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1.  A Comparative Prospective Study of Two Different Treatment Sequences i.e. Bottom Up–Inside Out and Topdown–Outside in, in the Treatment of Panfacial Fractures 
To compare the sequence bottom-up inside-out with top-down outside-in, in the treatment of pan facial fractures and to evaluate the outcome of these approaches.
Patients and Methods
The data from 11 patients with panfacial fracture are prospectively analysed. Five cases are treated with bottom-up approach and six patients with top-down approach.
There were 11 male patients (six in top-down approach and five in bottom-up approach), ranging in age from 24 to 50 years. All injuries were result of RTA (n = 11, 100 %). Final treatment outcome was excellent in 3 (50 %), 1 (16 %) good and 2 (32 %) cases were fair in topdown approach, 3 (60 %) excellent and 2 (40 %) fair in bottom up approach with contingency coefficient value (P < .632) which was insignificant. There was no significant deviation from the two groups in the final treatment outcome.
Within the limitation of low sample size we found that both bottom-up inside-out and top-down outside-in approaches have similar clinical outcomes. Hence it could be suggestive to start fixation of least disrupted (more stable) facial half as a guide for reconstruction of the remaining. Choice of the bottom-up inside-out or top-down outside-in sequence should be according to the pattern of fractures and preference of the surgeon. However, further controlled clinical trials, comparative studies with a larger sample size would be better to evaluate the final clinical outcome of individual techniques.
PMCID: PMC4648767  PMID: 26604474
Panfacial fractures; Bottom up-inside out approach; Topdown-outside in approach
2.  Comparative study on the tensile bond strength and marginal fit of complete veneer cast metal crowns using various luting agents: An in vitro study 
Journal of Pharmacy & Bioallied Sciences  2016;8(Suppl 1):S138-S143.
Several commercially available luting agents are used to cement the dental restorations such as intra-coronal, extra-coronal, and fixed partial dentures. Tensile bond strength (TBS) and accurate marginal fit are the essential factors to determine the good clinical results in fixed prosthesis. The retentivity of the luting cements is assessed by their adhesive capacity over the tooth surface and metal surface. Generally, the adhesive ability has been evaluated with in vitro testing, with tensile bond tests. The failure of fixed prosthesis may be happened as a result of incomplete seating during cementation. Most research on cementation of crowns relates seating failure to the thickness of the cement film.
Materials and Methods:
The study is divided into four groups with 10 samples for each of the luting cement taken up for testing TBS and four groups with 5 samples for each luting agent chosen for assessing marginal fit. The results were tabulated and statistically analyzed.
In this in vitro study, the TBS of luting cements, and marginal fit in relation to luting cements were tested by using appropriate testing devices. The TBS of cement is measured using universal testing machine, and the results are tabulated. The marginal gap that exists between the margin of the cast metal crown, and the finish line is measured using travelling microscope before and after cementation. The difference between these two values gives the discrepancy that is due to the film thickness of cement used for luting the restoration.
Summary and Conclusion:
The TBS value of zinc phosphate cement and glass ionomer cement were found to be almost same. The chemical adhesiveness of the glass ionomer with calcium ions of enamel and dentin may be the attributed reason (ionic bonding). In this study, the polycarboxylate is the one that showed low TBS, and it may be attributed to the weakness of the cement due to reduced film thickness, though this cement has a chemical bonding nature. The observation of results of marginal fit in this study is the increased gap found in zinc phosphate cement followed by resin cement, zinc polycarboxylate, and glass ionomer cement. It is agreeable to estimate the marginal fit of the restoration, which could be affected by the film thickness of the luting cement along with other factors.
PMCID: PMC5074017  PMID: 27829765
Crown retentivity; dental cements; marginal discrepancy; microleakage
3.  Why do Patients in Pre-Anti Retroviral Therapy (ART) Care Default: A Cross-Sectional Study 
Background and Objectives:
Approximately, 40% of the patients registered in the National AIDS Control Program in India are not on antiretroviral therapy (ART), i.e., are in pre-ART care. However, there are scarce data regarding the retention of pre-ART patients under routine program conditions. The main objective of this study was to find out the reasons for default among patients in pre-ART care.
Materials and Methods:
Patients enrolled in the ART Centre, Banaras Hindu University (BHU) between January and December 2009 and in pre-ART care were included in the study. Defaulters were those pre-ART patients who missed their last appointment of CD4 count by more than 1 month. Defaulters were traced telephonically in 2011 and those who returned and gave their consent for the study were interviewed using a semi-structured questionnaire.
Out of 620 patients in pre-ART care, 384 (68.2%) were defaulters. One hundred forty-four of the defaulters were traced and only 83 reached the ART center for interview. Among defaulters who did not reach the ART center, illiterate and unmarried were significantly more and mean duration from registration to default was also significantly less as compared to those who came back for the interview. Most defaulters gave more than one reason for defaulting that were as follows: Inconvenient clinic timings (98%), need for multiple mode of transport (92%), perceived improved health (65%), distance of center from home (61%), lack of social support (62%), and financial difficulty (59%).
Interpretation and Conclusion:
Active tracing of pre-ART patients through outreach and strengthening of the Link ART centers will improve the retention of patients in the program.
PMCID: PMC4919940  PMID: 27385880
Defaulter; Human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS); pre-ART
4.  Postoperative posterior ischemic optic neuropathy (PION) following right pterional meningioma surgery 
Postoperative visual loss (POVL) is an unpredictable complication of nonocular surgeries. Posterior ischemic optic neuropathy (PION) is particularly feared in spinal surgeries in the prone position. We report a rare case of PION occurring after surgery for a pterional meningioma and discuss the various factors implicated in POVL.
PMCID: PMC4980962  PMID: 27570391
PION; Post op blindness; meningioma and PION
5.  A Correlative Study of Splenic Parasite Score and Peripheral Blood Parasite Load Estimation by Quantitative PCR in Visceral Leishmaniasis 
Journal of Clinical Microbiology  2015;53(12):3905-3907.
Parasitological diagnosis of visceral leishmaniasis (VL) by splenic smear is highly sensitive, but it is associated with the risk of severe hemorrhage. In this study, the diagnosis of VL using quantitative PCR (qPCR) in peripheral blood was evaluated in 100 patients with VL. Blood parasitemia ranged from 5 to 93,688 leishmania parasite genomes/ml of blood and positively correlated with splenic score (P < 0.0001; r2 = 0.58). Therefore, quantification of parasite genomes by qPCR can replace invasive procedures for diagnostic and prognostic evaluations.
PMCID: PMC4652099  PMID: 26400788
6.  Acute kidney injury-incidence, prognostic factors, and outcome of patients in an Intensive Care Unit in a tertiary center: A prospective observational study 
Background and Aims:
The information regarding the incidence of acute kidney injury (AKI) in medical Intensive Care Units (ICUs) in South India is limited. The aim of the study was to find the incidence, prognostic factors, and outcome of patients with AKI. We also assessed whether only urine output criteria of risk, injury, failure, loss, end (RIFLE) classification can be used to look at the outcome of AKI.
Patients and Methods:
This was a prospective, cross-sectional study of 6 months duration in a 28 bedded medical ICU of a tertiary center. AKI was defined as an absolute creatinine value of>1.6 mg/dl or a 25% increase from baseline creatinine values.
The incidence of AKI was 16.1%, and mortality was 7.8% in our study population. Among patients with AKI 87 (75.7%) patients had sepsis. 71.3% patients had metabolic acidosis on admission, and 47.8% patients were in shock. 57.4% of patient's required mechanical ventilation (MV). 39.1% of AKI patients required renal replacement therapy (RRT). Requirement of RRT was significantly affected by increasing age, Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores on admission, serum creatinine, and use of vasopressors. 49.5% of patients with AKI died within 28 days. Increasing age, MV, hemodialysis (HD), hypertension, chronic kidney disease, and requirement of noradrenaline support were associated with increasing 28 days mortality. The maximum RIFLE score with urine output criteria showed association to the requirement of HD in univariate analysis but did not show relation to mortality.
The incidence of AKI was 16.1% in critically ill patients. In patients with AKI, 39.1% patients required HD and 28 days mortality was 49.5%. The study also showed good univariate association of urine output criteria of RIFLE classification to the requirement of HD in AKI patients.
PMCID: PMC4922285  PMID: 27390456
Acute kidney injury; end; failure; incidence; injury; loss; mortality; renal replacement therapy; risk
7.  Recent developments and future prospects in the treatment of visceral leishmaniasis 
Limited therapeutic options in visceral leishmaniasis (VL) make the treatment of this neglected disease very challenging. In addition to this, long treatment duration and toxic adverse effects make it even more difficult. With no effective vaccine available to date, treatment of VL is based only on chemotherapy. In the Indian subcontinent, a single dose of liposomal amphotericin B (L-AmB) and multidrug therapy (L-AmB + miltefosine, L-AmB + paromomycin [PM], or miltefosine + PM) are the treatments of choice for VL. In East Africa, however, combination therapy of pentavalent antimonials (Sbv) and PM remains the treatment of choice, and in the Mediterranean region and South America, L-AmB is the recommended drug. Fexinidazole and PA-824 are new promising drugs which have shown encouraging results in preclinical studies.
PMCID: PMC4971590  PMID: 27536354
kala-azar; liposomal amphotericin B; miltefosine; paromomycin
8.  Anatomical Variations of Cystic Ducts in Magnetic Resonance Cholangiopancreatography and Clinical Implications 
Radiology Research and Practice  2016;2016:3021484.
Background. Anatomical variations of cystic duct (CD) are frequently unrecognized. It is important to be aware of these variations prior to any surgical, percutaneous, or endoscopic intervention procedures. Objectives. The purpose of our study was to demonstrate the imaging features of CD and its variants using magnetic resonance cholangiopancreatography (MRCP) and document their prevalence in our population. Materials and Methods. This study included 198 patients who underwent MRCP due to different indications. Images were evaluated in picture archiving communication system (PACS) and variations of CD were documented. Results. Normal lateral insertion of CD at middle third of common hepatic duct was seen in 51% of cases. Medial insertion was seen in 16% of cases, of which 4% were low medial insertions. Low insertion of CD was noted in 9% of cases. Parallel course of CD was present in 7.5% of cases. High insertion was noted in 6% and short CD in 1% of cases. In 1 case, CD was draining into right hepatic duct. Congenital cystic dilation of CD was noted in one case with evidence of type IV choledochal cyst. Conclusion. Cystic duct variations are common and MRCP is an optimal imaging modality for demonstration of cystic duct anatomy.
PMCID: PMC4897729  PMID: 27313891
9.  Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent 
eLife  null;5:e12613.
Leishmania donovani causes visceral leishmaniasis (VL), the second most deadly vector-borne parasitic disease. A recent epidemic in the Indian subcontinent (ISC) caused up to 80% of global VL and over 30,000 deaths per year. Resistance against antimonial drugs has probably been a contributing factor in the persistence of this epidemic. Here we use whole genome sequences from 204 clinical isolates to track the evolution and epidemiology of L. donovani from the ISC. We identify independent radiations that have emerged since a bottleneck coincident with 1960s DDT spraying campaigns. A genetically distinct population frequently resistant to antimonials has a two base-pair insertion in the aquaglyceroporin gene LdAQP1 that prevents the transport of trivalent antimonials. We find evidence of genetic exchange between ISC populations, and show that the mutation in LdAQP1 has spread by recombination. Our results reveal the complexity of L. donovani evolution in the ISC in response to drug treatment.
eLife digest
The parasite Leishmania donovani causes a disease called visceral leishmaniasis that affects many of the world's poorest people. Around half a million new cases develop every year, but health authorities lack safe and effective drugs to treat them. Up to 80% of these cases occur in the Indian subcontinent, where devastating epidemics have occurred in the last decades.
One reason these epidemics continue to occur is that the parasites develop genetic mutations allowing them to adapt to and resist the drugs used to kill them. As there are few existing drugs that can kill L. donovani, it is crucial to understand how drug resistance emerges and spreads among parasite populations.
Imamura, Downing, Van den Broeck et al. have now investigated the history of visceral leishmaniasis epidemics by characterising the complete genetic sequence – or genome – of 204 L. donovani parasite samples. This revealed that the majority of parasites in the Indian subcontinent first appeared in the nineteenth century, matching the first historical records of visceral leishmaniasis epidemics.
The genomes show that most of the parasites are genetically similar and can be clustered into several closely related groups. These groups first appeared in the 1960s following the end of a regional campaign to eradicate malaria. The most common parasite group is particularly resistant to drugs called antimonials, which were the main treatment for leishmaniasis until recently. These parasites have a small genetic change that scrambles most of a protein known to be involved in the uptake of antimonials.
Parasites may also be able to develop resistance to drugs through additional mechanisms that allow them to produce many copies of the same gene. These mechanisms could allow the parasites to rapidly adapt to new drugs or changes in the populations it infects. The work of Imamura et al. looks only at parasites isolated from patients then grown in the laboratory, so further research is now needed to explore how variable the Leishmania genome is in both of the parasite’s hosts: humans and sandflies.
Imamura et al.’s study reveals how L. donovani has spread throughout the Indian subcontinent in fine detail. The genome data can be used to create simple molecular tools that could form an "early warning system" to track the success of disease control programs and to determine how well the current drugs are working.
PMCID: PMC4811772  PMID: 27003289
leishmania donovani; genomics; evolution; Other
10.  Comparative Analysis of Cellular Immune Responses in Treated Leishmania Patients and Hamsters against Recombinant Th1 Stimulatory Proteins of Leishmania donovani 
Our prior studies demonstrated that cellular response of T helper 1 (Th1) type was generated by a soluble antigenic fraction (ranging from 89.9 to 97.1 kDa) of Leishmania donovani promastigote, in treated Leishmania patients as well as hamsters and showed significant prophylactic potential against experimental visceral leishmaniasis (VL). Eighteen Th1 stimulatory proteins were identified through proteomic analysis of this subfraction, out of which 15 were developed as recombinant proteins. In the present work, we have evaluated these 15 recombinant proteins simultaneously for their comparative cellular responses in treated Leishmania patients and hamsters. Six proteins viz. elongation factor-2, enolase, aldolase, triose phosphate isomerase, protein disulfide isomerase, and p45 emerged as most immunogenic as they produced a significant lymphoproliferative response, nitric oxide generation and Th1 cytokine response in PBMCs and lymphocytes of treated Leishmania patients and hamsters respectively. The results suggested that these proteins may be exploited for developing a successful poly-protein and/or poly-epitope vaccine against VL.
PMCID: PMC4801884  PMID: 27047452
Leishmania donovani; recombinant Th1 stimulatory proteins; immunogenicity; cellular response; lymphocytes; PBMCs; treated Leishmania-infected hamster; treated Leishmania patients
11.  Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective 
Visceral leishmaniasis (VL) is a serious parasitic disease causing considerable mortality and major disability in the Indian subcontinent. It is most neglected tropical disease, particularly in terms of new drug development for the lack of financial returns. An elimination campaign has been running in India since 2005 that aim to reduce the incidence of VL to below 1 per 10,000 people at sub-district level. One of the major components in this endeavor is reducing transmission through early case detection followed by complete treatment. Substantial progress has been made during the recent years in the area of VL treatment, and the VL elimination initiatives have already saved many lives by deploying them effectively in the endemic areas. However, many challenges remain to be overcome including availability of drugs, cost of treatment (drugs and hospitalization), efficacy, adverse effects, and growing parasite resistance. Therefore, better emphasis on implementation research is urgently needed to determine how best to deliver existing interventions with available anti-leishmanial drugs. It is essential that the new treatment options become truly accessible, not simply available in endemic areas so that they may promote healing and save lives. In this review, we highlight the recent advancement and challenges in current treatment options for VL in disease endemic area, and discuss the possible strategies to improve the therapeutic outcome.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-016-0112-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4782357  PMID: 26951132
Visceral leishmaniasis; Treatment; Drug resistance; Multidrug therapy
12.  Single-Dose Indigenous Liposomal Amphotericin B in the Treatment of Indian Visceral Leishmaniasis: A Phase 2 Study 
Liposomal amphotericin B is an effective and safe alternative for the treatment of visceral leishmaniasis in the Indian subcontinent. In this study, we used a higher-dose regimen of an indigenously manufactured liposomal amphotericin B (FUNGISOME; L-AmBL), which was intended to improve the efficacy in terms of long-lasting cure rate. Thirty men and thirty women between 12 and 60 years old with parasitologically confirmed visceral leishmaniasis were enrolled in two cohorts of 15 patients each. Subjects in cohort I were administered one dose (10 mg/kg body weight) of L-AmBL intravenously. After the safety at this dose was confirmed in cohort I, patients were recruited in cohort II. They received one infusion of an escalated dose (15 mg/kg body weight). The safety of these two doses was evaluated over a period of 30 days, and efficacy was assessed for initial cure at day 30 and definitive cure at 6 months. FUNGISOME was found to be safe, with an initial cure rate of 100% at day 30 and a definitive cure rate of 93.3% at the 6-month follow-up in both the cohorts.
PMCID: PMC4350540  PMID: 25510715
13.  Differential Expression of miRNA Regulates T Cell Differentiation and Plasticity During Visceral Leishmaniasis Infection 
Visceral leishmaniasis (VL) is a tropical neglected disease caused by Leishmania donovani, results in significant mortality in the Indian subcontinent. The plasticity of T cell proliferation and differentiation depends on microRNA mediated gene regulation which leads Th1/Th2 or Th17/Treg type of immune response during human VL. This study depicts the identification of target immune signaling molecule and transcription factors, which play a role in T-cell proliferation and differentiation followed by the identification of miRNA controlling their gene expression using three web servers’ viz., TargetScan, miRPath and miRDB. This study provides the bioinformatics evidences that seed region present in the miRNAs miR-29-b, miR-29a, have the putative binding site in the 3′-untranslated region (UTR) of TBX21 transcription factor of CD4+ T helper (Th1), which may suppress the Th1 specific protective immune response. Development of Th2 type specific immune response can be suppressed by binding of miR-135 and miR-126 miRNAs over the 3′-UTR region of GATA-3 transcription factor of Th2 specific CD4+ T helper cells. MiRNA identified against Th2/Treg immune cells are important and their over expression or administration can be used for developing the Th1/Th17 type of protective immune response during VL infection. This study indicates that miRNAs have the capacity to regulate immune signaling, cytokine production and immune cell migration to control the VL infection in human. This observation warrants further investigation for the development of miRNA based therapy controlling T cell differentiation in human VL.
PMCID: PMC4766295  PMID: 26941729
MicroRNAs; Leishmania donovani; visceral leishmaniasis; Th1/Th2; CD4+ T cell; Th17/Treg
15.  Combined Immune Therapy for the Treatment of Visceral Leishmaniasis 
PLoS Neglected Tropical Diseases  2016;10(2):e0004415.
Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. Immune checkpoint blockade has recently been successfully employed to treat cancer. This strategy modulates immunoregulatory mechanisms to allow host immune cells to kill or control tumors. However, the utility of this approach for controlling established infections has not been extensively investigated. Here, we examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFNγ production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 signaling blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of Th1 cells expressing high levels of KLRG-1. Nevertheless, combined anti-IL-10 and anti-GITR mAb treatment could improve anti-parasitic immunity when used with sub-optimal doses of anti-parasitic drug. However, additional studies with VL patient samples indicated that targeting GITR had no overall benefit over IL-10 signaling blockade alone at improving anti-parasitic immune responses, even with drug treatment cover. These findings identify several important factors that influence the effectiveness of immune modulation, including parasite burden, target tissue and the use of anti-parasitic drug. Critically, these results also highlight potential negative effects of combining different immune modulation strategies.
Author Summary
Despite a decline in the numbers of visceral leishmaniasis (VL) cases and the availability of drugs to treat patients, there is still a need for more efficient treatment options. This is especially important as many VL endemic areas enter phases of disease elimination where parasite burdens need to be reduced as far as possible to minimize the risk of future parasite transmission. Immunotherapy involving the activation of anti-parasitic immunity in infected individuals is a promising approach to help achieve these goals. We tested whether immune modulation could improve anti-parasitic immunity using VL patient samples and an experimental mouse model of infection. Our results provide guidance on the utility of the experimental model, as well as highlighting potential problems associated with immune modulation to improve disease outcomes. These findings have implications for understanding how immunotherapy should be tested and implemented.
PMCID: PMC4752322  PMID: 26872334
16.  An Update on Pharmacotherapy for Leishmaniasis 
Expert opinion on pharmacotherapy  2014;16(2):237-252.
Leishmaniasis broadly manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). The treatment of leishmaniasis is challenging and the armamentarium of drugs is small, duration of treatment is long, and most drugs are toxic.
Areas covered
A literature search on treatment of leishmaniasis was done on PubMed. Single dose of liposomal amphotericin B (L-AmB) and multidrug therapy (L-AmB + miltefosine, L-AmB + paromomycin (PM), or miltefosine + PM) are the treatment of choice for VL in the Indian subcontinent. A 17-day combination therapy of pentavalent antimonials (Sbv) and paromomycin remains the treatment of choice for East African VL. L-AmB is the recommended regimen for VL in the Mediterranean region and South America. Treatment of CL should be decided by the severity of clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis.
Expert opinion
There is an urgent need to implement a single dose L-AmB or combination therapy in the Indian subcontinent. Combination therapy with newer drugs needs to be tested in Africa. Due to the toxicity of systemic therapy, a trend towards local treatment for New World CL (NWCL) is preferred in patients without risk of mucosal disease.
PMCID: PMC4293334  PMID: 25346016
leishmaniasis; visceral leishmaniasis; kala azar; cutaneous leishmaniasis
17.  Understanding the transmission dynamics of Leishmania donovani to provide robust evidence for interventions to eliminate visceral leishmaniasis in Bihar, India 
Parasites & Vectors  2016;9:25.
Visceral Leishmaniasis (VL) is a neglected vector-borne disease. In India, it is transmitted to humans by Leishmania donovani-infected Phlebotomus argentipes sand flies. In 2005, VL was targeted for elimination by the governments of India, Nepal and Bangladesh by 2015. The elimination strategy consists of rapid case detection, treatment of VL cases and vector control using indoor residual spraying (IRS). However, to achieve sustained elimination of VL, an appropriate post elimination surveillance programme should be designed, and crucial knowledge gaps in vector bionomics, human infection and transmission need to be addressed. This review examines the outstanding knowledge gaps, specifically in the context of Bihar State, India.
The knowledge gaps in vector bionomics that will be of immediate benefit to current control operations include better estimates of human biting rates and natural infection rates of P. argentipes, with L. donovani, and how these vary spatially, temporally and in response to IRS. The relative importance of indoor and outdoor transmission, and how P. argentipes disperse, are also unknown. With respect to human transmission it is important to use a range of diagnostic tools to distinguish individuals in endemic communities into those who: 1) are to going to progress to clinical VL, 2) are immune/refractory to infection and 3) have had past exposure to sand flies.
It is crucial to keep in mind that close to elimination, and post-elimination, VL cases will become infrequent, so it is vital to define what the surveillance programme should target and how it should be designed to prevent resurgence. Therefore, a better understanding of the transmission dynamics of VL, in particular of how rates of infection in humans and sand flies vary as functions of each other, is required to guide VL elimination efforts and ensure sustained elimination in the Indian subcontinent. By collecting contemporary entomological and human data in the same geographical locations, more precise epidemiological models can be produced. The suite of data collected can also be used to inform the national programme if supplementary vector control tools, in addition to IRS, are required to address the issues of people sleeping outside.
PMCID: PMC4729074  PMID: 26812963
Visceral leishmaniasis; Transmission; Leishmania donovani; Elimination; Control; Indian sub-continent; Phlebotomus argentipes
18.  Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology 
PLoS Pathogens  2016;12(1):e1005398.
Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.
Author Summary
Many parasitic diseases are associated with the generation of potent inflammatory responses. These are often needed to control infection, but can also cause tissue damage if not appropriately regulated. IL-10 has emerged as an important immune regulator that protects tissues by dampening inflammation. Recently, some T cells that initially produce inflammatory cytokines have been found to start producing IL-10 as a mechanism of auto-regulation. We identified an important transcriptional regulator called B lymphocyte-induced maturation protein 1 (Blimp-1), which promotes IL-10 production by IFNγ-producing CD4+ T (Tr1) cells during malaria and visceral leishmaniasis, two important diseases caused by protozoan parasites. We found that Tr1 cell-derived IL-10 suppressed anti-parasitic immunity, but played a critical role in preventing tissue damage caused by the potent pro-inflammatory cytokine TNF. Specifically, IL-10 protected macrophages from TNF-mediated destruction, and this enabled lymphocytes to continue to migrate to regions in the spleen where T and B cell responses are generated. These findings allow us to better understand how parasites persist in a host, but also identify new opportunities to control inflammation to prevent disease.
PMCID: PMC4713066  PMID: 26765224
19.  Prevalence of human papillomavirus infection & cervical abnormalities in HIV-positive women in eastern India 
Background & objectives:
India has the third highest burden of HIV and highest number of cervical cancer in the world. A cross-sectional study was performed to determine the prevalence and types of human papillomavirus (HPV) infection, and the factors associated with HPV infection and abnormal cervical cytology in HIV-positive women attending the Antiretroviral Therapy (ART) Centre in a tertiary care hospital in eastern India.
We screened 216 HIV- positive women with Papanicolau smear cytology and HPV testing. HPV DNA was detected by using consensus primers followed by sequencing.
Of the 216 HIV-positive women screened, 58 (26.85%) were HPV-positive; 56 (25.9%) were of high-risk (HR) HPV type. The most prevalent HPV type was HPV-16 (7.9%); non 16 and 18 HPV types were present in 17.6 per cent patients. Age ≤ 35 yr [(OR), 2.56 (1.26-5.19)], illiteracy [OR, 2.30 (1.19-4.46)], rural residence [OR, 3.99 (1.27-12.56)] and CD4 ≤350/μl [OR, 2.46 (1.26-4.83)] were associated with increased risk of acquisition of HPV. One hundred thirty nine (74.33%) patients had normal/ negative for intraepithelial lesions (NILM) cytology, three (1.60%) had atypical squamous cells of undetermined significance (ASCUS), 32 (17.11%) had low-grade squamous intraepithelial lesions (LSIL), 10 (5.35%) had high-grade squamous intraepithelial lesions (HSIL) and three (1.60%) had carcinoma cervix. WHO clinical Stage III and IV [OR, 2.83 (1.07-7.49)] and CD4 ≤350/μl [OR, 2.84 (1.30-6.20)] were risk factors for abnormal cytology.
Interpretation &conclusions:
Our study showed 26.85 per cent HPV positivity in HIV infected women in this region, with HPV-16 as the commonest genotype. Abnormal cervical cytology was seen in about 25 per cent women. Regular Pap smear screening as recommended by the National AIDS Control Organization will help in early detection of cervical abnormalities in HIV- positive women.
PMCID: PMC4822373  PMID: 26997018
Cervical cytology; human immunodeficiency virus; human papillomavirus; papanicolau smear cytology; polymerase chain reaction; sequencing
20.  Common and Uncommon Anatomical Variants of Intrahepatic Bile Ducts in Magnetic Resonance Cholangiopancreatography and its Clinical Implication 
Polish Journal of Radiology  2016;81:250-255.
Preoperative knowledge of intrahepatic bile duct (IHD) anatomy is critical for planning liver resections, liver transplantations and complex biliary reconstructive surgery. The purpose of our study was to demonstrate the imaging features of various anatomical variants of IHD using magnetic resonance cholangio-pancreatography (MRCP) and their prevalence in our population.
This observational clinical evaluation study included 224 patients who were referred for MRCP. MRCP was performed in a 1.5-Tesla magnet (Philips) with SSH MRCP 3DHR and SSHMRCP rad protocol. A senior radiologist assessed the biliary passage for anatomical variations.
The branching pattern of the right hepatic duct (RHD) was typical in 55.3% of subjects. The most common variant was right posterior sectoral duct (RPSD) draining into the left hepatic duct (LHD) in 27.6% of subjects. Trifurcation pattern was noted in 9.3% of subjects. In 4% of subjects, RPSD was draining into the common hepatic duct (CHD) and in 0.8% of subjects into the cystic duct. Other variants were noted in 2.6% of subjects. In 4.9% of cases there was an accessory duct. The most common type of LHD branching pattern was a common trunk of segment 2 and 3 ducts joining the segment 4 duct in 67.8% of subjects. In 23.2% of subjects, segment 2 duct united with the common trunk of segment 3 and 4 and in 3.4% of subjects segment 2, 3, and 4 ducts united together to form LHD. Other uncommon branching patterns of LHD were seen in 4.9% of subjects.
Intrahepatic bile duct anatomy is complex with many common and uncommon variations. MRCP is a reliable non-invasive imaging method for demonstration of bile duct morphology, which is useful to plan complex surgeries and to prevent iatrogenic injuries.
PMCID: PMC4886616  PMID: 27298653
Anatomic Variation; Bile Ducts, Intrahepatic; Cholangiopancreatography, Magnetic Resonance
21.  Investigational Drugs for Visceral Leishmaniasis 
The armamentarium of antileishmanials is small. It is further being threatened by development of resistance and decreasing sensitivity to the available drugs. Development of newer drugs are sorely needed.
Areas covered
Literature search on investigational drugs for visceral leishmaniasis (VL) was done on PubMed. Those candidates with at least in vitro and in vivo activity against leishmania species causing VL were reviewed. Among the investigational drugs the nitroimidazole compound fexinidazole is the one of the few drugs which has reached phase II trials. Although the (S)-PA-824 is in phase II trials for the treatment of tuberculosis its R enantiomer has shown good antileishmanial activity. Development of sitamaquin, which has completed phase II studies has been stopped for VL due to its low efficacy. Many novel delivery system and oral formulations of Amphotericin B which are cheap and less toxic are in investigational stages, and will go a long way in improving the treatment of VL.
Expert opinion
Very few new drugs have reached the clinical stage in the treatment of this neglected tropical disease. Thus, there is an urgent need for support from public private partnerships to ensure that drug candidates are promptly taken forward into development.
PMCID: PMC4262729  PMID: 25409760
Visceral leishmaniasis; investigational drugs; therapy
22.  Leishmania donovani-Induced Increase in Macrophage Bcl-2 Favors Parasite Survival 
Members of the Bcl-2 family are major regulators of apoptosis in mammalian cells, and hence infection-induced perturbations in their expression could result into elimination of the parasites or creation of a niche favoring survival. In this investigation, we uncover a novel role of host Bcl-2 in sustaining Leishmania donovani infection. A rapid twofold increase in Bcl-2 expression occurred in response to parasite challenge. Downregulation of post infection Bcl-2 increase using siRNA or functional inhibition using Bcl-2 small molecule inhibitors interfered with intracellular parasite survival confirming the necessity of elevated Bcl-2 during infection. An increased nitric oxide (NO) response and reduced parasitic burden was observed upon Bcl-2 inhibition, where restitution of the NO response accounted for parasite mortality. Mechanistic insights revealed a major role of elevated Th2 cytokine IL-13 in parasite-induced Bcl-2 expression via the transcription factor STAT-3, where blocking at the level of IL-13 receptor or downstream kinase JAK-2 dampened Bcl-2 induction. Increase in Bcl-2 was orchestrated through Toll like receptor (TLR)-2-MEK-ERK signaling, and changes in TLR-2 levels affected parasite uptake. In a mouse model of visceral leishmaniasis (VL), Bcl-2 inhibitors partially restored the antimicrobial NO response by at least a twofold increase that resulted in significantly reduced parasite burden. Interestingly, monocytes derived from the peripheral blood of six out of nine human VL subjects demonstrated Bcl-2 expression at significantly higher levels, and sera from these patients showed only marginally quantifiable nitrites. Collectively, our study for the first time reveals a pro-parasitic role of host Bcl-2 and the capacity of host-derived IL-13 to modulate NO levels during infection via Bcl-2. Here, we propose Bcl-2 inhibition as a possible therapeutic intervention for VL.
PMCID: PMC5078497  PMID: 27826299
Leishmania donovani; Bcl-2; macrophage; nitric oxide; IL-13; ABT-199
23.  Developments in Diagnosis of Visceral Leishmaniasis in the Elimination Era 
Visceral leishmaniasis (VL) is the most devastating parasitic infection worldwide causing high morbidity and mortality. Clinical presentation of VL ranges from asymptomatic or subclinical infection to severe and complicated symptomatic disease. A major challenge in the clinical management of VL is the weakness of health systems in disease endemic regions. People affected by VL mostly present to primary health care centers (PHCs), often late in their therapeutic itinerary. PHC physicians face a major challenge: they do not deal with a single disease issue but with patients presenting with complaints pointing to several diagnostic possibilities. Risk exists when some patients having less clinical manifestations are misdiagnosed. Therefore, field based accurate, sensitive, and cost effective rapid diagnostic tools that can detect disease in its mildest form are essential for effective control and reaching the goal of VL elimination. In this review, we discuss the current status and challenges of various diagnostic tools for the diagnosis of VL and assess their application in resource poor settings.
PMCID: PMC4710934  PMID: 26843964
24.  Enhanced expression of Toll Like Receptors (TLRs) 2& 4, but not 9, in spleen tissue from visceral leishmaniasis patients 
Parasite immunology  2014;36(12):721-725.
Toll like receptor (TLR) signaling is involved in first line defense against Leishmania parasites by triggering NF-κB activation and down-stream production of pro-inflammatory cytokines. Experimental models of visceral leishmaniasis (VL) support a protective role for TLRs 2, 4 and 9 in host immune responses to Leishmania infection. There is limited data available on expression of these TLRs in human VL, particularly in sites of infection, such as the spleen. This study aimed to determine if the expression of mRNA encoding the expression of TLRs 2, 4 and 9 were altered in VL and compare expression patterns in splenic biopsies and peripheral blood mononuclear cells.
PMCID: PMC4246031  PMID: 25244363
Visceral Leishmaniasis; Toll like Receptors; Splenic Aspirate
25.  Outcome of patients on second line antiretroviral therapy under programmatic condition in India 
BMC Infectious Diseases  2015;15:517.
The National AIDS Control Organization of India has been providing free second line antiretroviral therapy (ART) since 2008. This observational study reports the survival and virologic suppression of patients on second-line ART under programmatic condition and type of mutations acquired by those failing therapy.
170 patients initiated on second-line therapy between 2008 and 2012 were followed up till 2013. Viral Load (VL) was repeated at 6 months for all patients and at 12 months for those with VL >400 copies/ml at 6 months. Adequate virological response was defined as plasma HIV-1 VL <400 copies/ml and virological failure was defined as VL >1000 copies/ml. Genotyping was done in 16 patients with virological failure.
Out of 170 patients, 110 (64.7 %) were alive and on therapy and 35 (20.5 %) expired. In the first year the occurrence of death was 13.7 /100 person years while between1 and 5 year it was 3.88 /100 person years. In the first year, duration of immunological failure >12 months, weight <45 kg, WHO clinical stage 3 and 4 and WHO criteria CD4 count less than pretherapy baseline [hazard ratio HR 4.2. 15.8, 11.9 & 4.1 respectively] and beyond first year poor first and second line adherence and first line CD4 count < 200/μL [HR 5.2,15.8, 3.3 respectively] had high risk of death.
119/152 (78.2 %) had adequate virological response and 27/152 (17.7 %) had virological failure. High viral load at baseline and poor second line adherence (Odds Ratio 3.4 & 2.8 respectively) had increased risk of virological failure. Among those genotyped, 50 % had major Protease Inhibitor mutation (M46I commonest) however 87.5 % were still susceptible to darunavir.
Second line therapy has shown high early mortality but good virological suppression under programmatic conditions.
PMCID: PMC4647630  PMID: 26572102
HIV/AIDS; Antiretroviral therapy; Virological response

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