Search

Background Post–kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis. Oral miltefosine (MF) is the first-line treatment for PKDL patients in South Asia. This study assessed the safety and effectiveness of MF therapy after 12 months of follow-up to explore more precise data. Methods In this observational study, 300 confirmed PKDL patients were enrolled. MF with the usual dose was administered to all patients for 12 weeks and followed up for 1 year. Clinical evolution was recorded systematically by photographs at screening and at 12 weeks, 6 months, and 12 months after treatment onset. Definitive cure consisted of disappearance of skin lesions with a negative PCR at 12 weeks or with >70% of lesions, disappearing or fading at 12-month follow-up. Patients with reappearing clinical features and any positive diagnostics of PKDL during the follow-up were considered as nonresponsive. Results Among 300 patients, 286 (95.3%) completed 12 weeks of treatment. The per-protocol cure rate at 12 months was 97%, but 7 patients relapsed and 51 (17%) were lost to 12-month follow-up, resulting in a final cure rate of only 76%. Eye-related adverse events were noted in 11 (3.7%) patients and resolved in most (72.7%) within 12 months. Unfortunately, 3 patients had persistent partial vision loss. Mild to moderate gastrointestinal side effects were seen in 28% patients. Conclusions Moderate effectiveness of MF was observed in the present study. A significant number of patients developed ocular complications, and thus MF for treatment for PKDL should be suspended and replaced with a safer alternative regimen. [ABSTRACT FROM AUTHOR]

Summary The molecule Hedgehog is well known as an organizer of tissue morphogenesis. A recent report now demonstrates that it also plays the role of a gut hormone, orchestrating the nutrient response during fly development. [ABSTRACT FROM AUTHOR]

The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [ 125 I]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain. [ABSTRACT FROM AUTHOR]

Since 1984 the diagnosis of ankylosing spondylitis (AS) has been based upon the modified New York (mNY) criteria with mandatory presence of radiographic sacroiliitis, without which the diagnosis is not tenable. However, it may take years or decades for radiographic sacroiliitis to develop delaying the diagnosis for long periods. It did not matter in the past because no effective treatment was available. However, with the availability of a highly effective treatment, namely, tumour necrosis factor-α inhibitors (TNFi), the issue of early diagnosis of AS acquired an urgency. The Assessment of SpondyloArthritis International Society (ASAS) classification criteria published in 2009 was a significant step towards this goal. These criteria described an early stage of the disease where sacroiliitis was demonstrable only on MRI but not on standard radiograph. Therefore, this stage of the disease was labelled “nonradiographic axial SpA” (nr-axSpA). But questions have been raised if, in search of early diagnosis, specificity was compromised. The Federal Drug Administration (FDA, USA) withheld approval for the use of TNFi in patients with nr-axSpA because of issues related to the specificity of these criteria. This review attempts to clarify some of these aspects of the nr-axSpA-AS relationship and also tries to answer the question whether ASAS classifiable radiographic axial spondyloarthritis (r-axSpA) term can be interchangeably used with the term AS. [ABSTRACT FROM AUTHOR]

Animals adapt their growth rate and body size to available nutrients by a general modulation of insulin–insulin-like growth factor signaling. In Drosophila, dietary amino acids promote the release in the hemolymph of brain insulin-like peptides (Dilps), which in turn activate systemic organ growth. Dilp secretion by insulin-producing cells involves a relay through unknown cytokines produced by fat cells. Here, we identify Methuselah (Mth) as a secretin-incretin receptor subfamily member required in the insulin-producing cells for proper nutrient coupling. We further show, using genetic and ex vivo organ culture experiments, that the Mth ligand Stunted (Sun) is a circulating insulinotropic peptide produced by fat cells. Therefore, Sun and Mth define a new cross-organ circuitry that modulates physiological insulin levels in response to nutrients. [ABSTRACT FROM AUTHOR]

Factor VIII (FVIII) replacement and emicizumab have demonstrated efficacy for prevention of bleeds among patients with hemophilia A (PwHA) compared to on-demand (OD) use. Evidence investigating clinical outcomes and healthcare costs of non-inhibitor PwHA switching from prophylaxis with FVIII concentrates to emicizumab has not been well-established within large real-world datasets. This study aimed to investigate billed annualized bleed rates (ABRb) and total cost of care (TCC) among non-inhibitor PwHA switching from FVIII-prophylaxis to emicizumab-prophylaxis. This retrospective, observational study was conducted using IQVIA PharMetrics Plus, a US administrative claims database. The date of first claim for emicizumab was defined as the index date. OD patients and inhibitor patients were excluded. Bleeds were identified using a list of 535 diagnosis codes. Bayesian models were developed to estimate the probability ABRb worsens and TCC increases after switching to emicizumab. Wilcoxon rank-sum tests were used to test statistical significance of changes in ABRb and TCC after switch. Among the 121 identified patients, the difference in mean ABRb between FVIII-prophylaxis (0.68 [SD = 1.28]) and emicizumab (0.55 [SD = 1.48]) was insignificant (p =.142). The mean annual TCC significantly increased for patients switching from FVIII-prophylaxis ($518,151 [SD = $289,934]) to emicizumab ($652,679 [SD = $340,126]; p <.0001). The Bayesian models estimated a 21.0% probability of the ABRb worsening and a 99.9% probability of increasing TCC after switch. This study found that in male non-inhibitor PwHA, switching from FVIII prophylaxis to emicizumab incurs substantial cost increase with no significant benefit in ABRb. This evidence may help guide providers, payers, and patients in shared decision-making conversations around best treatment options. [ABSTRACT FROM AUTHOR]

• We report a FRET-based nanosensor for monitoring the levels tungsten in living cells. • This probe is nontoxic and non-invasive. • Highly selective pH sensing in wide pH range. • This nanosensor is applicable for prokaryotic and eukaryotic cellular environments. • The advantages of this sensor is simplicity, low-cost, high accuracy and good precision. Tungsten is considered a critical metal due to its unique properties and economic importance. Recent research has linked high tungsten concentrations to pulmonary diseases and increased cancer risk. Tungsten is on the list of critical metals at high risk maintained by the European Union. We have developed a genetically encoded fluorescence resonance energy transfer (FRET)-based nanosensor for the first time to determine tungsten ion efflux mechanisms and measure its concentration and distribution within living cells in real-time. For the construction of the nanosensor, TupA (tungsten binding protein), a highly selective protein, was sandwiched between ECFP and Venus, a FRET pair. SENTUN (SENsor for TUNgsten) was the name given to the newly developed nanosensor. SENTUN was highly specific and selective for tungsten and stable at physiological pH levels. We also created three mutants: SENTUN-118D, SENTUN-118K, and SENTUN-178W, with SENTUN-118K exhibiting the highest affinity for tungsten and its comprehensive range detection. The novelty of this sensor is that it is genetically encoded and can be used for real-time measurement of tungsten levels in living cells. [Display omitted] [ABSTRACT FROM AUTHOR]

The article presents the discussion on Molluscum contagiosum (MC) being a common benign cutaneous viral infection caused by a poxvirus. Topics include most common virus subtype affecting children where the individual lesion being shiny, pearly white, hemispherical, papule with a central umbilication; and eosinophilic at the base and turn basophilic in the dermis suggestive of Henderson–Paterson bodies.

Aim of the Study: The objective of this in-vitro study was to assess the screening capabilities of three endodontic sealers, namely the BioRoot RCS, the MTA Fillapex, and Sealapex (a calcium hydroxide-based sealer), and the gutta-percha cone by using a scanning electron microscopy to the dentine walls. The results from the research are presented here. Results: ZOE exhibited more gaps in the sealing materials evaluated with the least dental sealing performance, followed by the cervical third by the MTA Fillapex, the Sealapex, and the BioRoot RCS. The ZOE, followed by Sealapex, MTA Fillapex, and BioRoot RCS, exhibited inadequate dental wall sealing capacity in the middle of the third. The third apical ZOE exhibited more deficiencies in the formation of dental walls, followed by Sealapex, MTA Fillapex, and BioRoot RCS. Conclusion: Under the constraints of the investigation, it can be stated that for the bioceramic sealer, a minimal gap was seen, with RCS of BioRoot superior to Fillapex of MTA. In the middle third, Sealapex was better adapted to the calcium hydroxide-based sealant than the MTA Fillapex sealer. MTA Filllapex had lower gap development than Sealapex in cervical or apical thirds. [ABSTRACT FROM AUTHOR]

Background: Unlike adults, primary membranous nephropathy (PMN) comprises only 1–2% of childhood nephrotic syndrome. The clinical behaviour of PMN in children is not explicit and we report upon clinical presentation and outcome. Methods: This prospective study includes children and adolescents (< 20 years) with biopsy-proven PMN without secondary causes. Anti-PLA2R assessment: before and after completing therapy. Outcome: percentage of patients achieving remission. Results: Study cohort included 48 (M:F ratio 1.1:1) patients and median age 17 (IQR 15–18) years, with 35 (72.9%) PLA2R related. Median interval from symptom onset to presentation was 5 months, where median proteinuria, serum albumin and creatinine were 4.9 g/day, 2.1 g/dL and 0.63 mg/dL, respectively. Forty-seven patients received immunosuppressive therapy, with various agents used as first-line therapy: cyclical CYC/GC (53.1%), CNI/GC (21.3%), rituximab (14.9%), prednisolone alone (4.3%), azathioprine (4.3%) and mycophenolate mofetil (2.1%). Median follow-up was 29 (14, 59) months. At 6 months, 11 (24.4%) and 17 (37.7%) had complete remission (CR) or partial remission (PR), while at last follow-up (median 29 months), 20 (45.4%) and 14 (31.8%) had CR and PR respectively. No significant differences in outcome were observed with different agents. A total of 60% patients treated with rituximab as first line/for relapsing disease, and all cases with resistant disease receiving rituximab had CR or PR at last follow-up. PLA2R antibody presence was associated with clinical outcome. Conclusions: Three-quarters of PMN in children and adolescents is PLA2R related and two-thirds respond to immunosuppressive therapy. Rituximab is a promising agent to manage PMN in children. Anti-PLA2R is associated with clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: To assess the effects of the COVID-19 pandemic on obstetric care and outcomes.Methods: A prospective observational single-center study was performed, including all antenatal and parturient women admitted from April to August, 2020. Data were collected regarding number of admissions, deliveries, antenatal visits, reason for inaccessibility of health care, and complications during pregnancy, and compared with data from the pre-COVID period of October 2019 to February 2020.Results: There was a reduction of 45.1% in institutional deliveries (P < 0.001), a percentage point increase of 7.2 in high-risk pregnancy, and 2.5-fold rise in admission to the intensive care unit of pregnant women during the pandemic. One-third of women had inadequate antenatal visits. The main reason for delayed health-seeking was lockdown and fear of contracting infection, resulting in 44.7% of pregnancies with complications. Thirty-two symptomatic women who tested positive for COVID-19 were managed at the center with good maternal and fetal outcomes.Conclusion: Although COVID-19 does not directly affect pregnancy outcomes, it has indirect adverse effects on maternal and child health. Emergency obstetric and antenatal care are essential services to be continued with awareness of people while maintaining social distancing and personal hygiene. [ABSTRACT FROM AUTHOR]

Chorea has often been associated with lesions in the basal ganglia and in the sub thalamic nucleus. It is possible for a patient with chorea-ballismus to have hyperglycemia at the initial presentation. We hereby present a case of an 81-year-old female, who was on treatment for type 2 diabetes mellitus and presented to us with sub acute onset of abnormal movements of right side of the body. She had semi purposeful, rapid and jerky movements of right upper limb and lower limb along with abnormal tongue movements. Laboratory data showed very high blood glucose levels, urine ketones were positive and pH of arterial blood was normal. MRI brain showed hyperintensities in right basal ganglia. So, hyperglycemia induced hemichorea was considered as a possibility and she was treated with insulin. These abnormal movements decreased subsequently with treatment and patient is doing better in the follow-up visits. This presentation is extremely rare, as review of literature showed similar presentations in patients with non ketotic hyperglycemia but not reported so far in diabetic ketosis. [ABSTRACT FROM AUTHOR]

Malaria is an endemic infectious disease in India. It is often associated with other infective conditions but concomitant infection of malaria and meningitis are uncommon. We present a case of meningitis with vivax malaria infection in a 24-year-old lady. This case emphasizes the importance of high index of clinical suspicion to detect other infective conditions like meningitis when fever does not improve even after anti-malarial treatment in a patient of malaria before switching therapy suspecting drug resistance, which is quite common in this part of world. [ABSTRACT FROM AUTHOR]

Large-scale systemic mouse phenotyping, as performed by mouse clinics for more than a decade, requires thousands of mice from a multitude of different mutant lines to be bred, individually tracked and subjected to phenotyping procedures according to a standardised schedule. All these efforts are typically organised in overlapping projects, running in parallel. In terms of logistics, data capture, data analysis, result visualisation and reporting, new challenges have emerged from such projects. These challenges could hardly be met with traditional methods such as pen & paper colony management, spreadsheet-based data management and manual data analysis. Hence, different Laboratory Information Management Systems (LIMS) have been developed in mouse clinics to facilitate or even enable mouse and data management in the described order of magnitude. This review shows that general principles of LIMS can be empirically deduced from LIMS used by different mouse clinics, although these have evolved differently. Supported by LIMS descriptions and lessons learned from seven mouse clinics, this review also shows that the unique LIMS environment in a particular facility strongly influences strategic LIMS decisions and LIMS development. As a major conclusion, this review states that there is no universal LIMS for the mouse research domain that fits all requirements. Still, empirically deduced general LIMS principles can serve as a master decision support template, which is provided as a hands-on tool for mouse research facilities looking for a LIMS. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 8-year-old girl (weight 22 kg) brought to our emergency room (ER) with accidental ingestion of 15 tablets (each of 75 mg) of pregabalin at 51 mg/kg. Topics include the grandmother was prescribed this drug for anxiety disorder and the child ingested them out of curiosity, and the intermittent sleepiness but stable cardiovascular parameters of heart rate 124 beats per minute.

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016–2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP , MINPP1 , PNPLA8 , AIMP2 , ANKLE2 , NCAPD2 and TRIT1. [ABSTRACT FROM AUTHOR]

Tuberculosis of spine is common in a developing country like India. However, involvement of spine at multiple levels along with involvement of rib and tubercular breast abscess in an immunocompetent patient without any pulmonary involvement is extremely rare. Here we report a case of 53-year-old immunocompetent lady who presented with quadriparesis and MRI (magnetic resonance imaging) of spine revealed multiple lesions involving cervical, thoracic, lumbar, and sacral region without any involvement of intervertebral disc. On detailed examination she was found to have a lump in right breast. Fine needle aspiration cytology of both paravertebral collection and breast lump revealed presence of acid fast bacilli. She was put on antitubercular drug for one year and she responded well to therapy. [ABSTRACT FROM AUTHOR]

Ionic Ca2+functions as a second messenger to control several intracellular processes. It also influences intercellular communication. The release of Ca2+ from intracellular stores through the inositol 1,4,5-trisphosphate receptor (InsP3R) occurs in both excitable and nonexcitable cells. In Drosophila, InsP3R activity is required in aminergic interneurons during pupal development for normal flight behavior. By altering intracellular Ca2+ and InsP3 levels through genetic means, we now show that signaling through the InsP3R is required at multiple steps for generating the neural circuit required in air puff-stimulated Drosophila flight. Decreased Ca2+ release in aminergic neurons during development of the flight circuit can be compensated by reducing Ca2+ uptake from the cytosol to intracellular stores. However, this mode of increasing intracellular Ca2+ is insufficient for maintenance of flight patterns over time periods necessary for normal flight. Our study suggests that processes such as maintenance of wing posture and formation of the flight circuit require InsP3 receptor function at a slow timescale and can thus be modulated by altering levels of cytosolic Ca2+ and InsP3. In contrast, maintenance of flight patterns probably requires fast modulation of Ca2+ levels, in which the intrinsic properties of the InsP3R play a pivotal role. [ABSTRACT FROM AUTHOR]