Opportunistic infections and organ‐specific diseases in HIV‐1‐infected children: a cohort study (1990–2006)

Objectives

Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV infection in children, but there are few studies in the literature about the incidence of clinical manifestations after HAART in this population, compared with adults. The aim of this study was to describe the influence of the widespread use of HAART on the development of opportunistic infections and organ‐specific diseases in HIV‐infected children.

Methods

An observational study of a cohort of 366 vertically HIV‐infected children followed from 1990 to 2006 was carried out. According to the main antiretroviral protocol used, three calendar periods (CPs) were defined and compared: CP1 (1990–1996: no patients on HAART), CP2 (1997–1999: <60% on HAART) and CP3 (2000–2006: >60% on HAART).

Results

Children experienced a progressive increase in CD4 T cell count (P<0.05) and a decrease in HIV viral load from 1996 onwards (P<0.05). Similarly, rates of death, AIDS, opportunistic infections (bacteraemia, candidosis, cryptosporidiosis and bacterial pneumonia) and organ‐specific diseases (wasting syndrome, thrombocytopenia, cardiomyopathy, lymphoid interstitial pneumonia and HIV‐associated encephalopathy) were lower in CP2 and CP3 than in CP1.

Conclusions

This study provides evidence of improved clinical outcomes in HIV‐infected children over time and shows that mortality, AIDS, opportunistic infections and organ‐specific diseases declined as HAART was progressively instituted in this population.

     

Diagnosis of advanced fibrosis in HIV and hepatitis C virus-coinfected patients via a new noninvasive index: the HGM-3 index

Background

Noninvasive tests are increasingly being used for the assessment of liver fibrosis. We aimed to develop a serum index for the identification of advanced fibrosis (F≥3) in HIV/hepatitis C virus (HCV)‐coinfected patients.

Methods

We carried out a cross‐sectional study on a group of 195 patients comprised of an estimation group (EG; n=127) and a validation group (VG; n=68) who all underwent liver biopsy and had not received previous interferon therapy. Liver fibrosis was estimated using the METAVIR score. We developed a new serum index (HGM‐3) dependent on levels of platelets, alkaline phosphatase, hepatic growth factor, tissue inhibitor of metalloproteinase‐1 and hyaluronic acid.

Results

In the EG, the area under the receiver operating characteristic curve (AUC‐ROC) of HGM‐3 for identification of F≥3 was 0.939 [95% confidence interval (CI) 0.899, 0.979] which was significantly higher than the AUC‐ROC of the HGM‐2, FIB‐4, aspartate aminotransferase to platelet ratio (APRI) and Forns' indexes. With HGM‐3 <0.135 for F<3, 57 patients were correctly identified and two patients were misclassified. We found the presence of F<3 with 96.6% certainty. The negative likelihood ratio (LR) was <0.1 and the diagnostic odds ratio (DOR) was >40. With HGM‐3 >0.570 in the EG for F≥3, 31 patients were correctly identified, and five patients were misclassified. We found the presence of F≥3 with 86.1% certainty. The positive LR was >12 and the DOR was >40. For the VG, the diagnostic accuracy values were similar to the values for the EG.

Conclusions

HGM‐3 appears to be an accurate noninvasive method for the diagnosis of bridging fibrosis and cirrhosis in HIV/HCV‐coinfected patients.     

Aetiological factors for oral manifestations of HIV

OBJECTIVES: Describe the oral diseases in HIV-infected individuals in London, UK and identify social and medical factors related to the presence of specific oral diseases.
DESIGN: Cross-sectional analytic study.
SETTING: Dental clinics.
SUBJECTS: Consecutive sample of 456 patients with HIV infection.
METHODS: Social and medical history and clinical examinations. Univariate and logistic regression analysis.
OUTCOMES: Presence of HIV-associated oral disease.
RESULTS: 80% of patients with AIDS and 50% of patients with HIV had a specific oral disease. The most common diseases were hairy leukoplakia (30%), erythematous candidiasis (24%), pseudomembranous candidiasis (14%), angular chielitis (6%), necrotising periodontal disease (8%) and non-recurrent ulceration (6%).
CONCLUSIONS: The presence of erythematous candidiasis was not related to advanced HIV disease. Pseudomembranous candidiasis, hairy leukoplakia and mucosal ulceration were significantly associated with advanced HIV disease. Smoking was also identified as a strong aetiological factor in oral diseases. Longitudinal studies are required to further explore the prognostic significance of oral diseases in HIV infection.     

关于全基因组相关分析的研究--你首先想要什么：好消息,坏消息,或者好消息？

很久以来都认为遗传成分参与2型糖尿病（T2DM）的发病，但是有关遗传学上的发现一直进展缓慢，这是由于遗传成分的复杂性。有关糖尿病相关的各种表型的研究的大量资料提示，所谓的“T2DM”可能是许多疾病的统称，由于它们具有通常相互重叠的多种基本发病机制。因此，对曾抱有期望的T2DM的遗传学基础的寻求已经证明是很艰难的。     

Effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre randomised double-blind placebo-controlled trial

BackgroundPerhexiline is thought to modulate metabolism through the inhibition of mitochondrial carnitine palmitoyltransferase, reducing fatty acid uptake and increasing carbohydrate utilisation. Our group has shown that a glucose-insulin-potassium infusion enhances myocardial protection during coronary artery bypass graft (CABG) surgery through metabolic manipulation. This study assessed whether perhexiline improves clinical or biochemical markers of myocardial protection and analysed its effect on the myocardial metabolome.MethodsIn a prospective randomised double-blind placebo-controlled trial, patients undergoing CABG at two centres were randomised to receive oral perhexiline or placebo for at least 5 days before surgery. The primary outcome was a low cardiac output episode in the first 6 h after removal of the aortic cross-clamp. A low cardiac output episode was defined as a cardiac index of less than 2·2 L/min/m² in the presence of adequate preload, afterload, and heart rate. All analyses were conducted according to the intention-to-treat principle with a 90% power to detect a relative risk of 0·5 with a one-sided α of 0·025. Left ventricular biopsy samples were taken before ischaemia, snap-frozen, and analysed with mass spectrometry-based (MS) metabolomics. This trial is registered with ClinicalTrials.gov, number NCT00845364.FindingsOver a 3-year period, 286 patients were randomised, received the intervention, and included in the analysis. There were no important baseline differences between groups. The incidence of a low cardiac output episode in the perhexiline arm was 36·7% (51/139) versus 34·7% (51/147) in the control arm (odds ratio 0·92 [95% CI 0·56–1·50]; p=0·74). There were no significant differences in inotrope usage, myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction, or length of hospital stay. No difference in pre-ischaemia left ventricular metabolism was identified between groups.InterpretationPreoperative perhexiline does not improve myocardial protection in patients undergoing CABG. That perhexiline has no significant effect on the MS-visible polar myocardial metabolome in vivo in human beings supports the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition.FundingBritish Heart Foundation and Sussex Heart Charity.     

Characterisation and immunogenicity of a decellularised skeletal muscle scaffold for laryngeal tissue engineering

BackgroundSuccessful replacement of airways in patients has been done with tissue engineered constructs. However, replacing the larynx where active movement is crucial, requires functional muscle tissue.MethodsDecellularised scaffolds were characterised with histological, immunohistochemical, and molecular techniques and xenogenically implanted to determine the effect of implantation on scaffold biodegradation time and immunogenicity in vivo. The cellular host immune response to the scaffold was quantified by stereology and by fluorescence activated cell sorting in vitro.FindingsDecellularisation results in total DNA clearance and downregulation of MHC classes I/II and myosin heavy chain expression, with relative preservation of the scaffold's structural integrity (collagen, elastin, s-glycosaminoglycans content) and biomechanical properties. Decellularisation altered the host response to the scaffold in vivo, resulting in a prolonged degradation time and increased neoangiogenic potential relative to fresh tissue. In addition, we proved for the first time that decellularised scaffolds trigger a lower cellular mediated immune response, resulting in a reduced T-cell proliferative response in vitro, and alter the cellular immune profile towards the scaffolds in vivo, with a reduction in CD3+ cells and a shift towards the M2-macrophage phenotype.InterpretationDecellularised laryngeal muscles are non-immunogenic and may provide the optimum scaffold source for a tissue-engineered larynx.FundingUK Medical Research Council, Sparks Children's Charity, and Royal College of Surgeons of England.     

Terminal deoxynucleotidyl transferase expression can precede T cell receptor beta chain and gamma chain rearrangement in T cell acute lymphoblastic leukemia

The nuclear enzyme terminal deoxynucleotidyl transferase (TdT) is thought to contribute to the diversity of certain immunoglobulin and T cell receptor gene rearrangements through the addition of random nucleotides at their variable (V)-joining (J) region junctions. An acute lymphoblastic leukemia (ALL) with an immature T cell phenotype (CD7+, CD5+, CD1+/-, CD2+/-, CD3-, CD4-, CD8-) was found to be TdT+ with germline immunoglobulin heavy chain, T cell receptor beta chain, and T cell gamma chain genes. The data indicate that TdT expression can precede T gamma and T beta rearrangement during T lymphoid ontogeny consistent with its proposed association with the T cell receptor rearrangement process. Southern analysis of certain cases of T-ALL may not result in the detection of a monoclonal population of cells.     

T-cell death by apoptosis in vertically human immunodeficiency virus- infected children coincides with expansion of CD8+/interleukin-2 receptor-/HLA-DR+ T cells: sign of a possible role for herpes viruses as cofactors?

One mechanism proposed to play a role in T-cell depletion in human immunodeficiency virus (HIV) infection is apoptosis (activation-induced cell death). We assessed whether apoptosis is related to activation of T cells in vivo and its possible triggers. DNA was extracted from peripheral blood mononuclear cells (PBMC) taken from 16 vertically HIV- infected children and 9 HIV-negative children born to HIV-positive mothers (controls) and tested by agarose gel electrophoresis for the presence of DNA fragments specific for apoptosis. Signs of apoptosis were found on in vitro culture of PBMC from 12 of 16 HIV-infected children, but not in PBMC from the nine controls. Eleven of the 12 HIV- infected children with apoptosis showed an elevated (> 15%) proportion of CD3+/HLA-DR+ cells. This was due to an increased proportion of CD8+/HLA-DR+ cells, as shown in 7 of 7 further tested patients. In none of the probands an increased (> 5%) proportion of IL-2 receptor expressing CD3+ cells was found. T cells undergoing apoptosis were preferentially of the CD8+ phenotype. Expansion of circulating CD8+/interleukin-2 receptor (IL-2R)-/HLA-DR+ T cells is known to occur during active infection with herpes viruses. To investigate the possible role of herpes viral coinfections for apoptosis in HIV infection, we focused on Epstein-Barr virus (EBV) as an example for a herpes virus usually acquired during childhood. In 10 of 12 patients with apoptosis, we found increased levels of EBV genome in PBMC and/or tissues, indicating active EBV replication. By contrast, no increased burden of EBV was found in the four HIV-infected patients without apoptosis or in the controls. Our data indicate that in children the occurrence of apoptosis in HIV infection is closely related to activation of CD8+ T cells. Furthermore, primoinfection with or reactivation of herpes viruses, such as EBV, may substantially contribute to such T-cell activation and the ensuing apoptosis. Additional studies are warranted to evaluate the contribution of herpes virus-triggered apoptosis to the T-cell loss leading to the acquired immunodeficiency syndrome.     

Detection of maternal cells in human umbilical cord blood using fluorescence in situ hybridization

Cord blood is a potential source of hematopoietic stem cells for transplantation and is being used on a growing number of patients. However, there are concerns that cord blood might be contaminated with maternal cells that could lead to graft-versus-host disease. To ascertain the extent to which maternal cell contamination of cord blood occurs, we examined 49 cord blood samples from male babies for maternal cells by fluorescence in situ hybridization using probes to the X and Y chromosomes. A minimum of 1,000 nuclei were scored from each sample, and maternal cells were found in 7 of the 49 cord bloods, at levels ranging from 0.04% to 1.0%. In addition, in 39 and 27 of the cord blood samples, respectively, we examined the CD8+ and CD34+ cell populations for maternal cells. Maternal cells were found in 5 of the 39 CD8 fractions and in 1 of the 27 CD34 fractions, at levels similar to that found in the unfractionated cord blood. In sum, maternal cells were found in either the unseparated mononuclear fraction or the CD8 or CD34 fractions in 10 of the 49 cord blood samples (20%). These results show that maternal cells are present in a substantial number of cord bloods, and that some of these maternal cells are T cells.