The Challenges Facing African Court of Human and Peoples’ Rights

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Superior maturation and patency of primary brachiocephalic and transposed basilic vein arteriovenous fistulae in patients with diabetes

AbstractPurpose: Primary radiocephalic arteriovenous fistulas (RCAVFs) have classically been used for the initiation of dialysis. If a suitable forearm cephalic vein can be demonstrated, it is used to construct such a fistula. However, we have noted a tendency for RCAVF in patients with a history of diabetes mellitus (type I and type II) to remain patent but not mature to the point of cannulation. Therefore, the present study was undertaken. Methods: Fifty-eight consecutive patients with diabetes who required initial access for hemodialysis at an urban medical center and tertiary Veterans Medical Center underwent creation of an RCAVF (n = 10), brachiocephalic arteriovenous fistula (BCAVF; n = 22), or transposed basilic vein arteriovenous fistula (TBAVF; n = 26). The vein used was determined by physical examination with tourniquet compression. If neither forearm or upper-arm cephalic veins were 2 mm in diameter, a TBAVF was created after venography. Patency was determined by Kaplan-Meier estimate; differences between groups were assessed by Fisher's exact test. Results: The 70% rate of nonmaturation of RCAVFs was significantly greater than the 27% rate for BCAVFs and 0% for TBAVFs (p < 0.05). The 33% cumulative primary patency rate at 18 months for RCAVFs was significantly less than 78% for BCAVFs and 79% for TBAVFs (p < 0.001). Within and between groups, there were no significant differences in age, gender, aspirin use, history of congestive heart failure, erythropoietin use, hematocrit level, history of peripheral vascular disease, or mortality rate. Conclusions: In patients with renal failure and a history of diabetes, both primary BCAVFs and TBAVFs demonstrate significantly greater maturation and increased primary cumulative patency rates compared with RCAVFs; therefore, these autogenous conduits are considered to be optimal in this group of patients. Whether the discrepancy in lower-arm vein maturation is a result of a lack of compensatory increase in radial arterial flow or an intrinsic defect in the lower-arm cephalic vein is currently under investigation. (J Vasc Surg 1998;27:154-7.

Estradiol alters the immune-responsiveness of cervical epithelial cells stimulated with ligands of Toll-like receptors 2 and 4.

The mucosa of the female reproductive tract plays a pivotal role in host defence. Pregnancy must alter immunological mechanisms at this interface to protect the conceptus. We sought to determine how estradiol (E2) alters the immune-responsiveness of cervical epithelial cells to ligand stimulation of Toll-like receptor (TLR)-2 and -4. Human ectocervical epithelial cells (HECECs) were cultured and co-incubated with two concentrations of E2 and peptidoglycan (PGN) or lipopolysaccharide (LPS) over durations that ranged between 10 minutes and 18 hours. Cytometric Bead Array was performed to quantify eight cytokines in the supernatant fluid. In response to PGN, HECECs co-incubated with E2 released lesser quantities of IL-1ß and IFNγ, higher levels of RANTES, and variable levels of IL-6 and IL-8 than those not exposed to E2. In contrast, HECECs co-incubated with LPS and E2 secreted increased levels of IL-1ß, IL-6, IL-8, and IFNγ at 2 and 18 hours than HECECs not exposed to E2, and reduced levels of RANTES at same study time-points. Estradiol alters the immune-responsiveness of cultured HECECs to TLR2 and TLR4 ligands in a complex fashion that appears to vary with bacterial ligand, TLR subtype, and duration of exposure. Our observations are consistent with the functional complexity that this mucosal interface requires for its immunological roles

Interferon-inducible gene 202b controls CD8+ T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB × NZW) F1 lupus mice

Administration of an artificial peptide (pConsensus) based on anti-DNA IgG sequences that contain major histocompatibility complex class I and class II T-cell determinants, induces immune tolerance in NZB/NZW F1 female (BWF1) mice. To understand the molecular basis of CD8+ Ti-mediated suppression, we previously performed microarray analysis to identify genes that were differentially expressed following tolerance induction with pCons. CD8+ T cells from mice tolerized with pCons showed more than two-fold increase in Ifi202b mRNA, an interferon inducible gene, versus cells from untolerized mice. Ifi202b expression increased through weeks 1–4 after tolerization and then decreased, reapproaching baseline levels at 6 weeks. In vitro polyclonal activation of tolerized CD8+ T cells significantly increased Ifi202b mRNA expression. Importantly, silencing of Ifi202b abrogated the suppressive capacity of CD8+ Ti cells. This was associated with decreased expression of Foxp3, and decreased gene and protein expression of transforming growth factor (TGF)β and interleukin-2 (IL-2), but not of interferon (IFN)-γ, IL-10, or IL-17. Silencing of another IFN-induced gene upregulated in tolerized CD8+ T cells, IFNAR1, had no effect on the ability of CD8+ T cells to suppress autoantibody production. Our findings indicate a potential role for Ifi202b in the suppressive capacity of peptide-induced regulatory CD8+ Ti cells through effects on the expression of Foxp3 and the synthesis of TGFβ

Estradiol Regulates Expression of Estrogen Receptor ERα46 in Human Macrophages

BACKGROUND:Monocytes and macrophages are key innate immune effector cells that produce cytokines and chemokines upon activation. We and others have shown that 17beta-estradiol (E2) has a direct role in the modulation of monocyte and macrophage immune function. However, relatively little is known about the ability of E2 to regulate isoform expression of estrogen receptors (ERs) in these cells. METHODOLOGY/PRINCIPAL FINDINGS:In this study, we quantify expression of ERalpha and ERbeta in human monocytes and macrophages. We also show for the first time that the N-terminal truncated ERalpha variant, ERalpha46, is expressed in both cell types. Promoter utilization studies reveal that transcription of ERalpha in both cell types occurs from upstream promoters E and F. Treatment with E2 induces ERalpha expression in macrophages but has no effect on ERbeta levels in either cell type. During monocyte-to-macrophage differentiation, ERalpha is upregulated in a time-dependent manner. Previous studies by our group demonstrated that E2 treatment attenuates production of the chemokine CXCL8 in an ER-dependent manner. We now show that ERalpha expression levels parallel the ability of E2 to suppress CXCL8 production. CONCLUSIONS/SIGNIFICANCE:This work demonstrates for the first time that human macrophages predominantly express the truncated ER variant ERalphap46, which is estradiol-inducible. This is mediated through usage of the ERalpha F promoter. Alternative promoter usage may account for tissue and cell type-specific differences in estradiol-induced effects on gene expression. These studies signify the importance of ERalpha expression and regulation in the ability of E2 to modulate innate immune responses

Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer

The generation of antitumour immunity depends on the nature of dendritic cell (DC)–tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n=137) and advanced (stage IV, n=36) disease compared to healthy controls (n=66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation

Особенности оказания специализированной хирургической помощи пострадавшим при землетрясении в Непале

There is work analysis of pediatric team (Roshal’s Pediatric Team) while rescuing specialized surgical operation for earthquake-stricken in Nepal 25.04.20015.Materials and methods. Team of Russian doctors of GBUZ NII NDHiT DZ of Moscow rescued specialized medical operation for earthquake-stricken in Nepal from 30.04.2015 to 18.05.2015. The team consisted of 7 doctors: 2 surgeons, 2 traumatologists, 1 neurosurgeon and 2 anesthesiologists. During that period the team performed: 621 patients’ consultation, among which 184 are children. 59 patients needed complex surgical treatment. 32 of them were adults and 27 children. The age of patient was from 3 to 80 years. Open traumas of soft tissues and bones were complicated with purulent infection at all patients. Close traumas were represented by limb injuries and back bone trauma. The most often cases were lower limb injuries - 39 (49,3 %) patients. Among them the most part was with lower leg injuries – 21 (53,8 %). The second place took upper limbs traumas – 13 (19,7 %) with localization in shoulder area – 6 (46,2%).Results. 115 operartions were done for 59 patients, 362 bandages and 235 anaesthetic support were done. 52 surgical d-bridements were performed at purulent-necrotic wounds treatment, and 30,7 % needed repeated surgical d-bridement. For local treatment polypharmaceutical ointments based on polyethyleneglycol were used — 69,4 % and iodiphor solutions — 30,6 %. Wounds were ready for final phase of surgical treatment 10-14 days later after surgical d-bridement of purulent-necrotic places, which appeared due to one-time impact of traumatic agent, and 14-18 day later at crush syndrome. For substitution of wound defects and closing of wound surfaces different reparative and plastic operation were used: local tissues plasty of wound (48,1 %), dosed tissue stretching plasty of wound (29,7 %), fasciocutaneous flap with axial type of blood supply (3,7 %), free split autodermotransplantate plasty of wound (18,5 %). In all cases of patient treatment with open soft tissue and bone injuries a positive result was achieved. Only 2 (3,4 %) patients had some marginal flap necrosis, which was neutralized during next bondages. One patient had humid gangrene and sepsis of lower leg and it was decided to perform amputation at the level of upper third part of lower leg.Conclusions.The use of both methods: active surgical treatment and conveyor belt method of anesthesia providing (on two tables simultaneously) allowed to decrease timelines for recovering and improve treatment quality. Despite some organizational difficulties they could managed with purulent-inflammatory complications, refused from amputations planned by local surgeons and did reparative and plastic operation even in emergency conditions. В статье представлен анализ работы педиатрической бригады (Roshal’s Pediatric Team) в процессе оказания специализированной хирургической помощи пострадавшим от землетрясения в Непале 25.04.2015.Материалы и методы. С 30.04.2015 по 18.05.2015 бригада российских врачей ГБУЗ «НИИ НДХиТ» ДЗМ оказывала специализированную медицинскую помощь пострадавшим в результате землетрясения в Непале. В состав бригады вошли 7 врачей: 2 хирурга, 2 травматолога, 1 нейрохирург и 2 анестезиолога. За время нахождения в зоне бедствия специалисты провели 621 консультацию больных, из которых 184 – это дети. Комплексное хирургическое лечение потребовалось 59 пациентам (32 взрослым и 27 детям), возраст пациентов варьировал от 3 до 80 лет. У всех пострадавших открытые повреждения мягких тканей и костей осложнились присоединением гнойной инфекции. Закрытые травмы были представлены повреждениями конечностей и позвоночника, при этом наиболее часто встречались травмы нижних конечностей – 39 (49,3 %) больных. Среди них большинство составили повреждения голени – 21 (53,8 %), далее следуют верхние конечности – 13 (19,7 %) с преимущественной локализацией в области плеча – 6 (46,2 %).Результаты. Всего бригада произвела 115 оперативных вмешательств 59 пациентам, выполнила 362 перевязки и оказала 235 анестезиологических пособий. В процессе лечения гнойно-некротических ран были проведены 52 хирургические обработки, при этом 30,7 % больных в дальнейшем потребовалась повторная манипуляция. Для местного применения использовали многокомпонентные мази на полиэтиленгликолевой основе (69,4 %) и растворы йодофоров (30,6 %). Спустя 10-14 суток после хирургической обработки гнойно-некротических очагов, появившихся в результате одномоментного воздействия травмирующего агента, и через 14-18 суток при синдроме длительного раздавливания (краш-синдром) раны были готовы к окончательному этапу лечения. Для замещения дефектов и закрытия раневых поверхностей специалисты бригады использовали различные реконструктивные и пластические операции: пластика местными тканями (48,1 %), пластика методом дозированного тканевого растяжения (29,7 %), пластика кожно-фасциальным лоскутом с осевым типом кровоснабжения (3,7 %), пластика свободным расщепленным аутодермальным трансплантатом (18,5 %).Во всех случаях хирургического лечения пациентов с открытыми повреждениями костей и мягких тканей был достигнут удовлетворительный результат. Только у 2 (3,4 %) пациентов врачи отметили незначительные явления краевого некроза лоскута, которые затем успешно были купированы в процессе перевязок. Одному взрослому пациенту с диагнозом «влажная гангрена голени, сепсис» по жизненным показаниям выполнили ампутацию на уровне верхней трети голени.Выводы. Использование активного хирургического лечения и конвейерный метод обеспечения анестезиологического пособия (сразу на двух столах) позволили сократить сроки выздоровления и значительно повысить качество лечения. Несмотря на некоторые организационные трудности бригаде удалось справиться с гнойно-воспалительными осложнениями, отказаться от ранее планируемых местными хирургами ампутаций в пользу менее радикальных вмешательств, а также применить ранние реконструктивные и пластические операции даже в условиях чрезвычайной ситуации.

The genetics and neuropathology of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein (MAPT), the growth factor precursor gene granulin (GRN), and C9orf72 with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein (VCP) and charged multivesicular body protein 2B (CHMP2B). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition