Hemophagocytic Lymphohistiocytosis: A Rare Complication of Acute Hepatitis E Infection.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive hematological disorder caused by uncontrolled activation of cytotoxic T-cells (CTL), natural killer (NK) cells, and macrophages leading to hyperinflammation and cytokine storm. The clinical course is characterized by high-grade fever, cytopenia, and multiorgan dysfunction. HLH is classified as either primary/familial or secondary, the latter being most often triggered by infections, malignancies, and autoimmune disorders. Viral infections are commonly known to cause HLH with Epstein-Barr virus (EBV), cytomegalovirus (CMV), influenza virus, adenovirus, and parvovirus being most often implicated. Hepatitis E virus (HEV) has infrequently been reported to cause HLH with less than five cases being reported in the literature. We report a case of a young man who presented with hepatitis E-associated HLH.

An overview on mechanism, cause, prevention and multi-nation policy level interventions of dietary iron deficiency.

Iron deficiency anemia (IDA) is probably the most ignored situation in the world of malnutrition-largely due to its slow progression. Multiple reasons can be attributed as the cause of IDA, which is not limited to any specific region or population; therefore, making it a matter of global concern. Despite the human body's ability to absorb and conserve iron stores, the gradual loss due to various physiological conditions leads to net deficiency of iron. Countless commercial iron supplements are available, but at given physiological conditions, almost all of these "Bio-not-available" iron forms quite often become ineffective. World Health Organization and other government bodies have jointly developed health advisories and tried to developed nutrition supplements several times in the last two decades. IDA, when combined with other disease conditions, becomes a life-threatening situation. At the same time, an overdose of iron could also be very harmful to the body. Therefore, it is important to deal with this situation with caution. This article covers iron metabolism, available options for iron supplementation, regulatory aspects and strategies to prevent IDA.

A 12-lipoxygenase-Gpr31 signaling axis is required for pancreatic organogenesis in the zebrafish.

12-Lipoxygenase (12-LOX) is a key enzyme in arachidonic acid metabolism, and alongside its major product, 12-HETE, plays a key role in promoting inflammatory signaling during diabetes pathogenesis. Although 12-LOX is a proposed therapeutic target to protect pancreatic islets in the setting of diabetes, little is known about the consequences of blocking its enzymatic activity during embryonic development. Here, we have leveraged the strengths of the zebrafish-genetic manipulation and pharmacologic inhibition-to interrogate the role of 12-LOX in pancreatic development. Lipidomics analysis during zebrafish development demonstrated that 12-LOX-generated metabolites of arachidonic acid increase sharply during organogenesis stages, and that this increase is blocked by morpholino-directed depletion of 12-LOX. Furthermore, we found that either depletion or inhibition of 12-LOX impairs both exocrine pancreas growth and unexpectedly, the generation of insulin-producing ß cells. We demonstrate that morpholino-mediated knockdown of GPR31, a purported G-protein-coupled receptor for 12-HETE, largely phenocopies both the depletion and the inhibition of 12-LOX. Moreover, we show that loss of GPR31 impairs pancreatic bud fusion and pancreatic duct morphogenesis. Together, these data provide new insight into the requirement of 12-LOX in pancreatic organogenesis and islet formation, and additionally provide evidence that its effects are mediated via a signaling axis that includes the 12-HETE receptor GPR31.

Optimization and validation of RT-LAMP assay for diagnosis of SARS-CoV2 including the globally dominant Delta variant.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 pandemic, has infected more than 179 million people worldwide. Testing of infected individuals is crucial for identification and isolation, thereby preventing further spread of the disease. Presently, Taqman™ Reverse Transcription Real Time PCR is considered gold standard, and is the most common technique used for molecular testing of COVID-19, though it requires sophisticated equipments, expertise and is also relatively expensive. OBJECTIVE: Development and optimization of an alternate molecular testing method for the diagnosis of COVID-19, through a two step Reverse Transcription Loop-mediated isothermal AMPlification (RT-LAMP). RESULTS: Primers for LAMP were carefully designed for discrimination from other closely related human pathogenic coronaviruses. Care was also taken that primer binding sites are present in conserved regions of SARS-CoV2. Our analysis shows that the primer binding sites are well conserved in all the variants of concern (VOC) and variants of interest (VOI), notified by World Health Organization (WHO). These lineages include B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.427/B.1.429, P.2, B.1.525, P.3, B.1.526 and B.1.617.1. Various DNA polymerases with strand displacement activity were evaluated and conditions were optimized for LAMP amplification and visualization. Different LAMP primer sets were also evaluated using synthetic templates as well as patient samples. CONCLUSION: In a double blind study, the RT-LAMP assay was validated on more than 150 patient samples at two different sites. The RT-LAMP assay appeared to be 89.2% accurate when compared to the Taqman™ rt-RT-PCR assay.

Social Vulnerability Indices as a Risk Factor for Heart Failure Readmissions.

Objectives: The objective of our study was to use the parameters of social vulnerability index (SVI) to observe their association with the 30-day hospital readmissions in the heart failure population.Methods: Data required for analysis were extracted from the electronic medical record. The geographic SVI data was then merged with the clinical data. Qualitative variables and reported as frequency and quantitative variables and reported as the mean ± standard deviation. Variables from univariate analysis with a P value of ≤ 0.10 were evaluated using multivariate logistic regression with stepwise backward variable selection and receiver operating curve (ROC) analysis.Results: The odds ratio of readmission predicted by HOSPITAL score was 1.137 (P value = 0.004, 95% CI = 1.041-1.241). SVI parameter recording disability showed odds ratio of 1.521 (P value = 0.006, 95% CI = 1.125-2.058) and SVI parameter tracking vehicle ownership showed odds ratio of 15.355 (P value = 0.014, 95% CI = 1.755 - 134.383). The ROCs were generated for three scenarios: (i) HOSPITAL score only which had area under the curve (AUC) of 0.702 (P value = 0.015), (ii) SVI indicators tracking vehicle ownership and disability resulted in the AUC of 0.589 (P value = 0.016), and (iii) all of the above combined increased the AUC increased to 0.718 (P value = 0.015).Conclusions: Two social parameters (limited vehicle access and prevalence of disability) from the SVI showed a strong association with 30-day hospital readmissions.

Comprehensive Outcomes Evaluation After Percutaneous Coronary Intervention in Stable Ischemic Heart Disease and Acute Coronary Syndrome for Short- Versus Standard-Term Dual Antiplatelet Therapy: A Systematic Review and Meta-analysis of Randomized Control Trials.

Newer generation drug eluting stents (DES) and pharmacotherapy have decreased thrombotic events post-percutaneous coronary intervention (PCI). There is lack of wide-ranging safety and efficacy evaluation in both stable ischemic heart disease and acute coronary syndrome in short-term (3-6 months) versus Standard-term (12 months) dual antiplatelet therapy (DAPT). We searched electronic databases using specific terms to identify randomized control trials comparing different durations of DAPT after PCI with DES. The outcomes of interest included all-cause mortality, myocardial infarction, stent thrombosis, major bleeding, target lesion and vessel revascularization, and stroke at follow-up duration ≥12 months post index PCI. Studies that compared DAPT <3 months or DAPT ≥12 months were excluded. Thirteen randomized control trials (n = 31,831) were included; 8401 patients received DAPT for 3 months and 7482 patients received DAPT in the 6 months group. Major bleeding rate was lower in the short-term (3-6 months) versus Standard-term (12 months) group (risk ratio 0.66; 95% confidence interval, 0.52-0.84, P < 0.05). Repeat revascularization rate was higher in the short-term (3-6 months) versus Standard-term (12 months) (risk ratio 1.17; 95% confidence interval, 1.01-1.36, P < 0.05) of DAPT duration after PCI with DES. No difference in other outcomes were observed when comparing short versus standard duration of DAPT in both stable ischemic heart disease and acute coronary syndrome.

Nasal Glial Heterotopia with Cleft Palate.

Congenital midline nasal masses are rare anomalies of which nasal glial heterotopia represents an even rarer subset. We report a case of a 25-day-old male child with nasal glial heterotopia along with cleft palate suggesting embryonic fusion anomaly which was treated with excision and primary closure for nasal mass followed by palatal repair at later date.

Antileishmanial activity of novel indolyl-coumarin hybrids: Design, synthesis, biological evaluation, molecular docking study and in silico ADME prediction.

In present work we have designed and synthesized total twelve novel 3-(3-(1H-indol-3-yl)-3-phenylpropanoyl)-4-hydroxy-2H-chromen-2-one derivatives 13(a-l) using Ho(3+) doped CoFe2O4 nanoparticles as catalyst and evaluated for their potential antileishmanial and antioxidant activities. The compounds 13a, 13d and 13h were found to possess significant antileishmanial activity (IC50 value=95.50, 95.00 and 99.00µg/mL, respectively) when compared to the standard sodium stibogluconate (IC50=490.00 µg/mL). The compounds 13a (IC50=12.40 µg/mL), 13d (IC50=13.49 µg/mL), 13g (IC50=13.24 µg/mL) and 13l (IC50=13.74 µg/mL) had shown good antioxidant activity when compared with standards butylated hydroxy toluene (IC50=16.5 µg/mL) and ascorbic acid (IC50=12.8 µg/mL). After performing molecular docking studies, it was found that compounds 13a and 13d had potential to inhibit pteridine reductase 1 enzyme. In silico ADME pharmacokinetic parameters had shown promising results and none of the synthesized compounds had violated Lipinski's rule of five. Thus, suggesting that compounds from the present series can serve as important gateway for the design and development of new antileishmanial as well as antioxidant agent.

Growth and obesity status of children from the middle socioeconomic group in Lucknow, northern India: A comparison with studies on children from the upper socioeconomic group.

BACKGROUND: Children from the upper socioeconomic group in India currently show a modest positive secular trend in height, accompanied by a high prevalence of obesity. We examined the anthropometric pattern among children from the middle socioeconomic group. METHODS: A cross-sectional study of anthropometry in 3794 schoolchildren from the middle socioeconomic group in the city of Lucknow, Uttar Pradesh, India. RESULTS: A comparison with the data of a 20-year-old study of children from the upper socioeconomic group showed that the height of boys in our study was at par with or higher than that of boys of the same (Lucknow-Allahabad-Varanasi) region or national data, at all centiles. In contrast, girls in our study were shorter than national data at all centiles and shorter than girls of the same region at the 3rd centile. Children from the middle socioeconomic group did not show the large increase in weight centiles seen in the recent data of the upper socioeconomic group. The values of body mass index at the 85th and 95th percentile at 17 or 18 years of age in girls and boys were 23 and 25 kg/m2, respectively. Obesity was prevalent in 1% of children of the middle socioeconomic group and an additional 5.7% were overweight. CONCLUSIONS: Children from the middle socioeconomic group in Lucknow have grown taller than their 20-year-old counterparts from the upper socioeconomic group. Boys have fared better than girls. Children from the middle socioeconomic group in Lucknow are at present spared from the epidemic of obesity.

A Single-Stage Medial Opening Wedge High Tibial Osteotomy for Varus Alignment Correction With Revision Arthroscopic Anterior Cruciate Ligament (ACL) Reconstruction.

Anterior cruciate ligament (ACL) injuries are a common clinical entity among people involved in contact sports activities. With the number of primary ACL reconstructions increasing, there has been a proportional increase in the revision of failed ACL reconstruction surgeries. As our understanding of knee kinematics improves over time, there has been evidence that alignment of the lower limb weight-bearing axis also plays an important part in ACL functioning. Medial opening wedge high tibial osteotomy (MOWHTO) is one such procedure that has been used extensively worldwide to correct the varus lower limb alignment. This procedure is usually reserved for young active patients with varus lower limb weight-bearing alignment. The technical dilemma for the surgeon arises when there is a need to revise a failed ACL reconstruction while at the same time correcting the axis malalignment. The general dictum says that alignment correction is done first followed by ligament reconstruction in a dual-stage procedure. However, single-stage surgery is possible in certain indications. In this case report, we present the case of a 31-year-old male involved in recreational sports who sustained a repeat ACL tear five years post the index surgery. He also had a significant varus alignment of the lower limb weight-bearing axis which was considered to be one of the causes of index surgery failure. In this report, we would like to highlight the problems we encountered in a single-stage procedure and certain surgical facets of a single-stage alignment surgery with arthroscopic revision ACL reconstruction.

Asymptomatic paroxysmal ventricular standstill in an elderly male following revascularization of multivessel coronary disease: A case report and literature review.

Ventricular standstill is a dangerous arrhythmia that requires prompt diagnosis and intervention, especially in patients with structural heart disease. Clinicians should recognize ventricular standstill as a complication of cardiac revascularization and be cognizant of asymptomatic cases necessitating intervention. Early evaluation to facilitate pacemaker implantation portends good outcomes in this patient subgroup.

High-Grade Atrioventricular Block Reveals Rare Transthyretin Cardiac Amyloidosis With Unique Hemodynamics.

Atrioventricular (AV) block is a common cardiac conduction disorder that is frequently encountered in clinical practice; however, the association with rare systemic conditions such as transthyretin amyloidosis (ATTR) is heavily underdiagnosed. ATTR amyloidosis is a systemic disorder characterized by the deposition of abnormal transthyretin protein fibrosis in various organs including the heart and vasculature, resulting in progressive organ dysfunction. We present a rare case of high-grade AV block unveiling ATTR cardiac amyloidosis with unusual hemodynamics, specifically severe supine hypertension with severe orthostatic hypotension. These findings posed a diagnostic challenge, underscoring the importance of a comprehensive diagnostic approach and meticulous review of medical history. Following pacemaker placement and the diagnosis of ATTR cardiac amyloidosis, our patient was started on a Tafamidis regimen.

Axonal self-sorting without target guidance in Drosophila visual map formation.

The idea of guidance toward a target is central to axon pathfinding and brain wiring in general. In this work, we show how several thousand axonal growth cones self-pattern without target-dependent guidance during neural superposition wiring in Drosophila. Ablation of all target lamina neurons or loss of target adhesion prevents the stabilization but not the development of the pattern. Intravital imaging at the spatiotemporal resolution of growth cone dynamics in intact pupae and data-driven dynamics simulations reveal a mechanism by which >30,000 filopodia do not explore potential targets, but instead simultaneously generate and navigate a dynamic filopodial meshwork that steers growth directions. Hence, a guidance mechanism can emerge from the interactions of the axons being guided, suggesting self-organization as a more general feature of brain wiring.

Safety outcomes of sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes and other risk factors for cardiovascular disease: a systematic review and meta-analysis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) have emerged as standard therapy for heart failure. We aim to assess the safety of SGLT2-Is in patients with a high risk of cardiovascular disease. Areas covered: An electronic database search was conducted for randomized control trials comparing SGLT2-Is to placebo in patients with a high risk of cardiac disease or heart failure. Data were pooled for outcomes using random-effect models. The odds ratio (OR) and 95% confidence interval (CI) were used to compare eight safety outcomes between the two groups. The analysis included ten studies with 71 553 participants, among whom 39 053 received SGLT2-Is; 28 809 were male and 15 655 were female (mean age, 65.2 years). The mean follow-up period was 2.3 years with the range being 0.8-4.2 years. The SGLT2-Is group had a significant reduction in AKI (OR = 0.8;95% CI 0.74-0.90) and serious adverse effects (OR = 0.9; 95% CI 0.83-0.96) as compared to placebo. No difference was found in fracture (OR = 1.1; 95% CI 0.91-1.24), amputation (OR = 1.1; 95% CI 1.00-1.29), hypoglycemia (OR 0.98;95% CI 0.83-1.15), and UTI (OR = 1.1; 95% CI 1.00-1.22). In contrast, DKA (OR = 2.4; 95% CI 1.65-3.60) and volume depletion (OR = 1.2; 95% CI 1.07-1.41) were higher in SGLT2-Is group. Expert opinion/commentary: The benefits of SLGT2-Is outweigh the risk of adverse events. They may reduce the risk of AKI but are associated with an increased risk of DKA and volume depletion. Further studies are warranted to monitor a wider range of safety outcomes of SGLT2-Is.

Biallelic Mutations in P4HTM Cause Syndromic Obesity.

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

Inhibition of polyamine biosynthesis preserves ß cell function in type 1 diabetes.

In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing ß cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with ß cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during ß cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m2) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve ß cell function in T1D through islet cell-autonomous effects.

Quantum dot/plasmonic nanoparticle metachromophores with quantum yields that vary with excitation wavelength.

Coupled plasmonic/chromophore systems are of interest in applications ranging from fluorescent biosensors to solar photovoltaics and photoelectrochemical cells because near-field coupling to metal nanostructures can dramatically alter the optical performance of nearby materials. We show that CdSe quantum dots (QDs) near single silver nanoprisms can exhibit photoluminescence lifetimes and quantum yields that depend on the excitation wavelength, in apparent violation of the Kasha-Vavilov rule. We attribute the variation in QD lifetime with excitation wavelength to the wavelength-dependent coupling of higher-order plasmon modes to different spatial subpopulations of nearby QDs. At the QD emission wavelength, these subpopulations are coupled to far-field radiation with varying efficiency by the nanoprism dipolar resonance. These results offer an easily accessible new route to design metachromophores with tailored optical properties.

A zebrafish tailfin injury assay protocol for quantifying immune cell migration and infiltration.

Myeloid cells, such as macrophages, are critical components of the inflammatory response, in which infected, injured, or necrotic tissues are targeted for resolution. A key aspect of the inflammatory response is migration of myeloid cells to target tissues. Although studying immune cell migration in mammalian models in vivo is challenging, zebrafish are more tractable owing to their optical transparency and rapidity in generating transgenic lines. Here, we present a tailfin injury assay protocol for quantifying immune infiltration at injury sites. For complete details on the use and execution of this profile, please refer to Anderson-Baucum et al. (2021) and Kulkarni et al. (2021).

Role of Polyamines and Hypusine in ß Cells and Diabetes Pathogenesis.

The polyamines-putrescine, spermidine, and spermine-are polycationic, low molecular weight amines with cellular functions primarily related to mRNA translation and cell proliferation. Polyamines partly exert their effects via the hypusine pathway, wherein the polyamine spermidine provides the aminobutyl moiety to allow posttranslational modification of the translation factor eIF5A with the rare amino acid hypusine (hydroxy putrescine lysine). The "hypusinated" eIF5A (eIF5Ahyp) is considered to be the active form of the translation factor necessary for the translation of mRNAs associated with stress and inflammation. Recently, it has been demonstrated that activity of the polyamines-hypusine circuit in insulin-producing islet ß cells contributes to diabetes pathogenesis under conditions of inflammation. Elevated levels of polyamines are reported in both exocrine and endocrine cells of the pancreas, which may contribute to endoplasmic reticulum stress, oxidative stress, inflammatory response, and autophagy. In this review, we have summarized the existing research on polyamine-hypusine metabolism in the context of ß-cell function and diabetes pathogenesis.

Loperamide-Induced Ventricular Tachycardia Storm.

Loperamide is an over-the-counter antilaxative medication with minor opioid properties. For this reason, it has recently become a drug of concern for the Food and Drug Administration due to its potential for abuse. In addition, further apprehension pertaining to its over-the-counter availability has developed due to the recent increase in reported cases of loperamide overdose or prolonged use leading to arrhythmias. We described a rare case of loperamide-induced ventricular tachycardia storm.