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Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.

New prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza (HPAI) H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies (mAbs) and tested their efficacy for prophylaxis and therapy in a murine model of infection. Using Epstein-Barr virus we immortalized memory B cells from Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. Supernatants from B cell lines were screened in a virus neutralization assay. B cell lines secreting neutralizing antibodies were cloned and the mAbs purified. The cross-reactivity of these antibodies for different strains of H5N1 was tested in vitro by neutralization assays, and their prophylactic and therapeutic efficacy in vivo was tested in mice. In vitro, mAbs FLA3.14 and FLD20.19 neutralized both Clade I and Clade II H5N1 viruses, whilst FLA5.10 and FLD21.140 neutralized Clade I viruses only. In vivo, FLA3.14 and FLA5.10 conferred protection from lethality in mice challenged with A/Vietnam/1203/04 (H5N1) in a dose-dependent manner. mAb prophylaxis provided a statistically significant reduction in pulmonary virus titer, reduced associated inflammation in the lungs, and restricted extrapulmonary dissemination of the virus. Therapeutic doses of FLA3.14, FLA5.10, FLD20.19, and FLD21.140 provided robust protection from lethality at least up to 72 h postinfection with A/Vietnam/1203/04 (H5N1). mAbs FLA3.14, FLD21.140 and FLD20.19, but not FLA5.10, were also therapeutically active in vivo against the Clade II virus A/Indonesia/5/2005 (H5N1). These studies provide proof of concept that fully human mAbs with neutralizing activity can be rapidly generated from the peripheral blood of convalescent patients and that these mAbs are effective for the prevention and treatment of H5N1 infection in a mouse model. A panel of neutralizing, cross-reactive mAbs might be useful for prophylaxis or adjunctive treatment of human cases of H5N1 influenza.

Maize (Zea mays L.) releases specific volatiles in response to herbivory by caterpillars. These volatiles are known to serve as cues for parasitic wasps to locate the herbivores. In the present study the exact time of volatile emission after simulated herbivory (mechanical damage and treatment with caterpillar regurgitant) was measured for seedlings of the cultivars \"Ioana Sweet Corn\" and \"LG11\". Odours were collected every 0.5 h for a total of 12 h. Typical 'green leaf odours\", (Z)-3-hexenal, (E)-2-hexenal, (Z)-hexen-l-o1, and (Z)-3-hex-en-l-yl acetate, were emitted immediately upon damage and their amounts dropped rapidly after the first collections. Several of the induced compounds were released within 2 h after treatment, while others (mainly sesquiterpenoids) started to be released after 4 h. The LG11 seedlings emitted several compounds (e.g. beta-myrcene, (Z)-beta-ocimene, benzyl acetate, beta-caryophyllene. (E,E)-alpha-farnesene) that were not detected for Ioana. (E,E)-alpha-farnesene was continuously emitted by LG11 seedlings, even by undamaged plants. Timing of the release of volatile compounds that the two varieties had in common did not differ significantly, with the exception of indole for which the peak production was considerably earlier for LG11. These findings are discussed in the context of biosynthetic pathways and mechanisms involved in induced emissions of plant volatiles and the exploitation of the resulting odour by parasitoids and predators of herbivores.

At the end of WWII, after roughly thirty years of French colonialism, Morocco was facing a tremendous economic boom, but also an alarming rural exodus to the industrial cities on the coast which, in turn, had to deal with overpopulation and the phenomenon of the bidonvilles . At first, the article retraces the studies on traditional Moroccan urban, semi-rural, and rural settlements, carried out by Michel Écochard at the Service de l’Urbanisme from 1957 to 1951. Learning from local dwelling customs, the Service conceived a modern urban block model aimed at bringing wholesomeness to urban bidonvilles , as well as modernity in the countryside to stem the migrations. The essay then analyses the Service ’s typological studies on the courtyard housing unit, the basic cell of the urban fabric, and compares this with analogous coeval designs, influenced by Écochard’s ideas, realized both in Morocco and worldwide. The final goal is to form a genealogy of architectural designs that, reinterpreting from time to time the courtyard house, can show the existence of a direct relationship between rural landscape, dwelling modes, and modern architecture.

The aim of the present study is to assess the actual and lifetime frequency of neuropathic (trigeminal neuralgia, Lhermitte’s sign, dysesthesic pain) and somatic (painful muscle spasms and low back pain) pain and headache (tensive headache and migraine) in a cross-sectional sample of 428 consecutive multiple sclerosis (MS) outpatients followed-up in an Italian University MS center over a 3-month period. The impact of demographic and disease-related variables on pain and headache risk is also studied. A semi-structured questionnaire was administered during a face-to-face interview with MS patients and a multivariate logistic regression model is applied to obtain crude and adjusted risk measures. The mean age of the sample was 38.4 years, and female/male ratio was 1.65. The mean disease duration was 9.6 years and the median Expanded Disability Status Scale was 2.0, with most of the patients (74.8%) being affected by the relapsing–remitting form. Lifetime prevalence at the date of examination of at least one type of neuropathic or somatic pain was 39.8% in MS patients, with 58.5% also including headache, while the actual prevalence was 23.8% and 39.9%, respectively. After multivariate analysis, a progressive course of disease was shown to increase the risk of dysesthesic pain and painful muscle spasms, while greater disability was responsible for a higher risk of back pain. L’Hermitte’s sign was more frequent in younger patients, while females had a higher risk of headache. Pain and headache in MS are not negligible symptoms and a neurological examination should not miss the assessment of risk factors for specific types of pain for a more specific and individualized treatment.

The Plaine des Gonaïves houses a regionally significant yet data-scarce coastal aquifer in one of the driest regions of Haiti. It is the primary source of water for the region, including Haiti’s third largest city, Gonaïves. Pressure on groundwater resources will be compounded as municipal water services modernize and energy infrastructure enables the resurgence of commercial agriculture. In anticipation of increased stress and greater impacts, this study was undertaken (including data discovery, reconnaissance, and analysis) to gain insights and to advance understanding of the groundwater resources. The alluvial aquifer covers >115 km2, exceeds 100 m thickness, and supports pumping yields as high as 532 m3/h. The heterogeneous multilayer aquifer exhibits hydraulic conductivities that range by an order of magnitude, influencing groundwater flow, residence times, and chemistry. Significant recharge occurs in the central and upgradient portions of the plain; river infiltration appears to be a more significant recharge source than direct infiltration. In the downgradient portion of the plain, confined aquifer pressure increases and discharge areas include the Quinte River, springs, wetlands, ditches and canals. Underlying the alluvium, discontinuous groundwater in bedrock with structural influence may mix with the alluvial aquifer, affecting isotopic composition and water chemistry. Increased abstraction, climate change, and intensification of agriculture and urban development could have consequential impacts on water quantity, water quality and ecosystems. The results, insights, and supporting datasets are a baseline to guide planning and to advance a hydrogeological conceptual model that supports sustainable and informed groundwater management.

Background The essential branched-chain amino acids leucine, isoleucine and valine are considered anabolic and stimulate protein synthesis in the muscles as well in the liver. They also promote muscle recovery and contribute to glucose homeostasis. Recent studies in critically ill patients have demonstrated that depletion of plasma leucine is associated with increased mortality, but data in the non-critical care setting is lacking. Methods This secondary analysis of the randomized controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT), investigated the impact of leucine, isoleucine, and valine metabolism on clinical outcomes. The primary endpoint was 180-day all-cause mortality. Results Among 238 polymorbid patients with available metabolite measurements, low serum leucin levels were associated with a doubled risk of 180-day all-cause mortality in a fully adjusted regression model (adjusted HR 2.20 [95% CI 1.46–3.30], p  < 0.001). There was also an association with mortality for isoleucine (1.56 [95% CI 1.03–2.35], p  = 0.035) and valine (1.69 [95% CI 1.13–2.53], p  = 0.011). When comparing effects of nutritional support on mortality in patients with high and low levels of leucine, there was no evidence of significant differences in effectiveness of the intervention. The same was true for isoleucine and valine. Conclusion Our data suggest that depletion of leucine, isoleucine, and valine among malnourished polymorbid patients is associated with increases in long-term mortality. However, patients with low metabolite levels did not show a pronounced benefit from nutritional support. Further research should focus on the clinical effects of nutritional support in patients with depleted stores of essential branched-chain amino acids. Clinical trial registration clinicaltrials.gov as NCT02517476 (registered 7 August 2015).

Lysine, methionine, and threonine are essential amino acids with vital functions for muscle and connective tissue health, metabolic balance, and the immune system. During illness, the demand for these amino acids typically increases, which puts patients at risk for deficiencies with harmful clinical consequences. In a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), which compared individualized nutritional support to usual care nutrition in patients at nutritional risk, we investigated the prognostic impact of the lysine, methionine, and threonine metabolism. We had complete clinical and amino acid data in 237 patients, 58 of whom reached the primary endpoint of death at 30 days. In a model adjusted for comorbidities, sex, nutritional risk, and trial intervention, low plasma methionine levels were associated with 30-day mortality (adjusted HR 1.98 [95% CI 1.16 to 3.36], p = 0.01) and with a decline in functional status (adjusted OR 2.06 [95% CI 1.06 to 4.01], p = 0.03). The results for lysine and threonine did not show statistically significant differences regarding clinical outcomes. These findings suggest that low levels of methionine may be critical during hospitalization among patients at nutritional risk. Further studies should investigate the effect of supplementation of methionine in this patient group to improve outcomes.

Maturation of the humoral autoimmune response to epitopes of GAD in preclinical childhood type 1 diabetes. E Bonifacio , V Lampasona , L Bernasconi and A G Ziegler Istituto Scientifico San Raffaele, Milan, Italy. bonifacio.ezio@hsr.it Abstract GAD is a major target of autoimmunity in preclinical type 1 diabetes. Here we examine the maturation of the humoral response to GAD epitopes sequentially from birth to diabetes onset or current follow-up in 29 GAD antibody (GADA)+ offspring of parents with diabetes from the BABYDIAB Study. Antibodies were measured against GAD65, GAD67, and GAD65/67 chimeras by radiobinding assay. In 28 of 29 offspring, the first GADAs contained reactivity against epitopes within GAD65 residues 96-444, suggesting that the middle GAD65 region is a primary target of GAD humoral autoimmunity. In 7 of these 28 offspring, initial antibody reactivity was against all epitope regions tested (middle GAD65, COOH-terminal GAD65 residues 445-585, NH2-terminal GAD65 residues 1-95, and GAD67); in 16 offspring, reactivity was to middle and COOH-terminal GAD65 epitopes, and in 5 offspring, reactivity was only to the middle GAD65 epitopes. The single offspring without middle GAD65 reactivity had antibodies to the NH2-terminal epitopes in the absence of all other islet autoimmunity. Subsequent GADA epitope spreading was frequent and seen in 10 of 15 offspring with informative follow-up samples. Spreading was mostly (eight cases) to NH2-terminal GAD65 epitopes. In two offspring, spreading to new epitopes was found when antibody titers to GAD65 and early epitopes were declining, suggesting determinant-specific regulation of the humoral response. None of the GADA reactivities nor any changes in reactivity over time were specifically associated with diabetes onset. The findings suggest that the humoral autoimmune response to GAD found in childhood is dynamic, is initially against epitopes within the middle portion of GAD65, and spreads to epitopes in other regions of GAD65 and GAD67.

Hypogonadism is highly prevalent among obese men with metabolic syndrome. Chronic low-grade inflammation is suspected to be a major cause for low testosterone levels in obese individuals. To test the inflammatory hypothesis of testosterone deficiency in metabolic syndrome. In this randomized, placebo-controlled, double-blind trial involving men with metabolic syndrome, we randomly assigned 33 patients to receive 100 mg of anakinra (recombinant human IL-1 receptor antagonist) subcutaneously twice daily for 4 weeks and 34 patients to receive placebo. The primary endpoint was the change from baseline in total testosterone levels after 4 weeks. The mean age was 54 years and baseline total testosterone levels were 9.3 nmol/L (95% CI, 8.7 to 10.0). At 4 weeks, total testosterone levels increased by 1.2 nmol/L (95% CI, 0.3 to 2.0; P = 0.01) in the anakinra group as compared with no change in the placebo group (0.01 nmol/L; 95% CI, -0.5 to 0.5; P = 0.99), resulting in a between-group difference of 0.96 nmol/L (95% CI, 0.3 to 1.9; P = 0.04). The effects were most pronounced with baseline C-reactive protein >2 mg/L (between-group difference 2.14 nmol/L; 95% CI, 0.11 to 4.17; P = 0.04) and body mass index >40 kg/m2 (between-group difference 2.64 nmol/L; 95% CI, 0.19 to 5.09; P = 0.04). Anakinra treatment did not exert benefits on fatigue and sexual dysfunction, but it improved grip strength of nondominant hand by 3.5 kg (95% CI 0.23 to 6.81; P = 0.04) and reduced mean arterial blood pressure by 2.9 mm Hg (95% CI, -5.99 to 0.19; P = 0.07). Anti-inflammatory treatment with an antagonist of IL-1 led to an increase in testosterone levels in obese men with testosterone deficiency.