Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. Desensitization with allergen-specific ...immunotherapy (SIT) has been used for over a century, but the dominant protective mechanism remains unclear. One consistent observation is increased allergen-specific IgG, thought to competitively block allergen binding to IgE. Here we show that the blocking potency of the IgG response to Cat-SIT is heterogeneous. Next, using two potent, pre-selected allergen-blocking monoclonal IgG antibodies against the immunodominant cat allergen Fel d 1, we demonstrate that increasing the IgG/IgE ratio reduces the allergic response in mice and in cat-allergic patients: a single dose of blocking IgG reduces clinical symptoms in response to nasal provocation (ANCOVA, p = 0.0003), with a magnitude observed at day 8 similar to that reported with years of conventional SIT. This study suggests that simply augmenting the blocking IgG/IgE ratio may reverse allergy.
Enterotoxigenic Escherichia coli causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic ...E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CS5, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children.
We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24–59 months, 12–23 months, and 6–11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half 5·5 × 1010 cells, quarter 2·5 × 1010 cells, or eighth 1·25 × 1010 cells adult dose), with or without dmLT adjuvant (2·5 μg, 5·0 μg, or 10·0 μg), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02531802.
Between Dec 7, 2015, and Jan 10, 2017, we screened 1500 children across the three age groups, of whom 430 were enrolled and randomly assigned to the different treatment groups (130 aged 24–59 months, 100 aged 12–23 months, and 200 aged 6–11 months). All participants received at least one dose of vaccine. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting (ten 8% of 130 patients aged 24–59 months, 13 13% of 100 aged 12–23 months, and 29 15% of 200 aged 6–11 months; mostly of mild severity), which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Three serious adverse events occurred but they were not considered related to the study drug. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CS5, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6–11 months than in older children. Faecal secretory IgA immune responses were recorded against all vaccine antigens in infants aged 6–11 months. 78 (56%) of 139 infants aged 6–11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants.
The encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas.
PATH (Bill & Melinda Gates Foundation and the UK's Department for International Development), the Swedish Research Council, and The Swedish Foundation for Strategic Research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The provision of the glabrous skin with acceptable sensation is the main objective of any fingertip reconstruction. Thenar flaps can be medially based, laterally based and proximally based. However, ...all of them are randomly based. A distally based, axial pattern thenar flap could provide stable, like-with-like, palmar skin to the fingertip of an injured distal phalanx. We present a double, distally based axial pattern thenar flap, which we used to simultaneously reconstruct two fingers.
Highlights•The killed oral ETEC vaccine ETVAX ± dmLT adjuvant was safe in Bangladeshi adults. •All vaccinees responded to all 5 primary vaccine antigens in ALS specimens. •A majority of vaccinees ...responded to ≥4 antigens in plasma specimens. •A sensitive electrochemiluminescence assay was established for small sample volumes. •ALS responses measured by electrochemiluminescence and ELISA assays correlated well.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We sought to optimize a method for quantification of the calcium in the aortic-valvar complex for the prediction of significant paravalvular leak (PVL) after transcatheter aortic valve implantation ...(TAVI).
All patients had severe symptomatic aortic stenosis and were treated with balloon-expandable TAVI (Sapien/Sapien-XT, Edwards Lifesciences LLC, Irvine, CA, USA). In order to correct for precise annular sizing, only patients with available contrast computed tomography (CT) data for measurements were included (n = 198). Paravalvular leak was quantified using peri-procedural transoesophageal echocardiography by Valve Academic Research Consortium-2 (VARC-2) criteria (grade ≥ moderate was considered significant). A detailed region-of-interest methodology separated quantification of calcium in each of the aortic leaflets to that in the left ventricular outflow tract (LVOT) and was used to predict PVL in receiver operator characteristic curve analyses. For non-contrast scans, the greatest discriminatory value for PVL was seen at the 450 Hounsfield Unit (HU) threshold for detection (volume ≥626 mm(3)), whereas for contrast scans it was at 850 HU (≥235 mm(3)). Left ventricular outflow tract calcium predicted PVL but only as a binary variable with no incremental value of quantification. In a multivariable binary logistic regression model, annulus area ≥ prosthesis area (OR 3.5, 95% CI 1.5-8.2, P = 0.005), contrast leaflet calcium volume (850-HU threshold) ≥235 mm(3) (OR 2.8, 95% CI 1.2-6.7, P = 0.023), and presence of LVOT calcium (OR 2.8, 95% CI 1.2-7.0, P = 0.022) were independent predictors for PVL ≥ moderate.
Both leaflet and LVOT calcium are significant predictors of PVL and exert an important synergistic influence on this complication, even in appropriately sized valves. With careful attention to thresholds for detection, clinically relevant leaflet calcium volumes can be identified with either non-contrast or contrast CT scans.
Introduction: Theta burst stimulation (TBS) is a type of rTMS protocol which has the advantage of a shorter delivery time over traditional rTMS. When applied to motor cortex, intermittent TBS (iTBS) ...has been shown to yield excitatory aftereffects, whereas continuous TBS (cTBS) may lead to inhibitory aftereffects, both lasting from minutes to hours. The majority of TBS research has targeted motor, frontal, and parietal regions, and to date very few studies have examined its efficacy at visual areas. We designed a sham‐controlled study to investigate the immediate poststimulation and short‐term (1 h post‐stimulation) effects of iTBS and cTBS to V1.
Methods: Using multiecho functional magnetic resonance imaging, we measured the direct and indirect effects of TBS by comparing resting state functional connectivity (FC) before and after stimulation in whole brain networks, and seeds from V1 (stimulation site) and neighboring occipital and parietal visual networks. In addition, we also measured pre‐ and post‐TBS phosphene thresholds (PTs) to examine the modulatory effects of TBS on cortical excitability.
Results: We found no changes in FC for iTBS, cTBS or sham stimulation conditions from baseline to poststimulation timepoints. Additionally, cTBS and iTBS had no effect on visual cortical excitability.
Conclusions: Our results indicate that unlike our previous low frequency rTMS to V1 study, which resulted in widespread FC changes up to at least 1 h after stimulation, TBS to V1 does not affect FC. Contrary to the studies showing comparable TBS and rTMS aftereffects in motor and frontal regions, our findings suggest that a single session of cTBS or iTBS to V1 at 80% PT using a standard protocol of 600 pulses may not be effective in targeting FC, especially in clinical settings where therapy for pathological networks is the goal.
We investigated the short term (up to 1 hr) effects of continuous and intermittent theta burst stimulation (TBS) to primary visual cortex on resting state functional connectivity (FC) of focal visual networks and remote brain regions. Our findings suggest that a single session of TBS to V1 does not appear to produce significant short‐term alterations in functional connectivity following stimulation.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Increasing trend in antimicrobial resistance and failure of chemically synthesized antibiotics lead to discover alternative methods for the treatment of bacterial infections. Various ...medicinal plants are in use traditionally and their active compounds can be further applied for treatment of bacterial diseases. This study was designed to determine the antibacterial activity of Punica granatum (P. granatum L.) (pomegranate) peel extract against Enterobacteriaceae Escherichia coli (E. coli), Salmonella Typhimurium (S. Typhimurium) and Shigella Dysenteriae (S. Dysenteriae) and gram-positive bacterium Staphylococcus aureus (Staph aureus). Methanolic extract of P. granatum L. peel was prepared by Soxhlet apparatus method. Total flavonoid and phenolic contents from the extract were determined by High Performance Liquid Chromatography (HPLC). The antibacterial activity of P. granatum L. peel extract was evaluated through agar well diffusion method. HPLC showed the range of phenolics (gallic acid, caffeic acid, benzoic acid, cinnamic acid) and flavonoid compounds. The chemical structures of flavonoid and phenolics found in the methanolic extract of P. granatum L. peel have been reported for the first time. The methanolic peel extract (50 ul) of yellow P. granatum L. showed 26, 10, 10 and 9mm zones of inhibition (ZOI) against S. aureus, S. Typhimurium, S. Dysenteriae and E. coli, respectively. The methanolic extract of red P. granatum L. (100 ul) showed 27, 8, 12 and 15 mm ZOI against Staph. aureus, S. Typhimurium, S. Dysenteriae and E. coli, respectively. Highest ZOI was observed against Staph. aureus. Many of the bacteria studied in the present work may cause serious gastrointestinal infections, which can lead to hemorrhagic diarrhea in children. These infections can be life-threatening to young children and the elderly. There is an incentive to find alternative control measures, such as plant and herbal extracts, especially in lesser-developed countries where traditional antibiotics may not be readily available.
Resumo A tendência crescente na resistência antimicrobiana e na falha dos antibióticos sintetizados quimicamente leva à descoberta de métodos alternativos para o tratamento de infecções bacterianas. Várias plantas medicinais estão em uso tradicionalmente e seus compostos ativos podem ser posteriormente aplicados para o tratamento de doenças bacterianas. Este estudo foi desenhado para determinar a atividade antibacteriana do extrato de casca de Punica granatum (P. granatum L.) (romã) contra Enterobacteriaceae Escherichia coli (E. coli), Salmonella Typhimurium (S. Typhimurium) e Shigella Dysenteriae (S. Dysenteriae) e bactéria gram-positiva Staphylococcus aureus (Staph aureus). O extrato metanólico da casca de P. granatum L. foi preparado pelo método do aparelho de Soxhlet. O conteúdo total de flavonoides e fenólicos do extrato foi determinado por cromatografia líquida de alta eficiência (HPLC). A atividade antibacteriana do extrato da casca de P. granatum L. foi avaliada através do método de difusão em ágar. HPLC mostrou a gama de compostos fenólicos (ácido gálico, ácido cafeico, ácido benzoico, ácido cinâmico) e flavonoides. As estruturas químicas de flavonoides e fenólicos encontradas no extrato metanólico da casca de P. granatum L. foram relatadas pela primeira vez. O extrato metanólico da casca (50 ul) de P. granatum L. amarelo apresentou zonas de inibição (ZOI) de 26, 10, 10 e 9mm contra S. aureus, S. Typhimurium, S. Dysenteriae e E. coli, respectivamente. O extrato metanólico de P. granatum L. vermelho (100 ul) apresentou 27, 8, 12 e 15 mm IOI contra Staph. aureus, S. Typhimurium, S. Dysenteriae e E. coli, respectivamente. O ZOI mais alto foi observado contra Staph. aureus. Muitas das bactérias estudadas no presente trabalho podem causar infecções gastrointestinais graves, que podem levar à diarreia hemorrágica em crianças. Essas infecções podem ser fatais para crianças pequenas e idosos. Há um incentivo para encontrar medidas de controle alternativas, como extratos de plantas e ervas, especialmente em países menos desenvolvidos, onde os antibióticos tradicionais podem não estar prontamente disponíveis.
A ninety days nutritional trial was directed to explore the effects of dietary chromium on body composition, gut enzyme activity and physiological status of Cirrhinus mrigala by using G & NG corn. ...Six experimental diets were prepared by using different levels of chromium chloride hexahydrate (0, 0.2, 0.4 mg/kg, each with G & NG corn). For this experimental trial, 480 fingerlings, irrespective of sex were distributed in six aquariums each with replicate. Results revealed that gelatinized corn along with increasing level of Cr2Cl3.6H2O have a positive impact upon body composition of fish. Hematology was positively correlated with chromium chloride hexahydrate supplementation in gelatinized corn. Amylase gut enzyme also showed significant (P<0.05) increase in group fed with chromium chloride hexahydrate supplemented diet (G corn). However, corn with chromium chloride hexahydrate supplementation did not revealed any significant impact on gut protease enzyme activity. From these results it can be concluded that both chromium chloride hexahydrate and gelatinized corn in fish feed are very beneficial to improve body composition, enzymes activity and physiological health status of fish.
Introduction
Intrinsic network connectivity becomes altered in pathophysiology. Noninvasive brain stimulation can modulate pathological functional networks in an attempt to restore the inherent ...response. To determine its usefulness for visual‐related disorders, we developed procedures investigating repetitive transcranial magnetic stimulation (rTMS) protocols targeting the visual cortex on modulating connectivity associated with the visual network and default mode network (DMN).
Methods
We compared two low‐frequency (1 Hz) rTMS protocols to the visual cortex (V1)—a single 20 min session and five successive 20 min sessions (accelerated/within‐session rTMS)—using multi‐echo resting‐state functional magnetic resonance whole‐brain imaging and resting‐state functional connectivity (rsFC). We also explored the relationship between rsFC and rTMS‐induced changes in key inhibitory and excitatory neurotransmitters, γ‐aminobutyric acid (GABA) and glutamate. GABA (GABA+) and glutamate (Glx) concentrations were measured in vivo using magnetic resonance spectroscopy.
Results
Acute disruption with a single rTMS session caused widespread connectivity reconfiguration with nodes of interest. Changes were not evident immediately post‐rTMS but were observed at 1 h post‐rTMS. Accelerated sessions resulted in weak alterations in connectivity, producing a relatively homeostatic response. Changes in GABA+ and Glx concentrations with network connectivity were dependent on the rTMS protocol.
Conclusions
This proof‐of‐concept study offers new perspectives to assess stimulation‐induced neural processes involved in intrinsic functional connectivity and the potential for rTMS to modulate nodes interconnected with the visual cortex. The differential effects of single‐session and accelerated rTMS on physiological markers are crucial for furthering the advancement of treatment modalities in visual cortex related disorders.
Acute disruption to V1 with a single session of 1 Hz repetitive transcranial magnetic stimulation (rTMS) reconfigures intrinsic resting‐state functional connectivity (rsFC) to regions within and outside the visual and default mode networks. Accelerated 1 Hz rTMS sessions to V1 maintains a homeostatic response on rsFC. Changes in rsFC were influenced by rTMS‐induced changes in GABA and glutamate concentrations.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
OBJECTIVE:To investigate the efficacy of multiday repetitive transcranial magnetic stimulation (rTMS) to the occipital cortex in a patient with continuous visual phosphene hallucinations for more ...than 2 years following occipital stroke.
METHODS:Low-frequency rTMS (1 Hz) was applied to the lesion site for 30 minutes daily over 5 consecutive days. Functional MRI (fMRI) was performed before and after rTMS treatment.
RESULTS:Increased application of rTMS corresponded with a reduction in intensity of visual phosphene hallucinations and was reflected in altered blood oxygen level–dependent signal. fMRI revealed focal excitatory discharges at the border of the lesion, highlighting the origin of phosphenes. Post-rTMS, rTMS did not simply suppress activity in the patient but rather redistributed the previously imbalanced cortical activity not only at the stimulation site but in remote cortical regions so that it more closely resembled that of controls.
CONCLUSIONS:This case is rare in its presentation of chronic continuous visual phosphene hallucinations following occipital stroke. We present a case of multiday application of rTMS to visual cortex and demonstrate that rTMS provides a valuable therapeutic intervention in modulating visual hallucinations following occipital damage.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence in a single-case report that multiday rTMS reduces intrahemispheric and interhemispheric imbalance and associated visual phosphene hallucinations following occipital stroke.
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