Splenogonadal Fusion - A Rare Anomaly.

Splenogonadal fusion (SGF) is a rare congenital anomaly. Less than 200 cases of SGF have been documented till date. We present a case of 14-year-old male patient with swelling in the left scrotum for 3 years. Left orchidectomy was done. Histopathology showed ectopic splenic tissue surrounding testicular parenchyma suggestive of SGF. This rare congenital malformation may occur due to the proximity of developing gonad and spleen, resulting in abnormal connection between them during gestation. SGF presents a diagnostic challenge preoperatively; however, recent imaging methods can aid with the diagnosis. SGF as a rare cause of testicular swelling should be kept in mind and evaluated to avoid unnecessary orchidectomy.

Immune signatures for HIV-1 and HIV-2 induced CD4+T cell dysregulation in an Indian cohort.

BACKGROUND: HIV-2 infection is characterised by a longer asymptomatic phase and slower AIDS progression than HIV-1 infection. Identifying unique immune signatures associated with HIV-2 pathogenesis may thus provide therapeutically useful insight into the management of HIV infection. This study examined the dynamics of the CD4+T cell compartment, critical in disease progression, focussing on chronic HIV-2 and HIV-1 infected individuals at various stages of disease progression. METHODS: A total of 111 participants including untreated and treated HIV infected individuals and seronegative individuals were enrolled in this study. The relative proportion of CD4+T cell subsets, expressing CD25 (IL-2Rα) and CD127 (IL-7R), in HIV infected individuals and seronegative controls were assessed by multiparametric flow cytometry. Additionally, levels of immune activation and cytotoxic T lymphocytes in both the CD4+T and CD8+T cell compartments was evaluated. RESULTS: Both treated and untreated, HIV-1 and HIV-2 infected individuals showed apparent dysregulation in CD4+ T cell subset frequency that was associated with disease progression. Furthermore, longitudinal sampling from a group of HIV-1 infected individuals on virologically effective ART showed no significant change in dysregulated CD4+T cell subset frequency. For both ART naïve and receiving groups associations with disease progression were strongest and significant with CD4+ T cell subset frequency compared to per cell expression of IL-2Rα and IL-7Rα. In untreated HIV-2 infected individuals, T cell activation was lower compared to ART naïve HIV-1 infected individuals and higher than seronegative individuals. Also, the level of Granzyme-B expressing circulating T cells was higher in both ART-naïve HIV-1 and HIV-2 infected individuals compared to seronegative controls. CONCLUSION: Dysregulation of IL-2 and IL-7 homeostasis persists in CD4+T cell subsets irrespective of presence or absence of viremia or antiretroviral therapy in HIV infection. Furthermore, we report for the first time on levels of circulating Granzyme-B expressing CD4+T and CD8+T cells in chronic HIV-2 infection. Lower immune activation in these individuals indicates that persistent immune activation driven CD4+T cell depletion, as observed in untreated HIV-1 infected individuals, may not be as severe and provides evidence for a disparate pathogenesis mechanism. Our work also supports novel immunomodulatory therapeutic strategies for both HIV-1 and HIV-2 infection.

Idiopathic Systemic Capillary Leak Syndrome.

Idiopathic systemic capillary leak syndrome (ISCLS) is a very rare life-threatening disorder characterized by recurrent episodes of hypotension, hemoconcentration, and hypoalbuminemia. It is caused by transient endothelial dysfunction, leading to plasma leakage from intravascular to interstitial space. Here, we report a case of ISCLS with recurrent episodes of capillary leak which required a long-term prophylaxis with beta-2 adrenergic receptor agonist and theophylline. Although ISCLS is the rare entity, associated morbidity and mortality require physician's awareness to provide timely therapy. Under-recognition in the medical community and rarity of this syndrome has precluded analysis in rational clinical trial designs that are necessary to determine targeted and adequate therapy. This report is meant to enhance awareness of ISCLS among physician's community.

Tubercular skull base osteomyelitis - A case report.

Skull base osteomyelitis (SBO) is a complex and fatal clinical entity caused by infections in the structures surrounding the skull base. It is mainly seen in immune compromised individuals. We report one such rare case of an atypical skull base osteomyelitis in a young, immune-competent female child of 12 years of age, who presented in the ER with misleading symptoms of stroke and was diagnosed incidentally to have SBO on imaging. Adding to the uniqueness of the case is the causative organism, which was identified as Mycobacterium Tuberculosis, an unusual cause of SBO.

Highly dampened HIV-specific cytolytic effector T cell responses define viremic non-progression.

This study reports on HIV-specific T cell responses in HIV-1 infected Viremic Non-Progressors (VNPs), a rare group of people living with HIV that exhibit asymptomatic infection over several years accompanied by stable CD4+ T cell counts in spite of ongoing viral replication. We attempted to identify key virus-specific functional attributes that could underlie the apparently paradoxical virus-host equilibrium observed in VNPs. Our results revealed modulation of HIV-specific CD4+ and CD8+ effector T cell responses in VNPs towards a dominant non-cytolytic profile with concomitantly diminished degranulation (CD107a+) ability. Further, the HIV specific CD8+ effector T cell response was primarily enriched for MIP-1ß producing cells. As expected, concordant with better viral suppression, VCs exhibit a robust cytolytic T cell response. Interestingly, PuPs shared features common to both these responses but did not exhibit a CD4+ central memory IFN-γ producing Gag-specific response that was shared by both non-progressor (VC and VNP) groups, suggesting CD4 helper response is critical for non-progression. Our study also revealed that cytolytic response in VNPs is primarily limited to polyfunctional cells while both monofunctional and polyfunctional cells significantly contribute to cytolytic responses in VCs. To further understand mechanisms underlying the unique HIV-specific effector T cell response described here in VNPs we also evaluated and demonstrated a possible role for altered gut homing in these individuals. Our findings inform immunotherapeutic interventions to achieve functional cures in the context of ART resistance and serious non AIDS events.

Neurodegeneration with brain iron accumulation--late onset slowly progressive variant.

Neurodegeneration with Brain Iron Accumulation (NBIA) is a rare type of neuroaxonal dystrophy that can be familial or sporadic, characterized by progressive extrapyramidal degeneration. We report a case of 23 year old male who presented with cervical dystonia, dysarthria and MRI brain suggestive of characteristic "eye-of-the-tiger" appearance in the globus pallidus.

Teaching Children With Autism Spectrum Disorder to Mand "Why?"

For most children with autism spectrum disorder (ASD), manding for information is an important skill that must be systematically taught. Although previous studies have evaluated interventions for teaching other mands for information, to date no studies have demonstrated effective procedures for teaching the mand "why?" The purpose of the present study was to teach 3 children with ASD to mand "why?" under relevant establishing operation conditions in 3 distinct scenarios. A trial-unique multiple-exemplar procedure was used to promote generalization and increase the value of information provided across trials. All 3 participants learned to mand "why?" in all 3 scenarios within a mean of 18 sessions (range 14-21 sessions), demonstrated generalization to novel stimuli and settings, and maintained this skill over time. Social validity for the intervention had an overall mean of 5.88 (range 1-7).

Vaginal Epithelium Transiently Harbours HIV-1 Facilitating Transmission.

Vaginal transmission accounts for majority of newly acquired HIV infections worldwide. Initial events that transpire post-viral binding to vaginal epithelium leading to productive infection in the female reproductive tract are not well elucidated. Here, we examined the interaction of HIV-1 with vaginal epithelial cells (VEC) using Vk2/E6E7, an established cell line exhibiting an HIV-binding receptor phenotype (CD4-CCR5-CD206+) similar to primary cells. We observed rapid viral sequestration, as a metabolically active process that was dose-dependent. Sequestered virus demonstrated monophasic decay after 6 hours with a half-life of 22.435 hours, though residual virus was detectable 48 hours' post-exposure. Viral uptake was not followed by successful reverse transcription and thus productive infection in VEC unlike activated PBMCs. Intraepithelial virus was infectious as evidenced by infection in trans of PHA-p stimulated PBMCs on co-culture. Trans-infection efficiency, however, deteriorated with time, concordant with viral retention kinetics, as peak levels of sequestered virus coincided with maximum viral output of co-cultivated PBMCs. Further, blocking lymphocyte receptor function-associated antigen 1 (LFA-1) expressed on PBMCs significantly inhibited trans-infection suggesting that cell-to-cell spread of HIV from epithelium to target cells was LFA-1 mediated. In addition to stimulated PBMCs, we also demonstrated infection in trans of FACS sorted CD4+ T lymphocyte subsets expressing co-receptors CCR5 and CXCR4. These included, for the first time, potentially gut homing CD4+ T cell subsets co-expressing integrin α4ß7 and CCR5. Our study thus delineates a hitherto unexplored role for the vaginal epithelium as a transient viral reservoir enabling infection of susceptible cell types.

Analysis of sequence diversity and selection pressure in HIV-1 clade C gp41 from India.

Evaluation of viral diversity is critical for the rational design of treatment modalities against Human immunodeficiency virus (HIV). Predominated by HIV-1 clade C (HIV-1C), the epidemic in India represents the third largest population infected with HIV-1 globally. Glycoprotein 41 (gp41) is critical for viral replication and is a target for the design of therapeutic strategies. However, documentation of viral diversity of gp41 gene in infected individuals from India remains limited. Present study employed high throughput sequencing to examine variation in gp41 amplicons generated from blood derived viruses in 24 HIV-1C infected individuals from Mumbai, India. Sequence diversity profiles were documented in different functional domains of gp41. Furthermore, through a meta-analysis approach, all reported gp41 sequences from India (N = 70) were compared with those from South Africa (N = 126), country with the largest HIV epidemic globally, also predominated by HIV-1C. A total of 44 positions displayed statistically significant differential (p < 0.05) Shannon entropy in the two regions. This comparison also identified 11 codon sites undergoing distinct selection, 8 of which remained differentially selected in an extended comparison of data from Asia (N = 137) and Africa(N = 383). Assessment of correlated mutation networks associated with differentially selected residues revealed common as well as distinct interaction networks. Furthermore, codon usage analysis revealed 17 differentially selected codons (Mann-Whitney test, p < 0.001) in Asia and Africa. Dissimilar trends in GC content across codon positions were also observed. In depth understanding of these divergent evolutionary signatures through extended analysis with larger data-sets would assist development of effective interventions being considered for HIV-1C.

Delineation of Homeostatic Immune Signatures Defining Viremic Non-progression in HIV-1 Infection.

Viremic non-progressors (VNPs), a distinct group of HIV-1-infected individuals, exhibit no signs of disease progression and maintain persistently elevated CD4+ T cell counts for several years despite high viral replication. Comprehensive characterization of homeostatic cellular immune signatures in VNPs can provide unique insights into mechanisms responsible for coping with viral pathogenesis as well as identifying strategies for immune restoration under clinically relevant settings such as antiretroviral therapy (ART) failure. We report a novel homeostatic signature in VNPs, the preservation of the central memory CD4+ T cell (CD4+ T CM ) compartment. In addition, CD4+ TCM preservation was supported by ongoing interleukin-7 (IL-7)-mediated thymic repopulation of naive CD4+ T cells leading to intact CD4+ T cell homeostasis in VNPs. Regulatory T cell (Treg) expansion was found to be a function of preserved CD4+ T cell count and CD4+ T cell activation independent of disease status. However, in light of continual depletion of CD4+ T cell count in progressors but not in VNPs, Tregs appear to be involved in lack of disease progression despite high viremia. In addition to these homeostatic mechanisms resisting CD4+ T cell depletion in VNPs, a relative diminution of terminally differentiated effector subset was observed exclusively in these individuals that might ameliorate consequences of high viral replication. VNPs also shared signatures of impaired CD8+ T cell cytotoxic function with progressors evidenced by increased exhaustion (PD-1 upregulation) and CD127 (IL-7Rα) downregulation contributing to persistent viremia. Thus, the homeostatic immune signatures reported in our study suggest a complex multifactorial mechanism accounting for non-progression in VNPs.

Monocyte Based Correlates of Immune Activation and Viremia in HIV-Infected Long-Term Non-Progressors.

Background: Disease progression monitoring through CD4 counts alone can be inadequate in HIV infection as ongoing immune activation may result in Serious non-AIDS events (SNAEs). SNAEs involve monocyte activation driven chronic inflammation with significant sequelae observed even during HAART. Here, we attempted to delineate functional monocyte based signatures across stages of HIV disease progression. Methods: Participants spanning four cohorts were recruited-pre-ART (PA; <7 years of infection; n = 20), long-term non-progressors (LTNP; >7 years of infection, CD4 > 350 cells/µL, n = 20), individuals on therapy (ART; n = 18) and seronegative controls (SN; n = 15). Immunophenotyping of monocyte subsets and evaluation of expression of HIV-binding receptors-CD4 and CCR5, marker of immune activation- HLA-DR and M2 phenotype-mannose receptor (CD206) was followed by association of monocyte-specific parameters with conventional markers of disease progression such as absolute CD4 count, CD4/CD8 ratio, viral load, and T cell activation. Results: A significant expansion of intermediate monocytes (CD14++CD16+) with a concomitant decline in classical subset (CD14++CD16-) was observed in all infected cohorts compared to seronegative controls. In addition, an expansion of the non-classical subset (CD14+CD16++) was observed in long-term non-progressors. Dysregulation in monocyte subsets associated with CD4 count and CD4/CD8 ratio in PAs but not in LTNPs. We report for the first time that expression of CD206 is most prominent on intermediate monocytes which also have the highest expression of CD4, CCR5, and HLA-DR. Despite preserved CD4 counts, LTNPs had similar immune activation profiles to PAs, as evidenced by elevated HLA-DR expression across monocyte subsets. HLA-DR expression, similar to that in SNs, observed in the ART group indicated partial immune restoration within the monocyte compartment. Increased CD206 expression on monocytes together with frequency of activated CD4+ T lymphocytes (HLA-DR+CD38+) showed significant and positive association with viral load in LTNPs, but not PAs. Conclusion: Our results describe for the first time the presence of monocyte dysregulation involving increased activation in LTNPs, who, in spite of preserved CD4 counts, may remain susceptible to prolonged effects of systemic inflammation and highlight CD206, as a unique non-T correlate of viremia, in viremic non-progression.

Effect of diversity in gp41 membrane proximal external region of primary HIV-1 Indian subtype C sequences on interaction with broadly neutralizing antibodies 4E10 and 10E8.

Human Immunodeficiency Virus-1 Clade C (HIV-1C) dominates the AIDS epidemic in India, afflicting 2.1 million individuals within the country and more than 15 million people worldwide. Membrane proximal external region (MPER) is an attractive target for broadly neutralizing antibody (bNAb) based therapies. However, information on MPER sequence diversity from India is meagre due to limited sampling of primary viral sequences. In the present study, we examined the variation in MPER of HIV-1C from 24 individuals in Mumbai, India by high throughput sequencing of uncultured viral sequences. Deep sequencing of MPER (662-683; HXB2 envelope amino acid numbering) allowed quantification of intra-individual variation up to 65% at positions 662, 665, 668, 674 and 677 within this region. These variable positions included contact sites targeted by bNAbs 2F5, Z13e1, 4E10 as well as 10E8. Both major and minor epitope variants i.e. 'haplotypes' were generated for each sample dataset. A total of 23, 34 and 25 unique epitope haplotypes could be identified for bNAbs 2F5, Z13e1 and 4E10/10E8 respectively. Further analysis of 4E10 and 10E8 epitopes from our dataset and meta-analysis of previously reported HIV-1 sequences from India revealed 26 epitopes (7 India-specific), heretofore untested for neutralization sensitivity. Peptide-Ab docking predicted 13 of these to be non-binding to 10E8. ELISA, Surface Plasmon Resonance and peptide inhibition of HIV-1 neutralization assays were then performed which validated predicted weak/non-binding interactions for peptides corresponding to six of these epitopes. These results highlight the under-representation of 10E8 non-binding HIV-1C MPER sequences from India. Our study thus underscores the need for increased surveillance of primary circulating envelope sequences for development of efficacious bNAb-based interventions in India.

Computational Analysis of the Domain Architecture and Substrate-Gating Mechanism of Prolyl Oligopeptidases from Shewanella woodyi and Identification of Probable Lead Molecules.

Prolyl oligopeptidases (POPs) are serine proteases found in prokaryotes and eukaryotes which hydrolyze the peptide bond containing proline. The current study focuses on the analysis of POP sequences, their distribution and domain architecture in Shewanella woodyi, a Gram-negative, luminous bacterium which causes celiac sprue and similar infections in marine organisms. The POP undergoes huge interdomain movement, which allows possible route for the entry of any substrate. Hence, it offers an opportunity to understand the mechanism of substrate gating by studying the domain architecture and possibility to identify a probable drug target. In the present study, the POP sequence was retrieved from GenBank database and the best homologous templates were identified by PSI-BLAST search. The three-dimensional structures of the closed and open forms of POP from S. woodyi, which are not available in native form, were generated by homology modeling. The ideal lead molecules were screened by computer-aided virtual screening, and the binding potential of the best leads toward the target was studied by molecular docking. The domain architecture of the POP revealed that it has a propeller domain consists of [Formula: see text]-sheets, surrounded by [Formula: see text]-helices and [Formula: see text] hydrolase domain with catalytic triad containing Ser-564, Asp-646 and His-681. The hypothetical models of open and closed POP showed backbone RMSD value of 0.56 and 0.65 Å, respectively. Ramachandran plot of the open and closed POP conformations accounts for 99.4 and 98.7 % residues in the favoured region, respectively. Our study revealed that propeller domain comes as an insert between N-terminal and C-terminal [Formula: see text] hydrolase domain. Molecular docking, drug likeness properties and ADME prediction suggested that KUC-103481N and Pramiracetum can be used as probable lead molecules toward the POP from S. woodyi.

Computational analysis of the domain architecture and substrate-gating mechanism of prolyl oligopeptidases from Shewanella woodyi and identification probable lead molecules.

Prolyl oligopeptidases (POP) are serine proteases found in prokaryotes and eukaryotes which hydrolyze the peptide bond containing proline. The current study focuses on the analysis of POP sequences, their distribution and domain architecture in Shewanella woodyi, a Gram negative, luminous bacterium which causes celiac sprue and similar infections in marine organisms. The POP undergoes huge inter-domain movement, which allows possible route for the entry of any substrate. Hence, it offers an opportunity to understand the mechanism of substrate gating by studying the domain architecture and possibility to identify a probable drug target. In the present study, the POP sequence was retrieved from GenBank data base and the best homologous templates were identified by PSI-BLAST search. The three dimensional structures of the closed and open forms of POP from Shewanella woodyi, which are not available in native form, was generated by homology modeling. The ideal lead molecules were screened by computer aided virtual screening and the binding potential of the best leads towards the target was studied by molecular docking. The domain architecture of the POP revealed that, it has a propeller domain consist of ß-sheets, surrounded by α-helices and α/ß hydrolase domain with catalytic triad containing Ser-564, Asp-646 and His-681. The hypothetical models of open and closed POP showed backbone RMSD value of 0.56 Å and 0.65 Å respectively. Ramachandran plot of the open and closed POP conformations accounts for 99.4% and 98.7% residues in the favoured region respectively. Our study revealed that, propeller domain comes as an insert between N-terminal and C-terminal α/ß hydrolase domain. Molecular docking, drug likeliness properties and ADME prediction suggested that KUC-103481N and Pramiracetum can be used as probable lead molecules towards the POP from Shewanella woodyi.

Tooth loss--how emotional it is for the elderly in India?

BACKGROUND: Tooth loss can be distressing and sometimes devastating as it can lead to the serious psychosocial consequences which can affect the person's quality of life. The purpose of this study is to explore and investigate the emotional effect of tooth loss and its relationship with the person's wellbeing. The aim also extends to learn and understand the psychological status of elderly and to alleviate the management process by keeping it as a guide. METHODS: A total of 212 (69 completely and 143 partially) edentulous patients were investigated for the effects of tooth loss before the replacement of teeth. The demographic variables such as age, gender and socioeconomic status were used to collect the data. Post treatment change in the emotional level was assessed by using a seven point 'Terrible-Delighted' Scale. RESULTS: The tooth loss acceptance in completely edentulous category was 52% in the first year of loss, which increased to 80% after three years; while in partially edentulous patients it increased from 14.3% to 38.1%. The emotional effects of tooth loss varied from person to person with significant differences between the two groups. P-values were obtained using Chi-Square test, p-value<0.05 is considered to be statistically significant. CONCLUSIONS: It is important to understand the problems associated with tooth loss, its emotional effects and the attitude of the elderly towards it. It has a profound impact on the lives of some people, especially when the tooth loss is taken as a serious life event.

Immature germ cells in semen - correlation with total sperm count and sperm motility.

BACKGROUND: Current data regarding infertility suggests that male factor contributes up to 30% of the total cases of infertility. Semen analysis reveals the presence of spermatozoa as well as a number of non-sperm cells, presently being mentioned in routine semen report as "round cells" without further differentiating them into leucocytes or immature germ cells. AIM: The aim of this work was to study a simple, cost-effective, and convenient method for differentiating the round cells in semen into immature germ cells and leucocytes and correlating them with total sperm counts and motility. MATERIALS AND METHODS: Semen samples from 120 males, who had come for investigation for infertility, were collected, semen parameters recorded, and stained smears studied for different round cells. Statistical analysis of the data was done to correlate total sperm counts and sperm motility with the occurrence of immature germ cells and leucocytes. The average shedding of immature germ cells in different groups with normal and low sperm counts was compared. The clinical significance of "round cells" in semen and their differentiation into leucocytes and immature germ cells are discussed. CONCLUSIONS: Round cells in semen can be differentiated into immature germ cells and leucocytes using simple staining methods. The differential counts mentioned in a semen report give valuable and clinically relevant information. In this study, we observed a negative correlation between total count and immature germ cells, as well as sperm motility and shedding of immature germ cells. The latter was statistically significant with a P value 0.000.

The Babel effect: community linguistic diversity and extramarital sex in Uganda.

We examine the association of community linguistic diversity with non-spousal sexual activity in Uganda. We conducted a survey on rates of sexual contact in last 12 months among 1709 respondents age 18-60 living in Uganda in early 2001. Households were selected at random from Demographic and Health Survey (DHS) 2000 household sampling frame listings in 12 districts and 120 clusters. Household listings described the principal language spoken by every household in the cluster. Sexual contact was reported by 26 vs. 13% of unmarried women in multilingual vs. monolingual clusters respectively. Extramarital sexual contact occurred for 29 vs. 16% for married men in multilingual vs. monolingual clusters respectively. These results were robust to multivariate models which included confounders such as urbanity, and cluster distance to market places, cinemas, and transportation. Our results suggest a robust association between residence in a multilinguistic community and higher rates of non-spousal sex.