Calcitonin gene-related peptide inhibits Langerhans cell-mediated HIV-1 transmission.

International audienceUpon its mucosal entry, human immunodeficiency virus type 1 (HIV-1) is internalized by Langerhans cells (LCs) in stratified epithelia and transferred locally to T cells. In such epithelia, LCs are in direct contact with peripheral neurons secreting calcitonin gene-related peptide (CGRP). Although CGRP has immunomodulatory effects on LC functions, its potential influence on the interactions between LCs and HIV-1 is unknown. We show that CGRP acts via its receptor expressed by LCs and interferes with multiple steps of LC-mediated HIV-1 transmission. CGRP increases langerin expression, decreases selected integrins, and activates NF-κB, resulting in decreased HIV-1 intracellular content, limited formation of LC-T cell conjugates, and elevated secretion of the CCR5-binding chemokine CCL3/MIP-1α. These mechanisms cooperate to efficiently inhibit HIV-1 transfer from LCs to T cells and T cell infection. In vivo, HIV-1 infection decreases CGRP plasma levels in both vaginally SHIV-challenged macaques and HIV-1-infected individuals. CGRP plasma levels return to baseline after highly active antiretroviral therapy. Our results reveal a novel path by which a peripheral neuropeptide acts at the molecular and cellular levels to limit mucosal HIV-1 transmission and suggest that CGRP receptor agonists might be used therapeutically against HIV-1

The MAHA clue - A case report

Microangiopathic hemolytic anemia (MAHA), is one of the causes of extra vascular hemolysis. It is seen in settings with pathologically altered small blood vessels. Disseminated carcinomas may rarely present as MAHA. A case of a 28 year old female with carcinoma stomach, who presented with MAHA as a first manifestation is reported. Acute onset of MAHA, may be the first manifestation of malignancy. In the absence of relatively common causes like disseminated intravascular coagulation,/Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, MAHA warrants extensive rapid investigations including bone marrow aspiration for possible metastatic deposits

Evidence of fatal skeletal injuries on Malapa Hominins 1 and 2

Malapa is one of the richest early hominin sites in Africa and the discovery site of the hominin species, Australopithecus sediba. The holotype and paratype (Malapa Hominin 1 and 2, or MH1 and MH2, respectively) skeletons are among the most complete in the early hominin record. Dating to approximately two million years BP, MH1 and MH2 are hypothesized to have fallen into a natural pit trap. All fractures evident on MH1 and MH2 skeletons were evaluated and separated based on wet and dry bone fracture morphology/characteristics. Most observed fractures are post-depositional, but those in the right upper limb of the adult hominin strongly indicate active resistance to an impact, while those in the juvenile hominin mandible are consistent with a blow to the face. The presence of skeletal trauma independently supports the falling hypothesis and supplies the first evidence for the manner of death of an australopith in the fossil record that is not attributed to predation or natural death

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10-8).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee

Modeling community integration in workers with delayed recovery from mild traumatic brain injury

Background: Delayed recovery in persons after mild traumatic brain injury (mTBI) is poorly understood. Community integration (CI) is endorsed by persons with neurological disorders as an important outcome. We aimed to describe CI and its associated factors in insured Ontario workers with delayed recovery following mTBI. Methods: A cross-sectional study of insured workers in the chronic phase following mTBI was performed at a rehabilitation hospital in Ontario, Canada. Sociodemographic, occupational, injury-related, clinical, and claim-related data were collected from self-reports, medical assessments, and insurers’ referral files. Community Integration Questionnaire (CIQ) scores were compared using analysis of variance or Spearman’s correlation tests. Stepwise multivariable linear regression models were used to evaluate the associations with CI. Results: Ninety-four workers with mTBI (45.2 ± 9.9 years old, 61.2 % male) at 197 days post-injury (interquartile range, 139–416 days) were included. The CIQ total and subscale scores were similar to those reported in more severe TBI samples. The CIQ scores were moderately to strongly correlated with various sociodemographic, claim-related, and clinical variables. In the multivariable regression analysis, several covariates accounted for 36.4 % of the CIQ variance in the final fully adjusted model. Discussion: This study evaluated CI in workers with mTBI, and analyzed its associated variables. Analysis revealed insomnia, head or neck pain, being married or in a relationship, time since injury, and a diagnosis of possible/probable malingering were independently associated with limited CI. Conclusions: Workers with delayed recovery from mTBI experience difficulty with CI. Insomnia is a particularly relevant covariate, explaining the greater part of its variance. To enhance participation, care should focus on clinical and non-clinical covariates

Effectiveness of acupuncture, special dressings and simple, low-adherence dressings for healing venous leg ulcers in primary healthcare: study protocol for a cluster-randomized open-labeled trial

<p>Abstract</p> <p>Background</p> <p>Venous leg ulcers constitute a chronic recurring complaint that affects 1.0–1.3% of the adult population at some time in life, and which corresponds to approximately 75% of all chronic ulcers of the leg. Multilayer compression bandaging is, at present, the only treatment that has been proved to be effective in treating this type of ulcer. There is no consensus, however, about the dressings that may be applied, beneath the compression, to promote the healing of this type of ulcer, as there does not seem to be any added benefit from using special dressings rather than simple, low-adherence ones. As well as analgesia, acupuncture provokes peripheral vasodilation, in skin and muscles – which has been demonstrated both experimentally and in clinical practice – probably due to the axon reflex, among other mechanisms. The aim of the present study is to measure the effectiveness and cost of compression treatment for venous leg ulcers combined with special dressings, in comparison with low-adherence ones and acupuncture.</p> <p>Methods/design</p> <p>Cluster-randomized open-labeled trial, at 15 primary healthcare clinics in the Sevilla-Sur Healthcare District, with a control group treated with compression bandaging and low-adherence dressings; the experiment will consist, on the one hand, of the compression treatment applied in combination with special dressings (Treatment 1), and on the other, the compression treatment applied in association with low-adherence dressings, together with acupuncture (Treatment 2).</p> <p>Discussion</p> <p>The results will be measured and recorded in terms of the median time elapsed until complete healing of the ulcer, and the rate of complete healing at 3 months after beginning the treatment. An economic analysis will also be made.</p> <p>This study, carried out in the context of real clinical practice, will provide information for decision-taking concerning the effectiveness of special dressings. Moreover, for the first time a high-quality study will evaluate the effectiveness of acupuncture in the process of healing venous leg ulcers.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN26438275.</p

The use of the Airtraq® optical laryngoscope for routine tracheal intubation in high-risk cardio-surgical patients

<p>Abstract</p> <p>Background</p> <p>The Airtraq^®optical laryngoscope (Prodol Ltd., Vizcaya, Spain) is a novel disposable device facilitating tracheal intubation in routine and difficult airway patients. No data investigating routine tracheal intubation using the Airtaq^®in patients at a high cardiac risk are available at present. Purpose of this study was to investigate the feasibility and hemodynamic implications of tracheal intubation with the Aitraq^®optical laryngoscope, in high-risk cardio-surgical patients.</p> <p>Methods</p> <p>123 consecutive ASA III patients undergoing elective coronary artery bypass grafting were routinely intubated with the Airtraq^®laryngoscope. Induction of anesthesia was standardized according to our institutional protocol. All tracheal intubations were performed by six anesthetists trained in the use of the Airtraq^®prior.</p> <p>Results</p> <p>Overall success rate was 100% (n = 123). All but five patients trachea could be intubated in the first attempt (95,9%). 5 patients were intubated in a 2nd (n = 4) or 3rd (n = 1) attempt. Mean intubation time was 24.3 s (range 16-128 s). Heart rate, arterial blood pressure and SpO₂were not significantly altered. Minor complications were observed in 6 patients (4,8%), i.e. two lesions of the lips and four minor superficial mucosal bleedings. Intubation duration (p = 0.62) and number of attempts (p = 0.26) were independent from BMI and Mallampati score.</p> <p>Conclusion</p> <p>Tracheal intubation with the Airtraq^®optical laryngoscope was feasible, save and easy to perform in high-risk patients undergoing cardiac surgery. In all patients, a sufficient view on the vocal cords could be obtained, independent from BMI and preoperative Mallampati score.</p> <p>Trial Registration</p> <p>DRKS 00003230</p

Elevated reticulocyte count – a clue to the diagnosis of haemolytic-uraemic syndrome (HUS) associated with gemcitabine therapy for metastatic duodenal papillary carcinoma: a case report

In adults, the haemolytic-uraemic syndrome (HUS) is associated with probable causative factors in the minority of all cases. Cytotoxic drugs are one of these potential causative agents. Although metastatic cancer by itself is a recognized risk-factor for the development of HUS, therapy with mitomycin-C, with cis-platinum, and with bleomycin carries a significant, albeit extremely small, risk for the development of HUS, compared with all other cytotoxic drugs. Gemcitabine is a novel cytotoxic drug with promising activity against pancreatic adenocarcinoma. We are reporting on one patient with metastatic duodenal papillary carcinoma developing HUS while on weekly gemcitabine therapy. The presenting features in this patient were non-cardiac pulmonary oedema, renal failure, thrombocytopenia and haemolytic anaemia. The diagnosis of HUS was made on the day of admission of the patient to this institution. Upon aggressive therapy, including one single haemodialysis and five plasmaphereses, the patient recovered uneventfully, with modestly elevated creatinine-values as a remnant of the acute illness. Re-exposure to gemcitabine 6 months after the episode of HUS instituted for progressive carcinoma, thus far has not caused another episode of HUS. © 1999 Cancer Research Campaig