Outcomes of liver transplantation in children with Langerhans cell histiocytosis: Experience from a quaternary care center.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare but important cause of end-stage liver disease in children. Conventional chemotherapeutic agents that are otherwise the standard-of-care in LCH may be counterproductive in patients with hepatic decompensation. Furthermore, the precise role of liver transplantation (LT) in the management of LCH remains unclear. METHODS: Review of a prospectively collected database (January 2014 to December 2020) of children with liver disease was performed. All clinical details of patients with LCH managed at our center were collected and data analyzed. Based on the outcomes, a management algorithm was proposed. RESULTS: Of the eight (five male) patients referred to our unit, six (75%) underwent LT (four and two for compensated and decompensated cirrhosis, respectively). Median age at diagnosis of LCH was 25 (range: 9-48) months. Two patients, who had previously completed LCH-specific chemotherapy, underwent upfront LT for compensated cirrhosis. Other two patients with compensated cirrhosis showed evidence of active disease. They underwent LT following completion of chemotherapy. Two children with decompensated cirrhosis also had evidence of active disease and were started on modified chemotherapy Both of them had progression of liver disease while on chemotherapy. Hence, an urgent LT was performed which was followed by completion of chemotherapy in these patients. On a median follow-up of 30.5 (10.5-50) months, all post-LT patients were alive with stable graft function and showed no disease recurrence. CONCLUSION: We demonstrate that an algorithmic approach, along with newer chemotherapeutic agents, results in excellent outcomes in LCH patients with liver involvement. Larger multicentric studies on this rare disease are, however, needed to validate our findings.

Role of health literacy and primary health-care access in self-care management of hypertension.

Background: Globally, hypertension is the leading risk factor for men and women and the largest contributor to premature deaths and diseases in India. Health literacy (HL) and health-care access are important determinants for self-care management of hypertension. Objectives: The purpose of this study was to estimate the prevalence of HL, health-care access, and their importance in the self-care management of hypertension. Methods: A community-based cross-sectional study was conducted among 104 known hypertensive patients for 2 months from May to June 2022. Data were collected by face-to-face interviews using a pretested, preformed, and validated questionnaire, and tabulated and analyzed using Microsoft Excel and SPSS version 20 software. Results: Most of the participants (80, 76.9%) have low levels of HL. However, more than half of the (62, 59.6%) participants were satisfied with their access to primary health care. The age of the participants ranged from 38 to 80 years, and half of them (54, 51.9%) were middle-aged adults. The majority (66, 63.5%) of the patients belonged to lower-middle socioeconomic status, and 15.4% (16) were living alone. We found poor HL, and primary health-care access is statistically significantly associated with poor self-care management. Conclusion: Our findings confirm that HL and access to primary health care are crucial factors in the self-care management of hypertension in hypertensive patients.

CARMIL2 Immunodeficiency with Epstein Barr Virus Associated Smooth Muscle Tumor (EBV-SMT). Report of a Case with Comprehensive Review of Literature.

Background: Primary immunodeficiency (PID) having defects related to lymphocyte cytotoxic pathway or T-cell dysfunction are well known for developing opportunistic infections and Epstein-Barr virus (EBV)-associated diseases. CARMIL2 deficiency is a recently described combined immunodeficiency (CID) disorder characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, susceptibility to various infections and Epstein Barr Virus smooth muscle tumor (EBV-SMT). Case report: We report a homozygous CARMIL2 pathogenic variant presenting with recurrent infections and EBV associated smooth muscle tumor (SMT) in a child. Conclusion: The present study reports that EBV SMT may occur in a child with CARMIL2 deficiency.

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy.

Cancer is the second leading cause of death worldwide responsible for about 10 million deaths per year. To date several approaches have been developed to treat this deadly disease including surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, and synthetic lethality. The targeted therapy refers to targeting only specific proteins or enzymes that are dysregulated in cancer rather than killing all rapidly dividing cells, has gained much attention in the recent past. Kinase inhibition is one of the most successful approaches in targeted therapy. As of 30 March 2021, FDA has approved 65 small molecule protein kinase inhibitors and most of them are for cancer therapy. Interestingly, several kinase inhibitors contain one or more fused heterocycles as part of their structures. Pyrrolo[2,1-f][1,2,4]triazine is one the most interesting fused heterocycle that is an integral part of several kinase inhibitors and nucleoside drugs viz. avapritinib and remdesivir. This review articles focus on the recent advances made in the development of kinase inhibitors containing pyrrolo[2,1-f][1,2,4]triazine scaffold.

Transfemoral amputee's limit of stability and sway analysis during weight shifting exercise with a vibrotactile feedback system.

Amputation in the transfemoral amputee (TFA) results in loss of sensory feedback of the amputated limb and therefore results in the poor postural stability. To assess the postural stability, the limit of stability (LOS) is a reliable parameter. In this study, we have investigated the effect of vibrotactile feedback (VF) on the LOS during the weight shifting exercise (WSE) for a TFA. The data of centre of pressure (COP) during WSE was collected from five TFA and five healthy individuals using a zebris force plate. The VF was provided on the amputated/healthy limb's anterior and posterior part of the stump/thigh during forward and backward WSE, respectively. A customized foot insole with 24 embedded dielectric sensors was used to drive the vibratory motor. The effect of VF was analyzed by pre and post-test. Results show that with the use of VF, TFA significantly improved (t-test, p < .05) the sound limb's LOS during forward WSE. Also, ANOVA analysis between WSE divisions shows that the prosthetic limb does not follow the path of WSE. We further examine the spectral power using the Welch method to determine the dominant sway frequency of COP. It shows a decreased frequency between 0.5-2 Hz in the healthy and decreased frequency between 0-0.5 Hz and >2 Hz in the amputee with VF. It concluded that VF could improve the LOS of TFA during WSE which ultimately leads to postural stability enhancement.

Experimental Zika virus infection in Aedes aegypti: Susceptibility, transmission & co-infection with dengue & chikungunya viruses.

BACKGROUND & OBJECTIVES: There are reports about the susceptibility of Aedes mosquitoes to ZIKV from various countries, however, no such information is available from Indian sub-continent, although, high level of group cross-reactivity of ZIKV with other flaviviruses has been reported. During outbreak situations, many cases of Dengue (DEN) and Chikungunya (CHIK) are reported. In such scenario, vector mosquitoes are likely to get co-infection/secondary-infection with one or other virus. The present study was carried out to determine the susceptibility of Indian strain of Aedes aegypti to Zika virus (ZIKV) strain (MR-766) and the effect of co-infection/super-infection with either dengue virus (serotype-2) (DENV) or chikungunya virus (CHIKV) on ZIKV replication. METHODS: Ae. aegypti mosquitoes used in this study were reared for many generations since 1980 at laboratory colony maintained at the ICMR-National Institute of Virology, Pune, India. Transmissibility of ZIKV from infected mosquitoes to suckling mice was also studied. Mosquitoes were experimentally infected with ZIKV and super-infected with either DENV or CHIKV via membrane-feeding route and incubated for 14 days at 28±2°C and humidity of 85±5 per cent. Replication of these viruses in mosquitoes was confirmed using real-time reverse transcription-polymerase chain reaction and immunofluorescence assay. Twenty infected mosquitoes were allowed to feed upon four suckling CD1 mice for about 30 min. Transmission of the ZIKV by infected mosquitoes to suckling mice was confirmed by the appearance of clinical signs and the presence of viral RNA in different organs. RESULTS: Concomitant infection of mosquitoes with all the three viruses showed simultaneous propagation of all three viruses, confirmed by real time RT-PCR and IFA. Infection of mosquitoes with CHIKV followed by ZIKV showed positivity in individual head squashes (7%) for both viruses using IFA; only 8.3 per cent showed dual positivity with primary infection of ZIKV followed by DENV; 8.3 per cent dual infection positivity was observed when infected with DENV followed by ZIKV; 5 per cent showed dual infection was observed when infected with ZIKV followed by CHIKV. Ae. aegypti was found to be susceptible to ZIKV strain as ZIKV could be detected from the second post-infection day (PID) in infected mosquitoes. Transmission of ZIKV to mice by the bite of infected Ae. aegypti establishes this species as a potential vector. INTERPRETATION & CONCLUSIONS: From super-infection experiments, it was concluded that ZIKV might have a relative advantage in replication dynamics over DENV. Vertical transmission was not observed for ZIKV in experimentally infected mosquitoes (n=920 larvae). Further studies are required to understand the possibility of silently circulating ZIKV in India, which remain non-detected because of lack of surveillance.

Zika virus Pathogenesis in Infant Mice after Natural Transmission by the Bite of Infected Mosquitoes.

OBJECTIVES: The objective of this study was to understand natural disease progression in infant CD1 mice after the bite of Aedes aegypti mosquitoes infected by the Zika virus (ZIKV, MR-766 strain). METHODS: A. aegypti mosquitoes were experimentally infected with ZIKV MR-766 strain via the oral feeding route. Infected mosquitoes were allowed to feed on infant CD1 mice. Sick mice were euthanized, and their organs were collected and subjected to real-time RT-PCR, histo-pathology, and immunohistochemistry. RESULTS: Clinical symptoms appeared in mice after 4-5 days of being bitten by mosquitoes, following which they were euthanized. Real-time RT-PCR analysis showed the presence of viral RNA in various organs such as the brain, liver, kidney, spleen, lungs, and intestines of the mice. The brain tissue specimens showed higher viral loads as determined by threshold values (Ct value) in the real-time RT-PCR assay. Histopathological and immunohistochemistry studies also revealed the presence of the virus and associated lesions in the brain, indicating that ZIKV shows tropism for neuronal tissue. CONCLUSIONS: This study demonstrates ZIKV pathogenesis in infant CD1 mice and that these mice are highly susceptible to natural infection with this ZIKV strain.

Multidisciplinary management of hepatoblastoma in children: Experience from a developing country.

BACKGROUND: Advances in chemotherapy, liver resection techniques, and pediatric liver transplantation have vastly improved survival in children with hepatoblastoma (HB). These are best managed by a multidisciplinary team (MDT) in a setting where all treatment options are available. Until recently, this was difficult to achieve in India. METHODS: All children (<16 years) with HB treated in a pediatric liver surgery and transplantation unit between January 2011 and July 2016 were reviewed. Data regarding the clinical presentation, preoperative management, surgical treatment, postoperative course, and outcomes were extracted from a prospectively managed database. RESULTS: Thirty children were treated for HB during the study period. Nine children were PRETEXT 4, 7 were PRETEXT 3, 13 were PRETEXT 2, and 1 was PRETEXT 1 (where PRETEXT is pretreatment extension). All children received a neoadjuvant chemotherapy before surgery followed by an adjuvant chemotherapy. Nineteen children had complete resection, while six underwent primary living donor liver transplantation. There were six mortalities including five children who poorly responded to chemotherapy with progressive tumor extension. At a median follow-up of 30 months, two children who underwent resection and one child who underwent liver transplant had disease recurrence. CONCLUSION: Improved outcomes can be achieved in children with HB even in countries with limited resources when they are managed by MDTs with expertise in pediatric oncology, liver resection, and liver transplantation.

Development of polymerase chain reaction-based diagnostic tests for detection of Malsoor virus & adenovirus isolated from Rousettus species of bats in Maharashtra, India.

BACKGROUND & OBJECTIVES: Bats are recognized as important reservoirs for emerging infectious disease and some unknown viral diseases. Two novel viruses, Malsoor virus (family Bunyaviridae, genus, Phlebovirus) and a novel adenovirus (AdV) (family, Adenoviridae genus, Mastadenovirus), were identified from Rousettus bats in the Maharashtra State of India. This study was done to develop and optimize real time reverse transcription - polymerase chain reaction (RT-PCR) assays for Malsoor virus and real time and nested PCR for adenovirus from Rousettus bats. METHODS: For rapid and accurate screening of Malsoor virus and adenovirus a nested polymerase chain reaction and TaqMan-based real-time PCR were developed. Highly conserved region of nucleoprotein gene of phleboviruses and polymerase gene sequence from the Indian bat AdV isolate polyprotein gene were selected respectively for diagnostic assay development of Malsoor virus and AdV. Sensitivity and specificity of assays were calculated and optimized assays were used to screen bat samples. RESULTS: Molecular diagnostic assays were developed for screening of Malsoor virus and AdV and those were found to be specific. Based on the experiments performed with different parameters, nested PCR was found to be more sensitive than real-time PCR; however, for rapid screening, real-time PCR can be used and further nested PCR can be used for final confirmation or in those laboratories where real-time facility/expertise is not existing. INTERPRETATION & CONCLUSIONS: This study reports the development and optimization of nested RT-PCR and a TaqMan-based real-time PCR for Malsoor virus and AdV. The diagnostic assays can be used for rapid detection of these novel viruses to understand their prevalence among bat population.

Extensive nail changes in a toddler with multisystemic Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a multisystem disorder involving various organs. Nail changes in LCH are extremely rare. We present this case report of extensive nail changes in an 18-month-old child with multisystem LCH.

Contribution of pharmaceuticals and personal care products (PPCPs) to whole toxicity of water samples collected in effluent-dominated urban streams.

Water samples were collected from effluent-dominated urban streams in Tokushima, Kyoto, and Saitama in Japan to roughly determine the contribution of pharmaceuticals and personal care products (PPCPs) and surfactants to whole toxicity of the water. Approximately 100 PPCPs including anionic surfactants such as linear alkylbenzene sulfonate (LAS), were chemically analyzed. Using 14 water samples, chronic or sub-chronic toxicity tests were conducted on three aquatic species, the green alga Raphidocelis subcapitata, the cladoceran Ceriodaphnia dubia, and the zebrafish Danio rerio. Bioassays for the selected individual PPCPs were conducted using the three species. Assuming the concentration addition (CA) model, the contribution of each PPCP to the whole toxicity of the riverwater was estimated based on toxicity unit (TU). The contribution of PPCPs, which primarily consists of a few antibiotic agents such as triclosan and clarithromycin, ranged from 0.9% to 69% of the whole toxicity of the water samples for algae, whereas the selected LAS congeners accounted for at most 5.3%. In contrast, the contribution of LAS ranged from 0.067% to 86% and from 0.021% to 27% of the whole toxicity for cladoceran and zebrafish, respectively, whereas that of PPCPs for these species was at most 2.1% at all sampling points. Our results suggest a limited contribution of PPCPs except for antimicrobial agents and the possible substantial contribution of LAS to toxicity in cladocerans and zebrafish.

Chikungunya Fever Presenting as Life Threatening Thrombotic Thrombocytopenic Purpura.

It is well known for Chikungunya fever to present as myriad of skin rash along with usual joint pain and fever, but probably this is the first case report of Chikungunya fever presenting as severe life threatening thrombotic microangiopathy, thrombotic thrombocytopenic purpura leading to multiple areas of skin necrosis, peripheral digital gangrene, haemolytic anemia, renal failure and severe thrombocytopenia with bleeding. This complication was most likely due to inhibitor autoantibody formation against ADAMTS13 triggered by chikungunya virus leading to thrombotic thrombocytopenic purpura. Patient was treated with plasmapheresis and other supportive careto which she responded. Her symptoms subsided, and she is symptom free and leading normal life in her follow up visits.

pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting.

We report on the design of glycosylated nanogels via core-cross-linking of amphiphilic non-water-soluble block copolymers composed of an acetylated glycosylated block and a pentafluorophenyl (PFP) activated ester block prepared by reversible addition-fragmentation (RAFT) polymerization. Self-assembly, pH-sensitive core-cross-linking, and removal of remaining PFP esters and protecting groups are achieved in one pot and yield fully hydrated sub-100 nm nanogels. Using cell subsets that exhibit high and low expression of the mannose receptor (MR) under conditions that suppress active endocytosis, we show that mannosylated but not galactosylated nanogels can efficiently target the MR that is expressed on the cell surface of primary dendritic cells (DCs). These nanogels hold promise for immunological applications involving DCs and macrophage subsets.

The challenge presented by progestins in ecotoxicological research: a critical review.

Around 20 progestins (also called gestagens, progestogens, or progestagens) are used today in assisting a range of medical conditions from endometrial cancer to uterine bleeding and as an important component of oral contraception. These progestins can bind to a wide range of receptors including progestin, estrogen, androgen, glucocorticoid, and mineralocorticoid receptor, as well as sex hormone and corticosteroid binding globulins. It appears that only five of these (four synthetic and one natural) progestins have so far been studied in sewage effluent and surface waters. Analysis has reported values as either nondetects or low nanograms per liter in rivers. Seven of the progestins have been examined for their effects on aquatic vertebrates (fish and frogs). The greatest concern is associated with levonorgestrel, norethisterone, and gestodene and their ability to reduce egg production in fish at levels of 0.8-1.0 ng/L. The lack of environmental measurements, and some of the contradictions in existing values, however, hampers our ability to make a risk assessment. Only a few nanograms per liter of ethynodiol diacetate and desogestrel in water would be needed for fish to receive a human therapeutic dose for these progestins according to modeled bioconcentration factors. But for the other synthetic progestins levels would need to reach tens or hundreds of nanograms per liter to achieve a therapeutic dose. Nevertheless, the wide range of compounds, diverse receptor targets, and the effect on fish reproduction at sub-nanogram-per-liter levels should prompt further research. The ability to impair female reproduction at very low concentrations makes the progestins arguably the most important pharmaceutical group of concern after ethinylestradiol.

Evaluation of Estrogenic Activity of Wastewater: Comparison Among In Vitro ERα Reporter Gene Assay, In Vivo Vitellogenin Induction, and Chemical Analysis.

The in vitro estrogen receptor (ER) reporter gene assay has long been used to measure estrogenic activity in wastewater. In a previous study, we demonstrated that the assay represents net estrogenic activity in the balance between estrogenic and antiestrogenic activities in wastewater. However, it remained unclear whether the net estrogenic activity measured by the in vitro ERα reporter gene assay can predict the in vivo estrogenic effect of wastewater. To determine this, we measured the following: estrogenic and antiestrogenic activities of wastewater and reclaimed water by the in vitro ERα reporter gene assay, expression of vitellogenin-1 (vtg1) and choriogenin-H (chgH) in male medaka (Oryzias latipes) by quantitative real-time PCR, and estrone, 17ß-estradiol, estriol, and 17α-ethynylestradiol concentrations chemically to predict estrogenic activity. The net estrogenic activity measured by the in vitro medaka ERα reporter gene assay predicted the in vivo vtg1/chgH expression in male medaka more accurately than the concentrations of estrogens. These results also mean that in vivo vtg1/chgH expression in male medaka is determined by the balance between estrogenic and antiestrogenic activities. The in vitro medaka ERα reporter gene assay also predicted in vivo vtg1/chgH expression on male medaka better than the human ERα reporter gene assay.