Changes in Lacto-Fermented Agaricus bisporus (White and Brown Varieties) Mushroom Characteristics, including Biogenic Amine and Volatile Compound Formation.
This study aimed to evaluate the changes in Agaricus bisporus (white and brown) characteristics (colour and acidity parameters, lactic acid bacteria (LAB) and mould/yeast counts, biogenic amine content, fatty acid (FA) and volatile compound (VC) profiles, overall acceptability, and emotions induced for consumers) during a 48 h lactic acid fermentation with Lacticaseibacillus casei No. 210, Lactiplantibacillus plantarum No. 135, Lacticaseibacillus paracasei No. 244, and Pediococcus acidilactici No. 29 strains. Fermented white and brown A. bisporus showed higher LAB count and lower pH, lightness, redness, and yellowness than non-fermented ones. Yeast and fungi counts were similar between non-fermented and fermented samples. All samples contained spermidine (on average, 191.5 mg/kg) and some of the fermented samples had tyramine (on average, 80.7 mg/kg). Saturated FA was the highest in non-fermented brown A. bisporus. The highest monounsaturated and polyunsaturated FA contents were found in Lp. plantarum No. 135 fermented white and brown A. bisporus, respectively. For the first time, the VC profile of fermented A. bisporus was analysed. 1-Octen-3-ol content significantly decreased while benzyl alcohol, acetoin, and 2,3-butanediol increased in most fermented samples. Fermented A. bisporus received good acceptability scores. The emotional evaluation showed that the LAB strain and the interaction of the LAB strain and A. bisporus variety were significant on the intensity of emotions "happy" and "sad", while all analysed factors and their interactions were significant on the intensity of "angry" and "disgusted" (p ≤ 0.05). The findings of this study show the potential of the selected LAB strains and contribute to the increasing body of research on fermented mushrooms.


1-3 piezoelectric composite transducers for swept-frequency calibration of hydrophones from 100 kHz to 2 MHz.
Rapid calibration of hydrophones used in biomedical ultrasound is possible with swept frequency techniques such as time delay spectrometry. However, calibrations below 2 MHz largely have been neglected because of insufficient transmitting transducer bandwidth, even though important medical applications operate in this range. To address this deficiency, several transmitting transducer designs were developed and tested, and two 1-3 piezoelectric composite designs were found to have the requisite bandwidth and uniformity of response. In one the element has a plane front face and spherically concave back face (plano-concave), and in the second both faces are concave, but with different radii of curvature (biconcave). The nonuniform thickness disperses the thickness resonance, and the composite structure suppresses radial-mode resonances. Also, the composite's lower acoustic impedance provides a more efficient match to water. The piezoelectric composite transducers were found to have transmitting pressure sensitivities superior to ceramic single-element and segmented designs having similar dimensions, and their responses were significantly more uniform (< 25 dB variation from 0.1-2 MHz, with < 1 dB fine structure variation), likely due to decreased contributions from radial modes.


Secondary structure and membrane interaction of PR-39, a Pro+Arg-rich antibacterial peptide.
PR-39 is a 4719-Da peptide isolated from pig intestine and belonging to the recently discovered family of Pro+Arg-rich antibacterial peptides. PR-39 does not lyse Escherichia coli, instead the lethal action is probably linked to the termination of DNA and protein synthesis [Boman, H. G., Agerberth, B. & Boman, A. (1993) Infect. Immun. 61, 2978-2984]. Circular dichroism and Fourier-transform infrared spectroscopy have been used to investigate the secondary structure of PR-39 in the absence or presence of lipids. According to the circular dichroic data, this structure is not altered upon incubation of PR-39 with negatively charged vesicles, although the infrared spectra suggest that the hydrogen bond pattern is modified upon the peptide-lipid interaction. This is detected by a shift in the maximum wavelength of absorption of PR-39 from 1636 cm-1 in the absence of lipids to 1645 cm-1 in the presence of lipids. We have further addressed the question of the possible mechanism of interaction of PR-39 with model membranes (liposomes and planar lipid bilayers) whose lipid compositions mimick that of the E. coli inner membrane. PR-39 induced a calcein release from large unilamellar vesicles, which is dependent upon the peptide concentration and upon the presence of negatively charged lipid (glycerophosphoglycerol) in the membrane. The binding study of PR-39 to dioleoylglycerophosphoglycerol vesicles suggests that nearly 100% of the added peptide is membrane-bound. Addition of PR-39 to a planar lipid bilayer induced a linear increase in the current but no channel formation was observed since no discrete steps of conductance occurred.


The ARTS (Avoiding Risks of Thrombosis and Bleeding in Surgery) Trial: Lessons Learnt in Setting Up an International Multicentre Clinical Trial of an Investigational Medicinal Product in the UK.
We describe our experience in setting up the UK arm of the ARTS trial and highlight regulatory and funding challenges in relation to an international multicentre setting for an investigational medicinal product.


Autoantibodies in children with type 2 diabetes mellitus.
To evaluate the frequency of autoantibodies to glutamic acid decarboxylase (GAD), protein tyrosine phosphatase-like protein (IA-2), and insulin (IAA) in children with type 2 diabetes mellitus (DM), we studied 37 children and adolescents whose type 2 DM was defined by fasting and 90-min standard liquid meal-stimulated serum C-peptide levels of >0.2 and >0.5 nmol/l (0.7 and 1.5 ng/ml), respectively. Mean fasting-stimulated serum C-peptide levels were 1.1 +/- 0.10 nmol/l (3.38 +/- 0.29 ng/ml) and 1.9 +/- 0.17 nmol/l (5.79 +/- 0.50 ng/ml), respectively. Eleven out of 37 patients (29.7%) were positive for at least one autoantibody: 8.1% (n = 3) had positive GAD, 8.1% (n = 3) had positive IA-2, and 27% (n = 10) had positive IAA. Nine of the 10 IAA-positive patients were on insulin treatment at the time of testing. Three of the 10 IAA-positive patients were also positive for GAD or IA-2. Since insulin treatment can stimulate IAA, we considered this to be less informative in classifying autoimmunity in DM. Therefore, GAD and IA-2 were considered primary autoimmune markers. Four out of 37 patients (10.8%) were positive for GAD (n = 3) or IA-2 (n = 3) or both (n = 2). Thus, low (10.8%) frequency of autoimmunity in children and adolescents is consistent with their clinical classification of type 2 DM based on the presence of residual C-peptide.


The detection of disease clustering in time.
This paper presents a new index for the level of disease clustering in time, which is devised to the case where the data are grouped into several equally spaced intervals. This index is applicable to both temporal and cyclical clustering. The asymptotic distribution of this index is derived under the null hypothesis of no clustering in time. Monte Carlo simulation studies show that the asymptotic results are good approximations when the sample size is as small as the number of intervals, an average of one per interval. The powers of the test based on this index for both types of clustering are compared with those of several existing procedures. Tables of upper percentage points of this index are given.


Effectiveness of percutaneous flexor tenotomies for the management and prevention of recurrence of diabetic toe ulcers: a systematic review.
Diabetic toe ulcers are a potentially devastating complication of diabetes. In recent years, the percutaneous flexor tenotomy procedure for the correction of flexible claw and hammer-toe contraction deformities has been proposed as a safe and effective technique for facilitating the healing of toe-deformity related diabetic ulcers. The aim of this review is to critically appraise the evidence for the effectiveness of this surgical procedure in achieving ulcer healing, prevention of re-ulceration, and to summarise the rate of post-operative complications. A search of medical databases, was performed to locate relevant literature. Titles were screened prior to abstract and full text review to identify articles relevant to the research question. Search terms included truncations of "tenotomy", "toe", "hallux", "digit", "diabetes" and "ulcer". Peer reviewed primary research study designs specified as suitable for systematic reviews by the Centre for Reviews and Dissemination were included. Studies were excluded if they used a concurrent secondary procedure or included non-diabetic patients without reporting outcomes separately. Included studies were appraised for quality using the Methodological Index for Non-Randomised Studies tool. Levels of evidence were subsequently assigned to each outcome of interest (healing rate and prevention of re-ulceration). From a total search yield of 42 articles, 5 eligible studies (all case series designs) were identified for inclusion. Included studies were of low-to-moderate methodological quality when assessed using the MINORS tool. A total of 250 flexor tenotomy procedures were performed in a total of 163 patients. Included studies generally reported good healing rates (92-100 % within 2 months) post-op follow-up), relatively few recurrences (0-18 % at 22 months median post-op follow-up), and low incidences of infection or new deformity. Transfer ulcers developing on adjacent areas as a result of shifted pressure were reported by several authors. The validity of these results is undermined by methodological limitations inherent to case series designs such as a lack of control groups, non-randomised designs, as well as inconsistent reporting of post-intervention follow-up periods. There was level 4 evidence for the flexor tenotomy procedure in facilitating ulcer healing and preventing re-ulceration. More definitive research evidence is needed in this area to determine whether or not the flexor tenotomy is a safe and effective treatment option for people with, or at risk of developing diabetic toe ulcers. Whilst the available literature reports that the procedure may be associated with high healing rates, relatively low recurrence rates and low incidences of post-op complications, methodological limitations restrict the value of these findings.


Intercropping of Faba Bean with Wheat Under Different Nitrogen Levels Reduces Faba Bean Rust and Consequent Yield Loss.
While intercropping can help control faba bean rust, the ability of intercropping to reduce this disease under different levels of nitrogen fertilization and its contribution to increasing yield is not clear. In this study, two planting patterns of faba bean monocropping and wheat/faba bean intercropping, together with two treatments for disease control and noncontrol, and four nitrogen application levels (N0 [0 kg/ha], N1 [45 kg/ha], N2 [90 kg/ha], and N3 [135 kg/ha]) were tested for 2 years in a continuous field experiment. The results revealed that nitrogen application increased the area under the disease progress curve (AUDPC) of faba bean rust from 41.9 to 47.3%, with the N3 treatment resulting in the largest increase. Nitrogen application decreased the relative control efficacy of intercropping on faba bean rust. Compared with monocropping, N0 to N3 with intercropping significantly reduced AUDPC by 33.1% for the first year and 28.7% for the second year (P < 0.05). Nitrogen application aggravated the faba beans grain yield loss, while the loss of yield components increased in the first year and then declined as the nitrogen application increased; the yield losses of monocropping were higher than those of intercropping. The N1 and N2 application levels significantly increased the total effect (TE) of intercropping yield advantage by 34.3 and 32.9% in the 2 years, respectively. During the 2 years, the overall partial land equivalent ratio of faba bean was greater than 0.33. The average disease control effect (DCE)/TE of intercropping was 56.1 and 49.3% for the 2 years, respectively, indicating that intercropping increased yields and that the contribution of the DCE was close to or higher than that of the other intercropping effects. A regression analysis of the grain yield loss and the AUDPC showed that reducing the nitrogen fertilizer input (N1) could effectively reduce the yield loss caused by rust and enhance the yield. Intercropping of faba bean combined with a suitable nitrogen application (45 kg/ha) is the best treatment to maximize yield by fully utilizing intercropping for managing faba bean rust.


Incidence of post-intubation subglottic stenosis in children: prospective study.
To evaluate the incidence of subglottic stenosis in children undergoing endotracheal intubation. Children in the paediatric intensive care unit of a tertiary care hospital were considered eligible for inclusion if they received endotracheal intubation for more than 24 hours. After extubation, children underwent flexible fibre-optic nasolaryngoscopy. Based on this first evaluation, they were divided into two groups: 'acute normal', with mild laryngeal alterations or normal findings; and 'acute alterations', with moderate to severe laryngeal alterations. Further laryngoscopic follow up (7-10 days later) was undertaken for those children in the acute normal group who developed symptoms during follow up (after discharge from the intensive care unit), and for all children in the acute alterations group. Children were then classified into two final groups: 'normal final examination', with no chronic changes; and 'subglottic stenosis'. We included 123 children. The incidence of subglottic stenosis was 11.38 per cent (95 per cent confidence interval, 6.63-17.94 per cent). All the children who developed subglottic stenosis had had moderate to severe alterations immediately after extubation. This incidence of subglottic stenosis is quite high and needs further investigation to identify risk factors.


Assessment of the effect of cold and hot temperatures on mortality in Ontario, Canada: a population-based study.
Ambient high temperature is associated with death; however, heat-related risk of death has not been quantified systematically in Ontario, the most populous province in Canada. Less is known about cold-related risk in this population. Our objective was to quantify the health impact from cold and hot temperatures in Ontario. The study population consisted of all residents of Ontario who died between Jan. 1, 1996, and Dec. 31, 2010, from any nonaccidental cause. A case-crossover analysis was applied to assess the relation between daily temperature fluctuation and deaths from nonaccidental and selected causes in cold (December-February) and warm (June-August) seasons, respectively, adjusting for various potential confounders. Risk estimates were obtained for each census division, then pooled across Ontario. We examined potential effect modification for selected comorbidities and sociodemographic characteristics. In warm seasons, each 5°C increase in daily mean temperature was associated with a 2.5% increase in nonaccidental deaths (95% confidence interval [CI] = 1.3% to 3.8%) on the day of exposure (lag 0). In cold seasons, each 5°C decrease in daily temperature was associated with a 3.0% (95% CI 1.8% to 4.2%) increase in nonaccidental deaths, which persisted over 7 days (lag 0-6). The cold-related effects (lag 0-6) were stronger for cardiovascular-related deaths (any cardiovascular death: 4.1%, 95% CI 2.3% to 5.9%; ischemic heart disease: 5.8%, 95% CI 3.6% to 8.1%), especially among people less than 65 years of age (8.0%, 95% CI 3.0% to 13.0%). Conversely, heat most strongly increased respiratory-related deaths during admission to hospital (26.0%, 95% CI 0% to 61.4%). Across Ontario, each 5°C change in daily temperature was estimated to induce 7 excess deaths per day in cold seasons and 4 excess deaths in warm seasons. Heat contributed to excess deaths in Ontario, although the effect of cold weather appeared to be greater. Further work is required to better define high-risk subgroups, which might include the homeless and people with inadequately heated housing.


[A questionnaire investigation on the way of delivery and its related factors in 415 women at child bearing age in one hospital].
To understand the changing trend on the way of delivery since 1970s and its related factors that influencing the attitude of choice on Cesarean section (C-section) in women at child-bearing age. A face-to-face interview was conducted anonymously in pregnant and lying-in women visited at the out-patient department of Gynecology and Obstetrics, Tiantan Hospital of Beijing. Totally, 415 women at child-bearing age, with a history of previous birth were interviewed on date, place and way of delivery of last birth, as well as on information that could have had impact on the choice of C-section. The average rate of C-section in Tiantan Hospital had been 29% since the year of 2000, much higher than that during 1970s, 1980s and 1990s (chi(2) = 22.81, P = 0.001) which showed an increasing trend. Rate of C-section among lying-in women with native Beijing origin was 25.0%, significantly higher than 9.6% (chi(2) = 21.96, P = 0.000 002) that in the migrants. Lying-in women with education level of high school or above had higher chance to choose C-section than those with lower level of education (chi(2) = 43.64, P < 0.000 01). Workers, managerial staff or clerks had more chance to choose C-section than those with other occupations (chi(2) = 20.07, P = 0.01). As reported by the interviewees, 93% (70/75) of C-section in the hospital were performed and recommended by obstetricians. Rate of C-section in the hospital showed an increasing trend which suggested that intervention with health education be carried out for both pregnant women and obstetricians.


Haematological changes in human immunodeficiency virus infection. Part II.
This second part of the review looks at change seen in the bone marrow haemostasis and malignancies found in HIV infection. Examination of bone marrow is requested in the presence of cytopaenias, splenomegaly, lymphomas and myelodysplasia. The findings include marrow hypocellularity, myelodysplasia and poor marrow recovery. Dysmegakaryocytpoiesis is found in 88% while dyserythropoeisis in 83% of cases. Mechanisms leading to these pertubations include direct HIV effect on marrow progenitor cells, effect of drugs and other infective diseases. Altered levels and functions of growth modifies IL6 and G-CSF are also to contribute. Haemostatic disorder frequently noted is bleeding due to thrombocytopaenia. Non-Hodgkin's lymphomas with aggressive characteristics and Kaposi's sarcoma are the commonly associated malignancies. Currently IL6 is being linked with the causation of KS and NHL. While standard approaches to the management of these malignancies tend to be the practices, adjustments are usually necessary in most patients.


Opioids or Steroids for Pneumonia or Sinusitis.
To compare the frequency of opioid and corticosteroid prescriptions dispensed for children with pneumonia or sinusitis visits on the basis of location of care. We evaluated 2016 South Carolina Medicaid claims data for 5 to 18 years olds with pneumonia or sinusitis. Visits were associated with 1 of 3 locations: the emergency department (ED), urgent care, or the ambulatory setting. Inclusion criteria were met by 31 838 children. Pneumonia visits were more often linked to an opioid prescription in the ED (34 of 542 [6.3%]) than in ambulatory settings (24 of 1590 [1.5%]; P ≤ .0001) and were more frequently linked to a steroid prescription in the ED (106 of 542 [19.6%]) than in ambulatory settings (196 of 1590 [12.3%]; P ≤ .0001). Sinusitis visits were more often linked to an opioid prescription in the ED (202 of 2705 [7.5%]) than in ambulatory settings (568 of 26 866 [2.1%]; P ≤ .0001) and were more frequently linked to a steroid prescription in the ED (510 of 2705 [18.9%]) than in ambulatory settings (1922 of 26 866 [7.2%]; P ≤ .0001). In logistic regression for children with pneumonia, the ED setting was associated with increased odds of receiving an opioid (adjusted odds ratio [aOR] 4.69) or steroid (aOR 1.67). Similarly, patients with sinusitis were more likely to be prescribed opioids (aOR 4.02) or steroids (aOR 3.05) in the ED than in ambulatory sites. School-aged children received opioid and steroid prescriptions for pneumonia or sinusitis at a higher frequency in the ED versus the ambulatory setting.


Intralabyrinthine schwannoma.
In the case presented, an intralabyrinthine schwannoma was discovered during translabyrinthine eighth nerve section. Analysis of this case and the 22 previously reported cases of intralabyrinthine schwannoma highlights the difficulty in preoperative diagnosis of this lesion. Concerns are raised about the frequency with which this diagnosis may be missed and its implication in neurotologic surgery for vertigo.


Enzymatic synthesis of p-nitrophenyl 3(5)-O-beta-N-acetylglucosaminyl-alpha-maltopentaoside by lysozyme; a novel substrate for human amylase assay.
Transglycosylation from di-N-acetylchitobiose to the 3-position at the nonreducing end glucosyl group of p-nitrophenyl alpha-maltopentaoside was regioselectively induced through the use of hen egg-white lysozyme. The enzyme formed p-nitrophenyl 3(5)-O-beta-N-acetylglucosaminyl-alpha-maltopentaoside (5% of the enzyme-catalyzed net decrease of p-nitrophenyl alpha-maltopentaoside) from di-N-acetylchitobiose as a donor and p-nitrophenyl alpha-maltopentaoside as an acceptor. The rate of the transglycosylation depended on the concentration of substrate, the temperature and the pH. The hydrolytic actions of human pancreatic and salivary alpha-amylase on this derivative were examined. The maltopentaoside derivative was shown to be useful as a substrate for alpha-amylase assay through a coupled reaction involving alpha-D-glucosidase and glucoamylase.


Cervical Subarachnoid Drain for the Treatment of Cerebrospinal Fluid Leak: 2-Dimensional Operative Video.
Cerebrospinal fluid (CSF) leak is a common phenomenon encountered by the neurosurgeon. It is most commonly come across after a neurosurgical procedure, but it can be seen idiopathically. Treatment usually ranges from conservative management through cerebrospinal fluid diversion to direct surgical repair. Continuous CSF drainage provides a path for diversion and allowing the site of the dural injury to heal effectively.1 Cervical subarachnoid drain is a safe and effective alternative when lumbar access is contraindicated or not achievable.2 Here we present a case of a 22-yr-old female with progressive symptomatic positional headaches due to a CSF leak from a prior deformity surgery treated with a cervical subarachnoid drain after a failed attempt at a direct repair. This 2-dimensional video illustrates the technique used for the placement of a cervical subarachnoid drain for the treatment of symptomatic CSF leak. Patient consented to the procedure and for the publication of their image.


Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA). To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs). This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018. The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2). A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD. This study found large phenotypic variability associated with individuals carrying a DRA with 7 to 8 RUs, in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis. These findings suggest that carriers of a DRA with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD. Based on these results, it is recommended that clinicians use the Comprehensive Clinical Evaluation Form for clinical classification and, whenever possible, study the extended family to provide the most adequate clinical management and genetic counseling.


A feasibility study of caregiver-provided massage as supportive care for Veterans with cancer.
To assess the feasibility of using a multimedia program to teach caregivers of Veterans with cancer how to offer basic massage for supportive care at home. Feasibility was assessed according to partner availability, compliance with watching training materials and practicing massage regularly, compliance with data collection; perceived study materials burden; clarity of instructional and other study materials. Pre- and post-massage changes in patients' symptom scores were measured using a numerical rate scale. A semistructured exit interview was answered by patient and caregiver at the end of the study. A total of 27 dyads were recruited. Veterans were 78% male. Forty-eight percent were diagnosed with hematologic malignancies (85%, advanced stage); 52% were diagnosed with solid tumors (64% advanced stage). Caregivers were 78% female; 81% were spouses. Out of the 27 pairs, 11 completed 8 weeks of data and practiced massage weekly. The majority of attrition (69%) was due to caregivers' burden. Caregivers reported instructional materials were clear, high quality, and easy to use. Patients were highly satisfied with receiving touch from their partners regularly. Post-massage symptom scores showed statistically significant decreases in pain, stress/anxiety, and fatigue. Perceived burden of data collection instruments was high, particularly for patients. It is feasible to use the TCC program to train caregivers of Veterans with cancer to offer massage for supportive care at home. Future studies should evaluate ways of providing support to caregivers, including offering massage to them, and easing the burden of data collection for patients.


A brief history of therapy for traumatic spinal cord injury.
There are few more devastating injuries that afflict man than those associated with spinal cord injury (SCI). The economic, psychological, and social impact are encompassing and enormous to the individual and society. During the last several years, there has been a renewed interest in the study of SCI, with the hope of finding a cure. It is appropriate, then, to examine the efforts accomplished throughout medical history. With this retrospective view, potential avenues for future treatment become more apparent and clear. As in the past, the integration of basic science and clinical innovation will create the path toward progress for treatment of this disease.


Unusual tandem expansion and positive selection in subgroups of the plant GRAS transcription factor superfamily.
GRAS proteins belong to a plant transcription factor family that is involved with multifarious roles in plants. Although previous studies of this protein family have been reported for Arabidopsis, rice, Chinese cabbage and other species, investigation of expansion patterns and evolutionary rate on the basis of comparative genomics in different species remains inadequate. A total of 289 GRAS genes were identified in Arabidopsis, B. distachyon, rice, soybean, S. moellendorffii, and P. patens and were grouped into seven subfamilies, supported by the similarity of their exon-intron patterns and structural motifs. All of tandem duplicated genes were found in group II except one cluster of rice, indicating that tandem duplication greatly promoted the expansion of group II. Furthermore, segment duplications were mainly found in the soybean genome, whereas no single expansion pattern dominated in other plant species indicating that GRAS genes from these five species might be subject to a more complex evolutionary mechanism. Interestingly, branch-site model analyses of positive selection showed that a number of sites were positively selected under foreground branches I and V. These results strongly indicated that these groups were experiencing higher positive selection pressure. Meanwhile, the site-specific model revealed that the GRAS genes were under strong positive selection in P. patens. DIVERGE v2.0 was used to detect critical amino acid sites, and the results showed that the shifted evolutionary rate was mainly attributed to the functional divergence between the GRAS genes in the two groups. In addition, the results also demonstrated the expression divergence of the GRAS duplicated genes in the evolution. In short, the results above provide a solid foundation for further functional dissection of the GRAS gene superfamily. In this work, differential expression, evolutionary rate, and expansion patterns of the GRAS gene family in the six species were predicted. Especially, tandem duplication events played an important role in expansion of group II. Together, these results contribute to further functional analysis and the molecular evolution of the GRAS gene superfamily.


A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia.
The antidepressant mirtazapine is an alternative to classical hypnotics, and this study investigated the efficacy and safety of esmirtazapine (Org 50081, the maleic acid salt of S-mirtazapine) in patients given a diagnosis of primary insomnia after acute (2-day) treatment. Patients aged 18 to 65 years with primary insomnia were randomized to receive placebo or 1.5-, 3.0-, or 4.5-mg esmirtazapine in a balanced 4-way crossover study; 2 sleep laboratory nights with polysomnography were separated by 5-day, single-blind placebo washout periods. Polysomnography-determined total sleep time (primary end point) and patient-reported total sleep time improved by at least 25 minutes with all 3 doses of esmirtazapine (P ≤ 0.001 vs placebo). Polysomnography-measured wake time after sleep onset (P ≤ 0.0001) and latency to persistent sleep also improved vs placebo (P ≤ 0.01, 3.0 and 4.5 mg). Patient-reported sleep quality improved with 3.0- and 4.5-mg esmirtazapine (P ≤ 0.01 and P ≤ 0.05, respectively, vs placebo). Morning alertness and contentment were not altered after esmirtazapine, and calmness increased with 4.5-mg esmirtazapine vs placebo. Evening questionnaires showed no difference in duration of daytime naps but reduced energy and ability to work/function after esmirtazapine treatment periods vs placebo (P < 0.05), although this effect was limited to the first night of each 2-night period. There were few adverse events, no serious adverse events, or clinically relevant treatment differences in vital signs, laboratory values, or electrocardiogram. Esmirtazapine doses of 1.5 to 4.5 mg/day significantly improved quantity and quality of sleep and were generally well tolerated, with no evidence of safety concerns or consistent pattern of residual effects.


Integrated approach to pain management for a patient with multiple bone metastases of uterine cervical cancer.
Background Pain management for multiple bone metastases is complex and often requires multidisciplinary treatment. We herein describe patient-centered multidisciplinary pain management for metastatic cancer. A 61-year-old woman with multiple bone metastases of uterine cervical cancer developed intractable low back pain. After external beam radiotherapy failed, we performed lumbar spinal intralesional curettage, pedicle screw fixation, and nerve decompression. However, the neuralgia persisted. We then percutaneously injected epirubicin into the intervertebral foramina under computed tomography guidance for L5 dorsal root ganglion destruction. Osteoplasty was performed under C-arm X-ray guidance; however, the sacrum was mistaken for the ilium, and treatment was ineffective. We administered zoledronic acid and strontium-89. The last resort was outpatient implantation of an epidural bupivacaine-morphine infusion system. A visual analog scale (VAS) was used for pain evaluation. Lumbar spinal intralesional curettage and fixation, epirubicin-induced ganglion destruction, and administration of zoledronic acid and strontium-89 decreased her VAS pain score from 7-8 to 3-4. Radiotherapy and nerve decompression and release were ineffective, as was osteoplasty because of the location error. The epidural infusion system decreased the VAS score from 7-8 to 2-3 and was highly efficient. Conclusions Multidisciplinary integrated treatment for metastatic cancer can be effective.


Potential Cost Savings by Switching from Subcutaneous to Intralymphatic Insect Venom Immunotherapy.
IgE-mediated bee venom allergy can be treated with allergen-specific immunotherapy (AIT). Subcutaneous immunotherapy (SCIT) is time and cost intensive due to the repeated consultations, but the costs are justified by the high risk of potentially life-threatening allergic reactions, including anaphylaxis. However, intralymphatic immunotherapy (ILIT) offers potential to reduce treatment costs due to a significant reduction in injections and a shorter duration of therapy. Therefore, we calculated the cost savings that arise when switching from SCIT to ILIT. Treatment protocols for ILIT were based on previous ILIT studies. Treatment protocols for SCIT were based on routine treatment at the University Hospital Zurich (USZ). The treatment costs were calculated based on the internal hospital information system (KISIM). The calculations revealed a potential two-fold reduction in treatment costs if ILIT is used instead of SCIT in patients with bee venom allergy. The costs could be reduced from EUR 11,612.59 with SCIT to EUR 5,942.15 with ILIT over 5 years. This study shows that bee venom ILIT has a cost-benefit potential for health insurances and patients, which should encourage further ILIT studies and which should be taken into account when considering future implementation of ILIT in the standard care of venom allergy.


Hospital Admissions in Pediatric Patients With Tracheostomies Based on Rurality and Insurance Status.
Determine whether rurality or public insurance status is associated with greater 30-day readmission after tracheostomy in pediatric patients. Retrospective cohort. Pediatric Health Information System (PHIS) Database. Patients within PHIS who underwent tracheostomy from 2013 to 2017 were included. Rural status was defined by rural-urban commuting area codes. Insurance status was based on the primary payer. All-cause 30-day readmissions and tracheostomy-related readmissions were recorded. Multivariate logistic regression was performed to test for differences in readmissions between cohorts. Among patients, 1092 were rural, and 4329 were publicly insured, with no significant association between rurality and insurance. Compared to nonrural patients, rural patients were more frequently white, less frequently ventilator dependent, and more likely discharged home rather than to a care facility. Publicly insured patients were more frequently non-white. Twenty-eight percent of patients were readmitted within 30 days of discharge. Odds of 30-day readmission were lower in rural patients (odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.68-0.95, p = .01) but higher in publicly insured (OR: 1.24, 95% CI: 1.09-1.42, p = .001) controlling for age at tracheostomy, sex, race, and ventilator dependence. The odds of tracheostomy-related admission did not differ by rurality but were higher in publicly insured children (1.39, 95% CI: 1.03-1.88, p = .03). Readmission within 30 days following tracheostomy was more likely in publicly insured patients and less likely in rural patients. These findings help identify at-risk patients when considering discharge planning and follow-up. More work is needed to understand long-term tracheostomy outcomes in these groups.


Nitration of specific tyrosine residues of cytochrome C is associated with caspase-cascade inactivation.
Peroxynitrite, a potent oxidative stress inducer, inhibits the mitochondrial electron transfer, induces cell death, and is considered to be involved in the pathology of various diseases. However, the intracellular mechanisms involved in the cell death process are not fully understood. Here we demonstrate that the enhanced nitration of specific tyrosine residues of cytochrome c, which are induced by continuous peroxynitrite exposure, attenuates cytochrome c-induced caspase-9 activation in vitro. Interestingly, cytochrome c nitrated with a single high dose of peroxynitrite preserved its potency, while this did not occur when cytochrome c was treated with continuous peroxynitrite exposure. Although both of these experiments resulted in cytochrome c nitration at the tyrosine residues, it was found that nitration at specific residues was enhanced only when cytochrome c was exposed to continuous peroxynitrite. This is the first report to demonstrate that cytochrome c nitration affects the apoptotic pathway by means of enhancement of nitration at specific tyrosine residues. This result implies that the nitration pattern of cytochrome c may affect the efficacy of the mitochondrial pathway in apoptotic cell death.


Antibacterial surfaces: the quest for a new generation of biomaterials.
In this review we attempt to clarify the notion of what is meant by the term antibacterial surfaces and categorise the approaches that are commonly used in the design of antibacterial surfaces. Application of surface coatings and the modification of the surface chemistry of substrata are generally considered to be a chemical approach to surface modification (as are surface polymerisation, functionalisation, and derivatisation), whereas, modification of the surface architecture of a substrate can be considered a physical approach. Here, the antifouling and bactericidal effects of antibacterial surfaces are briefly discussed. Finally, several recent efforts to design a new generation of antibacterial surfaces, which are based on mimicking the surface nanotopography of natural surfaces, are considered.


Cold Side-Effect Effect: Affect Does Not Mediate the Influence of Moral Considerations in Intentionality Judgments.
Research has consistently shown that people consider harmful side effects of an action more intentional than helpful side effects. This phenomenon is known as the side-effect effect (SEE), which refers to the influence of moral considerations in judgments of intentionality and other non-moral concepts. There is an ongoing debate about how to explain this asymmetric pattern of judgment and the psychological factors involved in it. It has been posited that affective reactions to agents that bring about harmful side-effects could bias intentionality attributions in these cases, explaining the asymmetric pattern of intentionality judgments that we observe in the SEE. We call this the affective bias hypothesis (ABH). Evidence for the ABH is mixed, with some findings suggesting a role for affective processes, while others suggesting that affective processes play no role in the SEE. A possible explanation for these apparently contradictory results points to affective processes involved in the SEE being confined to anger. In a series of empirical studies, we systematically measured and manipulated participants' anger in order to test this possibility. Our findings suggest that anger play no role in intentionality judgments in SEE cases, while providing support for a non-emotional motivation to blame as a factor underlying the SEE.


Unusual glass-forming ability of bulk amorphous alloys based on ordinary metal copper.
We report the unusual glass-forming ability (GFA) of a family of Cu-based alloys, Cu46Zr47-xAl7Yx (0<x< or =10, in at. %), and investigate the origin of this unique property. By an injection mold casting method, these alloys can be readily solidified into amorphous structures with the smallest dimension ranging from 4 mm up to 1 cm without detectable crystallinity. Such superior GFA is found primarily due to the alloying effect of Y, which lowers the alloy liquidus temperature and brings the composition closer to a quaternary eutectic. Other beneficial factors including appropriate atomic-size mismatch and large negative heat of mixing among constituent elements are also discussed.


Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine.
Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.


An abbreviated synthesis of tetrahydropteridines.
5,6,7,8-Tetrahydrobiopterin, the naturally occurring essential cofactor for the enzymatic hydroxylations of phenylalanine, tyrosine and tryptophan, and its synthetic analog 2-amino-6-methyl-5,6,7,8-tetrahydro-4(3H)-pteridinone, have been synthesized in good yield by the direct hydrogenation of 1-(2-amino-1,6-dihydro-5-nitro-6-oxopyrimidin-4-yl-amino)-1,5-dide oxy-L- erythro-pentulose and 2-amino-6-hydroxy-5-phenylazo-4-pyrimidylamino-acetone, respectively. The reactions were carried out at room temperature in trifluoroacetic acid over a platinum catalyst at 2 atm and the products, each containing a mixture of the two possible C-6 isomers, were isolated by precipitation. The simplicity of the preparative method suggests the procedure may be applied generally to the synthesis of all tetrahydropteridines derived from similar pyrimidine precursors.


Rational design of a highly efficient catalytic system for the production of PAPS from ATP and its application in the synthesis of chondroitin sulfate.
The compound 3'-phosphoadenosine-5'-phosphosulfate (PAPS) serves as a sulfate group donor in the production of valuable sulfated compounds. However, elevated costs and low conversion efficiency limit the industrial applicability of PAPS. Here, we designed and constructed an efficient and controllable catalytic system for the conversion of adenosine triphosphate (ATP) (disodium salt) into PAPS without inhibition from by-products. In vitro and in vivo testing in Escherichia coli identified adenosine-5'-phosphosulfate kinase from Penicillium chrysogenum (PcAPSK) as the rate-limiting enzyme. Based on analysis of the catalytic steps and molecular dynamics simulations, a mechanism-guided "ADP expulsion" strategy was developed to generate an improved PcAPSK variant (L7), with a specific activity of 48.94 U·mg-1 and 73.27-fold higher catalytic efficiency (kcat/Km) that of the wild-type enzyme. The improvement was attained chiefly by reducing the ADP-binding affinity of PcAPSK, as well as by changing the enzyme's flexibility and lid structure to a more open conformation. By introducing PcAPSK L7 in an in vivo catalytic system, 73.59 mM (37.32 g·L-1 ) PAPS was produced from 150 mM ATP in 18.5 h using a 3-L bioreactor, and achieved titer is the highest reported to date and corresponds to a 98.13% conversion rate. Then, the PAPS catalytic system was combined with the chondroitin 4-sulfotransferase using a one-pot method. Finally, chondroitin sulfate was transformed from chondroitin at a conversion rate of 98.75%. This strategy has great potential for scale biosynthesis of PAPS and chondroitin sulfate.


The complete mitochondrial genome of the Longnose skate: Raja rhina (Rajiformes, Rajidae).
The complete sequence of mitochondrial DNA of a longnose skate, Raja rhina was determined for the first time. It is 16,910 bp in length containing 2 rRNA, 22 tRNA and 13 protein coding genes with the same gene order and structure as those of other Rajidae species. The nucleotide of L-strand is composed of 30.1% A, 27.2% C, 28.5% T and 14.2% G, showing a slight A + T bias. The G is the least used base and markedly lower at the third codon position (5.4%). Twelve of the 13 protein coding genes use ATG as their start codon while the COX1 starts with GTG. As for stop codon, only ND4 shows incomplete stop codon TA. This mitogenome is the first report for a species of the genus Raja, and providing a valuable resource of genetic information for understanding the phylogenetic relationship and the evolution of the genus Raja as well as the family, Rajidae.


Polyclonal antibodies raised against Bacillus Calmette-Guerin, Mycobacterium duvalii, and Mycobacterium paratuberculosis used to detect mycobacteria in tissue with the use of immunohistochemical techniques.
Commercially available polyclonal antibodies raised against strains of mycobacteria were used to detect organisms in tissue sections from 34 cases of tuberculosis, leprosy, and atypical mycobacteria. Thirty-two cases of fungal infections, granulomatous inflammation, and sarcoidosis were used as negative controls. Sections stained with the use of antibodies raised against Bacillus Calmette-Guerin (BCG), Mycobacterium duvalii (MD), and Mycobacterium paratuberculosis (MP) were compared with Kinyoun and Fite-stained tissue sections. In caseating granulomata, clumps of mycobacterial debris, cells, and cell fragments stained. In histiocytic granulomata of mycobacterial infections, histiocyte cytoplasm contained both organisms and debris. The three antibodies showed cross-reactivity against the four groups of mycobacteria tested. Mycobacterial staining using immunoperoxidase was apparent in most cases at low-power (scanning) magnification. Thirty-two of 34 cases of mycobacterial infection, including all 24 Kinyoun-Fite-positive cases, were positive for immunoreactive organisms and debris using anti-MD, anti-BCG, and/or anti-MP. Eight of ten cases of culture-proven mycobacterial infection, in which Kinyoun and Fite stains were negative, had immunoreactive organisms or antigen with anti-BCG, MD, or MP. The antibodies also stained organisms in five cases of sporotrichosis in which the organisms were identified as yeast forms in tissue sections.


Autophagy as a target for development of anti-diabetes drugs derived from natural compounds.
Patients with diabetes have a high level of blood glucose because their body cannot produce enough insulin or properly respond to this hormone. In both situations, it has become evident that persistent high concentrations of glucose, insulin, insulin-like growth factor, and insulin resistance lead to dysfunction and destruction of autophagic activity in the cells of islet and other organs involved in complications of diabetes, including the liver, cardiovascular, and nervous systems. Accumulating evidences have revealed that autophagy is a novel therapeutic target with a wide range of beneficial effects on diabetes and that plenty of drugs and natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways. In this review, we summarize the roles of several clinical drugs and compounds derived from natural products in diabetes and its complications through regulation of autophagy, expecting to inspire further investigation of the underlying mechanisms of these compounds and to facilitate their better clinical application.


Sudden gains in PTSD symptoms and social functioning in cognitive processing therapy for posttraumatic stress disorder.
Sudden gains (SGs) are rapid symptom improvements between two consecutive therapy sessions that predict treatment outcomes. This study investigated SGs in posttraumatic stress disorder (PTSD) symptoms, interpersonal relationship functioning, and social role functioning in Cognitive Processing Therapy (CPT). Participants were 121 patients and 81 therapists involved in a parent randomized controlled hybrid implementation-effectiveness trial of CPT. Descriptive analyses examined the frequency and timing of different forms of SGs. Multilevel modeling examined the impact of the three SGs on outcomes. PTSD SGs occurred more often and at different sessions than SGs in facets of social functioning. Most individuals experienced only one form of SG and there were no significant clinical or demographic differences in those who had PTSD only SGs, social functioning only SGs, or both SGs. PTSD SGs and interpersonal relationship functioning SGs both predicted changes in PTSD symptoms and interpersonal difficulties over time, but not changes in social role functioning. SGs in social role functioning predicted all three forms of outcomes. The findings suggest that there are multiple forms of SGs in CPT beyond primary symptom changes that are predictive of patient outcomes. Clinicians should highlight various SGs that patients experience to further enhance outcomes.


Growth-dependent changes in arachidonic acid release from endothelial cells are mediated by protein kinase C and changes in diacylglycerol.
When stimulated, endothelial cells release arachidonic acid from phospholipids and oxidize it to eicosanoids. The rate-limiting step in this pathway is the initial release step, catalyzed by phospholipase(s), a process that exhibits growth-dependent changes. We examined the role of protein kinase C (PKC) as a regulator of this process. Activators and inhibitors of protein kinase C, used at different growth states, demonstrated distinct differences in their effects on arachidonic acid release, consistent with a growth-dependent change in PKC activity (with greater activity in proliferating cells compared with quiescent cells). Although immunoreactive PKC was slightly greater in the proliferating cells, there was a more striking redistribution of PKC activity between cytosol and membrane. To identify the cause, we measured the diacylglycerol (DG) content and found that DG concentrations decreased as cells progressed from preconfluence to confluence. Further studies demonstrated increases in DG kinase and DG lipase in confluent compared with preconfluent cells, consistent with the alterations in DG content. These findings suggest that growth-dependent changes in DG lipase and DG kinase activities regulate basal DG levels and PKC activity. The consequent alteration in PKC activity regulates the growth-dependent changes in arachidonic acid release.


Twisted-and-Coiled Actuators with Free Strokes Enable Soft Robots with Programmable Motions.
Various actuators (e.g., pneumatics, cables, dielectric elastomers, etc.) have been utilized to actuate soft robots. Besides widely used actuators, a relatively new artificial muscle-twisted-and-coiled actuators (TCAs)-is promising for actuating centimeter-scale soft robots because they are low cost, have a large work density, and can be driven by electricity. However, existing works on TCA-actuated soft robots in general can only generate simple bending motion. The reason is that TCAs fabricated with conventional methods have to be preloaded to generate a large contraction, and thus cannot actuate soft robots properly. In this work, an upgraded technique is presented to fabricate TCAs that can deliver 48% free strokes (contraction without preloading). We first compare the static performance of TCAs with free strokes with conventional TCAs, and then characterize how will the fabrication parameters influence the TCAs' stroke and force capability. After that, we demonstrate that such TCAs can actuate centimeter-scale soft robots with programmable motions (gripping, twisting, and three-dimensional bending). Finally, we combine those motions to demonstrate a soft robotic arm that can perform a pick-and-place task. We expect that TCAs with free strokes can enable miniature soft robots with rich three-dimensional motions for both locomotion and manipulation. Because TCAs are electrically driven, we can also potentially develop untethered soft robots by carrying onboard batteries and control circuits.


Clinical role of Sm-153 EDTMP in the treatment of painful bone metastatic disease.
Sm-153 EDTMP is an effective treatment of painful bone metastases from different neoplasms. However, there are few studies describing clinical experience with this therapeutic modality. The aim of this clinical study was to evaluate the efficacy of Sm-153 EDTMP in a group of patients with skeletal metastases and poor pain control with conventional therapies. Sixty-four patients with painful bone metastases treated with Sm-153 EDTMP were retrospectively evaluated. Nine patients were treated twice. The most common primaries were breast in 28 cases (44%) and prostate in 27 (41%). Treatment efficacy was assessed by a visual analog scale, analgesic consumption, and performance status before and after treatment. Response was graded as complete, moderate, or minor. Toxicity evaluation included analytic parameters (blood counts, renal function) and clinical follow up. Efficacy and toxicity were evaluated separately for each dose (total doses: 73), and complete follow up was only possible in 62 of 73 administrations. The response rate was 85% (21% complete, 40% moderate, and 24% minor). Onset of improvement took place a median of 7 days after Sm-153 EDTMP administration, and pain relief persisted for a mean of 3 months. No relevant toxicity was found in the early phase. Myelotoxicity appeared in 29% of the administrations and was mild in most cases (there was one case of grade 4 leukopenia). Sm-153 EDTMP is a good therapeutic option for patients with painful bone metastases. It is an effective treatment of pain relief without major secondary effects.


Upregulation of secreted aspartyl proteinase genes of fluconazole-sensitive Candida albicans isolates.
Candida albicans infection development depends on several factors associated with this etiological agent, including secreted aspartyl protease (Sap) production. Sap expression commonly occurs under selective pressure caused by the presence of antifungals. Fluconazole is the main antifungal drug used for treatment or prophylaxis. This study investigated the influence of inhibitory and sub-inhibitory fluconazole concentrations on Sap activity and their gene transcription for three clinical C. albicans isolates. Two isolates presented significant increases in Sap activity and transcription of SAP 1-8 genes in the presence of 1 MIC80 of fluconazole compared to the absence of the antifungal agent. The results suggest that the increase in Sap activity occurs due to an upregulation of the SAP gene transcription influenced by fluconazole. This suggests the importance of all SAP genes in the progression of bloodstream infections compared to primary tissue infection. However, this phenomenon does not occur everywhere, and it is multifactorial. This may be related to the selective pressure effect on transcription modulators. Although preliminary, these results open a new perspective for the study of virulence factors.


A data-driven simulation approach to quantify the effect of group counseling on system performance of college counseling centers.
Objective: To investigate the effectiveness, from a system's perspective, of offering group counseling options in college counseling centers. Methods: We achieve this through a data-driven simulation-based approach with the aim of providing administrators with a quantitative tool that informs their decision-making process. Results: Our simulation experiments reveal that offering group counseling options without resource reallocation does not have the desired positive impact on the system's performance. However, with resource reallocation, our results demonstrate that the introduction of group counseling options can significantly improve the performance of the system by as much as 40%. Conclusions: Group counseling options, coupled with proper resource reallocation strategies, are effective in reducing access time of first-time patients by as much as 40%. The effect of group counseling is highly dependent on both the number of offered groups as well as their scheduling policy. Scheduling policies have to be scrutinized in light of their resulting group waiting time and resource-utilization efficiency.


Hb Southampton [β106(G8)Leu→Pro; HBB: c.320T>C] and Codons 41/42 (-TTCT; HBB: c.124_127delTTCT) in a Chinese Girl.
Hb Southampton [β106(G8)Leu→Pro; HBB: c.320T>C] is a rare, unstable hemoglobin (Hb), variant. The main clinical presentation of this variant is hemolytic anemia. We detected this mutation in a 2-year-old Chinese girl with a history of regular transfusions. To the best of our knowledge, this is the first time that this variant has been found in the Asian population.


Predicting Intraoperative Hypothermia Burden during Non-Cardiac Surgery: A Retrospective Study Comparing Regression to Six Machine Learning Algorithms.
Inadvertent intraoperative hypothermia is a common complication that affects patient comfort and morbidity. As the development of hypothermia is a complex phenomenon, predicting it using machine learning (ML) algorithms may be superior to logistic regression. We performed a single-center retrospective study and assembled a feature set comprised of 71 variables. The primary outcome was hypothermia burden, defined as the area under the intraoperative temperature curve below 37 °C over time. We built seven prediction models (logistic regression, extreme gradient boosting (XGBoost), random forest (RF), multi-layer perceptron neural network (MLP), linear discriminant analysis (LDA), k-nearest neighbor (KNN), and Gaussian naïve Bayes (GNB)) to predict whether patients would not develop hypothermia or would develop mild, moderate, or severe hypothermia. For each model, we assessed discrimination (F1 score, area under the receiver operating curve, precision, recall) and calibration (calibration-in-the-large, calibration intercept, calibration slope). We included data from 87,116 anesthesia cases. Predicting the hypothermia burden group using logistic regression yielded a weighted F1 score of 0.397. Ranked from highest to lowest weighted F1 score, the ML algorithms performed as follows: XGBoost (0.44), RF (0.418), LDA (0.406), LDA (0.4), KNN (0.362), and GNB (0.32). ML is suitable for predicting intraoperative hypothermia and could be applied in clinical practice.


Ionization-Induced Multiwave Mixing: Terahertz Generation with Two-Color Laser Pulses of Various Frequency Ratios.
Ultrafast strong-field ionization is shown to be accompanied by atypical multiwave mixing with the number of mixed waves defined by the dependence of the ionization rate on the field strength. For two-color laser pulses of various frequency ratios, this results in the excitation of a free-electron current at laser combination frequencies and possibly in the excitation of the zero-frequency (residual) current responsible for terahertz (THz) generation in a formed plasma. The high-order nature of ionization-induced wave mixing may cause THz generation with uncommon laser frequency ratios (such as 2:3 and 3:4) to be virtually as effective as that with the commonly used frequency ratio of 1:2.


O6-methylguanine-DNA methyltransferase protects against nitrosamine-induced hepatocarcinogenesis.
We previously generated transgenic C3H/HeN mice by introducing the Escherichia coli O6-methylguanine-DNA methyltransferase (MGMT, DNA-O6-methylguanine:protein-L-cysteine S-methyltransferase, EC18.104.22.168) gene, ada, attached to the Chinese hamster metallothionein I gene promoter. One transgenic mouse line expressing both ada-specific mRNA and Ada protein could be propagated over many generations in a homozygous state with respect to the integrated DNA. Liver extracts from transgenic homozygous mice have consistently demonstrated about 3 times the control activity of normal mice. Furthermore, in the transgenic homozygotes treated with ZnSO4, activity is increased to 6-8 times the normal level in mice and is equivalent to that for man. To examine whether these increased levels of MGMT activity can actually decrease the susceptibility of animals to N-nitroso compounds, we studied liver carcinogenesis in our transgenic mice expressing high amounts of MGMT. Groups of transgenic and nontransgenic mice, each comprising about 200 suckling animals (14 +/- 1 days old), were divided each into eight subgroups, providing paired groups of transgenic and nontransgenic mice. They received an i.p. injection of ZnSO4 to induce MGMT, and 10 hr thereafter were given an i.p. injection of either dimethylnitrosamine or diethylnitrosamine. Liver tumor development was quantitatively assessed at 7-11 months. Here, we report statistically significant reduction of tumor formation in transgenic mice of four of the six paired groups that received treatment. The remaining two demonstrated results in line with dose dependence. Therefore, our data indicate that MGMT can indeed protect animals from low-dose exposure to environmental alkylating carcinogens.


In vitro degradation behavior of chitosan based hybrid microparticles.
The degradation properties of the MPs is important to the long-term benefits of the use of the chitosan (CS) based hybrid MPs in bone tissue-engineering, because the degradation kinetics could affect a multitude of processes within the cell, such as cell growth, tissue regeneration, and host response. The aim of this study was to investigate the degradation of solid, hybrid CS microparticles (MPs), CS-10% calcium phosphate (CaHPO4, w/w), and CS-10% calcium carbonate (CaCO3, w/w) MPs in phosphate buffered solution (PBS) over a 30-week period. The hybrid MPs were synthesized by emulsification technique, cross-linked with 64% sodium tripolyphosphate (TPP), purified and air dried overnight. Each sample had 30 mg of MPs was placed in a glass vial with 9 ml of PBS added and then the vial was closed to prevent evaporation. Every week 4 ml of the incubated solution was removed for sample measurement and all samples were replaced with an equivalent amount of fresh medium. The samples were maintained at 37°C under continuous shaking. The hybrid MPs were measured for pH and calcium release, every week in triplicate. At 0, 5, 10, 15, 20, 25, and 30 weeks, surface and bulk morphology were analyzed with a scanning electron microscope (SEM). The degradation data suggested that the hybrid MPs were stable at least up to 25 week and maintain the physiologically relevant pH. Therefore, we can use these hybrid MPs to apply in the bone tissue engineering applications since they do not degrade within a short period.


Cocaine smuggling in the gastrointestinal tract resulting in mechanical pylorostenosis.
A 45-year-old male, body packer, who confessed to have swallowed 44 packages of cocaine in a total dose of approx. 360 g, was admitted to hospital because of clinical signs of acute intoxication with cocaine followed by ileus. The emergency surgical gastrotomy was initiated, and the conglomerate of Scotch tape and packages with cocaine were removed. Small rupture of one package of cocaine in a body packer stomach caused acute poisoning with cocaine, confirmed additionally by the presence of its metabolites in the urine. Mechanical pylorostenosis provoked by cocaine packages required emergency surgical operation.


Treatment with growth factors in myelodysplastic syndromes.
In myelodysplastic syndromes (MDS), pancytopenia leads to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. While transfusions of red blood cells and platelets are still a cornerstone of the therapy, the clinical use of recombinant hematopoietic growth factors has enlarged the range of therapeutic applications in patients with MDS. It is possible to reverse neutropenia by administration of G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte-monocyte colony stimulating factor). In the case of a severe infection, therapeutic administration of G-CSF together with antibiotics might be justified in otherwise neutropenic MDS patients. Since especially patients with only slight impairment of erythropoiesis and no transfusion dependency have the highest response rates but need erythropoietin (EPO) the least, pharmacoeconomic analyses are urgently needed. Controlled randomized trials will have to ascertain wether combinations of EPO with G-CSF or GM-CSF are of benefit. Clinical studies with thrombopoietin (megakaryocyte growth and differentiation factor) have to be initiated to find out whether thrombocytopenia in MDS can be reversed.


Training pharmacists in the stage-of-change model of smoking cessation and motivational interviewing: A randomized controlled trial.
This study evaluated the effect of training pharmacists in the stage-of-change model for smoking cessation and motivational interviewing on smoking cessation outcomes. A training based on the stage-of-change model for smoking cessation and motivational interviewing was introduced to pharmacists. Pharmacists were randomly assigned to the intervention or control group. The control group attended a 3-hour training session, whereas the intervention group also attended a further 6-hour training session. At week 24, 12.2 percent of the smokers quit smoking in the intervention group, whereas 1.6 percent of the smokers quit smoking in the control group. The findings of this study showed that training pharmacists, in the stage-of-change model for smoking cessation and motivational interviewing, improves smoking reduction and cessation rates.


Immunodiagnosis of human melanoma: characterization of human melanoma antigens and their detection in sera of melanoma patients by radioimmunoassay.
Double antibody radioimmunoassay (RIA), using radioiodinated melanoma-associated antigens (MAA), rabbit antiserum raised against 3 M KCl extract of human melanoma (AHMS) and goat antirabbit IgG antibody, was employed for the detection of MAA in tumors as well as in sera of melanoma patients. MAA were partially purified from crude KCl extract of melanoma tissue by affinity column chromatography using AHMS and concanavalin A. A high content of MAA was detected in all but one melanoma extract, while normal tissue and nonmelanoma tumor extracts contained MAA to a much lesser extent than did melanoma extracts. MAA were also found in melanoma patients' sera (20/45) but not in sera of normal donors (0/10) and colon cancer patients (0/10). Immunochemical data suggest that AHMS-defined MAA consist of two major glycoproteins with molecular weights of 37K and 31K daltons, which does not cross-react either with carcinoembryonic antigen or beta 2-microglobulin or with BCG.


A rapid GC method of monitoring Mesurol (4-(methylthio)-3,5-xylyl-N-methyl carbamate) and its sulfoxide and sulfone metabolites and their persistence in lowbush blueberries.
A facile analytical procedure was developed for determining Mesurol (4-(methylthio)-3,5-xylyl-N-methyl carbamate) and its oxidation products in blueberries. It involved blending with acetone, partition with chloroform and derivatization with trifluoroacetic anhydride and quantitation by gas chromatography/flame photometric detector (GC/FPD). The method showed good recoveries for Mesurol and its sulfoxide at the 0.1 ppm level and Mesurol sulfone at the 0.3 ppm level with a 25 g sample. It was applied to monitor levels of the insecticide and its oxidation products on field-treated blueberries. The sensitivity of the method may be increased 5-fold by the inclusion of a clean-up step. The optimal conditions for the detection of Mesurol TFA by the modified Bendix sulphur/phosphorus emission detector operating in the sulphur mode required an oxygen/hydrogen ratio of 0.38, for a column flow of 60 ml/min. The minimum detectable amounts of the TFA derivatives of Mesurol, its sulfoxide and sulfone were calculated as 1.3, 2.3 and 5.8 X 10(-11) g/sec, respectively.


Conservative surgery for vesicocolic fistula.
Vesicocolic fistula due to diverticular disease of the colon is conventionally treated by resection of the diseased bowel and closure of the vesical defect. Three cases are described in which separation of the viscera and simple suture of the vesical and colonic defects was carried out. A greater omental graft was interposed between the rectum and bladder. Two of the patients are well 12 and 26 months postoperatively. The third patient died a year postoperatively from a complication of her diverticular disease.


[Influence of copper (II) complex on the activity of selected oxidative enzymes].
Coxarthrosis results in physical limitations (hypokinesis) and a necessity to change one's life style to the one that does not require much movement. Physical inactivity leads rapidly to metabolic processes inhibition. The processes of protein, carbohydrate and lipid catabolism intensify. Abnormal metabolism of polyunsaturated fatty acids occurs, which consequently leads to the development of reactive oxygen species (ROS) and to the acceleration of lipid peroxidation. Therefore, it is well-founded to seek for a new group of compounds demonstrating interesting biochemical properties. Among such already known compounds are chromone, azole and flavone derivatives, known for their oxidative properties. The aim of the study was to assess the antioxidant enzymes: catalase (CAT) and glutathione peroxidase (GPX) in erythrocytes in 25 patients suffering from coxarthrosis in comparison with healthy persons. The activity of catalase was determined in erythrocytes using the method of Beers and Sizer at 240 nm on the Beckman spectrophotometer. The activity of glutathione peroxidase was estimated using the method of Little and O'Brien at 412 nm on the Beckman spectrophotometer. The research was conducted with the permit of the Bioethics Committee No RNN/260/08/KB dated 20.05.2008. Blood for the tests was taken from periulnar vein to anticoagulant tubes (EDTA). The group consisted of 25 patients hospitalized in the Trauma and Orthopaedic Ward of the Hospital in Łódź. The results of the tests on erythrocytes in the patients with physical limitations reveal the increase of glutathione peroxidase and catalase activity by about 50% in all patients, who were administered the dichlorobis (N1-dichloromethyl-3,5-dimethylpyrazole, copper (II) compound in comparison to the control group, where the foregoing compound was not used. The research results significantly emphasise that adding of new chemical compounds to blood in investigation of oxidative properties has a considerable influence on the activity of the selected enzymes (catalase and glutathione peroxidase) in comparison to the control group. The research reveals an increase of the activity of all antioxidant enzymes, where newly synthesized chemical compounds were used. The results of antioxidative capacity tests confirmed that complex compounds with Cu (II) ions have a significant influence on the antioxidative status. The studies on the foregoing enzymes also indicate that overproduced free radicals participate in the whole course of the coxarthrosis.


Refractory gout - does it exist?
Refractory gout (RG) has been increasingly recognized to be a major problem in clinical care. Patients diagnosed with RG have been assumed to be non-adherent, or under-dosed, to the greater part. In a minority, pathophysiological mechanisms have been discussed. During the last two decades, however, none of the studies differentiated non-adherence from impaired response to drug treatment. A definition of adherence has been proposed in the case of allopurinol treatment (oxipurinol in serum, >20 µmol/l), which would seem to confirm a dose of about 50 mg/d being taken by the patients. Guidelines for treating gout published by national or international rheumatology societies do provide very little, if any, information on how to evaluate patients with RG. Coinciding with the development of the xanthine oxidase inhibitor, febuxostat, a moderate increase in the number of publications on RG was observed, with a sharp rise following after its approval for clinical use. It was demonstrated recently that intensive training and supervision of patients with gout resulted in very low numbers of patients not reaching treatment targets. It should be remembered that allopurinol, is an ideal instrument for differentiating non-adherence from true impaired response. We conclude that, apart from very rare patients, needing confirmation of such a diagnosis by metabolic ward studies, RG does not exist, and with close to hundred percent, treatment failure is due to patient and physician behavior.


Expression of active human blood clotting factor IX in transgenic mice: use of a cDNA with complete mRNA sequence.
Haemophilia B is a bleeding disorder caused by a functional deficiency of the clotting factor IX. A full length human factor IX complementary DNA clone containing all the natural mRNA sequences plus some flanking intron sequences was constructed with a metallothionein promoter and introduced into transgenic mice by microinjection into the pronuclei of fertilised eggs. The transgenic mice expressed high levels of messenger RNA, gamma-carboxylated and glycosylated protein, and biological clotting activity that are indistinguishable from normal human plasma factor IX. This study demonstrates the feasibility of expressing highly complex heterologous proteins in transgenic mice. It also provides the groundwork for the production of large amounts of human factor IX in larger transgenic livestock for therapeutic use, and the investigation of alternative genetic therapies for haemophilia B.


HOXB7 as a promising molecular marker for metastasis in cancers: a meta-analysis.
Numerous studies on carcinoma have revealed that the expression level of HOXB7 in cancerous tissues was significantly higher than that in noncancerous tissues. Elevated expression of HOXB7 is associated with the susceptibility to lymph node metastasis and distant metastasis in various tumors. In this study, a meta-analysis was performed to involve majority of relevant articles and explore the association of HOXB7 expression level with metastasis in cancer patients. Literature retrieval was conducted by searching in a number of electronic databases (up to December 1, 2015). The meta-analysis was conducted with RevMan 5.3 software and Stata SE12.0. A total of 1,532 patients with carcinoma from 14 studies were included in analysis. The results of meta-analysis demonstrated that lymph node metastasis was observed more frequently in the patients group with high expression level of HOXB7 than in the patients group with low expression level of HOXB7 (odds ratio =2.17, 95% CI: 1.74-2.71, P<0.00001, fixed-effects model). In addition, a similar result was observed in the association between HOXB7 expression and distant metastasis; the odds ratio was 1.77 (95% CI: 1.09-2.88, P=0.02, fixed-effects model). This meta-analysis demonstrated that the overexpression of HOXB7 was significantly associated with metastasis in cancer patients, which may be served as a common molecular marker for indicating cancer metastasis.


Towards Optimal Heart Failure Care: Couples-Oriented Strategies to Improve Patient Adherence and Health Outcomes.
Psychosocial factors play an important role in the development and progression of cardiovascular diseases (CVD), such as chronic heart failure (CHF). In particular, psycho-cognitive disturbance is common in CHF, which presents additional challenges to secondary prevention and management strategies. This review provides a summary of the contemporary psycho-cardiology literature, including coverage of common mood and cognitive symptoms, and explores some of the pathophysiologic evidence linking psycho-cognition to CHF, with particular emphasis on sympathetic nervous system activation and neuroendocrine functioning. Social support is identified as a strategy by which to reduce depressive symptoms, manage cognitive impairment and to, potentially, improve health outcomes through improved patient self care and adherence. Recent research outcomes suggest that the integration of family caregivers into CHF psycho-educational disease management programs, as providers and recipients of support, may achieve best outcomes. In this regard, couples-oriented strategies that promote communication, emotional attachment and support may enhance healthpromoting behaviours in patients and their partners.


Impact of a Chaxu Atmosphere on Nurses' Organizational Responsibility behavior-The Mediating Roles of Envy and Silence.
Chaxu atmosphere refers to the degree of differences, like the ripple effects in water, of the association between group members and the leader of the group resource. Unlike Western culture, China's nurses have been working in Chaxu atmosphere, which may boost their negative emotion and influence their workplace behavior. This study aimed to clarify the chain-mediating role of envy and silence in the association between Chaxu atmosphere and organizational responsibility behavior. A cross-sectional online survey was conducted, and a multistage stratified sampling method was employed to collect data. The study was conducted from September to October 2020 in China. Totally, 1740 nurses were recruited, and 1221 valid responses were collected. Socio-demographic factors, Chaxu atmosphere, employee envy, employee silence, and organizational responsibility behavior were assessed using questionnaires that included the Chaxu Atmosphere Scale, Employee Envy Scale, Employee Silence Scale, and Organizational Responsibility Behavior Scale. Hierarchical multiple regression was used to identify clusters of interrelationships among Chaxu atmosphere, envy, silence, and organizational responsibility behavior in nursing settings. Though the Chaxu atmosphere did not directly influence the organizational responsibility behavior of Chinese nurses, its effect is mediated by a chain of envy and silence. First, Chaxu atmosphere evoked envy in the nurses (β=-0.040, P<0.001), thereby leading to decreased organizational responsibility behavior. Second, the Chaxu atmosphere promoted silence toward organizational issues (β=-0.057, P<0.001), resulting in decreased organizational responsibility behavior. Third, the Chaxu atmosphere evoked envy in the nurses, which contributed to the formation of silence (β=-0.025, P<0.001), resulting in a further decrease in organizational responsibility behavior. Nurses working in a high-level Chaxu atmosphere are prone to remaining silent on critical organizational issues due to increased envy, which subsequently reduces their organizational responsibility behavior. A better understanding of the association between the Chaxu atmosphere and workplace behavior will help nursing managers to foster harmonious relationships between nurses and their teams and to improve each individual's organizational responsibility behavior.


Contextual Visualization.
Unseen information can lead to various "threats to validity" when analyzing complex datasets using visual tools, resulting in potentially biased findings. We enumerate sources of unseen information and argue that a new focus on contextual visualization methods is needed to inform users of these threats and to mitigate their effects.


Exercise Mediated Nrf2 Signaling Protects the Myocardium From Isoproterenol-Induced Pathological Remodeling.
Although exercise derived activation of Nrf2 signaling augments myocardial antioxidant signaling, the molecular mechanisms underlying the benefits of moderate exercise training (MET) in the heart remain elusive. Here we hypothesized that exercise training stabilizes Nrf2-dependent antioxidant signaling, which then protects the myocardium from isoproterenol-induced damage. The present study assessed the effects of 6 weeks of MET on the Nrf2/antioxidant function, glutathione redox state, and injury in the myocardium of C57/BL6J mice that received isoproterenol (ISO; 50 mg/kg/day for 7 days). ISO administration significantly reduced the Nrf2 promoter activity (p < 0.05) and downregulated the expression of cardiac antioxidant genes (Gclc, Nqo1, Cat, Gsr, and Gst-μ) in the untrained (UNT) mice. Furthermore, increased oxidative stress with severe myocardial injury was evident in UNT+ISO when compared to UNT mice receiving PBS under basal condition. Of note, MET stabilized the Nrf2-promoter activity and upheld the expression of Nrf2-dependent antioxidant genes in animals receiving ISO, and attenuated the oxidative stress-induced myocardial damage. Echocardiography analysis revealed impaired diastolic ventricular function in UNT+ISO mice, but this was partially normalized in the MET animals. Interestingly, while there was a marginal reduction in ubiquitinated proteins in MET mice that received ISO, the pathological signs were attenuated along with near normal cardiac function in response to exercise training. Thus, moderate intensity exercise training conferred protection against ISO-induced myocardial injury by augmentation of Nrf2-antioxidant signaling and attenuation of isoproterenol-induced oxidative stress.


[Frequency of menstrual disturbances in gynecology and obstetrics residents].
To determine the frequency of menstrual disorders in gynecology and obstetrics residents. MATERIAL AND MET HODS: All residents of the 2015-2016 academic cycle were studied. In all them the menstrual cycle characteristics such as: rhythm, duration and quantity were analyzed. For statistical analysis Mann Whitney U test and Spearman's correlation analysis were done. 61 residents, 18 of 2nd, 21 of 3rd and 22 of 4th year were studied. Body mass index was significantly greater in those of 4th grade when compared with those of 2nd. The waist hip ratio (WHR) was significantly smaller in those of 3rd when compared with those of 4th. The reported frequency of menstrual disturbances was 22.8%, 28.6% and 22.7% for the 2nd, 3rd and 4th years respectively. After comparing the groups, between them the total volume was greater in those of 2nd when compared with those of 3rd (p<0.009) and 4th (p<0.04) In the correlation analysis in those of 2nd grade the WHR negatively correlated with the duration of bled (p <0.483, p<0.049). In those of 3rd year the WHR positively correlated with the duration (p 0.544, p<0.024) and with the total volume (p 0.553, p<0.02 1). In those of 4th year any correlation was found. The 2nd year residents women's are more likely to suffer menstrual disorders compared with those of 3rd and 4th ear of residence.


Bilateral facial palsy as a manifestation of Japanese encephalitis.
Japanese encephalitis is a cause of substantial morbidity and mortality, prevalent mainly in South East nations. It is caused by group B arbovirus and transmitted with bite of infected culex mosquitoes. The clinical features described are: headache, vomiting, altered sensorium, convulsions and both hypokinetic and hyperkinetic movement disorders. In this submission, we described a 68-year-old man suffering from Japanese encephalitis, who presented with bilateral facial palsy with encephalitic features. The bilateral facial palsy has not been reported previously in association with Japanese encephalitis.


Role of resveratrol in the management of insulin resistance and related conditions: Mechanism of action.
Resveratrol (RES), a well-known antioxidant, is present in numerous plant species and, as a result, is easily obtained through dietary intake of plant-based foods and beverages. Several studies suggest that RES has anti-carcinogenic, anti-microbial, and anti-viral effects. It may also have beneficial metabolic properties that result in mitigation of insulin resistance (IR) and related metabolic abnormalities, including dyslipidemia, hyperglycemia, and hyperinsulinemia through regulation of gene expression or the activity of rate-limiting enzymes. A large body of evidence supports the beneficial effects of RES in the management and treatment of IR, type 2 diabetes, and related complications through a multitude of mechanisms. This review article focuses on the mechanisms of action of RES, the mechanisms leading to improved insulin sensitivity, and its clinical role in the management and treatment of type 2 diabetes.


Disruption of white matter structural integrity and connectivity in posttraumatic stress disorder: A TBSS and tractography study.
Most studies of brain white matter (WM) in posttraumatic stress disorder (PTSD) have focused on combat trauma, and often were confounded by neurological and substance dependence comorbidity. This study used tract-based spatial statistics (TBSS) and probabilistic tractography to characterize WM microstructure in a mixed-sex community sample of PTSD patients exposed to diverse and multiple traumas, and in trauma-exposed normal comparison (TENC) subjects. TBSS compared diffusion measures between 20 adults with DSM-IV PTSD and 17 TENC, using a whole-brain voxel-wise approach. Probabilistic tractography using Freesurfer's TRACULA was employed to measure diffusion tensor imaging (DTI) metrics within anatomically defined pathways. DTI metrics were compared between groups and correlated with PTSD symptom severity and trauma load. Controlling for age, sex, and motion, PTSD subjects had significantly reduced fractional anisotropy (FA) in a left frontal lobe cluster compared with TENC, at p < .05, family-wise error corrected. Tractography identified significant group differences in the inferior longitudinal fasciculus (ILF), including lower FA and higher radial diffusivity in PTSD compared with TENC. Within the PTSD group, FA values were not correlated with symptom severity or trauma load. Results remained significant after removing participants using psychotropic medication or those with comorbid major depression. PTSD patients had reduced WM integrity in left hemisphere frontal WM and temporal-occipital WM tracts, compared to trauma-exposed controls. Reduced frontal FA is consistent with compromised top-down attentional control and emotion regulation in PTSD, while reduced ILF FA may be related to sensory processing and gating abnormalities in this disorder.


Cognitive impairment in essential tremor assessed by the cerebellar cognitive affective syndrome scale.
Essential tremor (ET) is a movement disorder characterized by cerebellar neurodegenerative changes. ET is also associated with non-motor symptoms including cognitive impairment. The neuropsychologic profile of a patient with ET could relate to cerebellar cognitive affective syndrome (CCAS). This study aimed to assess the prevalence of cognitive impairment in patients with ET and identify whether the cognitive impairment in ET corresponds to a CCAS. Cognitive functions were evaluated with the CCAS-Scale (CCAS-S) in 20 patients with ET and 20 controls matched for age, sex, and level of education. The results of the CCAS-S were compared between patients and controls. The underlying determinant of CCAS inpatients with ET was identified through the correlation between the results of the CCAS-S and age at onset of symptoms, disease duration, and the Essential Tremor Rating Assessment Scale (TETRAS). On a group level, ET patients performed significantly worse than matched controls. In total, 13 individuals with ET had a definite CCAS (CCAS-S failed items ≥ 3). ASO and TETRAS scores significantly correlated with CCAS-S performances in ET patients. CCAS is highly prevalent in patients with ET which supports the cerebellar pathophysiology of associated cognitive impairment and supports a more systematic use of the CCAS-S to cognitively assessed patients with ET.


MHC-mismatched mixed chimerism mediates thymic deletion of cross-reactive autoreactive T cells and prevents insulitis in nonobese diabetic mice.
Type 1 diabetic NOD mice have defects in both thymic negative selection and peripheral regulation of autoreactive T cells, and induction of mixed chimerism can effectively reverse these defects. Our recent studies suggest that MHC-mismatched mixed chimerism mediates negative selection of autoreactive thymocytes in wild-type NOD and TCR-transgenic NOD.Rag1(+/+).BDC2.5 mice. However, it remains unknown how mismatched I-A(b) MHC class II can mediate deletion of autoreactive T cells positively selected by I-A(g7). In the present study, we directly tested the hypothesis that mismatched MHC class II in mixed chimeras mediates deletion of cross-reactive autoreactive thymocytes. We first identify that transgenic BDC2.5 T cells from NOD.Rag1(+/+).BDC2.5 but not NOD.Rag1(-/-).BDC2.5 mice possess cross-reactive TCRs with endogenous TCRα-chains; MHC-mismatched H-2(b) but not matched H-2(g7) mixed chimerism mediates thymic deletion of the cross-reactive transgenic T cells in NOD.Rag1(+/+).BDC2.5 mice. Second, by transplanting T cell-depleted (TCD) bone marrow (BM) cells from NOD.Rag1(+/+).BDC2.5 or NOD.Rag1(-/-).BDC2.5 mice into lethally irradiated MHC-mismatched H-2(b) C57BL/6 or MHC-matched congenic B6.H-2(g7) recipients, we demonstrate that NOD.Rag1(+/+).BDC2.5 BM-derived cross-reactive transgenic T cells, but not NOD.Rag1(-/-).BDC2.5 BM-derived non-cross-reactive transgenic T cells, can be positively selected in MHC-mismatched H-2(b) thymus. Third, by cotransplanting NOD.Rag1(+/+).BDC2.5 TCD BM cells with BM cells from MHC-mismatched T cell-deficient C57BL/6 mice into lethally irradiated MHC-matched B6.H-2(g7) recipients, we demonstrate that thymic deletion of the cross-reactive transgenic T cells is dependent on MHC-mismatched donor BM-derived APCs but not on donor BM-derived T cells. Taken together, our studies indicate that MHC-mismatched mixed chimerism can mediate thymic deletion of cross-reactive autoreactive T cells that express more than one TCR.


A Remotely Coached Multimodal Lifestyle Intervention for Alzheimer's Disease Ameliorates Functional and Cognitive Outcomes.
Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer's disease (AD). The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD. Participants with early-stage AD were randomized into two arms. Arm 1 (N = 24) received standard of care. Arm 2 (N = 31) additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant. The intervention arm ameliorated 2.1 [1.0] MPI points (mean [SD], p = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed. Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.


Future developments in radiotherapy.
Radiotherapy has advanced rapidly during the past two decades, mainly through developments in high-voltage equipment and diagnostic methods that can better define tumor boundaries. Methods to improve the application of these developments are constantly being refined. Knowledge is increasing about treatment plans for different types of tumors, mainly concerning dosage and fractionation. Continued optimization efforts and quality improvements should be able to increase the 5-year survival rate among radiotherapy patients in Sweden, just with the application of current knowledge. Based on extrapolations from estimates concerning potential improvements in radiotherapy methods, it is estimated that an additional 10% of radiotherapy patients could be cured during the next 10 years. Since approximately 30% of all cancer patients in Sweden receive radiotherapy with curative intent, an additional 3% of the total cancer population could be treated with curative results. Naturally, these estimates involve some uncertainty. For example, a report from EU (1) estimated that an improvement in the quality of radiotherapy in Western Europe should improve survival for 5% of the cancer patients, a somewhat higher value than has been estimated for Sweden. Trials are under way to use radiosensitizing substances and new laboratory tests to further define the radiosensitivity of tumors. The result may be improved, individually-oriented radiotherapy. The combination of radiotherapy and chemotherapy has mostly shown discouraging results thus far. The combination of radiotherapy and surgery is used often and further developments can be expected. The extent to which these new developments improve therapy is, however, difficult to project.


Rapid forgetting of social learning in the Ts65Dn mouse model of Down syndrome: New evidence for hippocampal dysfunction.
The Ts65Dn mouse model of Down syndrome recapitulates the hallmark areas of dysfunction that characterize the human disorder, including impaired performance in tasks designed to tap hippocampus-dependent learning and memory. Unfortunately, performance in the water maze tasks most commonly used for this purpose can be affected by behavioral and/or physiological abnormalities characteristic of Ts65Dn mice (e.g., thigmotaxis, susceptibility to hypothermia, stress reactivity), which complicates interpretation of impaired performance. The current study assessed hippocampal function in Ts65Dn mice using the social transmission of food preference (STFP) paradigm, which does not entail water escape or aversive reinforcement, and thus avoids these interpretive confounds. We tested Ts65Dn mice and disomic controls on this task using 1- and 7-day retention intervals. The Ts65Dn mice exhibited normal learning and memory following the 1-day retention interval, but rapid forgetting of the socially acquired information, evidenced by impaired performance following the 7-day retention interval. The STFP paradigm can be a valuable tool for studies using the Ts65Dn mouse model to evaluate potential therapies that may ameliorate hippocampal dysfunction and aging-related cognitive decline in Down syndrome. (PsycINFO Database Record


Serum glycated albumin: Potential use as an index of glycemic control in diabetic dogs.
Measurements of serum fructosamine, glycated hemoglobin, and glycated albumin (GA) complement serum glucose concentration for better management of diabetes mellitus (DM). Especially, the serum fructosamine test has long been used for diagnosing and monitoring the effect of treatment of DM in dogs. However, fructosamine tests are currently not performed in veterinary medicine in Japan. GA and fructoasmine levels have been shown to strongly correlate. However, the clinical implications of using GA remain to be elucidated. Therefore, the purpose of the current study was threefold: 1) Determine whether GA% is altered by acute hyperglycemia in normal dogs, simulating stress induced hyperglycemia; 2) Demonstrate that GA% does not dynamically change with diurnal variation of blood glucose concentration in diabetic dogs; and 3) Investigate whether GA% is capable of providing an index of glycemic control for 1-3 weeks in diabetic dogs as is the case with diabetic human patients. Our study demonstrated that serum GA% remains very stable and unaltered under acute hyperglycemic conditions (intravenous glucose injection) and in spite of diurnal variation of blood glucose concentration. Furthermore, serum GA% can reflect long-term changes (almost 1-3 weeks) in blood glucose concentration and the effect of injected insulin in diabetic dogs.