Nutritional status and serum zinc and selenium levels in Iranian HIV infected individuals

Background  

Human immunodeficiency virus infected individuals are prone to malnutrition due to increased energy requirements, enteropathy and increased catabolism. Trace elements such as zinc and selenium have major role in maintaining a healthy immune system. This study was designed to evaluate the nutritional status of Iranian subjects who were newly diagnosed with human immunodeficiency virus infection and to compare serum level of zinc and selenium in these patients with those of the sex and aged match healthy subjects.     

WONCA研究论文摘要汇编——基层抑郁症风险患者的连续性服务

背景目前已开展了对重性精神病患者进提供连续性服务的研究。目的探讨基层对有抑郁症风险患者提供连续性服务的水平,并与对心力衰竭患者的服务水平进行对比。方法采用抑郁症风险患者与心力衰竭患者对比的探索性研究。采用患者问卷评估服务的持续性,包含如下内容:(1)联系的服务提供者数(个人连续性);(2)诊所内服务提供者之间的合作(团队连续性)(6个项目,分数1~5分);(3)诊所外全科医师与服务提供者之间的合作(跨界连续性)(4个项目,分数1~5分)。结果大多数抑郁症风险患者在过去1年中寻遍整个服务提供界联系了几个服务提供者,曾遇到过高水平团队连续性服务及低水平跨界连续性服务。在诊所中可接触到的不同服务提供者要明显多于心力衰竭患者服务提供者(P<0.01)。抑郁症风险患者的服务提供者之间的合作更好一些,每项平均得分4.3分,心力衰竭患者得分为4.0分(P=0.03)。然而,跨界连续性服务方面正好相反:抑郁症风险患者每项平均得分3.5分,心力衰竭患者得分为4.0分(P=0.01)。结论抑郁症风险患者与心力衰竭患者之间的探索性对比显示:体验服务连续性方面的差距不大。对此还应行进一步分析。     

Different effects of exogenous cyclic adenosine monophosphate and its dibutryl derivative on plasma growth hormone, glucose, insulin and cortisol.

The effects of the infusion in four different dosages (0.001, 0.005, 0.02 and 0.2 mg/kg/min during 60 min) of cyclic 3',5'-adenosine monophosphate and of its dibutyryl derivative on plasma growth hormone and on glucose, immunoreactive insulin and cortisol were studied in 38 normal subjects and in 10 patients with idiopathic hypopituitarism. In normal subjects cyclic 3',5'-adenosine monophosphate provokes an increase in plasma growth hormone levels (only when a dosage of 0.2 mg/kg/min is used) without any changes in plasma glucose, insulin and cortisol. The maximal value of the means is observed 75 min after starting the infusion. Dibutyryl cyclic 3',5'-adenosine monophosphate (0.2 and 0.02 mg/kg/min) provokes a dose-related rise in plasma growth hormone levels which is always preceded by hyperglycaemia and hyperinsulinaemia. The peak of the mean growth hormone levels occurs at 135 min after initiation of the infusion. In all but one hypopituitary patients the nucleotides do not promote growth hormone secretion. It is concluded that exogenous cyclic 3',5'-adenosine monophosphate and its dibutyryl derivative may not be considered as analogous and that both compounds may contribute to study growth hormone release in normal subjects and in patients with growth abnormalities.     

ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Recessive loss-of-function mutations in ATP13A2 (PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in a Caenorhabditis elegans strain deficient in the ATP13A2 ortholog catp-6. These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated by atfs-1, the C. elegans ortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.

Loss-of-function mutations in ATP13A2 (PARK9) are causative for a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome (KRS, a juvenile onset parkinsonism with dementia) (1), early-onset Parkinson’s disease (PD) (2, 3), hereditary spastic paraplegia (HSP) (4), neuronal ceroid lipofuscinosis (5), and amyotrophic lateral sclerosis (6), which are commonly hallmarked by lysosomal and mitochondrial dysfunction (4, 6, 7). Also, ATP13A2 deficiency causes lysosomal and mitochondrial impairment in various models, as evidenced by decreased lysosomal functionality (8, 9), reduced mitochondrial clearance capacity (8–10), mitochondrial fragmentation, mitochondrial DNA damage, and increased oxygen consumption (11, 12).We recently discovered that ATP13A2 transports the polyamines spermidine and spermine from the late endo/lysosome to the cytosol (9). Polyamines are ubiquitous polycationic aliphatic amines that stabilize nucleic acids, influence protein folding, regulate ion channels, and modulate cell proliferation and differentiation (13–15). We found that the late endo-lysosomal transporter ATP13A2 strongly contributes to the total cellular polyamine content via a two-step process: Firstly, polyamines enter the cell via endocytosis and subsequently, polyamines are transported by ATP13A2 into the cytosol (9). This process complements polyamine biosynthesis via the ornithine decarboxylase (ODC) pathway (9). Importantly, ATP13A2’s polyamine transport function is crucial for its neuroprotective effect, since it prevents lysosomal polyamine accumulation and subsequent lysosomal rupture, while improving lysosomal health and functionality (9). Moreover, when activated by its two regulatory lipids—phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] and phosphatidic acid (PA)—ATP13A2 exerts a cell protective effect against the mitochondrial neurotoxin rotenone (16), an environmental risk factor for PD (17). Rotenone is a mitochondrial complex I inhibitor, which leads to high levels of reactive oxygen species (ROS), promoting protein aggregation and damaging organelles. However, how ATP13A2’s polyamine transport function exerts a cell protective effect against rotenone, or other mitochondrial neurotoxins, is not yet clear.Interestingly, the transported substrates spermine and spermidine reduce oxidative stress (14, 15). Spermine is a potent free radical scavenger (18) and a biologically important antioxidant (19–23). We therefore hypothesize that ATP13A2-mediated polyamine transport may counteract oxidative stress (16, 24) and preserve mitochondrial health (11, 12). Here, we demonstrate in complementary human cell models and Caenorhabditis elegans that lysosomal polyamine export by ATP13A2 effectively lowers ROS levels and promotes mitochondrial health and functionality, pointing to a lysosomal-dependent cell protective pathway that may be implicated in ATP13A2-related neurodegenerative disorders.     

Acceptance of self-testing for increased vaginal pH in different subsets of Ugandan women

We assessed the acceptance of self-testing for vaginal pH in 344 Ugandan women in different clinical settings. Women tested themselves by insertion of a gloved finger into the vagina to test vaginal pH and provide a smear on a glass slide. None of the tested women found the test very difficult: 8% found it somewhat difficult, 16% rather easy and 76% very easy to do. Of the 20% who found it difficult to read the test result, more women were attending a family planning clinic or had a higher diploma (P = 0.001). Pregnant women were least likely to understand of the meaning of the test, while those visiting family planning clinics had the opposite experience. HIV-infected women were most motivated to accept: 95% would be happy to use the test more often if requested, and another 3.5% felt they might be better motivated to do repeat testing after extra explanation. Self-sampling of vaginal pH is well accepted by Ugandan women. Our new method also allows diagnostic work-up by formal microscopy. Before commencing large-scale population screening, unexpected reactions of different subpopulations should be taken into account.     

Prediction of successful dose reduction or discontinuation of adalimumab,etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement

Background: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients.

Research design and methods: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1–1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined.

Results: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23–0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58–1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation.

Conclusions: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.