Increased monocyte activation with age among HIV-infected long term non-progressor children: implications for early treatment initiation.

OBJECTIVES: The key to newer therapeutic and eradication approaches often lies in understanding slow disease progression in HIV infection. The paediatric population has been poorly studied in this regard. We aimed to describe a cohort of perinatally infected long-term nonprogressor (LTNP) children living with HIV in India and to evaluate the immune biomarkers of disease progression. METHODS: LTNPs (ART-naïve, with a CD4 count ≥ 500 cells/µL at age ≥ 7 years) among the cohort of HIV-infected children were identified and monitored longitudinally, and their CD4 T-cell counts and plasma viral loads were measured every 6 months. The plasma monocyte/macrophage activation markers, namely soluble CD14 (sCD14), soluble CD163 (sCD163) and interferon-inducible protein-10 (IP-10) were measured by enzyme-linked immunosorbent assay (ELISA) in LTNPs and progressors. The Mann-Whitney U-test was used to compare the two groups and P values < 0.05 were considered statistically significant. Spearman's rank or Pearson's correlation coefficient (r) was calculated to determine the associations between variables. RESULTS: Among 378 children living with HIV-1 surveyed in our cohort, 40 (10.6%) were LTNPs. Longitudinal analysis of the LTNP data showed that both CD4 count and viral load declined significantly with age (P < 0.0001 for both). Plasma sCD14 levels were significantly (P < 0.005) higher in progressors and sCD163 levels were significantly (P < 0.0001) higher in LTNPs. CONCLUSIONS: The prevalence of LTNPs in our cohort of perinatally infected children living with HIV was 10.6%. We observed a trend for associations between the increasing sCD163 monocyte/macrophage activation marker levels, declining CD4 counts and the gradual loss of nonprogressor status with age in the LTNPs. These findings underscore the need for early antiretroviral therapy in those children with proven slow disease progression.

Scrub typhus and spotted fever among hospitalised children in South India: Clinical profile and serological epidemiology.

BACKGROUND: Rickettsial infections are re-emerging. In India, they are now being reported from several areas where they were previously unknown. OBJECTIVES: The objective of this study was to describe the epidemiology, clinical profile and outcome of serologically-confirmed scrub typhus and spotted fever among children in a tertiary care hospital in Bengaluru. MATERIALS AND METHODS: Hospitalised children aged <18 years, with clinical features suggestive of rickettsial disease admitted between January 2010 and October 2012 were included prospectively. Diagnosis was based on scrub typhus and spotted fever-specific IgM and IgG by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of 103 children with clinical features suggestive of rickettsial illness, ELISA test confirmed 53 cases for scrub typhus, 23 cases for spotted fever group and 14 with mixed infection. The average age was 7.3 (±3.9) years and 44 (71.0%) children were male. Majority of cases were from Karnataka (50%), Andhra Pradesh (32.3%) and Tamil Nadu (17.7%). Common clinical features included fever (100%, average duration 11 days), nausea and vomiting (44%), rash (36%); eschar was rare. Compared to the ELISA test, Weil-Felix test (OX-K titre of 1:80) had a sensitivity and specificity of 88.7% and 43.9%, respectively. Treatment with chloramphenicol or doxycycline was given to the majority of the children. Complications included meningoencephalitis (28%), shock (10%), retinal vasculitis (10%) and purpura fulminans (7%). CONCLUSIONS: These findings suggest that the burden of rickettsial infection among children in India is high, with a substantially high complication rate. Rickettsial-specific ELISA tests can help in early diagnosis and early institution of appropriate treatment that may prevent life-threatening complications.

Adherence to Antiretroviral Therapy Among Children Living with HIV in South India.

Adherence to ART, fundamental to treatment success, has been poorly studied in India. Caregivers of children attending HIV clinics in southern India were interviewed using structured questionnaires. Adherence was assessed using a visual analogue scale representing past-month adherence and treatment interruptions >48 h during the past 3 months. Clinical features, correlates of adherence and HIV-1 viral-load were documented. Based on caregiver reports, 90.9 % of the children were optimally adherent. In multivariable analysis, experiencing ART-related adverse effects was significantly associated with suboptimal adherence (p = 0.01). The proportion of children who experienced virological failure was 16.5 %. Virological failure was not linked to suboptimal adherence. Factors influencing virological failure included running out of medications (p = 0.002) and the child refusing to take medications (p = 0.01). Inclusion of drugs with better safety profiles and improved access to care could further enhance outcomes.

HIV-1 discordant couples in Karnataka, South India: is the sex ratio of index cases changing?

India has an estimated 2.5 million HIV infections, most of which are heterosexually transmitted. Women comprise 40% of infected adults. In India, 90% of women between the ages of 15 and 45 years are married. Previous literature has suggested that sexual intercourse with an HIV-infected husband represents a married woman's greatest risk for being infected. However, a recent meta-analysis of discordant couples from sub-Saharan Africa reported that women were the index case in half of all couples. Similar data are not available from India. This cross-sectional study describes the epidemiology of 925 discordant couples from five districts in Karnataka province, one of the high HIV prevalence provinces in India. Men were the index case in 74% of couples. However, in young couples (where the index case was aged <30 years), women were more likely to be the infected partner (64% of couples). Condom use was reported by 46% of these discordant couples. These results suggest an emerging predominance of female index case infections among younger discordant couples in India, and point to the need for focusing HIV preventive messages on youth and couples before marriage.

Glutathionyl hemoglobin is elevated in iron deficiency anemia.

There are few good biomarkers of iron deficiency anemia (IDA). Since IDA patients have evidence for increased oxidative stress, we used mass spectrometry (MS) [i.e. matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization] to identify novel biomarkers. Using MALDI-MS, the following oxidative modifications of hemoglobin with the following mass-to-charge ratios were identified: 1,087.5 (α32-40), 1,545.7 (α17-31), 1,290.0 (ß31-40) and 2,076.1 (ß41-59). On electrospray ionization MS, the IDA patients had significantly elevated glutathionyl hemoglobin (GSHb) compared with the controls (16.9 ± 9.6 vs. 7.7 ± 3.7%; p = 0.002). GSHb levels correlated inversely with serum ferritin (Spearman rho -0.485; p = 0.003) and positively with serum transferrin receptor (0.460; p = 0.002). GSHb also demonstrated inverse correlations with hemoglobin (-0.512; p = 0.001), mean cell volume (-0.419; p = 0.026), serum iron (-0.446; p = 0.008) and transferrin saturation (-0.460; p = 0.008). For the first time, we show that GSHb is elevated in patients with IDA and has potential as a biomarker of this form of anemia.

Risks of routine iron and folic acid supplementation for young children.

CONTEXT: Almost 70% of young children in India are anemic. Current policy recommends routine iron-folic acid (IFA) supplementation to all under 5 children. A potential risk of this approach is an increase in infectious diseases in general, and malaria in particular. EVIDENCE ACQUISITION: An extensive literature search including PubMed, the World Health Organization (WHO) document library, and the Indian Government database, for documents regarding IFA supplementation in under-5 children. RESULTS: Previously, systematic reviews had suggested adverse effects of IFA supplementation in malaria endemic settings. However, a recent large trial in Tanzania has found clear evidence of increased mortality, chiefly due to malaria, among children receiving routine IFA, whilst a simultaneous study in Nepal (a non-malarious region) found no adverse effects on morbidity or mortality from infectious disease attributable to IFA. These findings have prompted the World Health Organization to revise recommendations regarding IFA supplementation in malaria endemic areas. CONCLUSIONS: India has a non-homogenous distribution of malaria endemicity. We propose that although no change to IFA supplementation be made in non-malarious regions, routine IFA should be provided in malarious regions once malaria control and primary health care infrastructure are functioning well.

Melioidosis.

Melioidosis is an emerging infectious disease in India acquired through percutaneous inoculation or contaminated water. Known risk factors include diabetes mellitus, renal failure, cirrhosis, and malignancy. Melioidosis presents with a febrile illness, with protean manifestations ranging from septicemia to localized abscess formation. We present the case of a 42-year-old male from a non-endemic region who presented with fever of 2 months duration, sepsis, persistent pneumonia, right hip joint pain and hepatic and splenic abscesses. Aspiration of the joint and soft tissue fluid collection and subsequent culture yielded gram negative bacilli identified as Burkholderia pseudomallei. The epidemiology, clinical features, and laboratory diagnosis of this rare infection and its treatment is reviewed.

A guide to murine platelet structure, function, assays, and genetic alterations.

Platelets play an important role in hemostasis, thrombosis and several other biological processes. The adaptability of mice to genetic manipulation and their genetic similarity to humans has resulted in a plethora of murine models to study platelet function. Although murine platelets differ from human platelets with regard to size, number and structure, functionally they are very similar. Thus, studies which employed these model systems have greatly improved our current understanding of the contribution of platelets to hemostasis and thrombosis. This review presents general recommendations with respect to collection, isolation and processing of murine platelets. It also describes the assays currently available to study platelet function and critically assesses their utility. The extensive literature on the effects of genetic alterations on murine platelet function is considered in detail. This review is intended to provide a convenient source of reference for platelet investigators.

A guide to murine coagulation factor structure, function, assays, and genetic alterations.

Murine blood coagulation factors and function are quite similar to those of humans. Because of this similarity and the adaptability of mice to genetic manipulation, murine coagulation factors and inhibitors have been extensively studied. These studies have provided significant insights into human hemostasis. They have also provided useful experimental models for evaluation of the pathophysiology and treatment of thrombosis. This review contains recommendations for obtaining, processing and assaying mouse blood hemostatic components, and it summarizes the extensive literature on murine coagulation factor structure and function, assays and genetic alteration. It is intended to be a convenient reference source for investigators of hemostasis and thrombosis.

Successful liver transplantation in a patient with severe haemophilia A and a high-titre factor VIII inhibitor.

We present the case of a 61-year-old man with severe haemophilia A and a high-titre factor VIII inhibitor who underwent successful orthotopic liver transplantation (OLT) for hepatocellular carcinoma. Postoperatively, a modest early anamnestic response to FVIII was followed by immunological tolerance to FVIII. This case illustrates the technical feasibility of OLT in some patients with high-titre inhibitors to FVIII, and suggests that immune tolerance may be induced by endogenously produced FVIII from the transplanted organ.

Chronic myelogenous leukemia: mechanisms underlying disease progression.

Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABL-mediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed as increased oncogenic activity or loss of tumor suppressor activity. However, what causes transformation and disease progression to blast crisis is only poorly understood. This is in part due to the lack of a good in vivo model of chronic phase CML even though animal models developed over the last few years have started to provide insights into blast crisis development. Thus, additional in vitro and in vivo studies will be needed to provide a complete understanding of the contribution of BCR-ABL and other genes to disease progression and to improve therapeutic approaches for blast crisis CML.

Thrombotic stroke associated with the use of porcine factor VIII in a patient with acquired haemophilia.

Porcine factor VIII (pFVIII), which is used to control bleeding in patients with congenital or acquired haemophilia who have high-titre neutralizing antibodies to human FVIII, is not known to increase the risk of arterial or venous thrombosis. We have recently encountered a patient with acquired haemophilia who developed a thrombotic left middle cerebral artery distribution stroke while being treated with pFVIII. To our knowledge, this is the first such reported thrombotic event. We speculate that platelet activation induced by pFVIII may have contributed to thrombosis and suggest that pFVIII be used with caution in elderly patients with pre-existing cardiovascular risk factors.

Novel therapies for chronic myelogenous leukemia.

The BCR-ABL oncogene is essential to the pathogenesis of chronic myelogenous leukemia, and immune mechanisms play an important role in control of this disease. Understanding of the molecular pathogenesis of chronic myelogenous leukemia has led to the development of several novel therapies, which can be broadly divided into therapies based on 1) inhibition of the BCR-ABL oncogene expression, 2) inhibition of other genes important to the pathogenesis of chronic myelogenous leukemia, 3) inhibition of BCR-ABL protein function, and 4) immunomodulation. We have systematically reviewed each of these novel therapeutic approaches in this article.

Valvular dysfunction in uraemia.

Regurgitation of the pulmonary, mitral, tricuspid and aortic valves have been observed frequently in chronic renal failure (CRF) and dialysis patients. Two dimensional, M mode and doppler echocardiography were performed on 35 CRF patients and 37 end stage renal failure (ESRD) patients on maintenance haemodialysis. Though structurally normal, valvular dysfunction was noted in 50 per cent of the patients with renal failure. Mitral regurgitation was the commonest abnormality, occurring in 36.1 per cent of the patients. Calcification of the valve was observed in only 5.6 and 16.7 per cent of CRF and dialysis patients respectively. Multiple regression analysis underscored the large contribution of diabetic status in the development of valvular dysfunction. Though end systolic volume was higher in patients with valvular abnormalities, the ejection fraction was well preserved. However, follow up studies are required to assess the significance of the functional valvular regurgitation on the cardiac function of the patients.