Leishmania vaccine development: A comprehensive review.

Infectious diseases like leishmaniasis, malaria, HIV, tuberculosis, leprosy and filariasis are responsible for an immense burden on public health systems. Among these, leishmaniasis is under the category I diseases as it is selected by WHO (World Health Organization) on the ground of diversity and complexity. High cost, resistance and toxic effects of Leishmania traditional drugs entail identification and development of therapeutic alternative. Since the natural infection elicits robust immunity, consistence efforts are going on to develop a successful vaccine. Clinical trials have been conducted on vaccines like Leish-F1, F2, and F3 formulated using specific Leishmania antigen epitopes. Current strategies utilize individual or combined antigens from the parasite or its insect vector's salivary gland extract, with or without adjuvant formulation for enhanced efficacy. Promising animal data supports multiple vaccine candidates (Lmcen-/-, LmexCen-/-), with some already in or heading for clinical trials. The crucial challenge in Leishmania vaccine development is to translate the research knowledge into affordable and accessible control tools that refines the outcome for those who are susceptible to infection. This review focuses on recent findings in Leishmania vaccines and highlights difficulties facing vaccine development and implementation.

Unwelcome prevalence of leishmaniasis with several other infectious diseases.

Co-infection among leishmaniasis and other infectious diseases is common among natural populations especially in the endemic areas of the disease. It depends on the environmental factors, vector availability, host-parasite interactions and above all geographical boundaries. Leishmaniasis being an immunosuppressive disease empowers the invading opportunistic infections to invade and successfully colonize. A variety of infections coexist with leishmaniasis like HIV, leprosy, tuberculosis, schistosomiasis etc. With the different pathology and immune status, co-infection in most cases leads to disease severity and increased mortality.Inevitably, co-infection increases the complexity and poses a threat in the cure and control programmes. This is the first review which highlights the existing co-infections of leishmaniasis with other infectious diseases. The review also focuses on the immunology of co-infections together, diagnosis and the treatment options available for treating such cases. With the changing environment and the overlapping endemic areas of leishmaniasis with other diseases, it becomes difficult to treat a disease without accurate diagnosis. Thus, the review insists on the need for more research on development of newer and differential diagnostic methods for co-infected individuals with theoverlapping symptoms.

Predictors of mortality in premature babies with respiratory distress syndrome treated by early rescue surfactant therapy.

OBJECTIVE: To determine the predictors of mortality following early rescue surfactant therapy in preterm babies with respiratory distress syndrome. STUDY DESIGN: Prospective cohort study enrolling babies between 28 weeks to 34 weeks with respiratory distress syndrome requiring early rescue surfactant therapy. For statistical analysis babies were further divided into two subgroups: survivors and non-survivors. Maternal and neonatal variables were compared between the two groups to find out the predictors of mortality. RESULTS: Out of total 110 babies, 72 (65.45%) survived. The mean birth weight and mean gestational age of the study population was 1614.36 (±487.86) g and 31.40 (±2.0)1 weeks, respectively. Birth weight < 1500 g, gestational age < 32 weeks, primiparity, vaginal delivery, prolonged rupture of membranes, lack of antenatal steroid cover, bag and mask ventilation at birth, sepsis, apneic episodes and mechanical ventilation were significantly associated with death on univariate analysis. On multivariate analysis, very low birth weight, vaginal delivery, lack of antenatal steroid cover, bag and mask ventilation at birth and mechanical ventilation were found to be independent predictors of mortality. CONCLUSIONS: Some of the identified predictors of mortality are modifiable and can be used to draw up a screening tool to predict the clinical severity and mortality among these babies.

Immediate "Kangaroo Mother Care" and Survival of Infants with Low Birth Weight.

BACKGROUND: "Kangaroo mother care," a type of newborn care involving skin-to-skin contact with the mother or other caregiver, reduces mortality in infants with low birth weight (<2.0 kg) when initiated after stabilization, but the majority of deaths occur before stabilization. The safety and efficacy of kangaroo mother care initiated soon after birth among infants with low birth weight are uncertain. METHODS: We conducted a randomized, controlled trial in five hospitals in Ghana, India, Malawi, Nigeria, and Tanzania involving infants with a birth weight between 1.0 and 1.799 kg who were assigned to receive immediate kangaroo mother care (intervention) or conventional care in an incubator or a radiant warmer until their condition stabilized and kangaroo mother care thereafter (control). The primary outcomes were death in the neonatal period (the first 28 days of life) and in the first 72 hours of life. RESULTS: A total of 3211 infants and their mothers were randomly assigned to the intervention group (1609 infants with their mothers) or the control group (1602 infants with their mothers). The median daily duration of skin-to-skin contact in the neonatal intensive care unit was 16.9 hours (interquartile range, 13.0 to 19.7) in the intervention group and 1.5 hours (interquartile range, 0.3 to 3.3) in the control group. Neonatal death occurred in the first 28 days in 191 infants in the intervention group (12.0%) and in 249 infants in the control group (15.7%) (relative risk of death, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P = 0.001); neonatal death in the first 72 hours of life occurred in 74 infants in the intervention group (4.6%) and in 92 infants in the control group (5.8%) (relative risk of death, 0.77; 95% CI, 0.58 to 1.04; P = 0.09). The trial was stopped early on the recommendation of the data and safety monitoring board owing to the finding of reduced mortality among infants receiving immediate kangaroo mother care. CONCLUSIONS: Among infants with a birth weight between 1.0 and 1.799 kg, those who received immediate kangaroo mother care had lower mortality at 28 days than those who received conventional care with kangaroo mother care initiated after stabilization; the between-group difference favoring immediate kangaroo mother care at 72 hours was not significant. (Funded by the Bill and Melinda Gates Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12618001880235; Clinical Trials Registry-India number, CTRI/2018/08/015369.).

The helix-loop-helix transcriptional regulator Id4 is required for terminal differentiation of luminal epithelial cells in the prostate.

Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer. In this study we investigated the effect of loss of Id4 (Id4-/-) on mouse prostate development. Histological analysis was performed on prostates from 25 days, 3 months and 6 months old Id4-/- mice. Expression of Amacr, Ck8, Ck18, Fkbp51, Fkbp52, androgen receptor, Pten, sca-1 and Nkx3.1 was investigated by immunohistochemistry. Results were compared to the prostates from Nkx3.1-/- mice. Id4-/- mice had smaller prostates with fewer and smaller tubules. Subtle PIN like lesions were observed at 6mo. Decreased Nkx3.1 and Pten and increased stem cell marker sca-1, PIN marker Amacr and basal cell marker p63 was observed at all ages. Persistent Ck8 and Ck18 expression suggested that loss of Id4 results in epithelial commitment but not terminal differentiation in spite of active Ar. Loss of Id4 attenuates normal prostate development and promotes hyperplasia/ dysplasia with PIN like lesions. The results suggest that loss of Id4 maintains stem cell phenotype of "luminal committed basal cells", identifying a unique prostate developmental pathway regulated by Id4.

PredCRG: A computational method for recognition of plant circadian genes by employing support vector machine with Laplace kernel.

BACKGROUND: Circadian rhythms regulate several physiological and developmental processes of plants. Hence, the identification of genes with the underlying circadian rhythmic features is pivotal. Though computational methods have been developed for the identification of circadian genes, all these methods are based on gene expression datasets. In other words, we failed to search any sequence-based model, and that motivated us to deploy the present computational method to identify the proteins encoded by the circadian genes. RESULTS: Support vector machine (SVM) with seven kernels, i.e., linear, polynomial, radial, sigmoid, hyperbolic, Bessel and Laplace was utilized for prediction by employing compositional, transitional and physico-chemical features. Higher accuracy of 62.48% was achieved with the Laplace kernel, following the fivefold cross- validation approach. The developed model further secured 62.96% accuracy with an independent dataset. The SVM also outperformed other state-of-art machine learning algorithms, i.e., Random Forest, Bagging, AdaBoost, XGBoost and LASSO. We also performed proteome-wide identification of circadian proteins in two cereal crops namely, Oryza sativa and Sorghum bicolor, followed by the functional annotation of the predicted circadian proteins with Gene Ontology (GO) terms. CONCLUSIONS: To the best of our knowledge, this is the first computational method to identify the circadian genes with the sequence data. Based on the proposed method, we have developed an R-package PredCRG ( https://cran.r-project.org/web/packages/PredCRG/index.html ) for the scientific community for proteome-wide identification of circadian genes. The present study supplements the existing computational methods as well as wet-lab experiments for the recognition of circadian genes.

My Phenotype speaks: please do not harm me with biopsy needle.

Fibrodysplasia ossificans progressiva is characterized by congenital skeletal anomalies and progressive heterotopic ossification. We present a 4 year old male patient who underwent unnecessary harmful multiple biopsies before the diagnosis of fibrodysplasia ossificans progressiva is made. Though rare, diagnosis of fibrodysplasia ossificans progressiva should be considered whenever characteristic radiographic features of multifocal heterotopic bone formation is seen along with the valgus deformities of the big toes.

Diagnostic Yield of Xpert MTB/RIF in Bronchoalveolar Lavage in Children with Probable Pulmonary Tuberculosis.

OBJECTIVE: To evaluate utility of Xpert MTB/RIF in bronchoalveolar lavage fluid in children with probable pulmonary tuberculosis. METHODS: Children with probable pulmonary tuberculosis with negative smear and Xpert on induced sputum/gastric aspirate were subjected to bronchoalveolar lavage (BAL) for Xpert assay and mycobacterial liquid culture. Data of children <14 y undergoing bronchoscopy for suspected MDR-TB (n=12) were also analyzed. The sensitivity of Xpert in BAL fluid for diagnosis of probable and confirmed pulmonary tuberculosis was calculated with clinico-radiological diagnosis and culture as gold standards, respectively. RESULTS: Of 41 enrolled children, 24 (58.5%) had Xpert positive in BAL fluid and 11 (26.8%) had culture confirmed tuberculosis (BAL fluid;10; sputum,1). The sensitivity of Xpert in BAL fluid among probable and culture confirmed tuberculosis cases was 58.5% (24/41) and 81.8% (9/11), respectively. CONCLUSION: Xpert in bronchoalveolar lavage fluid has good sensitivity in both probable and confirmed pulmonary tuberculosis in children.

Juvenile systemic sclerosis: experience from a tertiary care center from India.

Juvenile systemic sclerosis (JSSc) is a rare disorder with paucity of information on its treatment and longterm  outcome. Herein, we are sharing our experience with this rare entity. Case records of children, diagnosed to have systemic sclerosis attending Pediatric Rheumatology Clinic at All India Institute of Medical Sciences, New Delhi from January 1998 to June 2016 were reviewed. The demographic, clinical, laboratory, treatment and outcome details were recorded. Disease outcome was classified arbitrarily as controlled, partly controlled or non-responsive/progressive based on: (A) ability to perform activities of daily life (ADL) and (B) presence or absence of musculoskeletal symptoms, skin changes (ulceration/progressive digital pitting/gangrene), and visceral organ involvement (dyspahgia, cardiopulmonary symptoms). Controlled: ability to perform ADL and absence of B features for at least 6 months. Partly controlled: inability to perform ADL or any of the B features. Non-responsive/progressive disease: presence of both A and any of B features. Thirty-two children (21, girls) diagnosed as systemic sclerosis for whom follow-up of more than 6 months was available were included for this retrospective analysis. Mean (SD) age at presentation was 112.79 (30.05) months, while the median (IQR) delay in diagnosis was 28.5 (9-47.25) months. Of the 32 children 17 (53.12%) had diffuse systemic sclerosis (dSSc), 5 (15.62%) had limited systemic sclerosis (lSSc) and 10 (31.25%) had sclerosis with overlap syndrome. The common clinical features apart from sclerosis/induration proximal to metacarpophalangeal joint were Raynauds phenomenon (n = 22, 68.7%), skin rash (n = 20, 62%), arthritis or arthralgia (n = 16, 50%), and muscular weakness (n = 10, 31.2%). Among those for whom data regarding investigations were available; ANA was positive in 50% (12/24), whereas Anti Scl70 was positive in one out three cases. Treatment regimen included naproxen, methotrexate, calcium channel blockers with or without steroids. HCQ was added in children with skin rash or in children with partial control. Median (IQR) follow-up period was 19.75 (12-31.75) months. With the above treatment protocol, 19 (59.3%) children achieved disease control on treatment, 8 (26.6%) had partial control while 5 (16.6%) showed no response or progressive disease. Esophageal dysmotility and intertitial lung disease (ILD) were documented in three children each. Complication (cataract and herpes zoster) related to immunosuppressive therapy were observed in two children. There was no mortality during the study period. Juvenile Sclerosis though rare is associated with significant morbidities and lacks a curative treatment but a reasonable quality of life to perform daily activities can be achieved using methotrexate and steroid-based immuosuppressive therapy.

Biologicals in Juvenile Idiopathic Arthritis.

We share our experience with biological agents in children with juvenile idiopathic arthritis with an aim to highlight the adverse events and response to treatment. Out of a total of 10 children treated with biological agents, one patient had serious infection, all showed good response and none had tuberculosis. High cost was limiting factor for their use.

Calcinosis in juvenile dermatomyositis: frequency, risk factors and outcome.

The aim was to retrospectively estimate the prevalence of calcinosis in patients with juvenile dermatomyositis (JDM) and to identify risk factors associated with development of calcinosis in these patients. Retrospective chart review of 39 children diagnosed with JDM between 2004 and 2015 in a tertiary care hospital was done. Patients were divided into two groups, depending on the presence or absence of calcinosis, and the two groups were compared with respect to demographic, clinical, laboratory and therapeutic characteristics. Calcinosis developed in nine (23.1 %) patients. Delay in diagnosis and initiation of treatment, prolonged duration of disease, the presence of joint contractures and cardiac involvement were significantly associated with increased frequency of calcinosis. Six out of nine (66.7 %) patients with calcinosis received alendronate therapy, out of which four showed partial reduction in calcinosis. In one case, surgical removal of tumorous clumps was done. Calcinosis remains a common complication of JDM. We found an association between calcinosis and delay in diagnosis and initiation of treatment, prolonged duration of disease and cardiac involvement. Our study suggests that alendronate may be beneficial in management of calcinosis of JDM.

Epidemiological Features of Aplastic Anemia in Indian Children.

OBJECTIVES: To study the socio-demographic profile and clinico-hematological features of aplastic anemia in children presenting at a single institution over 5 y. METHODS: Patients below the age of 15 y presenting with features of aplastic anemia were included in the study. Epidemiology, clinico-hematological features and treatment received were recorded in all the cases. Serology for hepatitis A, B, C, E, EBV, parvovirus and HIV was carried out. Cytogenetic studies were available in approximately half of the patients. RESULTS: One hundred eighty five patients were diagnosed with aplastic anemia. Ten patients with inherited bone marrow failure syndrome (IBMFS) were excluded. Median age was 8 y (range 4-14 y) with a male to female ratio of 2.4:1. Pallor (100 %) followed by bleeding manifestations (83.8 %) and fever (73.5 %) were most common presenting symptoms. One hundred twenty patients (70 %) were classified as severe, 36 (21 %) very severe and 17 (9 %) non-severe aplastic anemia. Viral markers for parvovirus, Epstein barr virus and hepatitis were positive in 25.8 %, 20 % and 6.7 % patients respectively. Six patients had history of varicella infection in recent past (within 6 mo). Very few patients (30) could afford immunosuppressive therapy (IST) and had suboptimal response (29.7 %). CONCLUSIONS: Majority of patients had idiopathic aplastic anemia. Very severe aplastic anemia and severe aplastic anemia were frequent. Few patients received IST and had suboptimal response. There is need to establish a national registry for aplastic anemia.

Cytogenetic profile of aplastic anaemia in Indian children.

BACKGROUND & OBJECTIVES: Aplastic anaemia is a rare haematological disorder characterized by pancytopenia with a hypocellular bone marrow. It may be inherited/genetic or acquired. Acquired aplastic anaemia has been linked to many drugs, chemicals and viruses. Cytogenetic abnormalities have been reported infrequently with acquired aplastic anaemia. Majority of the studies are in adult patients from the West. We report here cytogenetic studies on paediatric patients with acquired aplastic anaemia seen in a tertiary care hospital in north India. METHODS: Patients (n=71, age 4-14 yr) were diagnosed according to the guidelines of International Agranulocytosis and Aplastic Anaemia Study. Conventional cytogenetics with Giemsa Trypsin Giemsa (GTG) banding was performed. Karyotyping was done according to the International System for Human Cytogenetics Nomenclature (ISCN). RESULTS: Of the 71 patients, 42 had successful karyotyping where median age was 9 yr; of these 42, 27 (64.3%) patients had severe, nine (21.4%) had very severe and six (14.3%) had non severe aplastic anaemia. Five patients had karyotypic abnormalities with trisomy 12 (1), trisomy 8 (1) and monosomy 7 (1). Two patients had non numerical abnormalities with del 7 q - and t (5:12) in one each. Twenty nine patients had uninformative results. There was no difference in the clinical and haematological profile of patients with normal versus abnormal cytogenetics although the number of patients was small in the two groups. INTERPRETATION & CONCLUSIONS: Five (11.9%) patients with acquired aplastic anaemia had chromosomal abnormalities. Trisomy was found to be the commonest abnormality. Cytogenetic abnormalities may be significant in acquired aplastic anaemia although further studies on a large sample are required to confirm the findings.

Prevalence of parvovirus B 19 infection in children with aplastic anemia.

We studied the prevalence of parvovirus B19 infection in pediatric patients with acquired aplastic anemia. Detection of parvovirus B19 DNA by PCR and IgM antibodies by ELISA was carried out in 66 pediatric patients with acquired aplastic anemia. 45 healthy children acted as controls. Parvovirus B19 DNA was detected in significantly higher number of patients in comparison to controls (27% vs 2%, P = 0.001). Similarly, parvovirus B19 IgM antibodies were detected in 17 (25.8%) patients as against one control (2.2%) (P<0.05). Clinical and hematological profile of the patients with or without parvovirus infection was comparable.

Immunosuppressive therapy in aplastic anemia.

OBJECTIVE: To assess the response to antithymocyte globulin based immunosuppressive therapy (IST) in pediatric patients with idiopathic aplastic anemia. METHODS: Thirty patients (19 boys and 11 girls) with aplastic anemia received antithymocyte globulin and cyclosporine. Twenty-two patients had severe and 8 had very severe aplastic anemia. RESULTS: Mean age of the patients was 9.19 ± 2.56 y. Three patients died within 1 mo of therapy, two due to sepsis and one due to intracranial hemorrhage. Twenty-seven patients were analyzed for response to therapy. Eight patients (29.7%) responded at 3 mo: 3 complete response (CR) and 5 partial response (PR). Six mo after the therapy, overall response (OR) was seen in 9/27 (33.3%), with one more patient in no response group achieving partial response. At 1 year, patients in CR maintained their status and 1 patient in PR group relapsed. He again achieved partial response with repeat course of ATG. Responders had significantly shorter duration of illness and higher absolute neutrophil count as compared to non responders to IST. None of the patients developed acute leukemia in the follow up. CONCLUSIONS: The treatment of aplastic anemia in pediatric patients is a challenging task. One third of the patients achieved overall response which included both complete and partial response.