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Ajay Kumar Mishra,1 Harshad Arvind Vanjare,2 Anu Anna George,1 Kamal Kant Sahu1 1Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA, USA; 2Department of Radiology, Christian Medical College, Vellore, IndiaCorrespondence: Kamal Kant SahuDepartment of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, USAEmail drkksahu85@gmail.comAbstract: Individuals presenting with sudden and focal neurological findings are usually suspected to have stroke. However, there are other conditions that can simulate stroke, which are often referred to as stroke mimics. Awareness and understanding these stroke-like disorders are of extreme importance as the treatment of each of them might be variable. We hereby briefly discuss these stroke mimics, common differentials, and key features to differentiate amongst the various causes of acute neurological event. Stroke is one of the neurological emergencies that needs urgent intervention to prevent significant mortality and morbidity. At the same time, it is important to realize the importance of other conditions which may mimic to stroke. In this letter, we aim to discuss a few key features that could probably help to distinguish stroke from mimickers thereby helping emergency doctors, neurologists, and hospitalists in streamlining the correct treatment at the earliest.Keywords: COVID-19, stroke, virus, SARS-CoV-2, neurology

Scholarship in colonial and nineteenth-century Latin American studies often does not reach beyond specialized academic audiences. The majority of work continues to be largely traditional in nature, with monographs, journal articles, and book chapters remaining the most common types of publications.Only a small portion of that production is distributed in an open-access format online, and even when that is the case, such scholarly output is generally not conceived with broader publics in mind, and engagement with stakeholder communities seldom plays a role in its creation.Digital methodologies and tools present opportunities to explore new modes of scholarly production and publication in these fields. Researchers working in a digital realm are designing and carrying out projects that speak to contemporary communities and involve diverse constituencies in new ways. Without seeking to supplant the more conventional scholarship that grounds their fields, these scholars are asking questions about how we conduct academic work in the twenty-first century and how we can make the products of our work relevant to larger audiences.This article examines five digital projects through which scholars of colonial and nineteenth-century Latin America are conducting work that looks outward from the academy towards inclusive scholarship: Ticha, the Biblioteca Digital Soledad Acosta de Samper, the Mexico team of the multinational project Oceanic Exchanges, Rendering Revolution, and coloniaLab. Through a commitment to producing scholarship for, and in collaboration with, diverse communities,these projects suggest models for conducting the work of colonial and nineteenth-century Latin American studies in the public sphere.Les études sur l'Amérique latine coloniale et du XIXème siècle ne s'adressent souvent qu'à un public universitaire spécialisé. Seule une petite partie de cette production est distribuée en ligne dans un format à accès libre, et même lorsque c'est le cas, cette production scientifique n'est généralement pas conçue pour un public plus large, et l'engagement avec les communautés concernées joue rarement un rôle dans sa création.Les méthodologies et les outils numériques offrent la possibilité d'explorer de nouveaux modes de production et de publication scientifiques dans ces domaines. Sans chercher à supplanter la recherche plus conventionnelle qui fonde leurs domaines, ces chercheurs posent des questions sur la manière dont nous menons le travail universitaire au XXIe siècle et sur la manière dont nous pouvons rendre les produits de notre travail pertinents pour des publics plus larges. Cet article examine cinq projets numériques dans le cadre desquels des chercheurs de l'Amérique latine coloniale et du XIXème siècle mènent des travaux qui s'éloignent de l'académie pour s'ouvrir à un public plus large : Ticha, la Biblioteca Digital Soledad Acosta de Samper, l'équipe mexicaine du projet multinational Oceanic Exchanges, Rendering Revolution et coloniaLab. En s'engageant à produire des études pour diverses communautés et en collaboration avec elles, ces projets proposent des modèles pour mener à bien le travail des études latino-américaines coloniales et du dix-neuvième siècle dans la sphère publique.

BackgroundStress is an important predictor of mental health problems such as burnout and depression. Acute stress is considered adaptive, whereas chronic stress is viewed as detrimental to well-being. To aid in the early detection of chronic stress, machine learning models are increasingly trained to learn the quantitative relation from digital footprints to self-reported stress. Prior studies have investigated general principles in population-wide studies, but the extent to which the findings apply to individuals is understudied. ObjectiveWe aimed to explore to what extent machine learning models can leverage features of smartphone app use log data to recognize momentary subjective stress in individuals, which of these features are most important for predicting stress and represent potential digital markers of stress, the nature of the relations between these digital markers and stress, and the degree to which these relations differ across people. MethodsStudent participants (N=224) self-reported momentary subjective stress 5 times per day up to 60 days in total (44,381 observations); in parallel, dedicated smartphone software continuously logged their smartphone app use. We extracted features from the log data (eg, time spent on app categories such as messenger apps and proxies for sleep duration and onset) and trained machine learning models to predict momentary subjective stress from these features using 2 approaches: modeling general relations at the group level (nomothetic approach) and modeling relations for each person separately (idiographic approach). To identify potential digital markers of momentary subjective stress, we applied explainable artificial intelligence methodology (ie, Shapley additive explanations). We evaluated model accuracy on a person-to-person basis in out-of-sample observations. ResultsWe identified prolonged use of messenger and social network site apps and proxies for sleep duration and onset as the most important features across modeling approaches (nomothetic vs idiographic). The relations of these digital markers with momentary subjective stress differed from person to person, as did model accuracy. Sleep proxies, messenger, and social network use were heterogeneously related to stress (ie, negative in some and positive or zero in others). Model predictions correlated positively and statistically significantly with self-reported stress in most individuals (median person-specific correlation=0.15-0.19 for nomothetic models and median person-specific correlation=0.00-0.09 for idiographic models). ConclusionsOur findings indicate that smartphone log data can be used for identifying digital markers of stress and also show that the relation between specific digital markers and stress differs from person to person. These findings warrant follow-up studies in other populations (eg, professionals and clinical populations) and pave the way for similar research using physiological measures of stress.

This paper argues that the noun ‘body’, the accusative particle, and dative preposition man are synchronically three different parts of speech in modern Copala Triqui. However, in earlier recorded Copala Triqui (from about 1965-75), we find somewhat different grammatical patterns. In earlier Copala Triqui, the accusative particle and dative preposition man were not yet distinct. Thus, a distinct accusative case particle appears to have emerged out of a dative preposition in about the last sixty years. It is thus a contemporary example of a diachronic path from adposition to case-marker which has been proposed for several other languages.

This paper contrasts two passives in Kaqchikel, a Mayan language spoken in Guatemala. The first passive, which we label the ‘standard passive’ is already well-attested in the literature. However, the second passive, which we label the ‘ki-passive’, has not been previously described. A verb in the ki-passive shows active morphology, with ergative agreement for a third person plural subject, as would be appropriate for a verb with an impersonal ‘they’ subject. In Kaqchikel, however, we argue that this verb form has evolved into a new passive. The paper compares the properties of the standard passive and the ki-passive, and argues that while they involve the same change of grammatical relations, the two passives differ in the discourse functions they assign to the agent and patient.

Background: Infective endocarditis (IE) is a life-threatening infection with an annual mortality of 40%. Embolic events reported in up to 80% of patients. Vegetations of > 10 mm size are associated with increased embolic events and poor prognosis. There is a paucity of literature on the association of multiple vegetations with outcome., Aim: To study the echocardiographic (ECHO) features and outcomes associated with the presence of multiple vegetations., Methods: In this retrospective, single-center, cohort study patients diagnosed with IE were recruited from June 2017 to June 2019. A total of 84 patients were diagnosed to have IE, of whom 67 with vegetation were identified. Baseline demographic, clinical, laboratory, and ECHO parameters were reviewed. Outcomes that were studied included recurrent admission, embolic phenomenon, and mortality., Results: Twenty-three (34%) patients were noted to have multiple vegetations, 13 (56.5%) were male and 10 (43.5%) were female. The mean age of these patients was 50. Eight (35%) had a prior episode of IE. ECHO features of moderate to severe valvular regurgitation [odds ratio (OR) = 4], presence of pacemaker lead (OR = 4.8), impaired left ventricle (LV) relaxation (OR = 4), and elevated pulmonary artery systolic pressure (PASP) (OR = 2.2) are associated with higher odds of multiple vegetations. Of these moderate to severe valvular regurgitation ( P = 0.028), pacemaker lead ( P = 0.039) and impaired relaxation ( P = 0.028) were statistically significant. These patients were noted to have an increased association of recurrent admissions (OR = 3.6), recurrent bacteremia (OR = 2.4), embolic phenomenon (OR = 2.5), intensive care unit stay (OR = 2.8), hypotension (OR = 2.1), surgical intervention (OR = 2.8) and device removal (OR = 4.8). Of this device removal ( P = 0.039) and recurrent admissions ( P = 0.017) were statistically significant., Conclusion: This study highlights the associations of ECHO predictors and outcomes in patients with IE having multiple vegetations. ECHO features of moderate to severe regurgitation, presence of pacemaker lead, impaired LV relaxation, and elevated PASP and outcomes including recurrent admissions and device removal were found to be associated with multiple vegetations., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Around 1 million cases of medical termination of pregnancy (MTP) take place yearly in the United States of America with around 2 percent of this population developing complications. The cardiovascular (CVD) complications occurring post MTP or after stillbirth is not very well described., Aim: To help the reader better understand, prepare, and manage these complications by reviewing various cardiac comorbidities seen after MTP., Methods: We performed a literature search in PubMed, Medline, RCA , and google scholar, using the search terms "abortions" or "medical/legal termination of pregnancy" and "cardiac complications" or "cardiovascular complications"., Results: The most common complications described in the literature following MTP were infective endocarditis (IE) ( n = 16), takotsubo cardiomyopathy (TTC) ( n = 7), arrhythmias ( n = 5), and sudden coronary artery dissection (SCAD) ( n = 4). The most common valve involved in IE was the tricuspid valve in 69% ( n = 10). The most observed causative organism was group B Streptococcus in 81% ( n = 12). The most common type of TTC was apical type in 57% ( n = 4). Out of five patients developing arrhythmia, bradycardia was the most common and was seen in 60% (3/5) of the patients. All four cases of SCAD-P type presented as acute coronary syndrome 10-14 d post termination of pregnancy with predominant involvement of the right coronary artery. Mortality was only reported following IE in 6.25%. Clinical recovery was reported consistently after optimal medical management following all these complications., Conclusion: In conclusion, the occurrence of CVD complications following pregnancy termination is infrequently documented in the existing literature. In this review, the most common CVD complication following MTP was noted to be IE and TTC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Some dendrobatid poison frogs sequester the toxin epibatidine as a defense against predators. We previously identified an amino acid substitution (S108C) at a highly conserved site in a nicotinic acetylcholine receptor β2 subunit of dendrobatid frogs that decreases sensitivity to epibatidine in the brain-expressing α4β2 receptor. Introduction of S108C to the orthologous high-sensitivity human receptor similarly decreased sensitivity to epibatidine but also decreased sensitivity to acetylcholine, a potential cost if this were to occur in dendrobatids. This decrease in the acetylcholine sensitivity manifested as a biphasic acetylcholine concentration-response curve consistent with the addition of low-sensitivity receptors. Surprisingly, the addition of the β2 S108C into the α4β2 receptor of the dendrobatid Epipedobates anthonyi did not change acetylcholine sensitivity, appearing cost-free. We proposed that toxin-bearing dendrobatids may have additional amino acid substitutions protecting their receptors from alterations in acetylcholine sensitivity. To test this, in the current study, we compared the dendrobatid receptor to its homologs from two non-dendrobatid frogs., Results: The introduction of S108C into the α4β2 receptors of two non-dendrobatid frogs also does not affect acetylcholine sensitivity suggesting no additional dendrobatid-specific substitutions. However, S108C decreased the magnitude of neurotransmitter-induced currents in Epipedobates and the non-dendrobatid frogs. We confirmed that decreased current resulted from fewer receptors in the plasma membrane in Epipedobates using radiolabeled antibodies against the receptors. To test whether S108C alteration of acetylcholine sensitivity in the human receptor was due to (1) adding low-sensitivity binding sites by changing stoichiometry or (2) converting existing high- to low-sensitivity binding sites with no stoichiometric alteration, we made concatenated α4β2 receptors in stoichiometry with only high-sensitivity sites. S108C substitutions decreased maximal current and number of immunolabeled receptors but no longer altered acetylcholine sensitivity., Conclusions: The most parsimonious explanation of our current and previous work is that the S108C substitution renders the β2 subunit less efficient in assembling/trafficking, thereby decreasing the number of receptors in the plasma membrane. Thus, while β2 S108C protects dendrobatids against sequestered epibatidine, it incurs a potential physiological cost of disrupted α4β2 receptor function., (© 2023. The Author(s).)

Initiated by findings that Alzheimer's disease is associated with a profound loss of cholinergic markers in human brain, decades of studies have examined the interactions between specific subtypes of nicotinic acetylcholine receptors and amyloid-β [derived from the amyloid precursor protein (APP), which is cleaved to yield variable isoforms of amyloid-β]. We review the evolving understanding of amyloid-β's roles in Alzheimer's disease and pioneering studies that highlighted a role of nicotinic acetylcholine receptors in mediating important aspects of amyloid-β's effects. This review also surveys the current state of research into amyloid-β / nicotinic acetylcholine receptor interactions. The field has reached an exciting point in which common themes are emerging from the wide range of prior research and a range of accessible, relevant model systems are available to drive further progress. We highlight exciting new areas of inquiry and persistent challenges that need to be considered while conducting this research. Studies of amyloid-β and the nicotinic acetylcholine receptor populations that it interacts with provide opportunities for innovative basic and translational scientific breakthroughs related to nicotinic receptor biology, Alzheimer's disease, and cholinergic contributions to cognition more broadly., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests that could bias the contents of this article., (Published by Elsevier Ltd.)

Serratia marcescens is an aerobic, Gram-negative bacillus predominantly seen in patients with intravenous drug use, immunosuppression, previous antibiotic exposure, and indwelling catheterization. Gram-negative organism causing infective endocarditis (IE) is rare. Serratia marcescens IE is uncommon and is reported to be seen in 0.14% of all cases. In this report, we discuss in detail about a 38-year-old man with a history of intravenous drug abuse presenting with S. marcescens related prosthetic valve IE.

Background: Takotsubo cardiomyopathy (TTC) can be diagnosed in patients presenting with clinical features of acute coronary syndrome (ACS) by using Mayo clinic criteria. Multiple precipitators have been attributed to causing TTC. Rarely it has been reported to occur following an acute envenomation., Aim: This review describes the various patterns, mechanisms, and outcomes of envenomation induced TTC., Methods: In this review, we included all studies on "TTC" and "envenomation "published in the various databases before June 2022. To be included in the review articles had to have a distinct diagnosis of TTC and an envenomation., Results: A total of 20 patients with envenomation induced TTC were identified. Most episodes of envenomation induced TTC were reported following a bee sting, scorpion sting, and snake envenomation. Fear and anxiety related to the sting, direct catecholamine toxicity and administration of exogenous beta-adrenergic agents have been commonly postulated to precipitate TTC in these patients. 95% of these patients presented with a clinical picture of ACS. Most of these patients also fulfill at least 3 out of 4 criteria of Mayo clinic criteria for TTC. Echocardiographic evidence of Apical TTC was noted in 72% of patients. 94% of these patients had clinical improvement following optimal management and 35% of these patients were treated with guideline directed medications for heart failure., Conclusion: Envenomation following multiple insect stings and reptile bites can precipitate TTC. Most reported envenomation related TTC has been due to bee stings and scorpion bites. Common mechanisms causing TTC were fear, anxiety, and stress of envenomation. Most of these patients present with clinical presentation of ACS, ST elevation, and elevated troponin. The most common type of TTC in these patients is Apical, which improved following medical management., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Takotsubo cardiomyopathy (TTC) is a non-ischemic cardiomyopathy precipitated by stress. Various infections are reported to precipitate this form of cardiomyopathy. We report a patient presenting with TTC secondary to influenza.  In this article, we also discuss the various infections reported to precipitate this form of reversible cardiomyopathy in literature. We have also included the recent reports of TTC among patients with COVID-19.

Background and Aim: Umbilical cord milking (UCM) has been theorized to increase placental blood transfusion then again, the optimal method of cord clamping at birth is still contested. We aimed to analyse the effects of UCM on the neonatal haematological parameters at 72 h and 6 weeks of age and its association with any adverse effects., Materials and Methods: In this randomized control trial, mothers ≥ 34 weeks were randomized into two arms. Under the intervention group, the cord was milked three times before clamping and cutting whereas the controls had the cord clamped and cut without milking. Haemoglobin and haematocrit levels were measured at 72 h. and at 6 weeks., Results: A total of 170 mothers were enrolled with 85 subjects in each arm. Baseline characteristics were comparable. In the intervention arm, the mean haemoglobin [18.1 (2.4) g/dL] and haematocrit [54 (7) %] were significantly higher as compared to the control arm [16.4 (2.1) g/dL and 48 (6) %], at 72 h of age. There was also significant increase in the mean haemoglobin [11.6 (1.3) g/dL] and haematocrit [34 (4) %] compared to the controls [10.1 (1.1) g/dL and 30 (3) %], at 6 weeks. No statistical difference was found in the incidence of PPH and duration of third stage. There was no significant rise in hyperbilirubinaemia, phototherapy requirement and polycythaemia among neonates in the intervention group., Conclusion: Umbilical cord milking is a sound practical approach to raise the haemoglobin and haematocrit levels up to 6 weeks thereby decreasing the proportion of anaemic infants., Competing Interests: Conflict of interestBoth authors declare that they have no conflict of interest., (© Federation of Obstetric & Gynecological Societies of India 2021.)

Background Dapsone treatment may reduce HbA1c levels in patients with diabetes. Aims To assess the prevalence and characteristics of dapsone associated reduction of HbA1c in patients with Hansen's disease. Methods A retrospective data review of outpatient and inpatient charts of consecutive patients with Hansen's disease and type 2 diabetes mellitus was conducted over two years from January 2014 to January 2016 at the Department of Dermatology, CMC Vellore, India. Results Of the 245 patients with a confirmed diagnosis of Hansen's disease who were on oral dapsone 100 mg/day as part of their treatment regimen, 49 patients had diabetes and were eligible for the study as per predetermined inclusion criteria. Of these, 35 subjects (71%) had an HbA1c discordantly lower than the corresponding mean plasma glucose levels. Patients with discordant HbA1c levels were more likely to be male and to have a higher RBC mean corpuscular volume (MCV). A greater reduction in HbA1c levels was seen during the initial 3 months of therapy of dapsone treatment. Limitations The small sample size and retrospective design were limitations of this study. Also, we did not analyze the role of methemoglobinemia or the utility of alternative measures of glycemic control in these patients. Conclusion We describe a high prevalence of dapsone associated inappropriate HbA1c lowering in type 2 diabetes mellitus patients. This may have serious implications for the management of diabetes in patients on therapy with dapsone.

Patients with heart failure (HF) may be at a higher risk of coronavirus disease 2019 (COVID-19) infection and may have a worse outcome due to their comorbid conditions and advanced age. In this narrative review, we aim to study the interaction between COVID-19 and HF from a critical care perspective. We performed a systematic search for studies that reported HF and critical care-related outcomes in COVID-19 patients in the PubMed and Medline databases. From a total of 1050 papers, we identified 26 that satisfied the eligibility criteria for our review. Data such as patient demographics, HF, intensive care unit (ICU) admission, management, and outcome were extracted from these studies and analyzed. We reported outcomes in heart-transplant patients with COVID-19 separately. In hospitalized patients with COVID-19, the prevalence of HF varied between 4% and 21%. The requirement for ICU admission was between 8% and 33%. HF patients with COVID-19 had an overall mortality rate between 20% and 40%. We identified that HF is an independent predictor of mortality in hospitalized COVID-19 patients, and patients with HF were more likely to require ventilation, ICU admission and develop complications. Patients with HF with reduced ejection fraction did worse than those with HF with midrange ejection fraction, and HF with preserved ejection fraction. COVID-19 patients with HF should be identified early and managed aggressively in an attempt to improve outcomes in this cohort of patients., Competing Interests: Conflict-of-interest statement: Authors claim no conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Background: Cardiovascular complications of the coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), have been documented both in the acute phase and in convalescence. One such complication is the formation of the left ventricular (LV) thrombus. There is a lack of clarity regarding the incidence, risk factors, and management of this complication., Aim: The aim of the study is to identify the clinical presentation, risk factors and outcome of COVID-19 patients with left ventricular thrombus (LVT)., Methods: A literature search was conducted to identify all case reports of COVID-19 with LVT in PubMed/Medline, Embase, Web of Science, and Google Scholar., Results: Among the 65 patients identified, 60 had LVT, either at admission, or during the acute phase of the illness. Six patients with mild symptoms during the acute phase of viral illness had only the COVID-19 antibody test positivity at the time LV thrombus was detected. Few of the patients (23.1%) had no comorbidities. The mean age of the patients was 52.8 years, and the youngest patient was 4 years old. This suggests that LVT formation can occur in young COVID-19 patients with no co-morbid conditions. Most of the patients (69.2%) had more than one site of thrombosis. A mortality rate of 23.1% was observed in our review, and ST-elevation myocardial infarction (STEMI) was diagnosed in 33.3% of those who died., Conclusions: A high degree of suspicion for LVT must be maintained in patients with known cardiac disease and those with new-onset arterial or venous thromboembolism, and such patients may benefit from a screening echocardiography at admission., Relevance for Patients: The patients with preexisting cardiovascular disease must take added precautions to prevent acquiring COVID-19 infection as there is a higher risk of developing LV thrombus. In patients who develop LVT in COVID-19, mortality rate is higher., Competing Interests: The authors have no conflicts of interest to declare., (Copyright: © Whioce Publishing Pte. Ltd.)

Background: In the setting of the current pandemic, concerns have arisen regarding the multisystemic involvement of sarcoidosis and the possible exacerbations in response to the exposure to severe acute respiratory syndrome coronavirus 2., Aim: This study aims to compare the differences in clinical presentation, management, and outcome of coronavirus disease 2019 (COVID-19) between patients with sarcoidosis and those in the general population., Methods: A literature search was conducted by reviewing original research articles such as case reports, case series, observational studies, and questionnaire-based surveys published in PubMed/Medline, Web of Science, and Google scholar. Data from individual patients in case series and case reports have been pooled to create a data set that was compared with larger such cohorts obtained from several other observational studies., Results: Twenty-seven patients were identified from 14 original articles. No significant differences were found in the clinical manifestations of patients with sarcoidosis presenting with COVID-19 as compared to the general population. The rate of hospitalization in our study was found to be 48.1%. The overall mortality in our study was 7.4%, which is higher than the global average of 2.1%., Conclusion: Our observations have reinforced the hypothesis that the presence of additional medical comorbidities is associated with a higher risk of intensive care unit admission. Furthermore, the presence of moderate to a severe limitation in pulmonary functions is an additional risk factor associated with increased hospital admissions and mortality in sarcoidosis. However, neither the diagnosis of sarcoidosis nor ongoing treatment with steroids, methotrexate, or other immunosuppressants was associated with a poorer prognosis in patients with sarcoidosis., Relevance for Patients: Patients with sarcoidosis must take added precautions to mitigate the risk of acquiring COVID-19 infection in view of the COVID-19-related mortality rate in this group of patients. Specifically, immunocompromised patients (on immunomodulator drugs and high dose steroids) have been found to have an increased risk of contracting COVID-19. Overall impact on prognostication and outcome in cases requiring hospitalization remains yet to be determined., Competing Interests: The authors declare no conflicts of interest., (Copyright: © Whioce Publishing Pte. Ltd.)

Dear Editor, We read with much excitement in the article "Takotsubo syndrome and pheochromocytoma: an insidious combination" published by Maffé et al. in your esteemed journal...

Sleep-related hypermotor epilepsy (SHE) is a group of seizure disorders prominently associated with mutations in nicotinic acetylcholine receptors (nAChR). The most prevalent central nervous system nAChR subtype contains α4 and β2 subunits, in two ratios. (α4β2)2β2-nAChR have high agonist sensitivity (HS-isoform), whereas (α4β2)2α4-nAChR agonist responses exhibit a small high-sensitivity, and a predominant low-sensitivity, phase of function (LS-isoform). Multiple non-synonymous mutations in the second and third transmembrane domains of α4 and β2 subunits are associated with SHE. We recently demonstrated that two additional, SHE-associated, missense mutations in the major cytoplasmic loops of these subunits [α4(R336H) and β2(V337G)] cause increased macroscopic function-per receptor. Here, we use single-channel patch-clamp electrophysiology to show that these mutations influence single-channel amplitudes and open- and closed-state kinetics. Pure populations of HS- or LS-isoform α4β2-nAChR were expressed by injecting either 1:10 or 30:1 α4:β2 cRNA ratios, respectively, into Xenopus laevis oocytes. Functional properties of the resulting mutant α4β2-nAChR isoforms were compared to their wildtype counterparts. α4(R336H) subunit incorporation minimally affected single-channel amplitudes, whereas β2(V337G) subunit incorporation reduced them significantly in both isoforms. However, for both mutant subunits, increased function-per-receptor was predominantly caused by altered single channel kinetics. The α4(R336H) mutation primarily destabilizes desensitized states between openings. By contrast, the β2(V337G) mutation principally stabilizes receptor open states. The use of naturally-occurring and physiologically-impactful mutations has allowed us to define valuable new insights regarding the functional roles of nAChR intracellular domains. Further mechanistic context is provided by intracellular-domain structures recently published for other members of the Cys-loop receptor superfamily (α3β4-nAChR and 5-HT3AR)., Competing Interests: The authors have declared that no competing interests exist.

Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-β (Aβ) and contribute to cognitive deficits associated with Alzheimer's disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study, we tested the hypothesis that the oligomeric form of amyloid-β (oAβ 42 ), interacting with α7-containing nicotinic acetylcholine receptor (nAChR) subtypes, leads to subnucleus-specific alterations in BFCN excitability and impaired cognition. We used single-channel electrophysiology to show that oAβ 42 activates both homomeric α7- and heteromeric α7β2-nAChR subtypes while preferentially enhancing α7β2-nAChR open-dwell times. Organotypic slice cultures were prepared from male and female ChAT-EGFP mice, and current-clamp recordings obtained from BFCNs chronically exposed to pathophysiologically relevant level of oAβ 42 showed enhanced neuronal intrinsic excitability and action potential firing rates. These resulted from a reduction in action potential afterhyperpolarization and alterations in the maximal rates of voltage change during spike depolarization and repolarization. These effects were observed in BFCNs from the medial septum diagonal band and horizontal diagonal band, but not the nucleus basalis. Last, aged male and female APP/PS1 transgenic mice, genetically null for the β2 nAChR subunit gene, showed improved spatial reference memory compared with APP/PS1 aged-matched littermates. Combined, these data provide a molecular mechanism supporting a role for α7β2-nAChR in mediating the effects of oAβ 42 on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of α7β2-nAChR in oAβ 42 -induced cognitive decline., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 the authors.)

The saliva of blood-sucking leeches contains a plethora of anticoagulant substances. One of these compounds derived from Haementeria ghilianii , the 66mer three-disulfide-bonded peptide tridegin, specifically inhibits the blood coagulation factor FXIIIa. Tridegin represents a potential tool for antithrombotic and thrombolytic therapy. We recently synthesized two-disulfide-bonded tridegin variants, which retained their inhibitory potential. For further lead optimization, however, structure information is required. We thus analyzed the structure of a two-disulfide-bonded tridegin isomer by solution 2D NMR spectroscopy in a combinatory approach with subsequent MD simulations. The isomer was studied using two fragments, i.e., the disulfide-bonded N-terminal (Lys1-Cys37) and the flexible C-terminal part (Arg38-Glu66), which allowed for a simplified, label-free NMR-structure elucidation of the 66mer peptide. The structural information was subsequently used in molecular modeling and docking studies to provide insights into the structure-activity relationships. The present study will prospectively support the development of anticoagulant-therapy-relevant compounds targeting FXIIIa.

Coronavirus disease (COVID 19) has involved millions of people all over the world. Tuberculosis (TB) continues to affect millions of people every year with high mortality. There is limited literature on the occurrence of COVID 19 in patients with TB. We reviewed the available data on various clinical details, management, and outcome among patients with COVID-19 and TB. 8 studies reported a total of 80 patients with this coinfection. These patients were reported from ten different countries, with Italy reporting the largest number of cases. Migrant, males constituted a major proportion of cases. Most reported patients were symptomatic. Fever, dry cough, and dyspnea were the most commonly reported symptoms. Bilateral ground glass opacities were more common in COVID 19 infection and cavitary lesions were more common in patients with TB. Most reported TB patients had been found to have mycobacterium tuberculosis from sputum culture in the background of pulmonary TB. Most patients of TB were treated with multidrug regimen antitubercular therapy. In all 8 studies, COVID 19 was treated as per the local protocol. Mortality was reported in more than 10% of patients. Mortality was higher in elderly patients (> 70 years) and amongst patient with multiple medical comorbidities.

Coronavirus 19 disease (COVID-19) continues to be a pandemic with global implications.  Respiratory system involvement is the most common manifestation in symptomatic patients.  In this literature review, we describe the diagnosis, management, and implications of pulmonary hypertension (PH) among patients with COVID-19.  We defined pulmonary hypertension as increasing mean pulmonary artery pressure (mPAP) of ≥ 25 mm Hg at rest.  In our literature search, we identified 4 articles with details on pulmonary hypertension.  Among these, two reported various echocardiographic details for diagnosing pulmonary hypertension.  In 1 study evidence of pulmonary hypertension was noted in 13.4% of patients.  Patients with severe COVID-19 were reported to have a higher proportion of pulmonary hypertension as compared to mild COVID-19 disease [22% vs 2%].  Elevated pulmonary artery systolic pressure was significant in predicting mortality.  COVID-19 patients with chronic obstructive pulmonary disease, congestive heart failure, myocardial injury, pulmonary embolism, and prior pulmonary hypertension were at a higher risk of worsening pulmonary hypertension.  Multiple mechanisms for developing pulmonary hypertension that have been postulated are i) concomitant worsening myocardial injury, ii) cytokine storm, endothelial injury, hypercoagulability attributing to development of venous thromboembolism, iii) and the presence of thrombotic microangiopathy.  Among patients with severe COVID-19 disease and pulmonary hypertension, complications including acute respiratory distress syndrome, acute myocardial injury, the requirement of intensive care unit admission, the requirement of mechanical ventilation, and mortality are higher.

Introduction: As a result of increasing longevity, we are seeing more elderly patients with complex medical co-morbidities who sustain hip fractures requiring surgical management. The aim of this study is to understand and analyze the effect of preoperative medical comorbidities and associated low physiological reserve status on functional rehabilitation outcomes following surgical management of hip fractures., Materials and Methods: This study conducted a retrospective analysis of 73 patients who fulfilled the inclusion criteria .We utilized the de Morton Mobility Index (DEMMI) scores pre surgery and at the time of discharge from hospital following a period of rehabilitation as a measure of their pre and post-surgery functional status. The Physiological and Operative Score (POSSUM) was used as our tool to objectively quantify medical co-morbidities including but not limited to cardiovascular and pulmonary conditions., Results: The median age of our study population was 83 years of which 55(75%) were female. Time to surgery was a median of 21.0 hours, IQR (15.0-29.0), with a median physiological score of 21.0, IQR (19.0-26.0), the median pre surgery DEMMI was 85.0, IQR (55.5- 100.0) and the median DEMMI at discharge was 33.0, IQR (30.0-41.0).There is a moderate correlation between DEMMI pre and DEMMI at 3 months, 0.38 that is statistically significant, p = 0.001., Discussion: The effect of medical co- morbidities which causes the patient to have a poor physiological reserve even when coupled with the effect of the operative stress have no significant negative impact on the 90-day functional outcome of these patients., Conclusion: This study demonstrated that the presence of medical comorbidities in patients who require surgical management of hip fractures would not adversely affect their rehabilitation outcomes. The preinjury functional status of a patient is a significant factor in predicting functional rehabilitation outcomes., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Tuberculous meningitis (TBM) remains common in developing countries. Cerebrovascular infarct (CI) in TBM occurs in 15%-57% of patients. Literature regarding the predictors of central nervous system (CNS) infarct in patients with TBM is scanty, and the outcome of these events is unknown. The aim of this study is to evaluate the predictors of CI among patients with TBM at a tertiary care center in South India and to compare the impact of CI on the prognosis and outcomes in terms of mortality and morbidity., Methods: All patients who were confirmed to have TBM and CNS infarcts/stroke were included in this study retrospectively. Forty-six patients had appropriate imaging, and they were enrolled in the study as cases. Patients without infarct were matched with age and sex as controls. Details of the course of the disease, the extent of CNS involvement, and treatment were compared between the two arms., Results: The mean age of patients with and without infarct was similar. The presence of basal meningeal inflammation, hydrocephalus, focal neurological deficit, and cranial nerve palsy, was higher in patients with infarct. Independent predictors of infarcts in a patient with TBM were Medical Research Council (MRC) staging of II or more, presence of focal neurological deficit, cranial nerve palsy, and presence of hydrocephalus, meningeal enhancement on neuroimaging. Presences of infarcts were independently associated with a higher odds ratio of 2.58 for poor outcome, 4.48 for a longer duration of hospital stay, and odds ratio of 8.85 for the requirement of multiple hospitalizations., Conclusion: CI involvement in TBM has higher morbidity, with longer stay, recurrent admission., Competing Interests: None

Neurological manifestations in patients with COVID-19 are more frequently being reported. Cerebrovascular events have been reported in around 3% of patients. In this review we summarize the published literature on cerebrovascular events in patients with COVID-19 as available on the PubMed database. So far, 3 studies have reported cerebrovascular events. Cerebrovascular events were identified on screening patients with decreased consciousness or in the presence of focal neurological deficits. These events were common in elderly, critically ill patients and in patients with prior cardio-cerebrovascular comorbidities. The diagnosis of cerebrovascular events was confirmed with computed tomography of the brain in most studies reporting neurological events. Multiple pathological mechanisms have been postulated regarding the process of neurological and vascular injury among which cytokine storm is shown to correlate with mortality. Patients with severe illness are found to have a higher cardio- cerebrovascular comorbidity. With an increasing number of cases and future prospective studies, the exact mechanism by which these cerebrovascular events occur and attribute to the poor outcome will be better understood.

Background: The notion of heme as a regulator of many physiological processes via transient binding to proteins is one that is recently being acknowledged. The broad spectrum of the effects of heme makes it important to identify further heme-regulated proteins to understand physiological and pathological processes. Moreover, several proteins were shown to be functionally regulated by interaction with heme, yet, for some of them the heme-binding site(s) remain unknown. The presented application HeMoQuest enables identification and qualitative evaluation of such heme-binding motifs from protein sequences., Results: We present HeMoQuest, an online interface (http://bit.ly/hemoquest) to algorithms that provide the user with two distinct qualitative benefits. First, our implementation rapidly detects transient heme binding to nonapeptide motifs from protein sequences provided as input. Additionally, the potential of each predicted motif to bind heme is qualitatively gauged by assigning binding affinities predicted by an ensemble learning implementation, trained on experimentally determined binding affinity data. Extensive testing of our implementation on both existing and new manually curated datasets reveal that our method produces an unprecedented level of accuracy (92%) in identifying those residues assigned "heme binding" in all of the datasets used. Next, the machine learning implementation for the prediction and qualitative assignment of binding affinities to the predicted motifs achieved 71% accuracy on our data., Conclusions: Heme plays a crucial role as a regulatory molecule exerting functional consequences via transient binding to surfaces of target proteins. HeMoQuest is designed to address this imperative need for a computational approach that enables rapid detection of heme-binding motifs from protein datasets. While most existing implementations attempt to predict sites of permanent heme binding, this application is to the best of our knowledge, the first of its kind to address the significance of predicting transient heme binding to proteins.

Heme is an iron ion-containing molecule found within hemoproteins such as hemoglobin and cytochromes that participates in diverse biological processes. Although excessive heme has been implicated in several diseases including malaria, sepsis, ischemia-reperfusion, and disseminated intravascular coagulation, little is known about its regulatory and signaling functions. Furthermore, the limited understanding of heme's role in regulatory and signaling functions is in part due to the lack of curated pathway resources for heme cell biology. Here, we present two resources aimed to exploit this unexplored information to model heme biology. The first resource is a terminology covering heme-specific terms not yet included in standard controlled vocabularies. Using this terminology, we curated and modeled the second resource, a mechanistic knowledge graph representing the heme's interactome based on a corpus of 46 scientific articles. Finally, we demonstrated the utility of these resources by investigating the role of heme in the Toll-like receptor signaling pathway. Our analysis proposed a series of crosstalk events that could explain the role of heme in activating the TLR4 signaling pathway. In summary, the presented work opens the door to the scientific community for exploring the published knowledge on heme biology., (Copyright © 2020 Humayun, Domingo-Fernández, Paul George, Hopp, Syllwasschy, Detzel, Hoyt, Hofmann-Apitius and Imhof.)

Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins.

Cyclic µ-conotoxin PIIIA, a potent blocker of skeletal muscle voltage-gated sodium channel Na V 1.4, is a 22mer peptide stabilized by three disulfide bonds. Combining electrophysiological measurements with molecular docking and dynamic simulations based on NMR solution structures, we investigated the 15 possible 3-disulfide-bonded isomers of µ-PIIIA to relate their blocking activity at Na V 1.4 to their disulfide connectivity. In addition, three µ-PIIIA mutants derived from the native disulfide isomer, in which one of the disulfide bonds was omitted (C4-16, C5-C21, C11-C22), were generated using a targeted protecting group strategy and tested using the aforementioned methods. The 3-disulfide-bonded isomers had a range of different conformational stabilities, with highly unstructured, flexible conformations with low or no channel-blocking activity, while more constrained molecules preserved 30% to 50% of the native isomer's activity. This emphasizes the importance and direct link between correct fold and function. The elimination of one disulfide bond resulted in a significant loss of blocking activity at Na V 1.4, highlighting the importance of the 3-disulfide-bonded architecture for µ-PIIIA. µ-PIIIA bioactivity is governed by a subtle interplay between an optimally folded structure resulting from a specific disulfide connectivity and the electrostatic potential of the conformational ensemble.

Aim: This in vitro study was designed to evaluate and compare the effectiveness of a dentifrice containing 8% arginine and calcium carbonate, diode laser (810 nm) and the combined use of diode laser (810 nm) and the same dentifrice in occluding dentinal tubules., Materials and Methods: Forty sectioned dentine discs were observed in this study. The Samples were randomly divided into 4 groups. In group A, a dentifrice containing arginine and calcium carbonate was applied. In group B, the specimens were subjected to diode laser (810 nm) irradiation. In group C, the same dentifrice was applied and the specimens were subjected to diode laser (810 nm) treatment. Group D was left untreated and served as the control. The specimens were observed under the scanning electron microscope. Then the photomicrographs of each specimen were taken which were uploaded into Photoshop 7®, and the diameters of the dentinal tubules of each specimen were measured and the data were analyzed statistically., Results: The overall comparison between different treatment modalities using one-way analysis of variance (ANOVA) and multiple comparisons of two modalities assessed using post hoc Tukey method revealed that there is a highly significant difference ( p value = 0.0001) in the dentinal tubule diameter and rate of occlusion in different treatment modalities., Conclusion: The study concluded that all three treatment modalities caused significant occlusion of dentinal tubules. The combined use of desensitizing toothpaste and diode laser (810 nm) is the most effective, then comes the diode laser (810 nm) alone and finally the desensitizing toothpaste alone., Clinical Significance: This study suggests an effective treatment of dentinal hypersensitivity using diode laser and desensitizing toothpaste.

Central nervous system nicotinic acetylcholine receptors (nAChR) are predominantly of the α4β2 subtype. Two isoforms exist, with high or low agonist sensitivity (HS-(α4β2)2β2- and LS-(α4β2)2α4-nAChR). Both isoforms exhibit similar macroscopic potency and efficacy values at low acetylcholine (ACh) concentrations, mediated by a common pair of high-affinity α4(+)/(-)β2 subunit binding interfaces. However LS-(α4β2)2α4-nAChR also respond to higher concentrations of ACh, acting at a third α4(+)/(-)α4 subunit interface. To probe isoform functional differences further, HS- and LS-α4β2-nAChR were expressed in Xenopus laevis oocytes and single-channel responses were assessed using cell-attached patch-clamp. In the presence of a low ACh concentration, both isoforms produce low-bursting function. HS-(α4β2)2β2-nAChR exhibit a single conductance state, whereas LS-(α4β2)2α4-nAChR display two distinctive conductance states. A higher ACh concentration did not preferentially recruit either conductance state, but did result in increased LS-(α4β2)2α4-nAChR bursting and reduced closed times. Introduction of an α4(+)/(-)α4-interface loss-of-function α4W182A mutation abolished these changes, confirming this site's role in mediating LS-(α4β2)2α4-nAChR responses. Small or large amplitude openings are highly-correlated within individual LS-(α4β2)2α4-nAChR bursts, suggesting that they arise from distinct intermediate states, each of which is stabilized by α4(+)/(-)α4 site ACh binding. These findings are consistent with α4(+)/(-)α4 subunit interface occupation resulting in allosteric potentiation of agonist actions at α4(+)/(-)β2 subunit interfaces, rather than independent induction of high conductance channel openings., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the aforementioned awarding agencies.

Competing Interests: None

Deviant levels of available heme and related molecules can result from pathological situations such as impaired heme biosynthesis or increased hemolysis as a consequence of vascular trauma or bacterial infections. Heme-related biological processes are affected by these situations, and it is essential to fully understand the underlying mechanisms. While heme has long been known as an important prosthetic group of various proteins, its function as a regulatory and signaling molecule is poorly understood. Diseases such as porphyria are caused by impaired heme metabolism, and heme itself might be used as a drug in order to downregulate its own biosynthesis. In addition, heme-driven side effects and symptoms emerging from heme-related pathological conditions are not fully comprehended and thus impede adequate medical treatment. Several heme-regulated proteins have been identified in the past decades, however, the molecular basis of transient heme-protein interactions remains to be explored. Herein, we summarize the results of an in-depth analysis of heme binding to proteins, which revealed specific binding modes and affinities depending on the amino acid sequence. Evaluating the binding behavior of a plethora of heme-peptide complexes resulted in the implementation of a prediction tool (SeqD-HBM) for heme-binding motifs, which eventually led and will perspectively lead to the identification and verification of so far unknown heme-regulated proteins. This systematic approach resulted in a broader picture of the alternative functions of heme as a regulator of proteins. However, knowledge on heme regulation of proteins is still a bottomless barrel that leaves much scope for future research and development., (© 2019 The Author(s).)

Background: Stability in vitiligo is an important concept in guiding patient management and a vital prerequisite before vitiligo surgery. Disease activity of vitiligo based on patient's history is imprecise. It is practically impossible to perform biopsy from all lesions of vitiligo to ascertain stability. Dermatoscopy can be used to examine all clinical lesions in a patient of vitiligo. There is a need to validate many reported dermatoscopic findings for universal use., Aims: To analyze the significance of dermatoscopic findings in the activity of vitiligo and to devise a cutoff score for stable vitiligo., Materials and Methods: Dermatoscopic examination was performed in 85 patients clinically diagnosed with vitiligo. Six dermatoscopic parameters, namely, b order, p igment network, peri le sional hyperpigmentation, peri fo llicular pigmentation, s atellite lesions, and micro- K oebner phenomenon (acronym: BPLeFoSK) were evaluated against Wood's lamp findings as standard. Chi-square test was used to test association between categorical variables. Cutoff values for stability for these six parameters were plotted in receiver operating curve., Results: A total of 131 vitiligo lesions were analyzed with dermatoscopy. Absence of satellite lesions and absence of micro-Koebner phenomenon were the most sensitive parameters (96.7% and 100%, respectively). Sharp border and absent or reticulate pigment network within the vitiligo patch were the most specific findings (100% and 91.5%, respectively)., Conclusion: A cutoff score of more than or equal to 1.5 using the "BPLeFoSK criteria" indicates stability in the vitiligo lesion., Competing Interests: There are no conflicts of interest.

The study of protein conformations using molecular dynamics (MD) simulations has been in place for decades. A major contribution to the structural stability and native conformation of a protein is made by the primary sequence and disulfide bonds formed during the folding process. Here, we investigated μ-conotoxins GIIIA, KIIIA, PIIIA, SIIIA, and SmIIIA as model peptides possessing three disulfide bonds. Their NMR structures were used for MD simulations in a novel approach studying the conformations between the folded and the unfolded states by systematically breaking the distinct disulfide bonds and monitoring the conformational stability of the peptides. As an outcome, the use of a combination of the existing knowledge and results from the simulations to classify the studied peptides within the extreme models of disulfide folding pathways, namely the bovine pancreatic trypsin inhibitor pathway and the hirudin pathway, is demonstrated. Recommendations for the design and synthesis of cysteine-rich peptides with a reduced number of disulfide bonds conclude the study., Competing Interests: The authors declare no competing financial interest.

Background & Objectives: Dengue fever (DF) is a common cause of acute febrile illness. Skin involvement is seen in more than half of the patients. This study was aimed to compare the clinical profile and outcome in DF patients with or without skin involvement., Methods: This study included all the patients with DF from the acute febrile illness database of a tertiary care health centre in south India. These patients were further subgrouped into SP and SN (skin involvement positive and negative) based on the presence and absence of skin rash. Differences in clinical presentation, laboratory parameters, disease course, morbidity and outcome among patients with DF with or without skin rash were recorded and analysed statistically., Results: In total 387 patients (>16 yr) with DF were enrolled into the study. Among these 55 patients had evidence of skin rash. Presence of history of overt bleeding (OR = 4.96, p = 0.027) including gum bleeding (OR = 1.17, p = 0.23), epistaxis (OR = 5.52, p = 0.04), and haematuria (OR = 6.41, p = 0.01) were more among patients with SP as compared to SN. The SP patients were found to have lower levels of platelets during the disease course. Patients with SP had a higher percentage of platelet transfusion which was statistically significant. There was no difference in organ dysfunction and mortality among both the groups., Interpretation & Conclusion: Cutaneous involvement, though common, is not pathognomonic and can help in dengue diagnosis. Adult patients with skin rash can develop worsening thrombocytopenia requiring platelet transfusion. However, there are limited data to suggest that such patients have a worse outcome and higher mortality., Competing Interests: None

Eukaryotic chromosome segregation requires a protein complex known as the kinetochore that mediates attachment between mitotic spindle microtubules and centromere-specific nucleosomes composed of the widely conserved histone variant CENP-A. Mutations in kinetochore proteins of the fission yeast Schizosaccharomyces pombe lead to chromosome missegregation such that daughter cells emerge from mitosis with unequal DNA content. We find that multiple copies of Msc1-a fission yeast homolog of the KDM5 family of proteins-suppresses the temperature-sensitive growth defect of several kinetochore mutants, including mis16 and mis18 , as well as mis6 , mis15 , and mis17 , components of the Constitutive Centromere Associated Network (CCAN). On the other hand, deletion of msc1 exacerbates both the growth defect and chromosome missegregation phenotype of each of these mutants. The C-terminal PHD domains of Msc1, previously shown to associate with a histone deacetylase activity, are necessary for Msc1 function when kinetochore mutants are compromised. We also demonstrate that, in the absence of Msc1, the frequency of localization to the kinetochore of Mis16 and Mis15 is altered from wild-type cells. As we show here for msc1 , others have shown that elevating cnp1 levels acts similarly to promote survival of the CCAN mutants. The rescue of mis15 and mis17 by cnp1 is, however, independent of msc1 Thus, Msc1 appears to contribute to the chromatin environment at the centromere: the absence of Msc1 sensitizes cells to perturbations in kinetochore function, while elevating Msc1 overcomes loss of function of critical components of the kinetochore and centromere., (Copyright © 2017 by the Genetics Society of America.)

A 63-year-old man presented with a pulsatile cutaneous horn on the nose and multiple angiomatous nodules on the gingiva and scalp, which appeared over 2 months. He had severe hypercalcaemia, lytic lesions in multiple bones and acute kidney injury. Excision biopsy from the gingival nodule showed a clear cell neoplasm. The bone marrow showed atypical cells with similar morphology. Imaging showed a 7 cmx7.5 cm mass at the upper pole of the left kidney with metastases to the bones, liver and lung. Immunohistochemistry was consistent with metastatic renal cell carcinoma. Renal cell carcinoma presenting as a cutaneous horn is extremely rare and to the best of our knowledge only one other case was found in the literature. There was visible regression in the size of the cutaneous horn and nodules following initiation of pazopanib therapy. However, he succumbed to his illness a month later., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Inflammation involving the postcapillary venular wall is defined as small vessel vasculitis. Small vessel vasculitis has various clinical manifestations. Etiologically, it can be primary or secondary. Literature regarding secondary vasculitis in elderly is scanty., Aim and Objectives: In this case series, we aimed to assess the clinical features and etiologies of biopsy-proven secondary small vessel vasculitis in the elderly., Methodology: Twelve elderly patients with biopsy-proven small vessel vasculitis were included in this study. All patients were thoroughly evaluated to assess the etiology and presence of major organ involvement., Results: Secondary small vessel vasculitis involved both the sexes equally. Constitutional symptoms including fever and weight loss were noticed by most of the (70%) patients. Neurological deficits were present in 83% of the study population. The most common finding in an electromyographic examination was an asymmetric sensory motor distal predominant polyradiculopathy. Fifty percent of the patients did fulfill the criteria for a definite autoimmune disease. More than 30% of the vasculitis was secondary to malignancies., Conclusions: Neurological manifestations are the most common systemic involvement in elderly patients with secondary vasculitis. Meticulous search for underlying malignancies is mandatory in elderly patients with secondary small vessel vasculitis., Competing Interests: There are no conflicts of interest.

Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated Synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1-deficient zebrafish mutant, nrc a14 . We found that loss of SynJ1 leads to specific accumulation of late endosomes and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate due to a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrc a14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5' phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P 2 regulator, Arf6, rescued the disrupted trafficking pathways in nrc a14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P 2 participates in autophagy in a neuronal cell type.

Objective: Reflexive testing of bronchoalveolar lavage (BAL) specimens with Gomori methenamine silver (GMS) and acid-fast bacillus (AFB) stains is not routinely performed by most institutions. Instead, these stains are usually ordered to evaluate for the presence of fungal elements and/or acid-fast organisms if initial histopathologic assessment suggests the presence of these pathogens. Our institution, however, performs these stains on all BAL specimens. Thus, we sought to determine whether this practice was cost effective, considering the turnaround time and diagnostic efficacy of these tests., Methods: We retrospectively reviewed 488 BAL specimens performed at two military healthcare institutions over a 2-year period and performed a cost analysis with review of the impact on turnaround time., Results: Of the 488 cases, we identified only 3 (~0.6%) with infections by acid-fast or fungal organisms, at an estimated total cost of $12,151.20 and an average delay of 3.0 to 3.5 hours for slide preparation., Conclusion: Our results suggest that in a largely young and healthy population such as ours, it may be more feasible to perform these stains on BAL specimens on a case-by-case basis rather than automatically on every specimen, to control costs and enhance productivity., (Copyright© by the American Society for Clinical Pathology (ASCP).)