Clinical Trials for Immunosuppression in Transplantation; The Case for Reform and Change in Direction.

Currently trials of immunosuppression in transplantation are in decline because their objectives remain focused on improving acute rejection rates and graft survival in the first 12 months. With 1 year renal graft survival rates of greater than 90% the best that can be hoped for is noninferiority trial outcomes compared to current standard of care. Current trial design is not leading to novel therapies improving long term outcomes and safety, and hence important unmet clinical needs in transplantation remain unanswered. Issues that need to be addressed include but are not limited to: prevention of subclinical rejection in the first year, better 5 and 10 year graft outcomes, more effective treatment for high immunological risk and sensitized (including DSA) patients, immunosuppressive combinations that are better tolerated by patients with fewer side effects and less morbidity and mortality. In September 2015 the Transplantation Society convened a group of transplant clinical trial experts to address these problems. The aims were to substantially realign the priorities of clinical trials for renal transplant immunosuppression with the current unmet needs and to propose new designs for clinical trials for transplant immunosuppression. Moving forward, the transplant community needs to provide trial data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve timely regulatory approval. Trial designs for new transplant immunosuppression must be intelligently restructured in order to ensure that short- and long-term clinical outcomes continue to improve. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Laparoscopic Donor Hepatectomy: The Long and Winding Road.

No abstract available

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Are We Ready for Epitope-Based HLA Matching in Clinical Organ Transplantation?.

This overview describes recent developments demonstrating the significance of epitopes in HLA antibody responses and matching for organ transplantation. HLA epitopes are defined by molecular modeling and amino acid comparisons between HLA alleles and the HLAMatchmaker algorithm considers eplets as essential components. Each allele represents a distinct string of eplets and matching is done by aligning donor and recipient strings. Evidence is summarized how mismatched eplet loads affect antibody responses and transplant outcomes. Epitope-based matching has been applied not only to identify acceptable mismatches for sensitized transplant candidates but also to identify more suitably mismatched donors for nonsensitized patients. Three recently proposed theories will further our understanding of the immunogenicity of individual HLA eplets. It has become apparent that epitope-based matching is superior to antigen matching; we should be ready soon to apply this principle in the clinical transplant setting very soon. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Acute Liver Failure/Injury Related to Drug Reaction With Eosinophilia and Systemic Symptoms: Outcomes and Prognostic Factors.

Background: Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) is a rare severe adverse drug induced reaction with multiorgan involvement. The outcome and prediction of those patients who develop severe acute liver injury (sALI) or acute liver failure (ALF) remain little known. Methods: A multicenter retrospective study of patients admitted with a diagnosis of DRESS-related sALI or ALF. Histological review was performed on liver core biopsies from native livers. Results: Sixteen patients (11F, 5M; mean age: 39+/-17.2 years) were classified as having definite (n=13) or probable (n=3) DRESS. At admission, 3 patients had hepatic encephalopathy; median levels of prothrombin time, INR and total bilirubin were respectively 33% (Q1-Q3: 21-41); 2.74 (1.98- 4.50) and 94 [mu]mol/L (Q1-Q3: 39.5-243.5). Nine patients received corticosteroid therapy. Overall, 9 patients improved spontaneously and 7 worsened (liver transplantation (n=5), deceased (n=2)). Transplantation-free and postliver transplantation (LT) survival was 56% and 60% respectively. After LT, DRESS recurrence was observed in 3/5 patients. Systemic corticosteroid therapy was not significantly associated with a clinical improvement. In the multivariate analysis, factor V level =40% at admission but decreasing at day 2 were associated with worse outcome. Pathological findings (n=7) revealed atypical lymphoid infiltrates, kupffer cell hyperplasia with erythrophagocytosis and an inconstant presence of eosinophils. Conclusion: The spontaneous prognosis of patients with sALI/ALF due to DRESS is poor and was not improved by corticosteroid therapy. Histology is helpful to establish diagnosis. Dynamic variables regarding factor V values are predictive of a poor outcome. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Ethnic Background is a Potential Barrier to Living Donor Kidney Transplantation in Canada: A Single Center Retrospective Cohort Study.

Background: We examined if African or Asian ethnicity was associated with lower access to kidney transplantation (KT) in a Canadian setting. Methods: Patients referred for KT to the Toronto General Hospital from January 1, 2003 to December 31, 2012, who completed social work assessment, were included (n=1769). The association between ethnicity and the time from referral to completion of KT evaluation or receipt of a KT were examined using Cox proportional hazards models. Results: About 54% of the sample was Caucasian, 13% African, 11% East Asian, and 11% South Asian; 7% had "other" (n = 121) ethnic background. African Canadians (HR 0.75 [95% CI: 0.62, 0.92]) and patients with "other" ethnicity (HR 0.71 [95% CI: 0.55, 0.92]) were less likely to complete the KT evaluation compared to Caucasian Canadians, and this association remained statistically significant in multivariable adjusted models. Access to KT was significantly reduced for all ethnic groups assessed compared to Caucasian Canadians, and this was primarily driven by differences in access to living donor KT. The adjusted hazard ratios for living donor KT were 0.35 (95% CI: 0.24, 0.51), 0.27 (95% CI: 0.17, 0.41), 0.43 (95% CI: 0.30, 0.61) and 0.34 (95% CI: 0.20, 0.56) for African, East or South Asian Canadians and for patients with "other" ethnic background, respectively. Conclusion: Similarly to other jurisdictions, non-Caucasian patients face barriers to accessing KT in Canada. This inequity is very substantial for living donor KT. Further research is needed to identify if these inequities are due to potentially modifiable barriers. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Kidney Transplantation Rates Across Glomerulonephritis Subtypes in the United States.

Background: Whether kidney transplantation rates differ by glomerulonephritis (GN) subtype remains largely unknown. Methods: Using the US Renal Data System, we identified all adult patients with ESRD attributed to 1 of 6 GN subtypes who initiated dialysis in the US (1996-2013). Patients with diabetic nephropathy (DN) and autosomal-dominant polycystic kidney disease (ADPKD) served as "external" non-GN comparators. Using Cox proportional hazards regression, with death considered a competing risk, we estimated hazard ratios [HRs (95% confidence intervals)] for first kidney transplantation, controlling for year, demographics, comorbidities, socioeconomic factors, and Organ Procurement Organization (OPO). Results: Among 718,480 patients studied, unadjusted and multivariable-adjusted transplant rates differed considerably across GN subtypes. Adjusted transplant rates were highest for patients with IgA nephropathy (IgAN, referent) and lower for all other groups: focal segmental glomerulosclerosis, HR=0.80 (0.77-0.82); membranous nephropathy, HR=0.88 (0.83-0.93); membranoproliferative GN, HR=0.84 (0.76-0.92); lupus nephritis, HR=0.69 (0.66-0.71); vasculitis, HR=0.66 (0.61-0.70); DN, HR=0.50 (0.47-0.52); ADPKD, HR=0.85 (0.82-0.88). Reduced kidney transplantation rates among comparator groups were driven more so by lower rates of waitlisting [HRs, vs. IgAN, ranged from 0.49 for DN to 0.92 for membranous nephropathy or ADPKD] than by lower rates of deceased donor kidney transplantation after waitlisting [rates were only significantly lower, vs. IgAN, for those with secondary GN subtypes: lupus nephritis, HR=0.91 (0.86-0.97), vasculitis, HR=0.85 (0.76-0.94); DN, HR=0.73 (0.69-0.77)]. Conclusions: Identifying underlying reasons for apparent disease-specific barriers to kidney transplantation might inform center-specific transplant candidate selection procedures, along with national organ allocation policies, leading to more equitable patient care and improved patient outcomes. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Relationship Between Peripheral and Psychophysical Measures of Amplitude Modulation Detection in Cochlear Implant Users.

Objective: This study investigates the relationship between electrophysiological and psychophysical measures of amplitude modulation (AM) detection. Prior studies have reported both measures of AM detection recorded separately from cochlear implant (CI) users and acutely deafened animals, but no study has made both measures in the same CI users. Animal studies suggest a progressive loss of high-frequency encoding as one ascends the auditory pathway from the auditory nerve to the cortex. Because the CI speech processor uses the envelope of an ongoing acoustic signal to modulate pulse trains that are subsequently delivered to the intracochlear electrodes, it is of interest to explore auditory nerve responses to modulated stimuli. In addition, psychophysical AM detection abilities have been correlated with speech perception outcomes. Thus, the goal was to explore how the auditory nerve responds to AM stimuli and to relate those physiologic measures to perception. Design: Eight patients using Cochlear Ltd. Implants participated in this study. Electrically evoked compound action potentials (ECAPs) were recorded using a 4000 pps pulse train that was sinusoidally amplitude modulated at 125, 250, 500, and 1000 Hz rates. Responses were measured for each pulse over at least one modulation cycle for an apical, medial, and basal electrode. Psychophysical modulation detection thresholds (MDTs) were also measured via a three-alternative forced choice, two-down, one-up adaptive procedure using the same modulation frequencies and electrodes. Results: ECAPs were recorded from individual pulses in the AM pulse train. ECAP amplitudes varied sinusoidally, reflecting the sinusoidal variation in the stimulus. A modulated response amplitude (MRA) metric was calculated as the difference in the maximal and minimum ECAP amplitudes over the modulation cycles. MRA increased as modulation frequency increased, with no apparent cutoff (up to 1000 Hz). In contrast, MDTs increased as the modulation frequency increased. This trend is inconsistent with the physiologic measures. For a fixed modulation frequency, correlations were observed between MDTs and MRAs; this trend was evident at all frequencies except 1000 Hz (although only statistically significant for 250 and 500 Hz AM rates), possibly an indication of central limitations in processing of high modulation frequencies. Finally, peripheral responses were larger and psychophysical thresholds were lower in the apical electrodes relative to basal and medial electrodes, which may reflect better cochlear health and neural survival evidenced by lower preoperative low-frequency audiometric thresholds and steeper growth of neural responses in ECAP amplitude growth functions for apical electrodes. Conclusions: Robust ECAPs were recorded for all modulation frequencies tested. ECAP amplitudes varied sinusoidally, reflecting the periodicity of the modulated stimuli. MRAs increased as the modulation frequency increased, a trend we attribute to neural adaptation. For low modulation frequencies, there are multiple current steps between the peak and valley of the modulation cycle, which means successive stimuli are more similar to one another and neural responses are more likely to adapt. Higher MRAs were correlated with lower psychophysical thresholds at low modulation frequencies but not at 1000 Hz, implying a central limitation to processing of modulated stimuli. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Association Between Pretransplant Cancer and Survival in Kidney Transplant Recipients.

Background: Kidney transplantation in recipients with a previous malignancy is often deferred 2-5 years after cancer treatment due to fear of cancer recurrence. In Norway, the required waiting period has been 1 year. Methods: We compared patient and graft survival of recipients with pretransplant cancer to the outcomes of matched recipients without such cancer (comparators) using Cox regression. Results: From 1963 to 2010, 377 of 5867 recipients (6.4%) had a pretransplant cancer. During a median follow-up of 6.8 years, 256 recipients died, 35 (13.7%) from recurrent cancer and 27 (10.5%) from de novo cancer. Uncensored and death-censored graft loss occurred in 263 and 46 recipients, respectively. All-cause mortality was similar as in comparators (HR 1.06 [0.93-1.20], P=0.40), death-censored graft loss was lower (HR 0.63 [0.47-0.84], P=0.002), and uncensored graft loss was similar (HR 0.99 [0.87-1.12], P=0.87). Cancer mortality was higher than in comparators (hazard ratio [HR] 1.97 [95% confidence interval 1.51-2.56], P0.45). Results were similar within cancer subgroups, with most data in patients with a history of kidney cancer, prostate cancer, urothelial cancer and skin squamous cell carcinoma. Conclusion: Kidney transplant recipients with a pretransplant cancer had a similar overall patient and graft survival as recipients without such cancer. Cancer mortality was increased, particularly during the first 5 years after transplantation. A short waiting period was not associated with mortality. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Letter to the Editor: Reporting of Data to Inform the Design of a Definitive Trial Re: Henry, J.A., Frederick, M., Sell, S., Griest, S., Abrams, H. (2015). Validation of a Novel Combination Hearing Aid and Tinnitus Therapy Device, Ear Hear, 36, 42-52.

No abstract available

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The Efficacy of a Prevascularized, Retrievable Poly(D,L,-lactide-co-[epsilon]-caprolactone) Subcutaneous Scaffold as Transplantation Site for Pancreatic Islets.

Background: The liver as transplantation site for human pancreatic islets is a harsh microenvironment for islets and it lacks the ability to retrieve the graft. A retrievable, extrahepatic transplantation site that mimics the pancreatic environment is desired. Ideally this transplantation site should be located subdermal for easy surgical-access but this never resulted in normoglycemia. Here we describe the design and efficacy of a novel prevascularized, subcutaneously implanted, retrievable poly (D,L-lactide-co-[epsilon]-caprolactone) (PDLLCL) scaffold. Method: Three dosages of rat islets, ie, 400, 800, and 1200, were implanted in immune compromised mice to test the efficacy (n=5). Islet transplantation under the kidney capsule served as control (n=5). The efficacy was determined by nonfasting blood glucose measurements and glucose tolerance tests. Results: Transplantation of 800 (n=5) and 1200 islets (n=5) into the scaffold reversed diabetes in respectively 80 and 100% of the mice within 6.8 - 18.5 days posttransplant. The marginal dose of 400 islets (n=5) induced normoglycemia in 20%. The glucose tolerance test showed major improvement of the glucose clearance in the scaffold groups compared to diabetic controls. However, the kidney capsule was slightly more efficacious as all 800 (n=5) and 1200 islets (n=5) recipients and 40% of the 400 islets (n=5) recipients became normoglycemic within 8 days. Removal of the scaffolds or kidney grafts resulted in immediate return to hyperglycemia. Normoglycemia was not achieved with 1200 islets in the unmodified skin group. Conclusion: Our findings demonstrate that the prevascularized PDLLCL scaffold maintains viability and function of islets in the subcutaneous site. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The Impact of a Cochlear Implant Electrode Array on the Middle Ear Transfer Function.

Objectives: As a treatment for partial deafness with residual hearing in the lower frequency range, the combined acoustic and electric stimulation of the cochlea has become widespread. Acoustic stimulation is provided by a hearing aid's airborne sound and the electric stimulation by a cochlear implant electrode array, which may be inserted through the round window or a cochleostomy. To take advantage of that concept, it is essential to preserve residual hearing after surgery. Therefore, the intracochlear electrode array should not compromise the middle ear vibration transmission. This study investigates the influence of different electrode types and insertion paths on the middle ear transfer function and the inner ear fluid dynamics. Design: Sound-induced oval and round window net volume velocities were calculated from vibration measurements with laser vibrometers on six nonfixated human temporal bones. After baseline measurements in the "natural" condition, a cochleostomy was drilled and closed with connective tissue. Then, four different electrode arrays were inserted through the cochleostomy. Afterwards, they were inserted through the round window while the cochleostomy was patched again with connective tissue. Results: After having drilled a cochleostomy and electrode insertion, no systematic trends in the changes of oval and round window volume velocities were observed. Nearly all changes of middle ear transfer functions, as well as oval and round window volume velocity ratios, were statistically insignificant. Conclusions: Intracochlear electrode arrays do not significantly increase cochlear input impedance immediately after insertion. Any changes that may occur seem to be independent of electrode array type and insertion path. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Association of Local Intrapulmonary Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I with the Progression of Chronic Rejection of Lung Allografts.

Background: Antibody-mediated rejection may lead to chronic lung allograft dysfunction, but antibody-mediated rejection may develop in the absence of detectable donor-specific antibody (DSA) in recipient serum. This study investigated whether humoral immune responses develop not only systemically but locally within rejected lung allografts, resulting in local production of DSA. Methods: Lewis rats received orthotopic left lung transplantation from Lewis (syngeneic control) or Brown-Norway (major histocompatibility complex-mismatched allogeneic) donor rats. Rats that underwent allogeneic lung transplantation were subsequently administered cyclosporine until day 14 (short immunosuppression) or day 35 (long immunosuppression). The lung grafts and spleens of recipient animals were tissue cultured for 4 days, and the titer of antibody against donor major histocompatibility complex molecules was assayed by flow cytometry. Explanted lung grafts were also evaluated pathologically. Results: By day 98, DSA titers in supernatants of lung graft (p=0.0074) and spleen (p=0.0167) cultures, but not serum, from the short immunosuppression group were significantly higher than titers in syngeneic controls. Cultures and sera from the long immunosuppression group showed no production of DSA. Microscopically, the lung grafts from the short immunosuppression group showed severe bronchiole obliteration and parenchymal fibrosis, along with lymphoid aggregates containing T and B cells, accompanying plasma cells. These findings suggestive of local humoral immune response were not observed by days 28 and 63. Conclusions: DSA can be locally produced in chronically rejected lung allografts, along with intra-graft immunocompetent cells. Clinical testing of DSA in serum samples alone may underestimate lung allograft dysfunction. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Expansion of Prosodic Abilities at the Transition From Babble to Words: A Comparison Between Children With Cochlear Implants and Normally Hearing Children.

Objectives: This longitudinal study examined the effect of emerging vocabulary production on the ability to produce the phonetic cues to prosodic prominence in babbled and lexical disyllables of infants with cochlear implants (CI) and normally hearing (NH) infants. Current research on typical language acquisition emphasizes the importance of vocabulary development for phonological and phonetic acquisition. Children with CI experience significant difficulties with the perception and production of prosody, and the role of possible top-down effects is, therefore, particularly relevant for this population. Design: Isolated disyllabic babble and first words were identified and segmented in longitudinal audio-video recordings and transcriptions for nine NH infants and nine infants with CI interacting with their parents. Monthly recordings were included from the onset of babbling until children had reached a cumulative vocabulary of 200 words. Three cues to prosodic prominence, fundamental frequency (f0), intensity, and duration, were measured in the vocalic portions of stand-alone disyllables. To represent the degree of prosodic differentiation between two syllables in an utterance, the raw values for intensity and duration were transformed to ratios, and for f0, a measure of the perceptual distance in semitones was derived. The degree of prosodic differentiation for disyllabic babble and words for each cue was compared between groups. In addition, group and individual tendencies on the types of stress patterns for babble and words were also examined. Results: The CI group had overall smaller pitch and intensity distances than the NH group. For the NH group, words had greater pitch and intensity distances than babbled disyllables. Especially for pitch distance, this was accompanied by a shift toward a more clearly expressed stress pattern that reflected the influence of the ambient language. For the CI group, the same expansion in words did not take place for pitch. For intensity, the CI group gave evidence of some increase of prosodic differentiation. The results for the duration measure showed evidence of utterance final lengthening in both groups. In words, the CI group significantly reduced durational differences between syllables so that a more even-timed, less differentiated pattern emerged. Conclusions: The onset of vocabulary production did not have the same facilitatory effect for the CI infants on the production of phonetic cues for prosody, especially for pitch. It was argued that the results for duration may reflect greater articulatory difficulties in words for the CI group than the NH group. It was suggested that the lack of clear top-down effects of the vocabulary in the CI group may be because of a lag in development caused by an initial lack of auditory stimulation, possibly compounded by the absence of auditory feedback during the babble phase. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Predictors of Waitlist Mortality in Portopulmonary Hypertension.

Background: The current Organ Procurement Transplantation Network (OPTN) policy grants Model for End Stage Liver Disease (MELD) exception points to patients with portopulmonary hypertension (POPH), but potentially important factors, such as severity of liver disease and pulmonary hypertension, are not included in the exception score, and may affect survival. The purpose of this study was to identify significant predictors of waitlist mortality in patients with POPH. Methods: We performed a retrospective cohort study of patients in the OPTN database with hemodynamics consistent with POPH [defined as mean pulmonary arterial pressure (mPAP) >25mmHg and pulmonary vascular resistance (PVR) >=240 dynes-s-cm-5] who were approved for a POPH MELD exception between 2006 and 2014. Using a Cox proportional hazards model, we identified predictors of waitlist mortality (or removal for clinical deterioration). Results: One hundred ninety adults were included. Age (HR 1.04, 95% CI 1.00-1.08, P=0.0499), initial native MELD score (HR 1.11, 95% CI 1.05-1.17, P

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Response to Letter to the Editor: RE: Henry, J.A., Frederick, M., Sell, S, Griest, S., Abrams, H. (2015) Validation of a Novel Combination Hearing Aid and Tinnitus Therapy Device, Ear and Hear, 36, 42-52.

No abstract available

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Health-Related Quality of Life Among Young Children With Cochlear Implants and Developmental Disabilities.

Objective: The present study examined differences in health-related quality of life (HRQoL) between deaf children with cochlear implants (CI) with and without developmental disabilities (DD) and differences across HRQoL domains within both groups of children. Methods: Ninety-two parents of children with CI aged 3-7 years participated in this cross-sectional study. Of these children, 43 had DD (i.e., CI-DD group) and 49 had no DD or chronic illness, demonstrating overall typical development (i.e., CI-TD group). Parents of children in both groups completed the KINDLR, a generic HRQoL questionnaire. Parents also provided anecdotal comments to open-ended questions, and parent comments were evaluated on a CI benefits scale to assess parent-perceived benefits of CI for the deaf children with and without disabilities. Results: Children in the CI-DD group had significantly lower HRQoL compared to children in the CI-TD group, including lower scores on the self-esteem, friend, school, and family HRQoL subscales. No significant differences among groups were found on the physical well-being and emotional well-being subscales. For the CI-TD group, age at implantation correlated negatively with self-esteem and school HRQoL subscales. In the CI-DD group, children's current age correlated negatively with family and with the total HRQoL scores. Parent anecdotal comments and scores on the CI-benefits scale indicated strong parent perceptions of benefits of implantation for children in both groups. Conclusion: Based on parents' proxy report, findings suggest that having DD affects multiple domains of HRQoL among young children with CIs above and beyond that of the CI itself. Parents of deaf children with DD may need greater support through the CI process and follow-up than parents of deaf children without DD. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Reasons for rarity of anal melanocytic naevi

Abstract

In the last 16 years only seven definite cases of anal melanocytic naevi have been reported in the literature. We describe three new cases, none of which were suspected clinically and were incidentally diagnosed on histological examination of haemorrhoidectomy specimens. The infrequency of these special site flexural melanocytic lesions may be related to changes in the involutionary mechanisms of the anal melanocyte proliferation. However, other factors related to the low detection rates by clinicians and pathologists need also to be considered.

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Pemphigus, a pathomechanism of acantholysis

Abstract

Autoantibodies to the desmosomal proteins desmoglein 1 and 3 cause pemphigus foliaceus and pemphigus vulgaris, which are characterised by keratinocyte dissociation (acantholysis) and intraepidermal blister formation. The passive transfer of pathogenic anti-desmoglein antibodies induces blisters in mice in vivo and the loss of keratinocyte adhesion in vitro. The pathogenetic mechanisms of acantholysis due to anti-desmoglein autoantibodies are not fully understood. However, recent studies have revealed that signalling-dependent and signalling-independent pathways are operative in the loss of cell adhesion. In this review, we focus on the pathomechanism of acantholysis due to autoantibodies to desmogleins and recent therapeutic approaches.

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Editorial Board

Publication date: January 2017
Source:Clinical Immunology, Volume 174





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Reasons for rarity of anal melanocytic naevi

Abstract

In the last 16 years only seven definite cases of anal melanocytic naevi have been reported in the literature. We describe three new cases, none of which were suspected clinically and were incidentally diagnosed on histological examination of haemorrhoidectomy specimens. The infrequency of these special site flexural melanocytic lesions may be related to changes in the involutionary mechanisms of the anal melanocyte proliferation. However, other factors related to the low detection rates by clinicians and pathologists need also to be considered.

http://ift.tt/2loSJg5

Pemphigus, a pathomechanism of acantholysis

Abstract

Autoantibodies to the desmosomal proteins desmoglein 1 and 3 cause pemphigus foliaceus and pemphigus vulgaris, which are characterised by keratinocyte dissociation (acantholysis) and intraepidermal blister formation. The passive transfer of pathogenic anti-desmoglein antibodies induces blisters in mice in vivo and the loss of keratinocyte adhesion in vitro. The pathogenetic mechanisms of acantholysis due to anti-desmoglein autoantibodies are not fully understood. However, recent studies have revealed that signalling-dependent and signalling-independent pathways are operative in the loss of cell adhesion. In this review, we focus on the pathomechanism of acantholysis due to autoantibodies to desmogleins and recent therapeutic approaches.

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Diagnosis and Management of Mitochondrial Neuro-Ophthalmologic Disorders: Translating Scientific Advances Into the Clinic

No abstract available

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Invasive Aspergillosis Mimicking Sphenoid Wing Meningioma

No abstract available

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Swelling of the Optic Nerve Head: A Backstage View of a Staging Scheme

No abstract available

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Are Anemia and Hypotension Causally Related to Perioperative Ischemic Optic Neuropathy?

No abstract available

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Ganglion Cell Complex Loss in Chiasmal Compression by Brain Tumors

Background: Patterns of ganglion cell complex (GCC) loss detected by optical coherence tomography provide an objective measure of optic nerve injury. These patterns aid in early diagnosis and localization of chiasmal lesions. Methods: Twenty-three patients with chiasmal compression seen between 2010 and 2015 were imaged with the Cirrus high-definition optical coherence tomography macular cube 512 × 128, retinal nerve fiber layer (RNFL) scan protocols and automated (30-2 Humphrey) visual fields (VFs). Age-matched controls were included for comparison. Generalized estimating equations were performed comparing RNFL and GCC thicknesses between patients and their controls. Effect size (d) was calculated to assess the magnitude of difference between patients and controls. The average GCC and RNFL thicknesses also were correlated with VF mean deviation (MD). Pre operative average GCC thickness was correlated to post operative VF MD. Results: Patterns of GCC thinning corresponded to VF defects. The average GCC thickness was 67 ± 9 μm in patients and 86 ± 5 μm in controls (P

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Neuro-Ophthalmology in Portugal

No abstract available

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Invited Commentary: Ganglion Cell Complex Measurement in Compressive Optic Neuropathy

No abstract available

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A Giant Tumefactive Virchow-Robin Space: A Rare Cause of a Homonymous Quadrantanopia

Abstract: A 53-year-old woman was found to have a left inferior homonymous quadrantanopia. Brain MRI disclosed a giant Virchow–Robin space compressing the right optic tract. After fenestration of this cystic lesion, most of the visual field loss resolved. Giant Virchow–Robin spaces may cause homonymous field defects which, with appropriate management, may improve.

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Invited Commentary: Form Versus Function: A State of Disunion?

No abstract available

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Literature Commentary.

In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD, will discuss the following 6 articles: 1. Lee YC, Wang JH, Huang TL, Tsai RK. Increased risk of stroke in patients with nonarteritic anterior ischemic optic neuropathy: a nationwide retrospective cohort study. Am J Ophthalmol. 2016;170:183-189. 2. Ray JG, Vermeulen MJ, Bharatha A, Montanera WJ, Park AL. Association between MRI exposure during pregnancy and fetal and childhood outcomes. JAMA. 2016;316:952-961. 3. Kilduff CL, Casswell EJ, Salam T, Hersh D, Ortiz-Perez S, Ezra D. Use of alleviating maneuvers for periocular facial dystonias. JAMA Ophthalmol. 2016;134:1247-1252. 4. Eklund A, Johannesson G, Johansson E, Holmlund P, Qvarlander S, Ambarki K, Wahlin A, Koskinen LO, Malm J. The pressure difference between eye and brain changes with posture. Ann Neurol. 2016;80:269-276. 5. Cortes-Vicente E, Gallardo E, Martinez MA, Diaz-Manera J, Querol L, Rojas-Garcia R, Illa I. Clinical characteristics of patients with double-seronegative myasthenia gravis and antibodies to cortactin. JAMA Neurology. 2016;73:1099-1104. 6. Kim SH, Zee DS, du Lac S, Kim HJ, Kim JS. Nucleus prepositus hypoglossi lesions produce a unique ocular motor syndrome. Neurology. 2016;87:2026-2033. (C) 2017 by North American Neuro-Ophthalmology Society

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Spectrum of Magnetic Resonance Imaging Features in Unilateral Optic Tract Dysfunction

Background: Optic tract dysfunction may be the predominant or only clinical manifestation of an intracranial disorder including mass legion, ischemic infarct, inflammatory disease, and trauma. Documentation of the neuroimaging features of these lesions is limited to reports mostly published before the availability of MRI. This study was undertaken to document the spectrum of MRI features in patients presenting with optic tract dysfunction. Methods: A retrospective study from 2004 to 2015 at a single tertiary care neuro-ophthalmology service of 24 patients who had unilateral optic tract dysfunction defined by a homonymous hemianopia and a relative afferent pupil defect that could not be attributed to optic neuropathy or retinopathy. Two institutional neuroradiologists, who were privy to the presence of optic tract dysfunction but not to its side or cause, independently documented the MRI abnormalities on a standard data collection form and then convened for a consensus review of the imaging abnormalities with the 2 clinician authors. Results: The clinical diagnoses were 6 ischemic strokes, 5 malignant brain tumors, 5 postoperative neurosurgical cases, 4 intracranial hemorrhages, 2 traumatic brain injuries, 1 midbrain/optic tract primary demyelination, and 1 temporal lobe herpes simplex encephalitis. In their independent review, both neuroradiologists identified MRI abnormalities in 20 (83%) cases that were extrinsic to the optic tract in the neighboring temporal lobe, midbrain, thalamus, basal ganglia, or suprasellar space. In 5 of those cases, the extrinsic abnormality included features suggesting compression of the optic tract, but these compressive features were not appreciated by either neuroradiologist until the consensus conference. In 15 cases, MRI abnormalities intrinsic to the optic tract itself were eventually identified, including T2 or fluid-attenuated inversion recovery image (FLAIR) hyperintensity (9 cases) or hypointensity (1 case), thinning (6 cases), thickening (2 cases), and contrast enhancement (1 case). However, none of these intrinsic MRI abnormalities was identified during the independent review, being detected only in the consensus conference. Conclusions: Neuroradiologists aware of unilateral optic tract dysfunction but not of its side detected extrinsic (neighborhood) MRI abnormalities in most cases but did not appreciate that these extrinsic features sometimes included compression of the optic tract. MRI abnormalities intrinsic to the optic tract were entirely overlooked during independent review, being recognized only in a consensus conference with clinician authors. Neuroradiologists are more likely to detect MRI abnormalities pertinent to optic tract dysfunction once they have more complete clinical information and with higher resolution imaging, especially T1 postcontrast axial and coronal sequences and T2 or FLAIR coronal scans.

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Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?: Comment

No abstract available

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Detection of Thyroid Abnormalities in Aquaporin-4 Antibody–Seropositive Optic Neuritis Patients

Objective: This study retrospectively analyzed the frequency of anti-thyroid antibodies (ATAs) and thyroid disease in patients with optic neuritis (ON). Methods: Tests of serum thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies and thyroid function were performed in 97 ON patients. Blood also was drawn to test for AQP4-Ab using cell-based and enzyme-linked immunosorbent assays. Comparisons of the frequencies of ATAs, thyroid diseases and thyroid function were performed based on AQP4-Ab status. Results: Seropositive AQP4-Ab was found in 47/97 (48.5%) patients. ATA was considered positive in 34/97 (35.1%) patients. The prevalence of ATA was two times higher (P = 0.019) in the AQP4-Ab+ group compared to the AQP4-Ab- group. AQP4-Ab+ ON patients exhibited lower FT3 (P = 0.006) and FT4 (P = 0.025) levels and a higher prevalence of definite Hashimoto thyroiditis (HT) (P = 0.005). Among AQP4-Ab+ patients, those with HT had a worse visual outcome than non-HT patients. Conclusion: A high prevalence of ATAs and HT was found in AQP4-Ab+ ON patients, and AQP4-Ab+ patients with HT exhibited worse visual outcomes than non-HT patients.

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New Treatments in Neuro-Ophthalmology: The Role for Evidence

No abstract available

http://ift.tt/2loLPYb

Ciliary Body/Iris Appositioning Producing Mechanical Pupillary Defects in Carotid-Cavernous Sinus Fistula: An Overlooked Pathophysiologic Mechanism

Background: Variable pupillary responses have been described with carotid-cavernous sinus fistulas. These often are associated with a decrease in visual acuity and attributed to retinal ischemia. We propose a novel pathophysiologic mechanism for changes in pupillary reactivity involving anatomic changes secondary to choroidal effusion. Methods: To demonstrate proof-of-concept, we investigated 2 consecutive patients with carotid-cavernous sinus fistulas and pupillary disturbances using repeated refractions and anterior segment ultrasound biomicroscopy. Results: Ultrasound biomicroscopy demonstrated choroidal thickening and ciliary body effusion with forward rotation of the lens–iris diaphragm altering refraction and mechanically limiting iris movements. Conclusions: Where there are acute elevations in orbital venous pressure causing ciliary body effusion, changes in visual acuity and pupillary abnormalities can be produced by mechanical effects.

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IgG4 Disease: Is It or Isn't It?

No abstract available

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Diagnosing Light Chain Amyloidosis on Temporal Artery Biopsies for Suspected Giant Cell Arteritis

Abstract: Although still rarely diagnosed, amyloid light chain (AL) amyloidosis is the most common form of systemic amyloidosis. It is characterized by misfolded monoclonal immunoglobulin light chain fragments that accumulate extracellularly as amyloid fibrils, with consequent organ dysfunction. We report 2 such cases where initial symptoms and signs were identical to and mistaken for those of giant cell arteritis, associated with polymyalgia rheumatica. Neither patient responded to high-dose corticosteroids; instead, their temporal artery biopsies revealed amyloid deposits and other investigations confirmed a diagnosis of systemic AL amyloidosis. Review of the literature reveals similar cases of diagnostic confusion spanning 75 years. We have summarized the findings and learning points from cases reported in the past 30 years and highlight the need for increased awareness and investigation of this underrecognized syndrome.

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Ipsilateral Ophthalmic and Cerebral Infarctions After Cosmetic Polylactic Acid Injection Into the Forehead

Abstract: A 55-year-old woman developed no light perception vision in her right eye 5 days after an injection of polylactic acid cosmetic filler into her right forehead. Diffuse corneal edema and anterior chamber inflammation prohibited any view to the posterior segment to identify the cause of her profound vision loss. MRI of the orbits with diffusion-weighted imaging showed hyperintensity of the right optic nerve with signal reduction on apparent diffusion coefficient mapping, consistent with ischemia. Our patient also was found to have acute infarctions in the distribution of the right anterior cerebral artery on MRI of the brain despite having no permanent focal neurologic deficits aside from vision loss.

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In vitro cytotoxicity evaluation of nano-carbon particles with different sp2/sp3 ratios

Publication date: Available online 16 February 2017
Source:Materials Science and Engineering: C
Author(s): S.S. Li, B.J. Wu, Q.Y. Deng, Y.B. Guo, Y.X. Leng, N. Huang
Graphitization occurs during the long-term service of a diamond-like carbon (DLC) modified artificial joint. Then, DLC wear debris, which are carbon particles with different sp²/sp³ ratios and sizes ranging from the nano- to micro-meter scale produced. In this paper, to promote the application of DLC coating for artificial joint modification, the cytotoxicity of DLC debris (nano-carbon particles, NCs) with different sp²/sp³ ratios was studied. The microstructure and physical characteristics of NCs with different sp²/sp³ ratios were investigated by Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS). Meanwhile, osteoblasts and macrophages were applied to characterize the cytotoxicity of the NCs. In vitro cytotoxicity assay results indicated that cells incubated with NCs of different sp²/sp³ ratios had greater osteogenic capacity, and these particles caused a weaker immune response in comparison with CoCrMo particles. Taken together, the results indicated that NCs with different sp²/sp³ ratios presented a good cytocompatibility than CoCrMo particles. But no significant differences were observed among NCs with different sp²/sp³ ratios. The better cytocompatibility of NCs is mainly attributable to their surface charge.



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Screening for Lung Cancer

Publication date: Available online 16 February 2017
Source:Seminars in Oncology
Author(s): Heather F. Sateia, Youngjee Choi, Rosalyn W. Stewart, Kimberly S. Peairs
This review will comprise a general overview of the epidemiology of lung cancer, as well as lung cancer risk factors, screening modalities, current guideline recommendations for screening, and our approach to lung cancer screening.



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A granulomatous conundrum: Concurrent necrobiosis lipoidica, cutaneous sarcoidosis and erythema nodosum in a nondiabetic patient

Abstract

Necrobiosis lipoidica (NL) and cutaneous sarcoidosis are granulomatous disorders with a largely unknown aetiopathogenesis. Evidence of co-existing NL and sarcoidosis in the same patient may suggest a degree of overlap between these entities through shared granulomatous inflammatory pathways. Occasionally, one condition can mimic the other, making their distinction difficult. We report a novel case of a non-diabetic woman who presented with concurrent NL, cutaneous sarcoidosis and erythema nodosum. We discuss some of the complexities distinguishing these entities and propose that they may represent different stages of the same granulomatous process linked through yet unknown pathomechanisms.

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Correlation of Leptin, Adiponectin, and Resistin Levels in Different Types of Lipodystrophy in HIV/AIDS Patients

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


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Change in Body Weight from Age 20 Years Is a Powerful Determinant of the Metabolic Syndrome

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


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Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


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A granulomatous conundrum: Concurrent necrobiosis lipoidica, cutaneous sarcoidosis and erythema nodosum in a nondiabetic patient

Abstract

Necrobiosis lipoidica (NL) and cutaneous sarcoidosis are granulomatous disorders with a largely unknown aetiopathogenesis. Evidence of co-existing NL and sarcoidosis in the same patient may suggest a degree of overlap between these entities through shared granulomatous inflammatory pathways. Occasionally, one condition can mimic the other, making their distinction difficult. We report a novel case of a non-diabetic woman who presented with concurrent NL, cutaneous sarcoidosis and erythema nodosum. We discuss some of the complexities distinguishing these entities and propose that they may represent different stages of the same granulomatous process linked through yet unknown pathomechanisms.

http://ift.tt/2kELH2j

Using Dental Implants Concomitant With Onlay Bone Grafting for Auricular Reconstruction.

Conventional dental implants have been reported for nasal and orbital regions but due to limited thickness of calvarium they are not used in mastoid region. Onlay bone grafting in skull concomitant with implants is a predictable method and experimental animal studies confirm it. Parietal bone and lateral mandibular ramus are suggested source of bone grafts and dental implants with 7 mm length can be used safely. Increased fixture length may lead to increase survival in long term. (C) 2017 by Mutaz B. Habal, MD.

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What Are the Contributing Factors for Postsurgical Relapse After Two-Jaw Surgery in Patients With Cleft Lip and Palate.

The purpose of this study was to investigate the amount and pattern of postsurgical relapse after 2-jaw surgery in cleft lip and palate patients in terms of the sagittal and vertical aspects. The samples consisted of 21 adult patients who had the similar initial skeletodental pattern before surgery and underwent 2-jaw surgery. They were divided into high relapse (n = 11) and low relapse groups (n = 10) (criteria, 30% forward relapse of the B point). After the cephalometric variables of cephalograms taken at 1 month before surgery (T0), immediately after surgery (T1), and at least 1 year after surgery (T2) were measured, the Wilcoxon test, Mann-Whitney U test, and Pearson correlation test were performed for statistical analysis. When compared with the low relapse group, the high relapse group exhibited significant counterclockwise rotation of the distal segment of the mandible resulting in more forward movement of the mandible and significant labioversion of the maxillary incisors during T1-T2. The amount of postsurgical relapse of the mandible had a positive relationship with the amounts of setback and clockwise rotation of the mandible with surgery. In addition, the more decrease in overbite through surgery occurred, the more relapse (forward movement of the mandible) produced. Therefore, for the prevention of significant postsurgical relapse of the mandible in cleft patients, it is necessary to reduce unnecessary clockwise rotation of the mandible and to increase the vertical stability of maxilla during orthognathic surgery. (C) 2017 by Mutaz B. Habal, MD.

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Implantation of Thickened Artificial Bone for Reduction of Dead Space and Prevention of Infection Between Implant and Dura in Secondary Reconstruction of the Skull.

For the treatment of skull defect compensation after neurosurgery, a customized artificial bone is often employed owing to its toughness and the relative ease of producing cosmetically good result. However, implants are vulnerable to infection and removal of implant is sometimes necessary. Several other treatment options such as autologous bone graft or free flap are likely to be considered for the secondary reconstruction to avoid reinfection; however, reimplantation of artificial bone is beneficial for the patients, being not concerned with donor site morbidity. The authors consider one of risk factors of infection of artificial bone as dead space between the implant and dura. To attain reduction of the dead space, we have employed thickened artificial bone. Between 2010 and 2014, 6 patients underwent implantation of thickened artificial bone for the secondary reconstruction. First, the infected artificial material was removed with proper debridement. More than 3 months after the closure of the infected wound, tissue expander was inserted beneath the surrounding scalp to ensure the coverage of subsequently implanted artificial bone without skin tension. The thickened artificial bone was designed from the computed tomography findings so as not to leave any dead space between the implant and dura. After optimal expansion of the scalp, the artificial bone was implanted. Postoperative courses were uneventful and the appearance of the cranial vault was satisfactory in all patients. The authors consider the use of the thickened artificial bone is easier and more suitable for patients having a skull defect, particularly in secondary reconstruction. (C) 2017 by Mutaz B. Habal, MD.

http://ift.tt/2loyJdc

Modified Mallampati Score Improves Specificity of STOP-BANG Questionnaire for Obstructive Sleep Apnea.

Background: An accurate, clinical screening tool for obstructive sleep apnea (OSA) that identifies patients for further diagnostic testing would assist in the diagnosis of this comorbidity. One example, the STOP-BANG questionnaire (SBQ), has been validated as a screening tool with high sensitivity. However, its specificity may result in a high false-positive rate. The aim of this study to determine if addition of the Modified Mallampati score to the SBQ improves its specificity. Methods: The authors studied 162 patients referred to the Sleep Disorders Clinic at Yedikule Chest Disease Education and Research Hospital. All patients were prospectively screened for risk of OSA using the SBQ, their oral anatomy was assessed by Modified Mallampati scoring, and sleep quality characterized by polysomnography. Polysomnography results were reviewed when available and the predictive performance of the SBQ and the modified SBQ scoring models were compared. Results: In the authors' study an SBQ score >=3 yielded sensitivities of 0.85, 0.86, and 0.91 for Apnea-Hypopnea Index (AHI) >=5/h, AHI >=15/h, and AHI >=30/h, respectively, and specificities of 0.09, 0.10, and 0.18. The modified SBQ with a cutoff of >=4 (>3) points for AHI levels of >5, >15, and >30 yielded respective sensitivities of 0.84, 0.86, and 0.91 and specificities of 0.25, 0.26, and 0.27. Conclusions: The author's results from indicated the modified SBQ with a cutoff of >3 points in this study was more specific than the standard SBQ but no less sensitive, and may be used in identifying OSA patients for further diagnostic evaluation or avoiding unnecessary testing. (C) 2017 by Mutaz B. Habal, MD.

http://ift.tt/2m0ETgo

Two Rare Variants of Left Vertebral Artery.

Though the variations of vertebral artery are clinically asymptomatic yet abnormalities are of diagnostic importance either prior to vascular surgery in the neck region or in patients of intravascular diseases such as arteriovenous malformations or cerebral aneurysms. Therefore, the aim of the study is to bring out 2 variations in the configuration of vertebral artery and their clinical implication. During dissection of thorax of 2 female cadavers, 2 different variants of configurations of left vertebral arteries were observed. In 1 patient, the left vertebral artery arose aberrantly from arch of aorta between left common carotid artery and left subclavian artery. This artery then, following oblique course, abnormally entered into foramen transversarium of C4 vertebra. In the second patient, the left common stump emerged from arch of aorta in the left side of left common carotid artery and then instantly bifurcated into vertebral artery and subclavian artery. Then following the usual oblique course, the left vertebral artery anomalously entered into foramen transversarium of C3 vertebra at the level of upper border of thyroid cartilage. The knowledge of these rare variations in the origin of vertebral artery is of paramount importance to surgeons performing surgery in neck region, radiologist performing angiography to avoid misinterpretation of radiographs and to anatomists for rare variations in academics and research. (C) 2017 by Mutaz B. Habal, MD.

http://ift.tt/2loDiEG

The Subunit Principle in Scar Face Revision.

Facial scaring is considered one of the most difficult cosmetic problems for any plastic surgeon to solve. The condition is more difficult if the direction of the scar is not parallel to relaxed skin tension lines. Attempts to manage this difficult situation included revisions using geometric designs, Z plasties or W plasties to camouflage the straight line visible scaring. The use of long-lasting resorbable sutures was tried too. Recently, the use of botulinum toxin during revision improved the results. Fractional CO2 lasers, microfat grafts, and platelet-rich plasma were added to the armamentarium. The scar is least visible if placed in the junction between the facial subunits. The aim of this study is to investigate the use of the subunit principle to improve the results of scar revision. Four patients were included in this study. Tissue expansion of the intact part of the subunit allowed shifting the scar to the junction between the affected subunit and the adjacent one. Tissue expansion, delivery of the expanders, and advancement of the flaps were successful in all patients. The fact that this is a 2-stage procedure and sacrifices some of the intact skin from the affected facial subunit, makes this technique reserved to patients with ugly facial scars who are ambitious to improve their appearance. (C) 2017 by Mutaz B. Habal, MD.

http://ift.tt/2m0Hl6L

A Periodical Article Reviewer as Gottfried: The Uncle of Jean-Christophe.

No abstract available

http://ift.tt/2loCOhI

Significant Differences in the Bone of an Isogenic Inbred Versus Nonisogenic Outbred Murine Mandible: A Study in Rigor and Reproducibility.

Inattention to differences between animal strains is a potential cause of irreproducibility of basic science investigations. Accordingly, the authors' laboratory sought to ensure that cross-comparisons of results generated from studies of mandibular physiology utilizing the Sprague Dawley and Lewis rat strains are valid. The authors specifically investigated baseline histomorphometrics, bone mineral density, and biomechanical strength of the unaltered endogenous mandibles of the inbred, isogenic Lewis rat, and the outbred, nonisogenic Sprague Dawley rat to determine if they are indeed equal. The authors hypothesized that little difference would be found within these metrics. The authors' study utilized 20 male Lewis and Sprague Dawley rats, which underwent no manipulation other than final dissection and analysis. Ten rats from each strain underwent bone mineral density and biomechanical strength analysis. The remaining rats underwent histological analysis. Descriptive and bivariate statistics were computed and the P value was set at 0.05. Lewis rats had a significantly greater number of empty lacunae. Sprague Dawley rats exhibited a significantly greater ratio of bone volume-to-total volume, bone mineral density, tissue mineral density, bone volume fraction, and total mineral content. No differences were found during biomechanical testing. This study demonstrates that differences exist between the Lewis and Sprague Dawley rat within unaltered baseline mandibular tissue. However, these differences appear to have limited functional impact, as demonstrated by similar biomechanical strength metrics. Other specific differences not addressed in this manuscript may exist. However, the authors believe that researchers may confidently cross-compare results between the 2 strains, while taking into account the differences found within this study. (C) 2017 by Mutaz B. Habal, MD.

http://ift.tt/2m0RAYq

Anthropometric Outcome Measures in Patients With Metopic Craniosynostosis.

Purpose: Treatment of metopic craniosynostosis is performed by either fronto-orbital advancement (FOA) or endoscopic-assisted techniques. Interfrontal angle (IFA) is a validated measure of trigonocephaly, but requires a computed tomography scan. The most common direct measure to assess surgical outcome in patients with trigonocephaly is frontal width (ft-ft). The aim of this study is to determine if frontal width correlates with IFA and successful surgical correction 1 year after treatment. A review of current morphologic assessment techniques is also provided. Methods: Three-dimensional computed tomography scans (preoperative and 1 year postoperative) of patients who underwent FOA (n = 13) or endoscopic (n = 13) treatment of metopic craniosynostosis were reviewed. Age-matched scans of unaffected patients served as controls. Frontal width was measured by a straight line between the bilateral frontotemporal points. Measurements were performed by 2 experienced observers and compared to IFA. Results: Mean frontal width at preoperative scan for endoscopic and open patients was 55 +/- 0.6 and 64 +/- 0.7 mm, respectively (Z-score 1.6 and -3.7). Mean frontal width at postoperative scan for endoscopic and open patients was 80 +/- 0.4 and 81 +/- 0.7 mm (Z-score 0.0 for both groups). Frontal width for endoscopic correction significantly correlated with IFA (r = 0.536, P = 0.005), as well as for the open patients (r = 0.704, P

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Sequence of Surgical Reconstruction in a Child With Cleft Lip and Palate Associated With Congenital Facial Teratomas.

We describe a case of left homolateral complete cleft lip/palate associated with a congenital left maxillary teratoma and left orbital teratoma. The patient required step-by-step reconstruction that first included resection of the 2 teratomas in consideration of cleft lip repair, cleft palate repair, and correction of the left periorbital anomalies, which were performed later. After performing all the necessary procedures, complete resection of the tumors and correction of the anomalies associated with the lip, palate, and left orbit were achieved. The rare occurrence of this type of association and its devastating effect on a patient's growth, aesthetics, and function of craniofacial elements require careful surgical planning to enable restoration of the anatomy and proper functional development. At follow-up, the patient showed significant improvement in the functional and aesthetic aspects. (C) 2017 by Mutaz B. Habal, MD.

http://ift.tt/2m0C3rQ

Improving Functional and Aesthetic Outcomes in Syndromic Patients With Webbed Neck Deformity: Utilizing a Staged Endoscopic-Assisted Approach to Improve the Posterior Hairline and Decrease Scar Burden.

Introduction: Webbed neck deformity (WND) can have significant functional and psychosocial impact on the developing child. Surgical correction can be challenging depending on the extent of the deformity, and patients often also have low posterior hairlines requiring simultaneous correction. Current surgical techniques include various methods of single-stage radical excision that often result in visible scar burden and residual deformity. There is currently no general consensus of which technique provides the best outcomes. Methods: A modified approach to WND was designed by the senior author aimed to decrease scar burden. Endoscopic-assisted fasciectomy was performed with simultaneous posterior hairline reconstruction with local tissue rearrangement camouflaged within the hair-bearing scalp. Staged surgical correction was planned rather than correction in a single operation. A retrospective review was performed to evaluate all patients who underwent this approach over a 2-year period. Results: Two patients underwent the modified approach, a 17-year-old female with Noonan syndrome and a 2-year-old female with Turner syndrome. Both patients showed postoperative improvement in range of motion, contour of the jaw and neckline, and posterior hairline definition. Patients were found to have decreased scar burden compared with traditional techniques. Discussion: A staged, combination approach of endoscopic-assisted fasciectomy and strategic local tissue reconstruction of the posterior hairline to correct WND achieves good functional and aesthetic results and good patient satisfaction. This modification should be considered when managing WND. (C) 2017 by Mutaz B. Habal, MD.

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Improving the Aesthetic Outcome in Scaphocephaly Correction: Hairline Lowering During Vault Remodeling Procedures.

The bossed forehead in patients with scaphocephaly often leads to a high hairline. A new technique to improve the aesthetic outcome of patients undergoing scaphocephaly correction is described. Sixteen patients with scaphocephaly and having a high hairline due to frontal bossing who underwent scaphocephaly correction by subtotal or total vault remodeling were analyzed. The median age at surgery was 18 months. The mean distance between the nasofrontal suture and the hairline was preoperatively 70 mm (range 58-91). An obvious lowering of the hairline could be achieved in all 16 patients. The mean postoperative distance nasofrontal suture to hairline was 59 mm (range 50-73). There were no complications associated with the technique. The hairline lowering technique is a useful addition to vault remodeling techniques and can improve the postoperative aesthetic appearance considerably. The authors recommend this technique in scaphocephaly patients, who present with a high hairline. (C) 2017 by Mutaz B. Habal, MD.

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Intradiploic Epithelial Inclusion Cyst of the Cranium Mimicking Fibrous Dysplasia.

Intradiploic inclusion cysts are exceedingly rare in the pediatric population. The authors present a 16-year-old male patient who presented with a large growing calvarial mass with a preoperative diagnosis of fibrous dysplasia based on radiologic imaging. Craniectomy followed by autogenous reconstruction was performed. Histopathological examination revealed a relatively small inclusion cyst of the intradiploic space, surrounded by reactive bone. This patient demonstrates a highly unusual presentation of a rare entity, and the authors discuss the diagnosis and management of intradiploic inclusion cysts. (C) 2017 by Mutaz B. Habal, MD.

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Application of Computer-Aided Design and Customized Implants in the Reconstruction of Pyriform Aperture Defects Secondary to Unilateral Cleft Lip and Palate.

Purpose: To design and develop customized implants with the rapid prototyping (RP) technique in order to reconstruct the defected pyriform aperture. Methods: A 3-dimensional digital model was reconstructed with the software proplan CMF based on the computed tomography data of the patient's skeleton. Then an individualized implant was designed by computer-aided design (CAD) and prepared with the RP technique. A total of 5 patients (3 males and 2 females) with unilateral secondary nasal deformities received the customized implants in this study. Results: All the implants closely matched the surface of the defects. During the 12- to 24-month follow-up period, all the patients reported satisfactory outcomes except for 1 patient where exposure of the implant was observed and had to be removed 3 months after the surgery. Conclusion: With high precision and matching degree, individualized implants designed by CAD and prepared with the RP technique can be used to overcome the limitations of ready-made materials and improve the accuracy of the surgical procedure in reconstructing the defected pyriform aperture. (C) 2017 by Mutaz B. Habal, MD.

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Relative Location of Fundus Meatus Acustici Interni Via Porus Acusticus Internus in Facial Nerve Decompression.

Facial neural edema is the pathophysiological base of Bell's palsy. The middle cranial fossa approach is used to relieve the oppression of facial nerve at its most narrow course in the facial canal. In this research, the authors mainly discussed the internal auditory canal segment of facial nerve, completely in the shadow of the bony structure, which is inconvenient for transmastoid decompression. Therefore, the objective was to explore the definite position of the fundus meatus acustici interni from internal acoustic pore. Two hundred persons (age 22-60, 100 men and 100 women), presenting with healthy facial nerve, ear, and internal auditory canal, were investigated by computed tomography 3-dimensional reconstruction. Using statistical method to analyze, the authors obtained the definite position of the fundus meatus acustici interni, regarding the internal acoustic pore as the origin of coordinates. Our data provided more significant information for medical workers to improve the efficiency of operation and to prevent complications of surgery. (C) 2017 by Mutaz B. Habal, MD.

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Is canscore a good indicator of fetal malnutrition in preterm newborn

Publication date: Available online 16 February 2017
Source:Alexandria Journal of Medicine
Author(s): B.N. Ezenwa, V.C. Ezeaka
BackgroundFetal malnutrition is a risk factor for increased neonatal morbidities and mortalities worldwide. BMI and CANScore had been used for determining fetal malnutrition in term newborns.ObjectiveTo assess the nutritional status of preterm newborns at birth using BMI, PI and CANscore and determine the better indicator for FM.MethodsThe study was carried out on consecutive, live-born babies between 28 completed weeks through 36weeks gestation. Birth weights and lengths were recorded as per protocol. BMI was calculated and BMI <10th centile using Brock's chart is considered as FM and a PI <2.2 was considered as malnutrition. Using Metcoff's CANscore, score <25 is FM. Data was analyzed using the SPSS version 22.0.ResultsOne hundred and forty preterm newborns were assessed and 108 (77%) were of LBW. BMI, CANscore and PI identified 40.0%, 34.3% and 30.0% of the preterm newborns as FM. Using BMI as standard for detecting FM, CANscore and PI identified 33.9% and 51.8% of the babies as FM. PI had a better sensitivity for detecting FM in preterm infants compared to CANScore and this was statistically significant, p<0.00.ConclusionFM is common in preterm babies. BMI and PI are simple and easy tools to use in assessing FM in preterm babies. They are also better identifiers of FM in preterm newborns compared to CANScore.



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Ex utero intrapartum treatment (EXIT) for upper airway obstruction.

Purpose of review: Improvements in the antenatal diagnosis of congenital malformations have led to increased detection of fetal airway obstructing lesions, and pediatric ear, nose, and throat surgeons are increasingly involved in these cases. Recent findings: This article outlines the typical range of pathology seen, the logistics in providing support for anticipated deliveries and the multidisciplinary management of complex airway cases. Summary: Traditionally, difficulty in obtaining a patent airway at delivery was a major factor in the dismal prognosis of these pregnancies. The ex utero intrapartum treatment procedure, which involves controlled partial delivery of the fetus whilst maintaining placental circulation, allows various airway maneuvers to be performed to secure the airway in a controlled fashion. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hypoparathyroidism after thyroidectomy: prevention, assessment and management.

Purpose of review: Permanent hypoparathyroidism is the most common long-term complication after total thyroidectomy and it can cause significant morbidity and increased costs. Its incidence varies from 30% to 60%. Recent findings: The surgical technique and the extent of thyroidectomy are related to parathyroid injury and hypoparathyroidism. The glands should be identified in situ, carefully manipulated and preserved, as well as their vascularization. In case of incidental removal, routine autotransplantation is advocated. Low calcium levels, identification of fewer than two parathyroid glands at surgery, reoperation for bleeding, Graves disease and heavier thyroid specimens were considered independent predictors of permanent hypocalcemia. Intraoperative parathyroid hormone (PTH) measurements allows the early detection of hypocalcemia. Treatment is recommended for patients with symptoms of hypocalcemia or corrected serum calcium

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The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling

<span class="paragraphSection"><div class="boxTitle">Abstract</div>KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with <span style="font-style:italic;">KIAA0319</span>. Conversely, the deletion of <span style="font-style:italic;">Kiaa0319</span> in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.</span>

http://ift.tt/2ldFfRB

Open partial laryngectomy after failure of (chemo) radiation: indications, oncologic and functional outcomes.

Purpose of review: Early-stage squamous cell carcinoma of the larynx can be successfully treated with radiotherapy or surgery (transoral or open approaches). Oncologic results are comparable while functional results may be different according to the volume of resection. In some countries radiotherapy is often preferred as primary treatment. In case of recurrence, surgical salvage is the only option. Careful examination, endoscopic assessment, computed tomography or magnetic resonance imaging are necessary to assess superficial and deep extensions into the larynx, including cartilage framework and to restage the tumor. Recent findings: The choice between endoscopic and open partial laryngectomy is based on the extension and characteristics of the tumor. Oncologic results of open approaches are encouraging as local control, survival, and laryngeal preservation rates reported in the literature are close to those obtained in nonpreviously treated patients. Functional results are not significantly worse and major complications in the previously irradiated patients undergoing open neck surgery not increased. Supracricoid partial surgery seems to be more and more performed. Summary: With regards to the results, open partial surgery, like in nonpreviously treated patients, is still indicated for the surgical treatment of postradiotherapic recurrent/persistent disease. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2kZ52yJ

Ex utero intrapartum treatment (EXIT) for upper airway obstruction.

Purpose of review: Improvements in the antenatal diagnosis of congenital malformations have led to increased detection of fetal airway obstructing lesions, and pediatric ear, nose, and throat surgeons are increasingly involved in these cases. Recent findings: This article outlines the typical range of pathology seen, the logistics in providing support for anticipated deliveries and the multidisciplinary management of complex airway cases. Summary: Traditionally, difficulty in obtaining a patent airway at delivery was a major factor in the dismal prognosis of these pregnancies. The ex utero intrapartum treatment procedure, which involves controlled partial delivery of the fetus whilst maintaining placental circulation, allows various airway maneuvers to be performed to secure the airway in a controlled fashion. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2loKq3y

Hypoparathyroidism after thyroidectomy: prevention, assessment and management.

Purpose of review: Permanent hypoparathyroidism is the most common long-term complication after total thyroidectomy and it can cause significant morbidity and increased costs. Its incidence varies from 30% to 60%. Recent findings: The surgical technique and the extent of thyroidectomy are related to parathyroid injury and hypoparathyroidism. The glands should be identified in situ, carefully manipulated and preserved, as well as their vascularization. In case of incidental removal, routine autotransplantation is advocated. Low calcium levels, identification of fewer than two parathyroid glands at surgery, reoperation for bleeding, Graves disease and heavier thyroid specimens were considered independent predictors of permanent hypocalcemia. Intraoperative parathyroid hormone (PTH) measurements allows the early detection of hypocalcemia. Treatment is recommended for patients with symptoms of hypocalcemia or corrected serum calcium

http://ift.tt/2ldzVxw

Open partial laryngectomy after failure of (chemo) radiation: indications, oncologic and functional outcomes.

Purpose of review: Early-stage squamous cell carcinoma of the larynx can be successfully treated with radiotherapy or surgery (transoral or open approaches). Oncologic results are comparable while functional results may be different according to the volume of resection. In some countries radiotherapy is often preferred as primary treatment. In case of recurrence, surgical salvage is the only option. Careful examination, endoscopic assessment, computed tomography or magnetic resonance imaging are necessary to assess superficial and deep extensions into the larynx, including cartilage framework and to restage the tumor. Recent findings: The choice between endoscopic and open partial laryngectomy is based on the extension and characteristics of the tumor. Oncologic results of open approaches are encouraging as local control, survival, and laryngeal preservation rates reported in the literature are close to those obtained in nonpreviously treated patients. Functional results are not significantly worse and major complications in the previously irradiated patients undergoing open neck surgery not increased. Supracricoid partial surgery seems to be more and more performed. Summary: With regards to the results, open partial surgery, like in nonpreviously treated patients, is still indicated for the surgical treatment of postradiotherapic recurrent/persistent disease. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2kZ52yJ

Biological Evaluation of Pyridone Alkaloids on the Endocannabinoid System

Publication date: Available online 17 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Andrea Chicca, Regina Berg, Henning J. Jessen, Nicolas Marck, Fabian Schmid, Patrick Burch, Jürg Gertsch, Karl Gademann
Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10 µM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.

Graphical abstract

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Novel Pyrrolopyrimidines as Mps1/TTK Kinase Inhibitors for Breast Cancer

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yasuro Sugimoto, Dwitiya B. Sawant, Harold A. Fisk, Liguang Mao, Chenglong Li, Somsundaram Chettiar, Pui-Kai Li, Michael V. Darby, Robert W. Brueggemeier
New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC50 values ranging from 0.05 to 1.0 μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC50 values from 0.356 μM to 0.809 μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers.

Graphical abstract

http://ift.tt/2lRHsp0

Piperazines as nootropic agents: New derivatives of the potent cognition-enhancer DM235 carrying hydrophilic substituents

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Maria Vittoria Martino, Luca Guandalini, Lorenzo Di Cesare Mannelli, Marta Menicatti, Gianluca Bartolucci, Silvia Dei, Dina Manetti, Elisabetta Teodori, Carla Ghelardini, Maria Novella Romanelli
The piperazine ring of the potent nootropic drug DM235has been decorated with H-bond donor and acceptor groups (CH2OH, CH2OMe, CH2OCOMe, COOEt); the aim was to insert new functional groups, suitable for further chemical manipulation. The influence of these modifications on nootropic activity was assessed by means of the mouse passive avoidance test; some of the newly synthesized molecules (alcohol 7b, acetate 8b and ester 10d) showed interesting in vivo potency. This makes it possible to use these functional groups for adding other residues, in order to increase molecular diversity, or for anchoring a biotin group, to obtain compounds useful to capture the biological target. Moreover, the new compounds will improve our knowledge of structure activity relationships of this family of drugs.

Graphical abstract

http://ift.tt/2lRyKam

Synthesis of antisense oligonucleotides containing acyclic alkynyl nucleoside analogs and their biophysical and biological properties

Publication date: Available online 17 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Aya Ogata, Yusuke Maeda, Yoshihito Ueno
The synthesis of oligonucleotide (ON) analogs, which can be used as antisense molecules, has recently gained much attention. Here, we report the synthesis and properties of an ON analog containing acyclic thymidine and cytidine analogs with a 4-pentyl-1,2-diol instead of the d-ribofuranose moiety. The incorporation of these analogs into the ON improved its nuclease resistance to 3′-exonucleases. Furthermore, it was found that the incorporation of the acyclic thymidine analog into a DNA/RNA duplex accelerates the RNA cleavage of a DNA/RNA duplex by Escherichia coli RNase H.

Graphical abstract

http://ift.tt/2lRKxW7

Comparison of the anion inhibition profiles of the β- and γ-carbonic anhydrases from the pathogenic bacterium Burkholderia pseudomallei

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sonia Del Prete, Daniela Vullo, Pietro di Fonzo, Vincenzo Carginale, Claudiu T. Supuran, Clemente Capasso
We report the cloning, purification and characterization of BpsβCA, a β-class carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Burkholderia pseudomallei, the etiological agent of melioidosis, and compare its activity and inhibition with those of the γ-CA from the same organism, BpsγCA, recently investigated by our groups. BpsβCA showed a significant catalytic activity for the physiologic, CO2 hydration reaction, with the following kinetic parameters, kcat of 1.6x10⁵ s^-1 and kcat/Km of 3.4 x10⁷ M^-1x s^-1. The inhibition of BpsβCA with a group of anions and small molecules was also investigated. The best inhibitors were sulfamide, sulfamic acid and phenylarsonic acid, which showed KIs in the range of 83 – 92 µM, whereas phenylboronic acid, fluoride, cyanide, azide, bisulfite, tetraborate, perrhenate, perruthenate, peroxydisulfate, perchlorate, tetrafluoroborate, fluorosulfonate and hexafluorophosphate showed KIs> 100 mM. Other inhibitors of this new enzyme were bicarbonate, trithiocarbonate, some complex inorganic anions and N,N-diethyldithiocarbamate, which had inhibition constants of 0.32 – 8.6 mM. As little is known of the life cycle and virulence of this bacterium, this type of study may bring information of interest for the development of novel strategies to fight bacterial infection and drug resistance to commonly used antibiotics

Graphical abstract

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Identification of A New Class of Potent Cdc7 Inhibitors Designed by Putative Pharmacophore Model: Synthesis and Biological Evaluation of 2,3-Dihydrothieno[3,2-d]pyrimidin-4(1H)-ones

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Osamu Kurasawa, Yuya Oguro, Tohru Miyazaki, Misaki Homma, Kouji Mori, Kenichi Iwai, Hideto Hara, Robert Skene, Isaac Hoffman, Akihiro Ohashi, Sei Yoshida, Tomoyasu Ishikawa, Nobuo Cho
Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking analysis of a known inhibitor with Cdc7 homology model. The pharmacophore model provided a minimum structural motif of Cdc7 inhibitor, by which preliminary medicinal chemistry efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a,c,e. Furthermore, the high selectivity of 14c,e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.

Graphical abstract

http://ift.tt/2lREK30

Synthesis and evaluation of a [18F]BODIPY-labeled Caspase-inhibitor

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Christian Paul Ortmeyer, Günter Haufe, Katrin Schwegmann, Sven Hermann, Michael Schäfers, Frederik Börgel, Bernhard Wünsch, Stefan Wagner, Verena Hugenberg
BODIPYs (boron dipyrromethenes) are fluorescent dyes which show high stability and quantum yields. They feature the possibility of selective ¹⁸F-fluorination at the boron-core. Attached to a bioactive molecule and labeled with [¹⁸F]fluorine, the resulting compounds are promising tracers for multimodal imaging in vivo and can be used for PET and fluorescence imaging. A BODIPY containing a phenyl and a hydroxy substituent on boron was synthesized and characterized. Fluorinated and hydroxy substituted dyes were coupled to an isatin-based caspase inhibitor via cycloaddition and the resulting compounds were evaluated in vitro in caspase inhibition assays. The metabolic stability and the formed metabolites were investigated by incubation with mouse liver microsomes and LC-MS analysis. Subsequently the fluorophores were labeled with [¹⁸F]fluorine and an in vivo biodistribution study using dynamic PET was performed.

Graphical abstract

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Synthesis and Activity of Nucleoside-Based Antiprotozoan Compounds

Publication date: Available online 16 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Huu-Anh Tran, Zhaoyan Zheng, Xianghui Wen, Srinivasan Manivannan, Arnaud Pastor, Marcel Kaiser, Reto Brun, Floyd F. Snyder, Thomas G. Back
Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas' disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50 = 110 nM and SI = 1010, while a modified guanosine displayed potent activities against L. donovani (IC50 = 60 nM, SI = 2720) and T. brucei (IC50 = 130 nM, SI = 1250), as well as moderate activity against T. cruzi (IC50 = 3.4 µM, SI = 48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.

Graphical abstract

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Relationship Between Central Obesity and Spread of Spinal Anesthesia in Female Patients.

Central obesity may be related to the spread of spinal anesthesia in female patients. Fifty-seven female patients undergoing spinal anesthesia were allocated to either the central obesity or noncentral obesity group. After induction of spinal anesthesia, maximal sensory blockade (primary outcome), time for maximal sensory block, maximum motor block, time to maximum motor block, time to L2 regression, and time to Bromage scale 0 were evaluated. Multiple linear regression analyses showed that maximal sensory blockade was related to central obesity (P = .004). Central obesity is related to a more extensive spread of spinal anesthesia in female patients. (C) 2017 International Anesthesia Research Society

http://ift.tt/2m0nd4G

In Response.

No abstract available

http://ift.tt/2kYOc2W

Smart Phones Application for Intraoperative Patient Care.

No abstract available

http://ift.tt/2m0FKxG

The Need for Mandatory Random Drug Testing in Anesthesia Providers.

No abstract available

http://ift.tt/2kZ1DzG

A Reply to Epidural Local Anesthetics versus Opioid-Based Analgesic Regimens for Postoperative Gastrointestinal Paralysis, Vomiting, and Pain After Abdominal Surgery: A Cochrane Review.

No abstract available

http://ift.tt/2m0q5hJ

Delayed Detection of Esophageal Intubation in Anesthesia Malpractice Claims: Brief Report of a Case Series.

This retrospective case series analyzed 45 malpractice claims for delayed detection of esophageal intubation from the Anesthesia Closed Claims Project. Inclusion criteria were cases from 1995 to 2013, after adoption of identification of CO2 in expired gas to verify correct endotracheal tube position as a monitoring standard by the American Society of Anesthesiologists. Forty-nine percent (95% confidence interval 34%-64%) occurred in the operating room or other anesthesia location where CO2 detection equipment should have been available. The most common factors contributing to delayed detection were not using, ignoring, or misinterpreting CO2 readings. Misdiagnosis, as with bronchospasm, occurred in 33% (95% confidence interval 20%) (C) 2017 International Anesthesia Research Society

http://ift.tt/2kYSAyC