overexpression is sufficient to induce cNCC proliferation. Finally, analysis of a large multi-ethnic human population with cleft lip identified clusters of single-nucleotide polymorphisms in FOXF2. These data suggest that direct targeting of Foxf2 by Shh signaling drives cNCC mesenchyme proliferation during upper lip morphogenesis, and that disruption of this sequence results in cleft lip.

http://ift.tt/2qLioCD

Dmrt1 induces the male pathway in a turtle with temperature-dependent sex determination [RESEARCH ARTICLE]

Chutian Ge, Jian Ye, Haiyan Zhang, Yi Zhang, Wei Sun, Yapeng Sang, Blanche Capel, and Guoying Qian

The molecular mechanism underlying temperature-dependent sex determination (TSD) has been a long-standing mystery; in particular, the thermo-sensitive genetic triggers for gonadal sex differentiation are largely unknown. Here, we characterized a conserved DM domain gene, Dmrt1, in the red-eared slider turtle Trachemys scripta (T. scripta), which exhibits TSD. We found that Dmrt1 has a temperature-dependent, sexually dimorphic expression pattern, preceding gonadal sex differentiation, and is capable of responding rapidly to temperature shifts and aromatase inhibitor treatment. Most importantly, loss- and gain-of-function analyses provide solid evidence that Dmrt1 is both necessary and sufficient to initiate male development in T. scripta. Furthermore, the DNA methylation dynamics of the Dmrt1 promoter are tightly correlated with temperature and could mediate the impact of temperature on sex determination. Collectively, our findings demonstrate that Dmrt1 is a candidate master male sex-determining gene in this TSD species, consistent with the idea that DM domain genes are conserved during the evolution of sex determination mechanisms.

http://ift.tt/2qLf7mS

Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels [RESEARCH ARTICLE]

Shi Yin, Xiaohua Jiang, Hanwei Jiang, Qian Gao, Fang Wang, Suixing Fan, Teka Khan, Nazish Jabeen, Manan Khan, Asim Ali, Peng Xu, Tej K. Pandita, Heng-Yu Fan, Yuanwei Zhang, and Qinghua Shi

Proper oocyte development is critical for female fertility and requires timely and accurate control of gene expression. K (Lysine) Acetyltransferase 8 (KAT8), an important component of the X chromosome dosage compensation system in Drosophila, regulates gene activity by acetylating histone H4 preferentially at lysine 16. To explore the function of Kat8 during mouse oocyte development, we crossed Kat8^flox/floxmice with Gdf9-Cre mice to specifically delete Kat8 in oocytes. Oocyte Kat8 deletion resulted in female infertility with follicle development failure in the secondary and preantral follicle stages. RNA-seq analysis revealed that Kat8 deficiency in oocytes resulted in significant down-regulation of antioxidant genes with a subsequent increase in reactive oxygen species. Intraperitoneal injection of the antioxidant N-acetylcysteine rescued defective follicle and oocyte development resulting from Kat8 deficiency. Chromatin immunoprecipitation assay indicated that KAT8 regulates antioxidant gene expression by direct binding to promoter regions. Taken together, our findings demonstrate that KAT8 is essential for female fertility by regulating antioxidant gene expression and identify KAT8 as the first acetyltransferase with an essential function in oogenesis.

http://ift.tt/2rkVmQe