Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors.
BACKGROUNDAdoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications.METHODSWe provide results of a personalized T cell manufacturing program evaluating donor, patient, T cell product, and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T lymphocyte (EBV-CTL) products from stem cell donors (SCDs), related third-party donors (TPDs), or unrelated TPDs from the allogeneic T cell donor registry (alloCELL) at Hannover Medical School were manufactured by immunomagnetic selection using a CliniMACS Plus or Prodigy device and the EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated, and patient outcome and side effects were retrieved by retrospective chart analysis.RESULTSForty clinical-grade EBV-CTL products from SCDs, related TPDs, or unrelated TPDs were generated for 37 patients with refractory EBV infections or EBV-associated malignancies with and without a history of transplantation, within 5 days (median) after donor identification. Thirty-four patients received 1-14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to a complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients' blood were detectable in 16 of 18 monitored patients (89%) after transfer, and their presence correlated with clinical response.CONCLUSIONPersonalized clinical-grade manufacture of EBV-CTL products via immunomagnetic selection from SCDs, related TPDs, or unrelated TPDs in a timely manner is feasible. Overall, EBV-CTLs were clinically effective and well tolerated. Our data suggest EBV-CTL transfer as a promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT, as well as patients with preexisting organ dysfunction.TRIAL REGISTRATIONNot applicable.FUNDINGThis study was funded in part by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), Wilhelm-Sander-Stiftung (reference 2015.097.1), Ellen-Schmidt-Program of Hannover Medical School, and German Federal Ministry of Education and Research (reference 01EO0802).


Survival of very young children with medulloblastoma (primitive neuroectodermal tumor of the posterior fossa) treated with craniospinal irradiation.
Very young children with medulloblastoma are considered to have a worse prognosis than older children. As radiotherapy remains an important part of the treatment, the adverse prognosis could be due to inadequate radiation treatment rather than biological factors. We analyzed the published literature to examine the impact of radiotherapy on survival in this group. A Medline search was performed and we reviewed studies of treatment of medulloblastoma where radiotherapy was delivered using megavoltage equipment and the minimum follow-up allowed the calculation of 5-year survival rates. Thirty-nine studies were published between 1979 and 1996 with a treatment including craniospinal irradiation and boost to the posterior fossa. Eleven studies comprising 1366 patients analyzed survival by age at diagnosis. Eight of 11 studies showed a worse 5-year survival for the younger patient group which reached statistical significance in two. There is also a suggestion of a higher proportion of children with metastatic disease at presentation in the very young age group. The usual policy in younger children was to give a lower dose of radiotherapy to the craniospinal axis (CSA) and posterior fossa (PF) with reduction of dose in the range of 15 to 25% compared to standard treatment. As dose reduction to the posterior fossa is associated with worse survival and local recurrence is the predominant site of failure, the major determinant of worse survival in very young children with medulloblastoma may be suboptimal radiotherapy. Protocols including postoperative chemotherapy with delayed, omitted, or only local tumor irradiation do not reach survival rates of protocols with standard radiotherapy, also suggesting a continued importance for irradiation. Very young children with medulloblastoma have a worse prognosis than older children. Inadequate radiation dose and technique to the primary tumor region may be a major contributing factor. Current chemotherapeutic regimes alone are not sufficient to compensate for reduced radiation doses and volumes.


Social learning modulates the lateralization of emotional valence.
Although neuropsychological studies of lateralization of emotion have emphasized valence (positive vs. negative) or type (basic vs. complex) dimensions, the interaction between the two dimensions has yet to be elucidated. The purpose of the current study was to test the hypothesis that recognition of basic emotions is processed preferentially by the right prefrontal cortex (PFC), whereas recognition of complex social emotions is processed preferentially by the left PFC. Experiment 1 assessed the ability of healthy controls and patients with right and left PFC lesions to recognize basic and complex emotions. Experiment 2 modeled the patient's data of Experiment 1 on healthy participants under lateralized displays of the emotional stimuli. Both experiments support the Type as well as the Valence Hypotheses. However, our findings indicate that the Valence Hypothesis holds for basic but less so for complex emotions. It is suggested that, since social learning overrules the basic preference of valence in the hemispheres, the processing of complex emotions in the hemispheres is less affected by valence.


Eldecalcitol: a review of its use in the treatment of osteoporosis.
Eldecalcitol (1α,25[OH](2)-2β-(3-hydroxypropyloxy)vitamin D(3); ED-71; Edirol®) is an orally administered analogue of active vitamin D (calcitriol) that is available in Japan for the treatment of osteoporosis. Two randomized, double-blind, multicentre trials were conducted in patients with osteoporosis. In a placebo-controlled, dose-ranging trial, eldecalcitol significantly reduced serum bone-specific alkaline phosphatase (BALP) and serum osteocalcin, markers of bone formation, more than placebo. Eldecalcitol at a 1.0 μg/day dosage, but not at lower dosages, also significantly reduced urinary type I collagen N-telopeptide (NTX), a marker of bone resorption, more than placebo. In a comparison with alfacalcidol (a prodrug of calcitriol), eldecalcitol produced significantly greater reductions in serum BALP and urinary NTX, and had a positive effect on CT markers of femoral biomechanical properties. In the comparison with alfacalcidol, eldecalcitol 0.75 μg/day significantly reduced the 3-year incidence of vertebral fractures, with an absolute risk reduction of 4.1% over this period, representing a relative risk reduction of 26%. There was no significant difference in the rate of non-vertebral fractures. In both trials, eldecalcitol treatment was also associated with an increase in bone mineral density, whereas patients who received the comparators generally had a reduction in bone mineral density. Increases in blood calcium (to >2.6 mmol/L) and urinary calcium (to >0.1 mmol/L glomerular filtrate) were the most clinically important treatment-emergent adverse events. In the placebo-controlled, dose-ranging trial, 23% and 25% of patients in the eldecalcitol 1 μg/day group had increased blood and urinary calcium compared with 7% and 7%, 6% [corrected] and 9%, and 0% and 1.9% in the eldecalcitol 0.5 and 0.75 μg/day, and placebo groups, respectively. In the comparison with alfacalcidol, 21.0% and 13.5% of eldecalcitol 0.75 μg/day and alfacalcidol 1.0 μg/day recipients had increased blood calcium, whereas hypercalcaemia (defined as a serum calcium >2.9 mmol/L) occurred in 0.4% and urolithiasis in 1.3% of eldecalcitol recipients over 36 months of treatment. Eldecalcitol is an efficacious treatment for patients with osteoporosis that should be further investigated in head-to-head trials with other recommended first-line pharmacological treatments.


Rumen bypass and biodistribution of l-carnitine from dual-layered coated pellets in cows, in vitro and in vivo.
A ruman bypass delivery system was investigated to improve the delivery efficiency of L-carnitine in biological samples of cows. Highly water-soluble L-carnitine used for dietary supplement in ruminants was chosen. L-Carnitine-loaded compact pellets were prepared by extrusion method and then coated with various coating materials such as ethylcellulose (EC), Eudragit E100 (E100), Eudragit RS100 (RS100), stearyl alcohol and glyceryl monostearate, for single-layered coated pellets (SCP). Two types of dual-layered coated pellets (DCP) were also designed as DCP-A (inner E100/outer EC) or DCP-B (inner EC/outer E100). Preparation of compact pellet and methods of polymeric coatings are the most important strategies for modulated release and rumen bypass efficiency based on chewing behaviors and physiology of veterinary species. DCPs were more efficient in retarding L-carnitine release in rumen fluid (pH 6.8) than the SCP but DCP-B gave much faster release in abomasums fluid (pH 1.2). Both DCP-A and DCP-B showed high in vivo rumen bypass efficiency in cows compared with the nonprotected preparation and most of l-carnitine was readily absorbed. DCP-B was also efficient for delivering L-carnitine in biological samples of cows, mainly in muscle but no statistical differences were observed among the tested preparations after the multiple oral feeding to cows for 3 months. Interestingly, DCP-B produced higher L-carnitine levels in milk in a dose-dependent manner. However, delivery efficiency of L-carnitine preparations in biological samples of cows would rather be more dependent on feeding schedules.


Leptospirosis in patients from Grenada, West Indies.
Evidence of leptospirosis in humans from Grenada, W.I., is reported here for the first time. Of 139 hospital patients with pyrexia of undetermined origin, 94 were jaundiced, and 16 (17%) of these were positive for hepatitis B antigen (HBsAg) and not examined further. 20 of the remaining 123 (16%) febrile patients were positive for leptospiral antibodies; 11 of them were current or recent cases. 25 of 182 (14%) afebrile out-patients showed evidence of previous exposure to leptospiral organisms. The most frequently encountered serogroups in the 45 seropositive in- and out-patients were Icterohaemorrhagiae (38%), Panama (24%) and Canicola (11%).


A novel approach to estimate and control denitrification performance in activated sludge systems with respirogram technology.
Respirogram technology has been widely applied for aerobic process, however, the response of respirogram to anoxic denitrification is still unclear. To reveal such response may help to design a new method for the evaluation of the performance of denitrification. The size distribution of flocs measured at different denitrification moments demonstrated a clear expansion of flocs triggered by denitrification, during which higher specific endogenous and quasi-endogenous respiration rates (SOURe and SOURq) were also observed. Furthermore, SOURq increases exponentially with the specific denitrification rate (SDNR), suggesting that there should be a maximum SDNR in conventional activated sludge systems. Based on these findings, an index Rq/t, defined as the ratio of quasi-endogenous (OURq) to maximum respiration rate (OURt), is proposed to estimate the denitrification capacity that higher Rq/t indicates higher denitrification potential, which can be readily obtained without complex measurement or analysis, and it offers a novel and promising respirogram-based approach for denitrification estimation and control by taking measures to extend anoxic time to maintain its value at a high level within a certain range.


Estimation of salt water upconing using a steady-state solution for partial completion of a pumped well.
A new steady-state analytical solution to the two-dimensional radial-flow equation was developed for drawdown (head) conditions in an aquifer with constant transmissivity, no-flow conditions at the top and bottom, constant head conditions at a known radial distance, and a partially completed pumping well. The solution was evaluated for accuracy by comparison to numerical simulations using MODFLOW. The solution was then used to estimate the rise of the salt water-fresh water interface (upconing) that occurs under a pumping well, and to calculate the critical pumping rate at which the interface becomes unstable, allowing salt water to enter the pumping well. The analysis of salt water-fresh water interface rise assumed no significant effect on upconing by recharge; this assumption was tested and supported using results from a new steady-state analytical solution developed for recharge under two-dimensional radial-flow conditions. The upconing analysis results were evaluated for accuracy by comparison to those from numerical simulations using SEAWAT for salt water-fresh water interface positions under mild pumping conditions. The results from the equation were also compared with those of a published numerical sharp-interface model applied to a case on Cape Cod, Massachusetts. This comparison indicates that estimating the interface rise and maximum allowable pumping rate using the analytical method will likely be less conservative than the maximum allowable pumping rate and maximum stable interface rise from a numerical sharp-interface model.


Efficient method for visualization and isolation of proteins resolved in polyacrylamide gels.
Polyacrylamide gel electrophoresis is a popular method used to purify proteins for reconstitution experiments, amino acid composition and sequence determinations. In this report we describe methods that will be of general use in the isolation and characterization of proteins and the benefits of substituting boric acid for glycine in the electrophoresis tray buffers. We also describe how proteins resolved in a variety of gel systems (including those containing sodium dodecyl sulfate) may be rapidly visualized with 8-anilino-1-naphthalene sulfonic acid and efficiently transferred to a second gel for two-dimensional gel analysis, or isolated by electroelution for subsequent characterization.


Post-mortem radiology--a new sub-speciality?
Computed tomography (CT) and magnetic resonance imaging (MRI) examinations of deceased individuals are increasingly being utilized in the field of forensic pathology. However, there are differences in the interpretation of post-mortem and clinical imaging. Radiologists with only occasional experience in post-mortem imaging are at risk of misinterpreting the findings if they rely solely on clinical experience. Radiological specialists working in a co-operative environment with pathologists are pivotal in the understanding of post-mortem CT and MRI, and its appropriate integration into the autopsy. This has spawned a novel subspecialty called post-mortem radiology or necro-radiology (radiology of the deceased). In the future it is likely that whole-body CT will be incorporated into the routine forensic autopsy due its ability to accurately detect and localise abnormalities commonly seen in forensic practice, such as haematoma, abnormal gas collections, fractures, and metallic foreign bodies. In the next 5-10 years most forensic institutes will seek regular access to such CT facilities or install machines into their own mortuaries. MRI is technically more problematic in the deceased but the improved tissue contrast over CT means that it is also very useful for investigation of pathology in the cranial, thoracic, and abdominal cavities, as well as the detection of haematoma in soft tissue. In order for radiologists to be an integral part of this important development in forensic investigation, radiological organizations must recognize the subspecialty of post-mortem radiology and provide a forum for radiologists to advance scientific knowledge in the field.


Forecast predictions for the COVID-19 pandemic in Brazil by statistical modeling using the Weibull distribution for daily new cases and deaths.
COVID-19 has killed more than 500,000 people worldwide and more than 60,000 in Brazil. Since there are no specific drugs or vaccines, the available tools against COVID-19 are preventive, such as the use of personal protective equipment, social distancing, lockdowns, and mass testing. Such measures are hindered in Brazil due to a restrict budget, low educational level of the population, and misleading attitudes from the federal authorities. Predictions for COVID-19 are of pivotal importance to subsidize and mobilize health authorities' efforts in applying the necessary preventive strategies. The Weibull distribution was used to model the forecast prediction of COVID-19, in four scenarios, based on the curve of daily new deaths as a function of time. The date in which the number of daily new deaths will fall below the rate of 3 deaths per million - the average level in which some countries start to relax the stay-at-home measures - was estimated. If the daily new deaths curve was bending today (i.e., about 1250 deaths per day), the predicted date would be on July 5. Forecast predictions allowed the estimation of overall death toll at the end of the outbreak. Our results suggest that each additional day that lasts to bend the daily new deaths curve may correspond to additional 1685 deaths at the end of COVID-19 outbreak in Brazil (R2 = 0.9890). Predictions of the outbreak can be used to guide Brazilian health authorities in the decision-making to properly fight COVID-19 pandemic.


A different time for tubal surgery.
"An object in motion tends to remain in motion along a straight line unless acted upon by an outside force." -Isaac Newton.


Fatty change in the human temporomandibular joint disc. Light and electron microscopy study.
Joint pain has been associated with fatty infiltration of the knee articulation. The purpose of this study is to report on the histopathological findings, especially fatty changes, that are seen in surgical specimens from the temporomandibular joints (TMJ) of patients that had persistent pain after non-surgical therapy. Forty plicated TMJ retrodiscal samples from 25 patients were used in this study. The patients were previously treated with splints for variable periods but not less than 2 months. The specimens were obtained by 2 surgeons using standard TMJ plication techniques. Control disc specimens were obtained from normal appearing cadaveric TM joints. Samples were immediately immersed in glutaraldehyde and processed for light and electron microscopic examination. The specimens were composed mainly of moderately dense tissue with cells that appeared fibroblastic and intermittent chondrocytic type cells. Fatty change, exclusively in association with the perivascular areas, was observed in 27 of 40 specimens. Electron microscopy showed fibroblasts, as well as large fat inclusions adjacent to elastin macroglobules. Fatty infiltration of the TMJ has been interpreted as a degenerative change. It is postulated that kinins and prostaglandins generated in the fat pads can pass freely in tissue fluid to adjacent, highly innervated structures thus leading to joint pain. It is further postulated that the finding of associated elastin with fatty deposition is similar to the atherosclerotic changes encountered in large blood vessels and the aorta.


Chemical differences between thyrotropin isohormones.
Amide determinations have been carried out, with a newly developed g.l.c. method, on thyrotropin hormones prepared by isoelectric focusing. The observed differences in amide content fully account for the differences in the electrochemical properties of the isohormones.


Do constructed wetlands in grass strips reduce water contamination from drained fields?
This study evaluates the efficiency of two small constructed wetlands installed in the regulatory grass strips between a drained plot and a river. The observed nitrate removal efficiencies were independent of the season or type of constructed wetland and ranged from 5.4 to 10.9% of the inlet amounts. The pesticide mass budgets ranged from -618.5 to 100%, depending on the molecule. The negative efficiencies were attributed to runoff and remobilization. In contrast, the highest efficiencies were associated with pesticides with high Koc and low DT50 (half-life) values, suggesting sorption and degradation. However, the effectiveness of these wetlands is limited for pesticides with low Koc or high DT50 values; thus, the use of these molecules must be reduced. Increasing the number of these small, inexpensive and low-maintenance wetlands in the agricultural landscape would reduce the level of water pollution whilst preserving the extent of cultivated land, but their long-term effectiveness should be evaluated.


Spreading interviews over time in health surveys: do temporal variations of self-reported alcohol consumption affect measurement?
To address systematic variations related to the day of the interview in self-reports of alcohol consumption in telephone health surveys. The investigations include temporal clustering effects, prediction of alcohol consumption and variations across days by characteristics of respondents and interviewing period, and sensitivity to variations of measurements instruments. Data at baseline collected in Spring 1999 from 2846 participants in a longitudinal probabilistic general-population survey in Switzerland were used. The study is representative for drinkers in Switzerland. Alcohol consumption measures include a 6-month quantity frequency and a 1-week graduated frequency measure. Evidence for systematic variations in self-reports related to the day of interview was found on the graduated-frequency measure even after controlling for sample characteristics. Similar variations on the quantity frequency measure were found, but were no longer significant after statistical control of the sample characteristics. Statistical inference in alcohol survey research by telephone interviews based on graduated-frequency measures with short reference period may be plagued with errors related to clustering effects of the day of the interview. Temporal aspects of conducting the fieldwork should therefore be accounted for in statistical analysis.


3-O-Alkyl-2,3-dehydrosilibinins: Two synthetic approaches and in vitro effects toward prostate cancer cells.
Eight 3-O-alkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin through two synthetic approaches. A one-pot reaction, starting with aerobic oxidation of silibinin followed by direct alkylation of the phenolic hydroxyl group in the subsequent 2,3-dehydrosilibinin, furnishes the desired derivatives in 11-16% yields. The three-step procedure employing benzyl ether to protect 7-OH in silibinin generates the desired derivatives in 30-46% overall yields. The antiproliferative activity of the 2,3-dehydrosilibinin derivatives against both androgen-sensitive and androgen-insensitive prostate cancer cells have been assessed using a WST-1 cell proliferation assay. All derivatives exhibited greater antiproliferative potency than silibinin, with 2,3-dehydrosilibinins each possessing a three- to five-carbon linear alkyl group to 3-OH (IC50 values in a range of 1.71-3.06μM against PC-3 and LNCaP cells) as the optimal derivatives. The optimal potency was reached with three- to five-carbon alkyl groups. Our findings suggest that 3-O-propyl-2,3-dehydrosilibinin effectively inhibits the growth of PC-3 prostate cancer cells by arresting cell cycle in the G0/G1 phase, but not by activating PC-3 cell apoptosis.


Extending foldamer design beyond α-helix mimicry: α/β-peptide inhibitors of vascular endothelial growth factor signaling.
Diverse strategies have been explored to mimic the surface displayed by an α-helical segment of a protein, with the goal of creating inhibitors of helix-mediated protein-protein interactions. Many recognition surfaces on proteins, however, are topologically more complex and less regular than a single α-helix. We describe efforts to develop peptidic foldamers that bind to the irregular receptor-recognition surface of vascular endothelial growth factor (VEGF). Our approach begins with a 19-residue α-peptide previously reported by Fairbrother et al. (Biochemistry 1998, 37, 17754) to bind to this surface on VEGF. Systematic evaluation of α→β replacements throughout this 19-mer sequence enabled us to identify homologues that contain up to ~30% β residues, retain significant affinity for VEGF, and display substantial resistance to proteolysis. These α/β-peptides can block VEGF-stimulated proliferation of human umbilical vein endothelial cells.


The effect of bright light therapy on depression associated with premenstrual dysphoric disorder.
This systematic review summarizes the evidence from randomized clinical trials of bright light therapy for treatment of premenstrual dysphoric disorder. The authors performed a systematic review and meta-analysis of randomized clinical trials. They searched MEDLINE, AMED, CINAHL, Digital Dissertations, EMBASE, and the Cochrane Central Register of Controlled Trials. The main outcome measure was the change in depressive symptom scores as measured by the Hamilton Depression Rating Scale and the Beck Depression Inventory. Four crossover trials studying a total of 55 participants met inclusion criteria. Three trials showed similar results; one fully unblinded trial showed a much larger effect. The pooled effect size from the random-effects model of the 3 higher quality trials was -0.20 (95% CI -0.48 to 0.07). The small size of trials and correspondingly wide confidence limits, and methodologic limitations of the trials, leaves the impact of bright light therapy for relief of premenstrual depressive symptoms uncertain. The current evidence justifies neither enthusiastic dissemination nor confident rejection of this therapeutic modality.


Assessment of soft and hard tissue characteristics of ridge preservation at molar extraction sites with severe periodontitis: a randomized controlled trial.
Changes in alveolar bone dimension after tooth extraction may affect placement of the subsequent implant, resulting in ridge deficiency that can adversely impact long-term implant stability or aesthetics. Alveolar ridge preservation (ARP) was effective in reducing the amount of ridge resorption following tooth extraction. There is sparse evidence regarding the benefit of ARP at periodontally compromised molar extraction sockets. This study will be a randomized trial to assess the soft tissue contour, radiographical, and histological changes of ARP at molar extraction sites in order to compare severe periodontitis cases with natural healing results and determine the most beneficial and least traumatic clinical treatment for such patients. This research is designed as a two-group parallel randomized controlled trial. The total number of tooth extraction sites will be 70 after calculation with power analysis. Teeth will be randomly assigned to two groups with the test group conducting ridge preservation and the control group healing naturally. Periodontal examination, cone beam-computed tomography (CBCT) data, and stereolithographic (STL) files obtained by intraoral scanning will be collected through the follow-up period, and bone biopsy samples would be obtained during implant surgery. The primary outcomes are the vertical and horizontal change of alveolar ridge measured on CBCT images, soft tissue contour changes evaluated by superimposing the digital impressions, alterations of mucosa thickness (as measured by superimposing the CBCT data and STL files), histological features of implant sites and periodontal parameter changes. The secondary outcomes are patient-reported post-operative reaction and conditions of simultaneous bone graft or sinus lifting procedures during implantation. This study will provide information about hard and soft tissue dimension changes and histomorphology evaluation following ARP and natural healing in periodontally compromised molar sites, which may contribute to complement the missing information of ARP at periodontally compromised molar extraction sockets. Chinese Clinical Trial Register (ChiCTR) ChiCTR2200056335. Registered on February 4, 2022, Version 1.0.


Folate deficiency-induced hyperhomocysteinemia attenuates, and folic acid supplementation restores, the functional activities of rat coagulation factors XII, X, and II.
Hyperhomocysteinemia (HH) constitutes a risk marker for thrombosis, but the pathophysiological mechanisms in thrombus formation are still unresolved. We investigated the influence of HH on single coagulation factor functions and evaluated the platelet GpIIb/IIIa receptor function in HH-induced changes in whole-blood coagulation profiles (WBCP). Three groups of 12 rats were investigated: control rats, folate deficient-HH (FD-HH) rats, and treated rats. Plasma total homocysteine was 7.1 micromol/L in controls, 31.3 micromol/L in FD-HH rats, and 7.6 micromol/L in treated rats. Factor (F) II:C, FX:C, and FXII:C were reduced in FD-HH rats compared with controls and normalized in treated rats (P < 0.05). FVII:C activity did not differ among the groups. Factor VIII:C activity was greater in FD-HH rats than in controls (P < 0.05). Blockage of the platelet GpIIb/IIIa receptor by Integrilin (Schering-Plough A/S) did not abolish the FD-HH-induced increase in whole-blood coagulation velocity, irrespective of the dosage of Integrilin. In conclusion, FD-HH reduced the functional activities of FXII:C, FX:C and FII:C, whereas FVII:C was unchanged and FVIII:C increased. These findings may partially explain the prolonged initiation phase of WBCP in FD-HH rats. The changes in single coagulation factor functions and WBCPs in FD-HH rats were reversed by treatment with folic acid.


Fasciola gigantica and Schistosoma mansoni: vaccine potential of recombinant glutathione S-transferase (rFgGST26) against infections in mice.
Recombinant Fasciola gigantica glutathione S-transferase (rFgGST26) was expressed in Escherichia coli. This protein had 86% and 56% sequence identity with 26 kDa GST from Fasciola hepatica and Schistosoma mansoni, respectively. Polyclonal antibody raised in ICR mice against rFgGST26 recognized immunoblotted 26 kDa native GSTs from F. gigantica and S. mansoni. rFgGST26 was used as a vaccine in combination with Freund's adjuvant to evaluate the induction of immune responses and protection against F. gigantica and S. mansoni infection in mice. Mice were immunized via subcutaneous (s.c.), intramuscular (i.m.) or intradermal (i.d.) routes. Strong protection (77-84%) against F. gigantica was observed in all routes. Immunization via s.c. route induced immune response with IgG1 isotype predominating, while i.m. and i.d. routes resulted in mixed IgG1/IgG2a immune responses. Passive intraperitoneal transfer of IgG1 predominating antisera from s.c. rFgGST26-immunized donors to naive recipient mice resulted in 47% protection against F. gigantica infection. This suggests that the mechanism of resistance depends on the presence of specific antibody against rFgGST26. Immunization with rFgGST26 via i.m. and i.d. routes resulted in significant cross protection (55%) against S. mansoni infection in the i.d. route with mixed IgG1/IgG2a response with IgG1 isotype predominating. This indicated that rFgGST26 is a good vaccine candidate against F. gigantica in mice and could also provide cross protection against S. mansoni.


Routine exercise testing or thallium-201 scintigraphy for prediction of cardiac events post-myocardial infarction?
The efficacy of 12 lead exercise testing and rest/exercise 201Tl scintigraphy as indicators of coronary anatomy and prognosis was compared in 46 low risk survivors of acute myocardial infarction. The non invasive procedures were performed at discharge, and cardiac catheterization was performed six weeks post discharge. On exercise testing, ST depression in leads remote from the site of infarction was considered to indicate multivessel disease and reversible ischaemia. On 201Tl scintigraphy, a perfusion defect remote from the site of infarction indicated multivessel disease, while a defect which reperfused at rest indicated reversible ischaemia. During the mean follow-up of 13 +/- 3 months, 14(30%) patients experienced cardiac events. Thallium scintigraphy was a more sensitive, but less specific, indicator of multivessel disease than exercise testing. Both exercise testing and 201Tl scintigraphy had a similar sensitivity (79% vs 79%), specificity (78% vs 88%) and predictive accuracy (78% vs 85%) for predicting subsequent cardiac events. Thus, in our patient population, 201Tl scintigraphy could not be demonstrated to be superior to routine exercise testing in low risk patients post myocardial infarction.


Plasma endothelin-1 in patients with left-to-right shunt.
Endothelin-1 (ET-1) has been implicated in the pathogenesis of pulmonary vascular disease in patients with congenital heart disease. We studied the effect of pulmonary blood flow on plasma ET-1 concentrations. Systemic venous, pulmonary arterial, and pulmonary venous blood samples were obtained from 40 patients with atrial septal defect II (n = 21), ventricular septal defect (n = 10), persistent ductus arteriosus (n = 6), and complete (n = 2) and partial (n = 1) atrioventricular canal at cardiac catheterization and analyzed by radioimmunoassay. Median age (range) was 5.2 years (8 months to 66 years), and the resistance ratio (Rp/Rs) was 0.08 (0.03 to 0.67). Pulmonary vein to pulmonary artery ET-1 ratio in patients with "high flow" (n = 26, Qp/Qs > or = 1.5; ET-1 ratio = 0.8) did not differ from those with "low flow" (n = 14, Qp/Qs < 1.5; ET-1 ratio = 1.0). We conclude that an increase in pulmonary blood flow alone does not result in an increase in plasma ET-1.


Altered ganglioside composition in virally transformed rat embryo fibroblasts.
The composition of gangliosides was examined in a normal rat embryo fibroblast cell line (REF52) and in two viral transformants: a polyoma transformant (REF52-PyMLV) and a simian viral 40 transformant (REF52-SV40). The distribution of gangliosides in the cell lines was determined using gas-liquid chromatography and high-performance thin-layer chromatography. N-acetylneuraminic acid was the predominant sialic acid species detected in the three cell lines. The total ganglioside concentration (microgram/100 mg dry weight of cells) in the normal, PyMLV, and SV40 lines was 144.7 +/- 10.4, 153.8 +/- 9.2, and 86.1 +/- 6.8, respectively. Gangliosides GM3, GM2, GM1, and GD1a were the major species in the normal and transformed lines. The distribution of these gangliosides, however, differed markedly between the normal and the transformed lines and also between the transformed lines themselves. The transformed cells also differed from the normal cells in growth rate, morphology, and social behavior. The cell line with highest GM3 content (PyMLV) formed islands, whereas the normal and SV40 cell lines, which had lower GM3 levels, grew as monolayers. The findings suggest that PyMLV and SV40 transformation can have multiple and different effects on cellular ganglioside distribution and growth behavior.


Electrophoretic protein profiles of rat gonads during differentiation.
The protein patterns of fetal rat gonads (14 1/2-21 1/2 days of gestation) were examined by SDS gel electrophoresis. Male gonads contained more protein components at all stages.


High ligation in adolescents: Is it enough?
In adults, the gold standard for surgical repair of an inguinal hernia is a mesh repair, whereas, in children, the standard is high ligation of the hernia sac. However, adolescents represent a "gray zone" between children and adults, and there is no consensus on the most appropriate operation for inguinal hernias in these patients. We aimed to describe the outcomes in adolescents undergoing high ligation for inguinal hernia repair and determine what factors may portend an increased risk of recurrence in this population. A retrospective cohort study was performed of all children that underwent open high ligation for an inguinal hernia at our tertiary children's hospital from January 2000 to January 2018, who were 12 to 18 years old at the time of surgery. We compared the patient demographic data, medical history, and repair characteristics for the cohort of hernias that developed a recurrence to the cohort that did not. During our study period, 256 adolescent patients underwent repair with 11 of those patients having both sides repaired for a total of 267 hernias repaired. The median age at surgery was 14.7 years, and 83.9% of the hernias were in male patients. There was a 6.0% recurrence rate, and all patients that developed recurrence underwent a reoperation. The median time from surgery to reoperation for recurrence was 3.1 years. Patients with recurrence were more likely to have cardiac (25.0% vs. 5.8%, p = 0.02) and gastrointestinal comorbidities (25% vs. 7.1%, p = 0.01). There were no other significant differences between the two cohorts. High ligation of the hernia sac in adolescents is effective and has an acceptable risk of recurrence while avoiding any additional morbidity that may come from the use of mesh. Patients with cardiac and gastrointestinal comorbidities should be counseled on the higher risk of recurrence.


Flutamide versus stilboestrol in the management of advanced prostatic cancer. A controlled prospective study.
In a prospective randomised study the effect of flutamide 750 mg daily was compared with that of stilboestrol 3 mg daily in the treatment of 40 previously untreated patients with advanced prostatic cancer. There was a good subjective response to both treatments. After 12 months, a response was demonstrated in 13 of 20 patients treated with flutamide and 8 of 20 patients treated with stilboestrol. The difference was not statistically significant. Treatment with stilboestrol caused more frequent, and more severe, side effects than flutamide.


Resection of peritoneal metastases causing malignant small bowel obstruction.
Resection of peritoneal metastases has been shown to improve survival in patients with abdominal metastatic disease from abdominal or extra abdominal malignancy. This study evaluates the benefit of peritoneal metastatic resection in patients with malignant small bowel obstruction and a past history of treated cancer. Patients undergoing laparotomy for resection of peritoneal metastases from recurrence of previous cancer between 1992-2003 were reviewed retrospectively. Data were collected about type of primary cancer, interval to recurrence, extent of the disease and completeness of resection, morbidity and mortality and long-term survival. Between 1992 and 2003 there were 79 patients (median age 62, range 19-91) who had laparotomy for small bowel obstruction due to recurrent cancer. The primary cancer was colorectal (31), gynaecologic cancer (19), melanoma (16) and others (13). Overall, the rate of complications was 35% and mortality was 10%. Median survival was 5 months; patients with history of colorectal cancer had better survival than other cancer (median survival 7 months vs. 4 months; p = 0.02). Multivariate analysis showed that the extent of recurrent disease was the only factor that affected overall survival. Laparotomy for small bowel obstruction is a worthwhile option for patients with malignant small bowel obstruction. Although it is associated with significant morbidity and mortality it offers a reasonable survival benefit in particular for patients with completely resectable disease.


How hydrophobically modified chitosans are stabilized by biocompatible lipid aggregates.
Nanostructured hydrogels composed by biocompatible molecules are formulated and characterized. They are based on a polymer network formed by hydrophobically modified chitosans (HMCHIT or CnCHIT) in which vesicles of monoolein (MO) and oleic acid or sodium oleate (NaO), depending on pH, are embedded. The best conditions for gel formation, in terms of pH, length of the hydrophobic moieties of chitosan, and weight proportion among the three components were estimated by visual inspection of a large number of samples. Among all possible combinations, the system C12CHIT-MO-NaO in the weight proportion (1:1:1) is optimal for the formation of a well-structured gel-like system, which is also confirmed by rheological experiments. Electron paramagnetic resonance (EPR) measurements unambiguously show the presence of lipid bilayers in this mixture, indicating that MO-NaO vesicles are stabilized by C12CHIT even at acid pH. A wide small angle neutron scattering investigation performed on several ternary systems of general formula CnCHIT-MO-NaO shows that the length of the hydrophobic tail Cn is a crucial parameter in stabilizing the polymer network in which lipid vesicles are embedded. Structural parameters for the vesicles are determined by using a multilamellar model that admits the possibility of displacement of the center of each shell. The number of shells tends to be reduced by increasing the polymer content. The thickness and the distance between consecutive lamellae are not influenced by either the polymer or MO-NaO concentration. The hydrogel presented in this work, being fully biocompatible and nanostructured, is well-suited for possible application in drug delivery.


Long-term simulations of the 137Cs dispersion from the Fukushima accident in the world ocean.
The LAMER calculation code was used for simulation of the distribution of (137)Cs released after the Fukushima accident into the Pacific and Indian Oceans. The maximum (137)Cs concentration predicted for surface waters of the open NW Pacific Ocean in 2012 (21 Bq/m(3) at 38 °N, 164 °E) will be comparable to that observed during the early 1960s after atmospheric nuclear weapons tests. The (137)Cs in surface waters of the Pacific Ocean will reach the US coast 4-5 y after the accident, however, the levels will be low (<3 Bq/m(3)). All the North Pacific Ocean will be labeled with Fukushima (137)Cs 10 y after the accident with concentrations below 1 Bq/m(3). Thirty years after the accident the (137)Cs levels in the Pacific and Indian Oceans will be below 0.1 Bq/m(3), i.e. undetectable on the present global fallout background. The effective dose commitment with ingestion of marine biota found in 2012 in the open NW Pacific Ocean was estimated to be 1.7 μSv/y, mostly delivered by (134,137)Cs. The estimated dose is by about a factor of 500 lower than the present dose limit for the public.


Cultured cell lines from human breast cancer biopsies and xenografts.
Eighty-five breast cancer specimens were processed as part of a program in tumor acquisition, propagation, and preservation for biotherapy. Nine long-term culture cell lines were developed. Four cell lines were from solid tumor metastases, two lines were from pleural fluid specimens, and three were from xenograft tumors grown in nude mice. Two of the xenograft-derived cell lines were from biopsies which produced tumor cell lines as well. Success in establishing cultures did not correlate with the viability of the biopsy received. Poor tumor cell attachment to culture plastic was the most common problem. For certain specimens, attachment and growth were enhanced on collagen and extracellular matrix substrates. Collagen was beneficial in the development of one cell line. The cell lines were characterized and each of the lines contained more nuclear DNA than found in normal cells. Four of five lines tested were tumorigenic in nude mice. Five of nine were clonogenic in soft agar. Each of the cell lines tested reacted with at least two anti-tumor monoclonal antibodies. Xenograft and biopsy-derived cell lines from the same tumor were similar in their characteristics. While breast cancers are indeed difficult to establish and propagate in culture, the use of xenografts and special substrates appears to be beneficial in the development of cell lines from some tumors.


Evaluation of apoptotic effect of cyclic imide derivatives on murine B16F10 melanoma cells.
Cyclic imides are a large class of compounds obtained by organic synthesis including several sub-classes (succinimides maleimide, glutarimide, phthalimides naphtalimides, and its derivatives). Recently, some cyclic imide derivatives have shown important results as potential antitumor agents, as a Mitonafide and Amonafide. Based on this fact, we have studied antitumoral properties of nine cyclic imide derivatives, four of which are unpublished compounds, against Murine Melanoma Cells (B16F10). Initially, the MTT assay was used to select the compound with the best cytotoxic potential. After this selection, the compound 2-benzyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (4), which showed the best cytotoxic effects, was evaluated by flow cytometry, and a significant increase was observed in the proportion of cells in the subG0/G1, S and G2/M phases accompanied by a significant decrease in the G0/G1 phases. Then the mechanism involved on the death route (necrosis or apoptosis) was evaluated the by bromide and acridine orange method and by an Annexin V-FITC Apoptosis Detection kit. These results confirm that the percentage of B16F10 cells observed in the sub G0/G1 phase were undergoing apoptosis. The biological effects observed in the current study for the cyclic imide derivatives suggested promising applications, especially for the prototype compound 4.


The use of the key grip procedure for improving hand function in quadriplegia.
Reconstruction of the quadriplegic hand can give marked functional improvement. In 1975 the key grip procedure was introduced on the Spinal Injuries Unit at Rancho Los Amigos Hospital. Twenty of the first twenty-four cases operated on have obtained a useful improvement, and the reasons for the four failures are readily seen. In correctly cases the key grip procedure is of benefit to the patient and complications are relatively minor.


Social Responsibility: Sustainable Development Goals and COVID-19-Perception Scale of Students from Higher Education Institutions.
Social movements and the consequences of the current health crisis resulting from COVID-19 have deepened social injustices and inequities, which can be addressed through the benchmarks set by the Sustainable Development Goals (SDGs). This research is related to the perspective of Higher Education Institutions (HEIs) as social transformation agents. The purpose of this research is to create a scale to measure students' perception of the social responsibilities developed by HEIs from the SDGs' perspective. A matrix solution was found after Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) composed of four dimensions. The constructs that form the four dimensions can be used to design strategies which contribute to the SDGs' goals, for which it is necessary to have the opinions of the actors that are part of the educational community. Future research should consider carrying out comparative studies according to sociodemographic variables for a better understanding of the social phenomenon.


Rapid construction of a dendritic cell vaccine through physical perturbation and apoptotic malignant T cell loading.
We have demonstrated that adherence and release of monocytes from a plastic surface drives their differentiation into immature dendritic cells (DC,) that can mature further during overnight incubation in the presence of apoptotic malignant T cells. Based on these results, we sought to develop a clinically, practical, rapid means for producing DC loaded with malignant cells. A leukapheresis harvest containing the clonal, leukemic expansion of malignant CD4+ T cells was obtained from the blood of patients with cutaneous T cell lymphoma (CTCL). CTCL cells were purified with a CD3-magnetic bead column where CD3 engagement rendered the malignant T cells apoptotic. The monocyte fraction was simultaneously activated by column passage, re-added to the apoptotic CTCL cells and co-cultured overnight. CTCL cell apoptosis, DC differentiation and apoptotic malignant T cell ingestion were measured by immunostaining. The results demonstrate that as monocytes passed through the column matrix, they became activated and differentiated into semi-mature DC expressing significantly increased levels of class II, CD83 and CD86 (markers associated with maturing DC) and reduced expression of the monocyte markers CD14 and CD36. Apoptotic malignant T cells were avidly engulfed by the phagocytic transitioning DC. The addition of supportive cytokines further enhanced the number of DC that contained apoptotic malignant T cells. Functional studies confirmed that column passaged DC increased class II expression as shown by significantly enhanced stimulation in mixed leukocyte culture compared to control monocytes. In addition, DC loaded with apoptotic CTCL cells stimulated an increase in the percentage and absolute number of CD8 T cells compared to co-cultivation with non-loaded DC. After CD8 T cells were stimulated by DC loaded with malignant cells, they mediated increased apoptosis of residual CTCL cells and TNF-alpha secretion indicating development of enhanced cytolytic function. We report a simple one-step procedure where maturing DC containing apoptotic malignant T cells can be prepared rapidly for potential use in vaccine immunotherapy. Ready access to both the DC and apoptotic cells provided by this system will allow extension to other malignancies through the addition of a variety of apoptotic tumor cells and maturation stimuli.


The dendritic extent of motoneurons in frog brachial spinal cord: a computer reconstruction of HRP-filled cells. With comments on dendritic reconstruction methodologies.
A lateral and a medial motoneuron in the brachial spinal cord of the leopard frog, Rana pipiens, were labeled by horseradish peroxidase applied to the ventral root. Their dendritic trees were traced, analyzed, and plotted using a computer-microscope system. Some dendrites of the medial motoneuron crossed the midline of the spinal cord, but no dendrites of the lateral motoneuron crossed the midline. Nevertheless, the total dendritic length of the lateral motoneuron exceeded that of the medial motoneuron. The peak number of dendritic branch segments of the medial motoneuron was located at a greater distance from its soma than that of the lateral motoneuron. Three-dimensional reconstruction and rotation of the dendritic trees revealed that the dendrites of the medial motoneuron had a greater rostrocaudal extent than those of the lateral motoneuron. When compared to reports of Golgi-impregnated motoneurons, our results suggest that the HRP technique labels dendrites more completely. However, use of the HRP technique may introduce greater errors in the subsequent measurement of dendritic segments due to nonuniform tissue shrinkage.


Harnessing the power of collective intelligence in dentistry: a pilot study in Victoria, Australia.
In many dental settings, diagnosis and treatment planning is the responsibility of a single clinician, and this process is inevitably influenced by the clinician's own heuristics and biases. Our aim was to test whether collective intelligence increases the accuracy of individual diagnoses and treatment plans, and whether such systems have potential to improve patient outcomes in a dental setting. This pilot project was carried out to assess the feasibility of the protocol and appropriateness of the study design. We used a questionnaire survey and pre-post study design in which dental practitioners were involved in the diagnosis and treatment planning of two simulated cases. Participants were provided the opportunity to amend their original diagnosis/treatment decisions after viewing a consensus report made to simulate a collaborative setting. Around half (55%, n = 17) of the respondents worked in group private practices, however most practitioners (74%, n = 23) did not collaborate when planning treatment. Overall, the average practitioners' self-confidence score in managing different dental disciplines was 7.22 (s.d. 2.20) on a 1-10 scale. Practitioners tended to change their mind after viewing the consensus response, particularly for the complex case compared to the simple case (61.5% vs 38.5%, respectively). Practitioners' confidence ratings were also significantly higher (p < 0.05) after viewing the consensus for complex case. Our pilot study shows that collective intelligence in the form of peers' opinion can lead to modifications in diagnosis and treatment planning by dentists. Our results lay the foundations for larger scale investigations on whether peer collaboration can improve diagnostic accuracy, treatment planning and, ultimately, oral health outcomes.


Supplementation of lycopene attenuates oxidative stress induced neuroinflammation and cognitive impairment via Nrf2/NF-κB transcriptional pathway.
Oxidative stress, considered as a major culprit in brain aging, triggers cognitive and memory impairment. Lycopene (LYC), a carotenoid pigment, possesses potent antioxidative, anti-inflammatory, and neuroprotective properties. In the present study, the effects of LYC on oxidative stress-induced cognitive defects and the underlying mechanisms were determined. The behavioral tests, including Y-maze test, locomotor activity and Morris water maze test, revealed that chronic LYC supplementation (50 mg/kg bodyweight per day) alleviated d-galactose induced CD-1 male mice cognitive impairments. LYC ameliorated histopathological damage and restored brain derived neurotrophic factor (BDNF) levels in the hippocampus of mice. LYC also significantly elevated antioxidant enzymes activities and reduced levels of inflammatory cytokines in the d-galactose-treated mice serum. Moreover, LYC treatment activated the mRNA expressions of antioxidant enzymes HO-1 and NQO-1, and downregulated inflammatory cytokines IL-1β and TNF-α in mice hippocampus. Immunohistochemical results also demonstrated that LYC significantly restored the expression of glial cells inflammatory makers Iba-1 and GFAP. Furthermore, LYC attenuated neuronal oxidative damage through activation of Nrf2 signaling and inactivation of NF-κB translocation in a H2O2-induced SH-SY5Y cell model. Therefore, these results illustrated that LYC could ameliorate oxidative stress induced neuroinflammation and cognitive impairment possibly via mediating Nrf2/NF-κB transcriptional pathway.


Perceptual improvement following repetitive sensory stimulation depends monotonically on stimulation intensity.
Electrical repetitive sensory stimulation (rSS) is a direct and effective means of inducing plasticity processes in human beings, and is increasingly being used as a therapeutic intervention. Suprathreshold intensities induce beneficial effects on tactile perception and sensorimotor abilities. However, it is not known whether there is an optimal range of stimulus intensity. We investigated the effect of varied intensities (low, 1.19 ± 0.07 mA; intermediate, 3.33 ± 0.27 mA; and high, 4.42 ± 0.56 mA) on the outcome of a 30-minute electrical rSS applied to the index finger (intermittent high-frequency stimulation, 20 Hz and interburst interval, 5 seconds) in three groups (n = 10 each) of participants. As a marker of perceptual changes, we measured tactile spatial two-point discrimination on the stimulated finger and on the heel of the hand before and after the rSS. rSS improved discrimination performance, with the gain being the highest in the high-intensity group and the lowest in the low-intensity group. Measurements on the heel of the hand revealed small improvements in the high-intensity group, indicative of recruitment processes. rSS of maximal intensity induced the strongest effects, indicative of a monotonic intensity-gain characteristic with no U-shaped dependency.


Attenuation of adjuvant-induced arthrits by Stereospermum colais and Stereospermum suaveolens via modulation of inflammatory mediators.
The plants selected for this study, Stereospermum colais and Stereospermum suaveolens are named as Patala in Ayurvedic medicine. Patala is a component of the reputed dasamula (ten roots) used for various imperative Ayurvedic formulations. The roots of Patala have rich traditional value especially in the treatment of inflammation and rheumatism. Nevertheless no methodical study has been consummated in these plants. Consequently, an endeavor to ascertain the anti-arthritic potential of the two plants was made besides to impart the fact with regards to the supreme one. The aim of the study is to evaluate the anti-arthritic potential of Stereospermum colais and Stereospermum suaveolens using Complete Freund's Adjuvant induced arthritic model. The freshly collected root material of Stereospermum colais (SC) and Stereospermum suaveolens (SS) were successively extracted with solvents such as petroleum ether, chloroform, ethyl acetate and ethanol by cold maceration and the ethanolic extract of Stereospermum colais (EESC) and Stereospermum suaveolens (EESS) were standardized using lapachol as standard. The extracts were further subjected to acute oral toxicity and in vivo anti-arthritic evaluation by Complete Freund's Adjuvant induced arthritic model using methotrexate as standard. Body weight changes, reduction in paw volume, biochemical, histopathological and the expression of Cluster of differentiation 4 cells, inflammatory cytokines such as Tumor necrosis factor-α, Interleukin-2 and Tranforming growth factor-β through immunohistochemical analysis were studied to access the anti-arthritic potential. s: The Extracts EESC and EESC were standardized using lapachol by HPLC method and the amount was found to 3.9% w/w and 0.9% w/w respectively. The LD50 of the tested extracts EESC and EESS were found to be greater than 2000 mg/kg b.w through acute oral toxicity study. The extracts EESC (58.97%) and EESS (20.51%) were significantly reduced the paw volume in a dose dependent manner. The reduction in the paw volume exhibited the anti-inflammatory potential of the ethanolic extract of both the plants. The extracts at the dose of 400 mg/kg has markedly inhibited the change in joint architecture as compared to arthritic control. Also the study revealed that the extracts may possibly act by affecting the T cell mediated inflammatory process which was evident by decreased expression of Cluster of Differentiation 4 cells, Interleukin-2 and Tumor necrosis factor-α. The Extracts were found to have rich phytochemicals such as terpenoids, flavonoids, quinones, phenols and tannins may probably attribute to the anti-arthritic property of the plants. The lapachol a naphthaquinone present in both the extracts also contributed for its property. The study concludes that ethanolic extract of both the plants (EESC and EESS) exhibited significant anti-arthritic activity and Stereospermum colais was found to be more potent than Stereospermum suaveolens which corroborates the traditional use of roots of Stereospermum colais and Stereospermum suaveolens in the treatment of arthritis.


Nutritional status, dental caries and tooth eruption in children: a longitudinal study in Cambodia, Indonesia and Lao PDR.
Untreated dental caries is reported to affect children's nutritional status and growth, yet evidence on this relationship is conflicting. The aim of this study was to assess the association between dental caries in both the primary and permanent dentition and nutritional status (including underweight, normal weight, overweight and stunting) in children from Cambodia, Indonesia and Lao PDR over a period of 2 years. A second objective was to assess whether nutritional status affects the eruption of permanent teeth. Data were used from the Fit for School - Health Outcome Study: a cohort study with a follow-up period of 2 years, consisting of children from 82 elementary schools in Cambodia, Indonesia and Lao PDR. From each school, a random sample of six to seven-year-old children was selected. Dental caries and odontogenic infections were assessed using the World Health Organization (WHO) criteria and the pufa-index. Weight and height measurements were converted to BMI-for-age and height-for-age z-scores and categorized into weight status and stunting following WHO standardised procedures. Cross-sectional and longitudinal associations were analysed using the Kruskal Wallis test, Mann Whitney U-test and multivariate logistic and linear regression. Data of 1499 children (mean age at baseline = 6.7 years) were analyzed. Levels of dental caries and odontogenic infections in the primary dentition were significantly highest in underweight children, as well as in stunted children, and lowest in overweight children. Dental caries in six to seven-year old children was also significantly associated with increased odds of being underweight and stunted 2 years later. These associations were not consistently found for dental caries and odontogenic infections in the permanent dentition. Underweight and stunting was significantly associated with a lower number of erupted permanent teeth in children at the age of six to seven-years-old and 2 years later. Underweight and stunted growth are associated with untreated dental caries and a delayed eruption of permanent teeth in children from Cambodia, Indonesia and Lao PDR. Findings suggest that oral health may play an important role in children's growth and general development. The study was restrospectively registered with the German Clinical Trials Register, University of Freiburg (trial registration number: DRKS00004485 ; date of registration: 26th of February, 2013).


Carabid fecundity as affected by extrinsic and intrinsic factors.
Eight species of carabids (six of them represented by two subpopulations) were sampled. It appeared that the mean number of ripe eggs in the ovaries could be regressed on the specific body weight (ranging from 20 to 285 mg dry wt.): the mean decreased in heavier species, and was higher in the autumn breeders than in the spring breeders. The rate of disappearance of ripe eggs from ovaries, estimated at the end of the reproductive season, was regarded as the egg deposition rate. It turned out to be inversely correlated with the actual female mobility. The calculated fecundities in the separate species and subpopulations with the same type of development could be satisfactorily regressed on the specific body weight. Thus, the developmental type, the specific body weight, and actual female mobility are involved in egg production and deposition.


[The military intensive care field hospital, a unique experience in the fight against covid-19].
The militaryintensive care field hospital is a new tool set up by the military medical service as part of Operation Resilience to provide medical support in the regions of France most affected by the SARS-Cov-2 pandemic. Deployed in Mulhouse and Mayotte, this hospital facility is a functional intensive care unit set up to support an existing hospital structure. The caregivers and logistics specialists are all from the military medical service, active personnel or reservists, predominantly nurses. The implementation of this intensive care field hospital in a constrained environment requires an efficient provision of care in accordance with medical guidelines, while protecting the healthcare staff and, notably, the frontline nursing staff.


Outcomes of men who present with elevated serum PSA (>20 ng/mL) to an inner-city hospital.
We report the incidence, clinicopathologic features, and outcomes of men who presented to an inner-city hospital with serum PSA >20 ng/ml. Five-hundred-sixty men underwent a transrectal ultrasound needle-guided biopsy of the prostate for elevated PSA >4 ng/ml with or without an abnormal digital rectal examination. Of the 560 men, 65 (12%) were found to have a serum PSA >20 ng/ml, and 57 (10%) were diagnosed with prostate cancer. In the group of 57 men with cancer, the positive predictive value of PSA alone was 72% for PSA levels of 20-29.99 ng/ml and 100% for PSA >30 ng/ml. Of the 57 men, 18 underwent definitive therapy, 24 underwent androgen deprivation, 8 refused treatment or were lost to follow-up, and 7 were treated on protocol. An additional seven men with cancer refused therapy or were lost to follow-up, thus giving a total of 15 (26%) men who were noncompliant to medical advice. Serum PSA >30 ng/ml is an almost certain predictor of the presence of prostate cancer. Aggressive prostate cancer education and screening programs are needed in our inner cities in order to detect prostate cancer at an earlier, treatable stage.


Exploring the victim offender overlap among people with an intellectual disability.
While there is growing international evidence pointing to the increased risks of crime perpetration and victimisation for some people with an intellectual disability, the overlap between offending and victimisation (the victim-offender overlap) remains unclear. This study utilised a data linkage methodology of 2600 people with an intellectual disability, exploring their contacts with public mental health services and the police in Victoria, Australia. Victim-offenders accounted for a small proportion of the sample (n = 148, 5.7%). The victim-offender overlap was evident for both violent and nonviolent nonsexual crimes, particularly for theft, burglary, and threat-related crimes. Key differences were also noted between males and females. People with an intellectual disability who are both victim and offenders comprise a small but particularly complex justice-involved population. Future research should explore the victim offender overlap for males and females separately, as well as any additional risks and vulnerabilities associated with specific mental health diagnoses.


Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients.
To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used. There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. The results demonstrate a concentration-response relation for paroxetine in late-life depression and support the hypothesis for both a direct main effect and a moderating influence of 5-HTTLPR alleles on this concentration-response relation.


Metal bioaccumulation and mutagenesis in a Tradescantia clone following long-term exposure to soils from urban industrial areas and closed landfills.
Soil mutagens, particularly metals, may persist long after the source of pollution has been removed, representing a hazard to plants, animals, and humans in or near contaminated areas. Often, due to urban growth, previous land uses may be forgotten and hazards overlooked. We exposed Tradescantia clone #4430 plants to soil from two industrial areas (with different former uses) and two urban waste landfills in the city of Vilnius, all of which were long disused. Two modes of exposure were used: long-term exposure of growing plants in test soils for 0.5 or 1.0y, and short-term exposure of cuttings to water and dimethyl sulfoxide (DMSO) soil extracts. An increased frequency of micronuclei (MN) was observed with both modes of exposure. The concentrations of 24 metals and other elements were analyzed in the test soils and in above-ground plant parts, under both exposure modes, and the concentration coefficients (Cc) for various elements, the total contamination index (Zs) for soils and plants, and the bioaccumulation factor (BAF) for plants were calculated. These measurements allow a comparison of the contamination levels of soils and plants with equalized values. Metal accumulation levels in plants and soils showed significant differences, providing a better understanding of the genotoxicity of soils from closed landfills and highlighting the need to determine the concentrations of metals and other genotoxicants in plants in relation to genotoxicity.


Biological feasibility of measles eradication.
Because of the success of global measles control programs, the World Health Organization (WHO), along with its partner agencies, is once again considering the possibility of setting a target date for measles eradication. Measles would be the fourth viral agent to be eradicated joining the successful programs to eradicate smallpox and rinderpest virus, and the continuing effort to eradicate polio virus. A description of the recent progress toward measles eradication was recently published as a supplement in the Journal of Infectious Diseases (15 July, 2011, 204 (Suppl. 1)) and the reader is referred to this document for a detailed summary of the global status of measles control. This review will focus on the biologic and virologic aspects of measles eradication.


Deciphering the role of plant plasma membrane lipids in response to invasion patterns: how could biology and biophysics help?
Plants have to constantly face pathogen attacks. To cope with diseases, they have to detect the invading pathogen as early as possible via the sensing of conserved motifs called invasion patterns. The first step of perception occurs at the plasma membrane. While many invasion patterns are perceived by specific proteinaceous immune receptors, several studies have highlighted the influence of the lipid composition and dynamics of the plasma membrane in the sensing of invasion patterns. In this review, we summarize current knowledge on how some microbial invasion patterns could interact with the lipids of the plasma membrane, leading to a plant immune response. Depending on the invasion pattern, different mechanisms are involved. This review outlines the potential of combining biological with biophysical approaches to decipher how plasma membrane lipids are involved in the perception of microbial invasion patterns.


High moisture extrusion cooking on soy proteins: Importance influence of gums on promoting the fiber formation.
The influence of gums on the quality of extrudates prepared by the high moisture extrusion cooking of soy protein was studied. Three food gums, iota carrageenan (ICGN), carboxymethylcellulose sodium (CMC) and sodium alginate (SA), were investigated for their effects on promoting the fiber formation of extrudates. Results obtained indicated that lamellar structures were formed at the cooling zone for samples containing 6% CMC and 6% SA. The addition of 6% SA enhanced the quality of extrudates, such as improved rehydration rate and digestion rate. Furthermore, interactions between protein molecules over the extrusion process were also analyzed, and the importance of the type of molecular bonds responsible for the formation of extrudates was determined to be: disulfide bonds ≥ hydrogen interactions > hydrophobic interactions. Results of this work would be of importance in the design of meat analogs using soy protein concentrate, and more importantly, in the understanding of protein-protein interactions during extrusion for sustainable health.


Effects of orthostatic stress on forearm endothelial function in normal subjects and in patients with hypertension, diabetes, or both diseases.
Sympathetically mediated vasoconstriction, to compensate for reduced venous return and cardiac output, characterizes the circulatory adaptation to head-up tilting (HUT). It has not been clarified whether this is coupled with a modulating endothelial vasorelaxation and whether diseases causing endothelial dysfunction, such as diabetes and hypertension, may impair this counterregulatory mechanism. In patients with hypertension (group 1), diabetes (group 2), or both diseases (group 3) and in healthy control subjects (12 subjects per group) we investigated the brachial artery vasodilating response to the release of distal circulatory arrest (DCA) while they were supine and during 60 degrees HUT. The supine increase in lumen was smaller (P<.01) in groups 1 (+4.5%+/-1.5%), 2 (+4.8%+/-1.4%), and 3 (+3.9%+/-1.3%) than in the control group (+8.6%+/-1.6%). Vasorelaxation by nitroglycerin was similar in each population. During HUT, the lumen response to DCA was enhanced (P<.01 v supine) in control subjects (+15.4%+/-2.5%) and group 1 (+10.0+/-2.4%) and was reduced (P<.01 v supine) in groups 2 (+2.9%+/-0.5%) and 3 (+2.1%+/-0.4%), even though the hyperemic reaction to DCA was similar. The ratio of lumen changes to changes in flow (mm/mL/min x 1000) during reactive hyperemia to DCA increased (P<.01) with HUT, compared with that in the supine position, in control subjects (1.75v1.19) and group 1 (1.61v0.95), and decreased (P<.01) in groups 2 (0.62v0.87) and 3 (0.48v0.77). The HUT posture is characterized by an increased endothelium-dependent, flow-mediated vasodilation as a possible modulator of the neural vasoconstriction. This effect is persistent but blunted in hypertension and is abolished in diabetes, either alone or in association with high BP. Thus, vasoconstrictor factors could remain unmodulated during an event such as orthostasis, making the risk posed by these disorders more critical.


Stress stimuli-induced histopathological changes in the prostate: an experimental study in the rat.
To elucidate a suggested relationship between stress stimuli and prostatis, a histological study on the genital organs of seven rats was performed. The specimens were histopathologically examined after a 10-day period, during which the rats had been submitted to standardized stress stimuli, and compared with corresponding organs from a control group of seven male rats. Inflammatory histopathological changes and large numbers of inflammatory cells were seen in the prostatic glands of all rats submitted to the long-term stress stimuli. The findings agreed with those from the prostatic glands of human males with prostatis. No corresponding changes were observed in the control group. There was no evidence indicating a bacterial origin. The results indicate a connection between stress stimuli and prostatitis.


An integrated lab-on-a-chip platform for pre-concentration and detection of colorectal cancer exosomes using anti-CD63 aptamer as a recognition element.
Colorectal cancer (CC) is one of the common causes of cancer-related deaths around the globe. Identification of a novel biomarker for CC is of paramount importance for early diagnostics and reducing its mortality. Among the most promising biomarker candidates, exosomes hold great potential for cancer diagnosis, management, and treatment. Exosomes are extracellular vesicles secreted from cells and they contribute to the intercellular communication, immune response and the pathogenesis of many diseases including cardiovascular diseases, neurodegenerative diseases, and cancer. Several methods have been developed/utilized for exosome isolation and purification. However, these methods are time-consuming and have low purification efficiency. In this work, we developed the "apta-magnetic biosensor" platform for isolation, purification and detection of exosomes from cell culture. Anti-CD63 aptamer, which is conjugated to the surface of magnetic nanobeads, was used as a recognition element. A dynamic separation system was used which employs a transverse magnetic field along a microfluidic channel. The channel was exposed to an alternate magnetic field which imposes alternate magnetic force onto the magnetic bead-exosome complex. The combination of the fluid flow and magnetic force generates several "alternate trapping and releasing" events under continuous-flow conditions with each event representing a washing cycle. The graphene coated onto the surface of the magnetic nanobeads was used as a quencher for the fluorescently labeled aptamer (OFF state) in the absence of the target. Upon the addition of CD63 target protein, the aptamer dissociates from the graphene and binds to the target hence increasing the fluorescence intensity (ON state). A calibration plot of variable concentrations of exosomes vs fluorescence intensity was obtained and the detection limit was calculated as 1457 particles/mL. The specificity of the sensor was tested using closely associated proteins. The results showed that the aptamagnetic isolation, pre-concentration of exosomes and quantification demonstrate great potential for various clinical applications.


Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities.
COL27A1 encodes a collagen type XXVII alpha 1 chain. It is the product of this gene that provides the structural support of connective tissue and is reported to be the causative gene of Steel syndrome (OMIM #615155). The primary symptoms of patients with this defect are consistent with systemic bone disease; however, recent reports note findings of intellectual disability and hearing loss. In this study, we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome. This variant, of maternal origin, caused an amino acid substitution of arginine for glycine, c.2026G>C or p.G676R, in the collagen helix domain, which is assumed to damage the structure of the helix. The paternally transmitted variant, c.2367G>A, is located at the 3' end of exon 12, and cDNA analysis revealed a splicing alteration. These novel, compound heterozygous COL27A1 variants might indicate an association of the gene with tooth and genital abnormalities.


Early Post-Rewarming Fever Is Associated with Favorable 6-Month Neurologic Outcomes in Patients with Out-Of-Hospital Cardiac Arrest: A Multicenter Registry Study.
We investigated the association between post-rewarming fever (PRF) and 6-month neurologic outcomes in cardiac arrest survivors. This was a multicenter study based on a registry of comatose adult (≥18 years) out-of-hospital cardiac arrest (OHCA) survivors who underwent targeted temperature management between October 2015 to December 2018. PRF was defined as peak temperature ≥ 38.0 °C within 72 h after completion of rewarming, and PRF timing was categorized as within 24, 24-48, and 48-72 h epochs. The primary outcome was neurologic outcomes at six months after cardiac arrest. Unfavorable neurologic outcome was defined as cerebral performance categories three to five. A total of 1031 patients were included, and 642 (62.3%) had unfavorable neurologic outcomes. PRF developed in 389 (37.7%) patients in 72 h after rewarming: within 24 h in 150 (38.6%), in 24-48 h in 155 (39.8%), and in 48-72 h in 84 (21.6%). PRF was associated with improved neurologic outcomes (odds ratio (OR), 0.633; 95% confidence interval (CI), 0.416-0.963). PRF within 24 h (OR, 0.355; 95% CI, 0.191-0.659), but not in 24-48 h or 48-72 h, was associated with unfavorable neurologic outcomes. Early PRF within 24 h after rewarming was associated with favorable neurologic outcomes.


Prefrontal activity during working memory is modulated by the interaction of variation in CB1 and COX2 coding genes and correlates with frequency of cannabis use.
The CB1 cannabinoid receptor is targeted in the brain by endocannabinoids under physiological conditions as well as by delta9-tetrahydrocannabinol under cannabis use. Furthermore, its signaling appears to affect brain cognitive processing. Recent findings highlight a crucial role of cyclooxygenase-2 (COX-2) in the mechanism of intraneuronal CB1 signaling transduction, while others indicate that two single nucleotide polymorphisms (SNPs) (rs1406977 and rs20417) modulate expression of CB1 (CNR1) and COX-2 (PTGS2) coding genes, respectively. Here, our aim was to use fMRI to investigate in healthy humans whether these SNPs interact in modulating prefrontal activity during working memory processing and if this modulation is linked with cannabis use. We recruited 242 healthy subjects genotyped for CNR1 rs1406977 and PTGS2 rs20417 that performed the N-back working memory task during fMRI and were interviewed using the Cannabis Experience Questionnaire (CEQ). We found that the interaction between CNR1 rs1406977 and PTGS2 rs20417 is associated with dorsolateral prefrontal cortex (DLPFC) activity such that specific genotype configurations (CNR1 C carriers/PTGS2 C carriers and CNR1 TT/PTGS2 GG) predict lower cortical response versus others in spite of similar behavioral accuracy. Furthermore, DLPFC activity in the cluster associated with the CNR1 by PTGS2 interaction was negatively correlated with behavioral efficiency and positively correlated with frequency of cannabis use in cannabis users. These results suggest that a genetically modulated balancing of signaling within the CB1-COX-2 pathway may reflect on more or less efficient patterns of prefrontal activity during working memory. Frequency of cannabis use may be a factor for further modulation of CNR1/PTGS2-mediated cortical processing associated with this cognitive process.


Microbiological characteristics of medically important Trichosporon species.
Trichosporon species are opportunistic pathogens associated with a high mortality rate in immunocompromised patients. Disseminated trichosporonosis is uncommon but reports are increasing. In this study, using 16 stock clinical isolates of suspected Trichosporon species and 4 known Trichosporon strains, we investigated the morphology, physio-biochemistry, molecular biology and antifungal susceptibility characteristics of these Trichosporon spp. and discovered that ITS sequence-based identification is a rapid and accurate identification alternative to most phenotypic or physio- biochemical methods. In vitro antifungal susceptibility tests showed high amphotericin B, itraconazole and terbinafine MIC value in these Trichosporon strains.


A cross sectional survey to assess healthcare professionals' attitudes to and understanding of probiotics.
Consumers' belief in the benefits of probiotics is influenced by information they receive from healthcare professionals (HCPs). HCPs therefore need to be aware of the current evidence base in order to advise consumers appropriately. This survey aimed to establish HCP attitudes towards, and understanding of, the use of probiotics in healthcare. An online, cross-sectional survey was distributed to dietitians, paediatricians and General Practitioners (GPs) through three medical/health professional bodies: the British Dietetic Association (BDA), the European Society for Primary Care in Gastroenterology (ESPCG) and the European Paediatric Association (EPA). Paper copies of the survey were distributed at relevant medical congresses. There were 1360 respondents representing all three groups of HCPs. The majority of respondents (86.3%, n = 1068) agreed that probiotics have a place in clinical medicine and were likely to recommend them (72.1%, n = 882), yet only 55.7% (n = 230) of dietitians were familiar with the World Health Organisation (WHO) definition of a probiotic. There was a positive, however, weak correlation between a high level of training and the likelihood of a respondent recommending a probiotic (r = 0.24, p < 0.005). Inadequate knowledge appeared to be a limiting factor in patients receiving evidence-based information and appropriate recommendations. The more concerns an HCP had, the less likely they were to recommend a probiotic regularly (p < 0.005). The majority (91%, n = 1099) of respondents cited a need for more education. HCPs recognise that probiotics have a place in clinical medicine and would recommend them if they had more information to support informed decision-making within patient care.


Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.
In metastatic colorectal cancer (mCRC), acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), was shown to be frequently caused by activating alterations in the RAS genes KRAS or NRAS. To this day, no efficient follow-up treatment option has emerged to treat mCRC in such a setting of resistance. To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome reprogramming in an established cellular model of acquired, KRAS-associated CET resistance. This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly, all investigated resistant cell lines displayed upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of traits of progression. Expectedly resistant cell lines displayed increased migration (p < 0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (RNAi) (p < 0.001), ephrin-A1 stimulation (p < 0.001), dasatinib (p < 0.01), or anti-EPHA2 antibody treatment (p < 0.001), identifying it as an actionable target in mCRC with acquired CET resistance. These results highlight EPHA2 and its role in mCRC with KRAS-gene mutated acquired CET resistance and support its use as a potential actionable target for the development of future precision medicine therapies.


Association between urine protein/creatinine ratio and cognitive dysfunction in Lewy body disorders.
Impaired renal function and proteinuria have been associated with cognitive impairment and dementia. Chronic kidney disease is considered to be an independent risk factor for Lewy body spectrum disorders (LBD). However, few studies have mentioned an association between proteinuria and cognition in LBD. We investigated the relationship between proteinuria and cognitive dysfunction in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Among 186 patients with LBD, 53 had PD-normal cognition (PD-NC), 76 had PD-mild cognitive impairment (PD-MCI), 43 had PD-dementia (PDD) and 14 had DLB. The urine protein/creatinine ratio was calculated using the spot urine test and brain magnetic resonance scans was obtained in all patients. The urine protein/creatinine ratio was significantly higher in patients with PDD and DLB than in those with PD-MCI, PD-NC patients and healthy controls, and was correlated with white matter hyperintensities on magnetic resonance imaging. All abnormal neuropsychological test results were associated with increased urine protein/creatinine ratio. After controlling for age, education, symptom duration, diabetes mellitus, hypertension, and parkinsonian motor severity, the urine protein/creatinine ratio was significantly associated with decreased cognition. The urine protein/creatinine ratio was associated with cognitive status in LBD. These finding suggests that increased protein excretion is associated with cognitive dysfunction in patients with LBD.


The efficacy of an HIV risk reduction intervention for Hispanic women.
Culturally-specific HIV risk reduction interventions for Hispanic women are needed. SEPA (Salud/Health, Educación/Education, Promoción/Promotion, y/and Autocuidado/Self-care) is a culturally-specific and theoretically-based group intervention for Hispanic women. The SEPA intervention consists of five sessions covering STI and HIV prevention; communication, condom negotiation and condom use; and violence prevention. A randomized trial tested the efficacy of SEPA with 548 adult U.S. Hispanic women (SEPA n = 274; delayed intervention control n = 274) who completed structured interviews at baseline and 3, 6, and 12 months post-baseline. Intent-to-treat analyses indicated that SEPA decreased positive urine samples for Chlamydia; improved condom use, decreased substance abuse and IPV; improved communication with partner, improved HIV-related knowledge, improved intentions to use condoms, decreased barriers to condom use, and increased community prevention attitudes. Culturally-specific interventions have promise for preventing HIV for Hispanic women in the U.S. The effectiveness of SEPA should be tested in a translational community trial.


[Expert recommendation: treatment of nonambulatory patients with Duchenne muscular dystrophy].
Duchenne muscular dystrophy (DMD) is the most frequent genetic neuromuscular disease in childhood with loss of ambulation usually occurring around the age of 9-11 years. Based on current guidelines and clinical trials, neuropediatric and neurological experts developed recommendations for the treatment of nonambulatory DMD patients focusing on drug treatment of adults. This advisory board was sponsored by PTC Therapeutics, the distributers of the substance ataluren. Loss of ambulation is heterogeneously defined across clinical trials. Among others, the need of a wheelchair, ambulation without mobility aids or maximum walking distance can be suitable parameters for assessment. Treatment of DMD patients at any stage of the disease is based on supportive and symptomatic measures, which should be continued after loss of ambulation. In addition, disease-modifying drugs are available for the treatment of DMD and glucocorticoids are the usual standard of care treatment even beyond the loss of ambulation. Ataluren, a potentially dystrophin restorative, disease-modifying treatment, has been approved for patients with DMD due to a nonsense mutation (nmDMD), which applies to approximately 13% of DMD patients and is usually combined with steroids. Clinical data from the STRIDE registry demonstrated a delayed disease progression even after loss of ambulation. Currently, no reliable data are available for exon skipping approaches in adult DMD patients. The antioxidant idebenone could be an option in nonambulant adolescent patients not treated with glucocorticoids and without other therapeutic options. A combination treatment of idebenone and glucocorticoids is currently being investigated in a clinical trial. Add-on treatment with idebenone in addition to ataluren may be considered for nonambulant nmDMD patients. Some of the discussed treatment options are still in clinical trials or there are not enough data for older DMD patients; therefore, these expert recommendations correspond to evidence class IV.


Diesel exhaust in the occupational setting. Current understanding of pulmonary health effects.
Doll's landmark 1959 study of the epidemiology of occupational lung cancer failed to find an increased risk in workers exposed to petrol fumes and emissions. In it, he pointed out a critical issue that is not resolved today. With theoretically increased risk based on biological plausibility but an absence of positive findings, epidemiologic methodology cannot reliably distinguish between no risk and very little risk. Despite the ensuing nearly 40 years of research, neither human epidemiologic studies nor animal studies can support a causal relationship between either lung cancer or noncancer respiratory health effects at current levels of occupational exposure. Even with statistically significant but low relative risks, neither evidence of causality nor level of risk can be definitively established. Epidemiologic data suggest that an increased risk of lung cancer for diesel exhaust exposed workers may be comparable with that for environmental tobacco smoke. Monitoring and control of the particulate is necessary. Prudent policy dictates continued efforts to reduce emissions of soot from diesel engines and decrease occupational exposure as a matter of good health and safety practice. Improvements in engine design, soot filters, and fuel modification will provide the best approach to exposure control. Further research is also needed in the areas of carcinogenic mechanisms and development and validation of biomarkers of exposure before reliable estimates of risk of human health effects in the occupational setting can be made.


Mucous glands in the developing human rhinopharynx.
In 42 fetuses and prematures, the entire mucosa from the rhinopharynx was stained by various whole-mount methods. The development, growth, spread, distribution, situation, and size of the glands were determined. The development starts in the 11th week below the tubal orifice, whence the glands spread to the entire rhinopharynx. The number increases gradually by about 60-70 glands a week. By the 23rd week, there are 1,100-1,200 glands in the rhinopharynx. After that juncture, there is presumably no further new formation. The density and size of the glands were at a maximum in Rosenmüller's recess, below the tubal orifice, and in the salpingopharyngeal fold, least anterior to the tubal orifice and at the junction to the pharynx. The role of the sero-mucous glands in the rhinopharynx under normal and abnormal conditions is dicussed.


Genome Sequence of Novel Clostridium perfringens Bacteriophage vB_CpeS-17DYC, Isolated from Wastewater in China.
Phage vB_CpeS-17DYC was isolated from wastewater from a poultry market using Clostridium perfringens strain DYC. The vB_CpeS-17DYC genome is 39,184 bp long, with 65 open reading frames and a GC content of 30.6%. It shared 93.95% nucleotide identity, with 70% query coverage, with Clostridium phage phiCP13O (GenBank accession number NC_019506.1). Virulence factor genes were not found in the vB_CpeS-17DYC genome.


Medical management of epilepsy.
The treatment of epilepsy depends on an accurate diagnosis of the specific type of epilepsy. Where possible it is important to prescribe the minimum amount of medication for seizure control, preferably with monotherapy. The ultimate aim of treatment is to achieve maximal improvement in the quality of life for the patient.


A simplified math approach to predict ICU beds and mortality rate for hospital emergency planning under Covid-19 pandemic.
The different stages of Covid-19 pandemic can be described by two key-variables: ICU patients and deaths in hospitals. We propose simple models that can be used by medical doctors and decision makers to predict the trends on both short-term and long-term horizons. Daily updates of the models with real data allow forecasting some key indicators for decision-making (an Excel file in the Supplemental material allows computing them). These are beds allocation, residence time, doubling time, rate of renewal, maximum daily rate of change (positive/negative), halfway points, maximum plateaus, asymptotic conditions, and dates and time intervals when some key thresholds are overtaken. Doubling time of ICU beds for Covid-19 emergency can be as low as 2-3 days at the outbreak of the pandemic. The models allow identifying the possible departure of the phenomenon from the predicted trend and thus can play the role of early warning systems and describe further outbreaks.


Effects of bleaching and regeneration on the purple membrane structure of Halobaterium halobium.
Sequential bleaching in the presence of hydroxylamine and subsequent regeneration of the purple membrane of Halobacterium halobium was studied by concomitant monitoring of its absorption and circular dichroic spectra in order to ascertain its effects on protein interaction(s) (which may result in possible excitonic interaction between the retinal chromophores), chromophore-apoprotein interaction(s), and protein conformational stability in the membrane. It was concluded that (a) although experimental results are consistent with an exciton mechanism for the interaction between retinal pi - pi* (NV(1)) transition movements in the purple membrane, no evidence for such a mechanism for interaction between retinaloxime transition moments is apparent in the case of the bleached membrane; (b) the bacteriorhodopsin molecules organized in clusters of three in the membrane appear to bleach simultaneously; (c) the retinaloxime produced on bleaching the purple membrane in the presence of hydroxylamine is strongly optically active, because of dissymmetry-inducing and/or -selecting constraints on the chromophore by a component of the membrane (most likely the apoprotein), and when the membrane is regenerated by the addition of retinal, these constraints are lost; and (d) evidence from ultraviolet absorption and circular dichroic spectra suggests that the membrane apoprotein undergoes appreciable conformational changes involving tertiary structure on bleaching with no significant secondary structure involvement. These results are compared with recently reported results from this laboratory on the effects of bleaching on the bovine rod outer segment disk membrane structure.


[Aswer to "Comment on article "Bibliometric analysis of scientific publications on COVID-19 elaborated by staff of the Instituto Mexicano del Seguro Social""].
We thank the group headed by Jorge Valencia Alonso for taking the time to review in detail and prepare the letter about our article entitled: " Bibliometric analysis of scientific publications on COVID-19 elaborated by staff of the Instituto Mexicano del Seguro Social", which has recently been published in the Medical Journal of the Mexican Social Security Institute. Based on your observations and comments, we allow ourselves to make the following clarifications following the same sequence of your letter to the Editor.