The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder

Recent studies demonstrate that rapid antidepressant response to ketamine is mediated by activation of the mammalian target of rapamycin (mTOR) signaling pathway, leading to increased synaptic proteins in the prefrontal cortex (PFC) of rats. Our postmortem studies indicate robust deficits in prominent postsynaptic proteins including N-methyl-d-aspartate (NMDA) receptor subunits (NR2A, NR2B), metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic density protein 95 kDa (PSD-95) in the PFC in major depressive disorder (MDD). We hypothesize that deficits in the mTOR-dependent translation initiation pathway contribute to the molecular pathology seen in the PFC of MDD subjects, and that a rapid reversal of these abnormalities may underlie antidepressant activity. The majority of known translational regulation occurs at the level of initiation. mTOR regulates translation initiation via its downstream components: p70-kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic initiation factors 4E and 4B (eIF4E and eIF4B). In this study, we examined the expression of mTOR and its core downstream signaling targets: p70S6K, eIF4E, and eIF4B in the PFC of 12 depressed subjects and 12 psychiatrically healthy controls using Western blot. Levels of eIF4E phosphorylated at serine 209 (p-eIF4E-Ser209) and eIF4B phosphorylated at serine 504 (p-eIF4B-Ser504) were also examined. Adjacent cortical tissue samples from both cohorts of subjects were used in our previous postmortem analyses. There was a significant reduction in mTOR, p70S6K, eIF4B and p-eIF4B protein expression in MDD subjects relative to controls. No group differences were observed in eIF4E, p-eIF4E or actin levels. Our findings show deficits in mTOR-dependent translation initiation in MDD particularly via the p70S6K/eIF4B pathway, and indicate a potential association between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD.     

Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3 mg/kg, p.o.; n = 7) or placebo (n = 6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+ 67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.     

Geographical Disparities in HIV Seroprevalence Among Men Who Have Sex with Men and People Who Inject Drugs in Nigeria: Exploratory Spatial Data Analysis

BackgroundThe assessment of geographical heterogeneity of HIV among men who have sex with men (MSM) and people who inject drugs (PWID) can usefully inform targeted HIV prevention and care strategies.ObjectiveWe aimed to measure HIV seroprevalence and identify hotspots of HIV infection among MSM and PWID in Nigeria.MethodsWe included all MSM and PWID accessing HIV testing services across 7 prioritized states (Lagos, Nasarawa, Akwa Ibom, Cross Rivers, Rivers, Benue, and the Federal Capital Territory) in 3 geographic regions (North Central, South South, and South West) between October 1, 2016, and September 30, 2017. We extracted data from national testing registers, georeferenced all HIV test results aggregated at the local government area level, and calculated HIV seroprevalence. We calculated and compared HIV seroprevalence from our study to the 2014 integrated biological and behavioural surveillance survey and used global spatial autocorrelation and hotspot analysis to highlight patterns of HIV infection and identify areas of significant clustering of HIV cases.ResultsMSM and PWID had HIV seroprevalence rates of 12.14% (3209/26,423) and 11.88% (1126/9474), respectively. Global spatial autocorrelation Moran I statistics revealed a clustered distribution of HIV infection among MSM and PWID with a <5% and <1% likelihood that this clustered pattern could be due to chance, respectively. Significant clusters of HIV infection (Getis-Ord-Gi* statistics) confined to the North Central and South South regions were identified among MSM and PWID. Compared to the 2014 integrated biological and behavioural surveillance survey, our results suggest an increased HIV seroprevalence among PWID and a substantial decrease among MSM.ConclusionsThis study identified geographical areas to prioritize for control of HIV infection among MSM and PWID, thus demonstrating that geographical information system technology is a useful tool to inform public health planning for interventions targeting epidemic control of HIV infection.     

Epidemiology of glaucoma in central Ethiopia

AIM: To evaluate the prevalence of glaucoma, treatment patterns and patient attitudes in Ethiopia. METHODS: A survey was administered to glaucoma patients in hospitals in Addis Ababa, Ethiopia. RESULTS: Of the 415 qualified patients, exfoliative glaucoma (17%) was most commonly found in the Gurage population(33%), whereas chronic angle-closure glaucoma (5%) was found in the Amhara/Tigre (6%) population (P =0.006). Patients were treated with an average of 1.4±0.8 medications: 52% admitted recent noncompliance and 36% had undergone filtering surgery. Patients believed their physician was trying to help them (93%). God wanted them to receive treatment (89%) and their spouse was sympathetic to their disease (82%). Patients noted their community was unaware of their condition (87%) with Muslims [most common in the Gurage population (31%, P <0.0001)] reporting this the most(25%,P =0.01).Amhara/Tigre patients strongly believed their doctors were concerned about them (94%, P = 0.04). CONCLUSION: The prevalence of glaucoma type varies among ethnic groups in Ethiopia with exfoliation more common in the Gurage population and chronic angle-closure glaucoma more frequent in the Amhara/Tigre population.     

Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-D-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, beta-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 microM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property.     

Field evaluation of FD-DAT, rK39 dipstick and KATEX (urine latex agglutination) for diagnosis of visceral leishmaniasis in northwest Ethiopia

Three novel diagnostic tests for visceral leishmaniasis (VL), namely FD-DAT, rK39 dipstick and KATEX, were evaluated under field conditions using 101 clinical cases suspected of having VL enrolled in a trial either by active (63 patients) or passive (38 patients) surveillance. VL was confirmed in 49 patients: 35 by both aspirate smear microscopy and NNN culture, 10 by NNN culture alone and 4 by aspirate smear microscopy alone. Based on tests performed in the field, sensitivity for FD-DAT, rK39 dipstick and KATEX was determined to be 95.3% (95% CI 82.9-99.2%), 71.7% (95% CI 56.3-83.5%) and 57.4% (95% CI 42.3-71.4%), respectively. Similarly, the specificity was determined to be 62.7% (95% CI 48.1-75.5%), 82.4% (95% CI 68.6-91.1%) and 84.3% (95% CI 70.9-92.5%), respectively. A higher sensitivity of KATEX (73.9% vs. 41.7%) and higher specificity of FD-DAT (100.0% vs. 48.6%) were demonstrated under passive case detection compared with active case detection. FD-DAT is recommended for confirmation of VL diagnosis in hospital settings, whereas its use in the field will be limited to exclude VL in clinical suspects. The sensitivity of KATEX and rK39 dipstick tests needs to be improved to promote their use as first-line diagnostic tests in the field setting of northwestern Ethiopia.     

Assessing the Practice of Birth Defect Registration at Addis Ababa Health Facilities

BackgroundBirth defects are conditions that exist at birth and cause structural changes in one or more parts of the body. In order to plan proper management and design preventive activities of these conditions, accurate tracking, registration and analyses of the registered data are important. We assessed the practice of birth defect registration at Addis Ababa health facilities.MethodsWe retrospectively checked the existence of a separate birth defect registry book and assessed the delivery room registration book for completeness in registering birth defects. We also assessed the total number of birth defects registered during 2010–2015.ResultsWe assessed the practice of birth defect registration at 37 delivery service providing health facilities in Addis Ababa, 20 public and 17 private institutions. Of the 37 health institutions assessed, 23 registered birth defects (3 of them used a separate birth defect registry books, and 20 used a regular registration book to register birth defects). The remaining 14 did not register any congenital anomaly. Of the institutions that do not register congenital anomalies, 10 are private and four are public.ConclusionOnly three delivery providing health facilities had a dedicated birth defect registry book which is close to ideal for a birth defect registration. There is a need for others to do the same until an electronic birth defect registration is established. This registration will serve as a resource for clinical governance and studies into quality of life, quality of care, etiology and prevention.     

埃塞俄比亚中部的青光眼流行病学

目的:探讨埃塞俄比亚的青光眼的流行状况、治疗方式以及患者的心态。方法:观察埃塞俄比亚亚的斯亚贝巴的住院青光眼患者。结果:在研究的415例青光眼患者中,Gurage(33%)人群最常见的为剥脱综合征(17%),而在Amhara/Tigre(6%)人群中,慢性闭角型青光眼为5%,二者间有显著差异性(P=0.006)。患者接受平均1.4±8种药物治疗:52%的患者没有短期的不适症状,36%的患者接受了滤过手术。93%的患者相信他们的主管医师试图给予帮助,89%认为是上帝让其接受治疗,82%感到他们的配偶体谅其病情。有87%的患者注意到社区不体察其病情,这在Gurage人群中更为多见(31%,P<0.0001),而穆斯林人群中有此感受的患者为25%(P=0.01),Amhara/Tigre患者则坚信其医师更关注他们的病痛(94%,P=0.04)。结论:不同类型的青光眼在埃塞俄比亚的不同种族人群中的发病有差异,在Gurage人群以剥脱综合征多见,而慢性闭角型青光眼则在Amhara/Tigre人群中的发病较高。