Frailty phenotype is associated with antiretroviral exposure among older persons living with HIV.

PURPOSE OF REVIEW: This multicentre, cross-sectional study was carried out in the South of France to assess the association between frailty phenotype and antiretroviral therapy (ART) in older persons living with HIV (PLWHIV). Sociodemographic and HIV data, geriatric assessment, comorbidities, behavioral and age-related variables and the five frailty markers of Fried were recorded. Exposure to any pharmacological class of ART and all regimens were retrieved from medical records. RECENT FINDINGS: The 509 PLWHIV analysed (72.7% male) received a mean of 6.01 ART regimens and 12.5 years exposure to ART. The prevalence of at least one frailty marker [frail and prefrail phenotype (FPFP)] was 66.4%. Duration of exposure to protease inhibitors and reverse transcriptase inhibitors, number of ART regimens and comorbidities, dyslipidaemia, cancer, depression, falls, disability and pain were significantly associated with FPFP by univariate analysis. In logistic regression multivariable analysis, independent predictors for FPFP were a large number of ART regimens, presence of cancer and pain. No significant association was found with HIV-related parameters neither with ART class and duration. SUMMARY: A significant association was found between FPFP and a large number of different ART regimens among older PLWHIV. The burden of cancer and pain in these patients shows the importance of comprehensive care.

[Frailty phenotype in older people living with HIV: concepts, prevention and issues]. / Le phénotype de fragilité chez les personnes vieillissantes avec le VIH : concepts, prévention et enjeux de prise en charge.

The life-span of people aging with HIV (PHIV) tends to reach people without infection, reflecting the effectiveness and tolerance of antiretroviral treatment and improvement of multidisciplinary management. Comorbidities or HIV-inflammaging seems to be the main determinants of frailty phenotype in PHIV. Prevalence of frailty in PHIV is frequent (5% from 28%) and appears earlier than in general population (50 versus 65 years). Almost half of people with HIV present prefrail phenotype before 50 years. The usefulness of integrate routinely measures of frailty phenotype is not yet known but several data are encouraging in terms of feasibility and prediction. Early determination of frailty in PHIV could lead to target interventions to improve global health and decrease adverse outcomes such as incapacities and early death.

Factors associated with social deprivation among older persons living with HIV.

Aging persons living with HIV may develop multiple health problems, including comorbidities, and altered physical and mental health, earlier than non-infected people. They may also experience social deprivation. We assessed the prevalence of social deprivation and its relationship with health indicators in older persons living with HIV. An 18-month, multicenter, cross-sectional study was carried out between 2013 and 2014 focusing on patients ≥50-years of age followed-up in 12 dedicated HIV medical hospital units located in the South of France and involved the VISAGE study group. Social deprivation was measured with the EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centers) score (ES) and defined as ES ≥30.17. The following data were recorded: health indicators (gender, age, body mass index), comorbidities, frailty markers, socioeconomic, behavioral and age-related variables. Among 509 patients recruited, 494 completed the ES social deprivation evaluation. Mean age was 58.5 ± 7.0 years and 72.9% were male. The prevalence of social deprivation was 49.0%. Multivariable logistic regression analysis showed that higher social deprivation was significantly linked to alcohol consumption (OR = 4.07 [95%CI: 1.23-13.48]), risk of depression (OR = 3.59 [95%CI: 2.26-5.70]), chronic obstructive pulmonary disease (OR = 3.10 [95%CI: 1.36-7.09]), hepatitis C (OR = 1.96 [95%CI: 1.10-3.52]), and chronic pain (OR = 1.11 [95%CI: 1.01-1.21]). Social deprivation was not related to HIV status. Our study showed that not only did older patients with HIV suffer from social deprivation, but they also received little support from social workers. Physicians should be aware of this situation and should systematically evaluate social deprivation in order to provide comprehensive targeted care involving global, social, and psychological support to reduce the burden of social deprivation.

Frail and pre-frail phenotype is associated with pain in older HIV-infected patients.

As HIV-infected patients grow older, some accumulate multiple health problems earlier than the noninfected ones in particular frailty phenotypes. Patients with frailty phenotype are at higher risk of adverse outcomes (worsening mobility, disability, hospitalization, and death within three years).Our study aimed to evaluate prevalence of frailty in elderly HIV-infected patients and to assess whether frailty is associated with HIV and geriatric factors, comorbidities, and precariousness in a French cohort of older HIV infected.This 18-month cross-sectional multicenter study carried in 2013 to 2014 had involved 502 HIV-infected patients aged 50 years and older, cared in 18 HIV-dedicated hospital medical units, located in South of France.Prevalence of frailty was 6.3% and of pre-frailty 57.2%. Low physical activity and weakness were the main frailty markers, respectively 49.4% and 19.9%. In univariate models, precariousness, duration of HIV antiretroviral treatment >15 years, 2 comorbidities or more, risk of depression, activities of daily living disability, and presence of pain were significantly associated with frail and pre-frail phenotype. Multivariate logistic regression analyses showed that only pain was significantly different between frail and pre frail phenotype versus non frail phenotype (odds ratio = 1.2; P = .002).Our study is the first showing a significant association between pain and frailty phenotype in older patients infected by HIV. As frailty phenotype could be potentially reversible, a better understanding of the underlying determinant is warranted. Further studies are needed to confirm these first findings.

Total radiation dose and overall treatment time are predictive for tumor sterilization in cervical carcinoma treated with chemoradiation and pulsed-dose-rate brachytherapy.

BACKGROUND AND PURPOSE: Treatment of locally advanced cervical cancer involves multidisciplinary care using external beam radiotherapy, chemotherapy, brachytherapy, and surgery. We aimed to compare both tumor and treatment characteristics between patients with complete pathologic response (CR) and patients with residual disease (RD). PATIENTS AND METHODS: This monocentric retrospective study included 40 consecutive patients, treated with external beam radiotherapy, pulsed-dose-rate brachytherapy, and completion surgery. Treatment planning was performed to obtain a cumulative D90 value for the intermediate-risk clinical target volume (CTV) ≥60 Gy(α/ß=10). Different clinical and dosimetric parameters were analyzed and compared between patients with RD and those with CR. RESULTS: We observed 18 (45%) patients with CR and 22 (55%) patients with RD. In univariate analysis, patients with RD had a significantly longer overall treatment time than those with CR (59.5 vs. 53 days, p = 0.0321). The D90 value for the high-risk CTV (HR-CTV) was higher in the group with CR than in the group with RD (65.9 vs. 64.2 Gy(α/ß=10); p = 0.0439). In multivariate analysis, overall treatment time remained the only predictive factor for CR (p = 0.033), even if the difference for D90 HR-CTV kept a trend toward significance (p = 0.057). CONCLUSIONS: This study showed that tumor sterilization is significantly correlated with overall treatment time and probably with cumulative dose delivered to the HR-CTV. These results emphasize the attention that must be given to treatment organization and dosimetry optimization.

Perinatal outcome of twins compared to singletons of the same gestational age: a case-control study.

Our objective was to determine the perinatal outcome of first- and second-born twins compared to singletons, born at the same gestational age. To that end we conducted a case-control study in Flanders (Northern Belgium). During a 10-year period (01.01.1999-31.12.2008), the entire twin population - 11,154 first- and 11,118 second-born twins (cases) - was compared to 22,228 singletons (controls) with respect to fetal and neonatal (0-27 days) mortality. Only case and control infants of ≥ 500 grams were included, which explained the unequal number of first- and second-born twins. Mothers and their infants of cases and of controls were derived from the Flemish perinatal database and were matched for maternal age and parity, gestational age and gender of the offspring. The main outcome measures were fetal and neonatal mortality according to gestational age. The frequency of fetal death was statistically significantly less frequent in preterm born twins than in singletons, except at term where the reverse was seen in second-born twins compared to controls. After adjustment for congenital malformations, the results stayed unchanged. Below 28 weeks gestation, singletons had a significantly lower neonatal mortality rate than twins that persisted after adjustment for congenital malformations: the first-born twin versus singleton OR 1.71 (1.17-2.51) and second-born versus singleton OR 2.09 (1.43-3.05). Between 28 and 32 weeks, the second-born twin showed a survival advantage over the control singleton. Between 32 and 36 6/7 weeks both twins had a significantly higher survival rate than the corresponding singleton controls. However, after adjustment for congenital malformations, the aforementioned differences between 28 and 36 6/7 weeks disappeared. When at term, twins and singletons had a comparable, though very low, neonatal death rate. These results confirm previous published data. In conclusion, we demonstrated that the neonatal death rate was lower for twins between 32 and 36 weeks (from 28 weeks for the second born twin) when compared to a singleton of the same gestational age. After adjusting for congenital malformations, there was no statistical significant difference.

Colon luminal content and epithelial cell morphology are markedly modified in rats fed with a high-protein diet.

Hyperproteic diets are used in human nutrition to obtain body weight reduction. Although increased protein ingestion results in an increased transfer of proteins from the small to the large intestine, there is little information on the consequences of the use of such diets on the composition of large intestine content and on epithelial cell morphology and metabolism. Rats were fed for 15 days with either a normoproteic (NP, 14% protein) or a hyperproteic isocaloric diet (HP, 53% protein), and absorptive colonocytes were observed by electron microscopy or isolated for enzyme activity studies. The colonic luminal content was recovered for biochemical analysis. Absorbing colonocytes were characterized by a 1.7-fold reduction in the height of the brush-border membranes (P = 0.0001) after HP diet consumption when compared with NP. This coincided in the whole colon content of HP animals with a 1.8-fold higher mass content (P = 0.0020), a 2.2-fold higher water content (P = 0.0240), a 5.2-fold higher protease activity (P = 0.0104), a 5.5-fold higher ammonia content (P = 0.0008), and a more than twofold higher propionate, valerate, isobutyrate, and isovalerate content (P < 0.05). The basal oxygen consumption of colonocytes was similar in the NP and HP groups, but ammonia was found to provoke a dose-dependent decrease of oxygen consumption in the isolated absorbing colonocytes. The activity of glutamine synthetase (which condenses ammonia and glutamate) was found to be much higher in colonocytes than in small intestine enterocytes and was 1.6-fold higher (P = 0.0304) in colonocytes isolated from HP animals than NP. Glutaminase activity remained unchanged. Thus hyperproteic diet ingestion causes marked changes both in the luminal environment of colonocytes and in the characteristics of these cells, demonstrating that hyperproteic diet interferes with colonocyte metabolism and morphology. Possible causal relationships between energy metabolism, reduced height of colonocyte brush-border membranes, and reduced water absorption are discussed.

Tissue-specific conditional CCM2 knockout mice establish the essential role of endothelial CCM2 in angiogenesis: implications for human cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) are vascular malformations of the brain that lead to cerebral hemorrhages. In 20% of CCM patients, this results from an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. High expression levels of the CCM genes in the neuroepithelium indicate that CCM lesions might be caused by a loss of function of these genes in neural cells rather than in vascular cells. However, their in vivo function, particularly during cerebral angiogenesis, is totally unknown. We developed mice with constitutive and tissue-specific CCM2 deletions to investigate CCM2 function in vivo. Constitutive deletion of CCM2 leads to early embryonic death. Deletion of CCM2 from neuroglial precursor cells does not lead to cerebrovascular defects, whereas CCM2 is required in endothelial cells for proper vascular development. Deletion of CCM2 from endothelial cells severely affects angiogenesis, leading to morphogenic defects in the major arterial and venous blood vessels and in the heart, and results in embryonic lethality at mid-gestation. These findings establish the essential role of endothelial CCM2 for proper vascular development and strongly suggest that the endothelial cell is the primary target in the cascade of events leading from CCM2 mutations to CCM cerebrovascular lesions.

Comparison of operator radiation exposure with optimized radiation protection devices during coronary angiograms and ad hoc percutaneous coronary interventions by radial and femoral routes.

AIMS: Although underestimated by interventional cardiologists for a long time, radiation exposure of operators and patients is currently a major concern. The objective of the present operator-blinded registry was to compare related-peripheral arterial route radiation exposure of operators. METHODS AND RESULTS: During 420 consecutive coronary angiograms (CAs) and percutaneous coronary interventions (PCIs), four interventional cardiologists were blindly screened. Radiation exposures were assessed using electronic personal dosimeters. Protection of operator was ensured using a lead apron, low leaded flaps, and leaded glass. Radiation exposure of operators was significantly higher using the radial route when compared with the femoral route for both CAs and CAs followed by ad hoc PCIs: 29.0 [1.0-195.0] microSv vs. 13.0 [1.0-164.0] microSv; P < 0.0001 and 69.5 [4.0-531.0] microSv vs. 41.0 [2.0-360.0] microSv; P = 0.018, respectively. Similarly, radiation exposure of patients was significantly higher using the radial route when compared with the femoral route for both CAs and CAs followed by ad hoc PCIs. Moreover, procedural durations and fluoroscopy times were significantly higher throughout the radial route. CONCLUSIONS: Although the radial route decreases peripheral arterial complication rates, increased radiation exposure of operators despite extensive use of specific protection devices is currently a growing problem for the interventional cardiologist health. Radial route indication should be promptly reconsidered in the light of the present findings.

A single homozygous point mutation in a 3'untranslated region motif of selenoprotein N mRNA causes SEPN1-related myopathy.

Mutations in the SEPN1 gene encoding the selenoprotein N (SelN) have been described in different congenital myopathies. Here, we report the first mutation in the selenocysteine insertion sequence (SECIS) of SelN messenger RNA, a hairpin structure located in the 3' untranslated region, in a patient presenting a classical although mild form of rigid spine muscular dystrophy. We detected a significant reduction in both mRNA and protein levels in the patient's skin fibroblasts. The SECIS element is crucial for the insertion of selenocysteine at the reprogrammed UGA codon by recruiting the SECIS-binding protein 2 (SBP2), and we demonstrated that this mutation abolishes SBP2 binding to SECIS in vitro, thereby preventing co-translational incorporation of selenocysteine and SelN synthesis. The identification of this mutation affecting a conserved base in the SECIS functional motif thereby reveals the structural basis for a novel pathological mechanism leading to SEPN1-related myopathy.

Patterns of expression of the three cerebral cavernous malformation (CCM) genes during embryonic and postnatal brain development.

Cerebral Cavernous Malformation (CCM) is a disease characterized by capillary-venous lesions mostly located in the central nervous system. It occurs both as a sporadic and hereditary autosomal dominant condition. Three CCM genes have been identified and shown to encode the KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3) proteins whose functions are so far unknown. In an attempt to get some insight into the role of the 3 CCM genes, we used in situ hybridization to conduct a comparative analysis of their expression pattern at several time points during murine embryonic, postnatal and adult stages particularly within the central nervous system. A strong expression of the 3 Ccm genes was detected in the various neuronal cell layers of the brain, cerebellum and spinal cord, from embryonic to adult life. By E14.5 a moderate labelling was observed in the heart, arterial and venous large vessels with all 3 Ccm probes. Ccm2 and Ccm3 mRNAs, but not Ccm1, were clearly detected within meningeal and parenchymal cortical vessels at P8. This expression was no more detected by P19 and in adult murine brain, strongly suggesting a role for these 2 proteins in the intensive angiogenesis process occuring within the central nervous system during this period.

Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non-nucleoside reverse transcriptase inhibitor.

AIMS: To evaluate the interindividual variability in the plasma concentrations of lopinavir in the context of routine monitoring with or without treatment with a non-nucleoside reverse transcriptase inhibitor and to assess the interaction between the coformulation of lopinavir/ritonavir and efavirenz or nevirapine. METHODS: Plasma trough and peak concentrations (C(trough), C(max)) of lopinavir from 182 HIV-1-infected patients were analysed by high-performace liquid chromatography. Three lopinavir/ritonavir regimens were assessed, namely (A) 400 mg lopinavir/100 mg ritonavir twice daily given alone (n = 125), (B) 400/100 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 25), and (C) 533/133 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 32). RESULTS: Median (ng ml(-1)) C(trough) and C(max) lopinavir (interquartile range, CV) were: (A) 4852 (3198-6891, 56%) and 8501 (6333-11 584, 41%), (B) 2979 (1704-5186, 74%) and 5612 (3362-11 704, 76%) and (C) 5082 (2696-7226, 74%) and 9757 (4883-12 963, 60%). Median C(trough) of lopinavir was lower in patients taking both efavirenz [P = 0.01, 95% confidence interval (CI) for difference between medians 343, 2713] and nevirapine (P = 0.019, 95% CI for difference between medians 354, 3681) compared with those taking lopinavir/ritonavir alone. A higher interindividual variability was observed when lopinavir/ritonavir was given with a non-nucleoside reverse transcriptase inhibitor. The risk of achieving a 'suboptimal'C(trough) of lopinavir (below a threshold of 3000 ng ml(-1)) was statistically higher in patients treated with a non-nucleoside reverse transcriptase inhibitor (P < 0.001, 95% CI for difference between percentages 8.8, 43.1%) compared with those receiving lopinavir/ritonavir alone. CONCLUSIONS: Our results confirmed the interaction between lopinavir and efavirenz, and also demonstrated a significant interaction between the former drug and nevirapine, resulting in lower C(trough) of lopinavir. The wide interpatient variability in this interaction suggests that therapeutic drug monitoring may be useful in optimizing the dose of lopinavir.

Selenoprotein N: an endoplasmic reticulum glycoprotein with an early developmental expression pattern.

Rigid spine muscular dystrophy and the classical form of multiminicore disease are caused by mutations in SEPN1 gene, leading to a new clinical entity referred to as SEPN1-related myopathy. SEPN1 codes for selenoprotein N, a new member of the selenoprotein family, the function of which is still unknown. In a previous study, two isoforms were deduced from SEPN1 transcript analyses. Using polyclonal antibodies directed against SEPN1 and cDNA constructs encoding for the two isoforms, we show that the main SEPN1 gene product corresponds to a 70 kDa protein, containing a single selenocysteine residue. Subcellular fractionation experiments and endoglycosidase H sensitivity indicate that SEPN1 is a glycoprotein-localized within the endoplasmic reticulum. Immunofluorescence analyses confirm this subcellular localization and green fluorescent protein fusion experiments demonstrate the presence of an endoplasmic reticulum-addressing and -retention signal within the N-terminus. SEPN1 is present at a high level in several human fetal tissues and at a lower level in adult ones, including skeletal muscle. Its high expression in cultured myoblasts is also down-regulated in differentiating myotubes, suggesting a role for SEPN1 in early development and in cell proliferation or regeneration.

Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1).

We report clinical and imaging findings in six cases from five families affected by the form of congenital muscular dystrophy with rigid spine linked to the locus rigid spine muscular dystrophy 1 on chromosome 1p35-36. All cases showed rigidity of the spine, predominant neck and trunk weakness and frequent and severe thoracic scoliosis. Respiratory impairment was always observed in the first decade. Muscle imaging showed a marked involvement of adductors, sartorius and biceps femoris while rectus femoris and gracilis were relatively spared. This pattern of selective muscle involvement was consistent in all six cases and could be easily observed on either computerised tomography or magnetic resonance imaging. The results of this study suggest that muscle imaging, in combination with clinical assessment can help to identify the rigid spine muscular dystrophy 1 form of congenital muscular dystrophy and can help to target the appropriate genetic investigations.

The nuclear genome is involved in heteroplasmy control in a mitochondrial mutant strain of Drosophila subobscura.

Most (78%) mitochondrial genomes in the studied mutant strain of Drosophila subobscura have undergone a large-scale deletion (5 kb) in the coding region. This mutation is stable, and is transmitted intact to the offspring. This animal model of major rearrangements of mitochondrial genomes can be used to analyse the involvement of the nuclear genome in the production and maintenance of these rearrangements. Successive backcrosses between mutant strain females and wild-type males yield a biphasic change in heteroplasmy level: (a) a 5% decrease in mutated genomes per generation (from 78 to 55%), until the nuclear genome is virtually replaced by the wild-type genome (seven to eight crosses); and (b) a continuous decrease of 0.5% per generation when the nuclear context is completely wild-type. In parallel with these changes, NADH dehydrogenase activity, which is halved in the mutant strain (five subunits of this complex are affected by the mutation), gradually increases and stabilizes near the wild-type activity. A return to a nuclear context is accompanied by the opposite phenomena: progressive increase in heteroplasmy level and stabilization at the value seen in the wild-type strain and a decrease in the activity of complex I. These results indicate that the nuclear genome plays an important role in the control of heteroplasmy level and probably in the production of rearranged genomes.