Effectiveness of pelvic floor muscle training in treating urinary incontinence in women: A current review.
To analyse the content of various published studies related to physical exercise and its effects on urinary incontinence and to determine the effectiveness of pelvic floor training programmes. We conducted a search in the databases of PubMed, CINAHL, the Cochrane Plus Library, The Cochrane Library, WOS and SPORTDiscus and a manual search in the Google Scholar metasearcher using the search descriptors for documents published in the last 10 years in Spanish or English. The documents needed to have an abstract or complete text on the treatment of urinary incontinence in female athletes and in women in general. We selected 3 full-text articles on treating urinary incontinence in female athletes and 6 full-text articles and 1 abstract on treating urinary incontinence in women in general. The 9 studies included in the review achieved positive results, i.e., there was improvement in the disease in all of the studies. Physical exercise, specifically pelvic floor muscle training programmes, has positive effects on urinary incontinence. This type of training has been shown to be an effective programme for treating urinary incontinence, especially stress urinary incontinence.


The pathobiological basis of depression in Parkinson disease: challenges and outlooks.
Depression, with an estimated prevalence of about 40% is a most common neuropsychiatric disorder in Parkinson disease (PD), with a negative impact on quality of life, cognitive impairment and functional disability, yet the underlying neurobiology is poorly understood. Depression in PD (DPD), one of its most common non-motor symptoms, can precede the onset of motor symptoms but can occur at any stage of the disease. Although its diagnosis is based on standard criteria, due to overlap with other symptoms related to PD or to side effects of treatment, depression is frequently underdiagnosed and undertreated. DPD has been related to a variety of pathogenic mechanisms associated with the underlying neurodegenerative process, in particular dysfunction of neurotransmitter systems (dopaminergic, serotonergic and noradrenergic), as well as to disturbances of cortico-limbic, striato-thalamic-prefrontal, mediotemporal-limbic networks, with disruption in the topological organization of functional mood-related, motor and other essential brain network connections due to alterations in the blood-oxygen-level-dependent (BOLD) fluctuations in multiple brain areas. Other hypothetic mechanisms involve neuroinflammation, neuroimmune dysregulation, stress hormones, neurotrophic, toxic or metabolic factors. The pathophysiology and pathogenesis of DPD are multifactorial and complex, and its interactions with genetic factors, age-related changes, cognitive disposition and other co-morbidities awaits further elucidation.


An in vitro comparison of capillary flow dialyzer performances on a single needle system (double headpump).
The ultrafiltration, clearance and priming characteristics of six capillary dialyzers (C-DAK 2.5 D, C-DAK 1.8 D, Tri-Ex 1, CF M 1500, N16F160 and HF 150) were studied in single needle dialysis by way of the double headpump (BL 760, Bellco Ltd). A good control of the ultrafiltration by an appropriate choice of the mean bloodcompartment pressures (Pbo) is present in all dialyzers. After correction of the clearance for ultrafiltration the clearances of urea, creatinine, sodiumiothalamate-l125 and cyanocobalamine-Co58 (vit. B 12) rise with increasing mean pressures in the bloodcompartment of all dialyzers. We assume that a better use of available surface area due to the characteristics of the double headpump such as TMP mainly influenced by Pbo pressures and other such as tidal flow are responsible for the excellent in vitro clearances of these dialyzers with this type of single needle system.


Associations of Education and Training with Perceived Singing Voice Function Among Professional Singers.
The educational backgrounds of professional singers vary greatly and span from no formal training to advanced degrees in music or theater. Consequently, professional singers have a wide range of knowledge regarding basic voice care. The objective of this study was to examine associations between singers' educational backgrounds, specifically their knowledge of vocal pedagogy and awareness of vocal health, and their perceptions of their current vocal function associated with singing. Cross sectional survey. An online survey was distributed nationwide to over 1,000 self-identifying as a professional singer working full time as a performer. The survey included 54 questions about their background education, performance history, years of professional experience, affiliation to a professional union, general health and wellness, and the Evaluation of the Ability to Sing Easily (EASE), a 20-item scale to assess singers' perceptions of the current status of their vocal function. A total of 396 amateur and professional singers completed the survey yielding a 40% response rate. Of 396 surveys received, 154 were excluded because the respondent was not a professional singer and/or the survey was incomplete and four were excluded because the respondent was <19 years old (396-158 = 238). Of 238, 199 completed the EASE (included in this analysis sample). The respondents identified their primary singing genre(s) as follows: 29% classical, 22% musical theatre, 45% both classical and musical theatre, and 5% other contemporary styles. Overall mean (SD, range) Rasch converted EASE score was 19.9 units (9.0, 0-50). Mean EASE score was 19.6 for primary classical, 22.7 for primary musical theatre, 18.4 for both classical and musical theatre, and 23.3 for other contemporary styles (P = 0.03). Participants who were older, had more years of singing training, had a college degree or higher in music, studied classical singing in an academic or private setting, and those who received education in vocal health had significantly lower (better) EASE scores (P-values <0.05). Professional singers' perception of their current vocal function differed according to their singing genre, age, extent and type of vocal training and vocal health education. Singing teachers, speech-language pathologists, and physicians could use these results to tailor voice education messages to professional singers. This knowledge could help voice care professionals to educate and treat this elite group of voice users to avoid long-term sequelae from suboptimal voice care.


Disturbed eating behavior and omission of insulin in adolescents receiving intensified insulin treatment: a nationwide population-based study.
To establish the prevalence of disturbed eating behavior (DEB) and insulin omission among adolescents with type 1 diabetes using intensive insulin treatment in a nationwide population-based study. The Diabetes Eating Problem Survey-Revised (DEPS-R) is a diabetes-specific screening tool for DEB. Clinical data and HbA1c were obtained from the Norwegian Childhood Diabetes Registry. A total of 770 children and adolescents 11-19 years of age with type 1 diabetes completed the DEPS-R. A total of 27.7% of the females and 8.6% of the males scored above the DEPS-R cutoff. Participants scoring above the cutoff had significantly higher HbA1c (9.2% [77 mmol/mol]; SD, 1.6) than participants scoring below the cutoff (8.4% [68 mmol/mol]; SD, 1.3; P < 0.001). The prevalence of DEB increased significantly with age and weight, from 7.2% in the underweight group to 32.7% in the obese group, and from 8.1% in the youngest age-group (11-13 years) to 38.1% in the oldest age-group (17-19 years). A total of 31.6% of the participants reported insulin restriction and 6.9% reported insulin omission after overeating. Patients reporting insulin restriction had significantly higher HbA1c (9.0% [75 mmol/mol]; SD, 1.7) than nonrestrictors (8.3% [67 mmol/mol]; SD, 1.2; P < 0.001). One-fourth of girls with type 1 diabetes scored above the cutoff for DEB and one-third reported skipping their insulin dose entirely at least occasionally after overeating. Both DEB and insulin restriction were associated with poorer metabolic control, which may increase the risk of serious late diabetes complications.


A new syndrome with pigmentation, scleroderma, gynaecomastia, Raynaud's phenomenon and peripheral neuropathy.
A middle-aged man developed impotence, gynaecomastia, peripheral neuropathy, pigmentation lymphadenopathy, scleroderma, malabsorption and Raynaud's phenomenon following prolonged exposure to trichlorethylene. Somes, but not all, of these features have previously been reported in vinyl chloride disease, and trichlorethylene is related chemically to vinyl chloride. Seven patients with a similar but not identical syndrome have been described in Japan and U.S.A., apparently unrelated to exposure to industrial toxins.


Topiramate Utilization After Phentermine/Topiramate Approval for Obesity Management: Risk Minimization in the Era of Drug Repurposing.
The US FDA required a Risk Evaluation and Mitigation Strategy (REMS) for phentermine/topiramate, an anti-obesity medication, to prevent congenital malformations. No REMS is required for single-ingredient topiramate, which may be used off-label for the same purpose. The aim of this study was to evaluate the impact of phentermine/topiramate approval in 2012 on subsequent topiramate use among patients with obesity. We used a national insurance claims database to conduct an interrupted time-series study (2009-2015). Enrollees aged 18-65 years in each examined calendar quarter had full insurance benefits during that quarter and the preceding 6 months. We required patients to have an obesity diagnosis and no other conditions warranting topiramate use. We calculated topiramate or comparator drug (atorvastatin, metformin) initiation rates and evaluated changes in trends before and after 2012 (transition period). Among topiramate users, 80% were female, and demographic characteristics remained consistent during the study period. Between 2009 and 2011, the topiramate initiation rate (95% confidence interval) among patients with obesity was 0.85 (0.73-0.98) per 1000 patients, with no significant upward or downward trend. In the first quarter of 2013, this rate had increased more than 2.5-fold (change: + 1.36 [1.19-1.52]). Metformin and atorvastatin initiation rates did not change. Topiramate initiation rates were threefold higher than phentermine/topiramate rates during the post-approval period. Phentermine/topiramate approval was associated with increased topiramate use among patients with obesity. Prescribers are encouraged to enhance patient education and monitoring in such clinical use since topiramate prescribing information, compared with REMS for phentermine/topiramate, has less emphasis on preventing prenatal exposure.


Quinidine syncope in children.
Quinidine syncope and factors associated with it are well known among adult patients treated for cardiac arrhythmias. To define factors that may influence the occurrence of syncope in children taking quinidine, the clinical, anatomic, electrocardiographic, roentgenographic and pharmacologic data were compared in six patients with syncope (Group A) and 22 patients without syncope (Group B). There was a significant (chi-square = 10.2, p = 0.001) relation between heart disease and quinidine syncope: all six Group A (syncopal) patients had heart disease whereas 15 of the 22 Group B (non-syncopal) patients had no structural heart disease. In contrast, no significant difference was noted between Group A and Group B patients in mean age (11.4 versus 11.4 years), mean quinidine serum concentration (2.9 versus 2.3 micrograms/ml), mean corrected QT interval before quinidine (0.43 versus 0.40 second) or mean corrected QT interval during quinidine therapy (0.46 versus 0.46 second) or between those taking digitalis and those not. Two of the six Group A (syncopal) patients died during therapy, one 6 days after initiating therapy and one suddenly at home 6 months after beginning quinidine. Another two of the six Group A patients exhibited hypokalemia (both 2.9 mEq/liter) at the time of syncope, 2 weeks and 6 months, respectively, after initiation of quinidine therapy; both survived. Syncope occurred within 8 days of initiation of quinidine therapy in three of the six patients. Sustained ventricular tachycardia was observed during quinidine associated arrhythmia in three of six patients with syncope; nonsustained ventricular tachycardia or complex ventricular ectopic activity while on this therapy was observed before syncope in the other three patients in Group A.(ABSTRACT TRUNCATED AT 250 WORDS)


Down-regulation of RIP1 by 2-deoxy-D-glucose sensitizes breast cancer cells to TRAIL-induced apoptosis.
TNF-related apoptosis-inducing ligand (TRAIL) appears to be a promising anticancer agent as it specifically kills a wide variety of cancer cells. However, resistance of subpopulations of cancer cells to TRAIL-induced cell death remains a major obstacle for successful treatment of cancer using TRAIL-based therapy. In this report we show that the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) efficiently enhances TRAIL-induced apoptosis through downregulation of receptor-interacting protein kinase 1 (RIP1) in breast cancer cells. Although 2-DG alone did not kill breast cancer cells, it sensitized the cells to TRAIL-induced cell death. This could be efficiently inhibited by blockage of the caspase cascade, suggesting 2-DG augments TRAIL-mediated apoptotic signaling. Indeed, treatment with 2-DG resulted in upregulation of TRAIL receptor 2 (TRAIL-R2), downregulation of cIAP1 and XIAP, and reduction in RIP1. The latter appeared to play an important role in regulating sensitivity of breast cancer cells to TRAIL, in that knockdown of RIP1 recapitulated, at least in part, the effect of 2-DG on TRAIL-induced apoptosis. Taken together, these results indicate that 2-DG enhances TRAIL-induced apoptosis in breast cancer cells by multiple mechanisms including suppression of RIP1, and highlight the potential therapeutic benefit of combinations of 2-DG and TRAIL in the treatment of breast cancer.


Wine consumption reduced postprandial platelet sensitivity against platelet activating factor in healthy men.
Platelet activating factor (PAF) is a potent inflammatory and thrombotic mediator that participates in the initiation and prolongation of atherosclerosis. The aim of the present study was to evaluate the potential effect of wine consumption on platelet aggregation against PAF. The study had cross-over design. Ten healthy men participated in four daily trials on separate days: They consumed a standardized meal along with white wine, Robola variety (trial R), or red wine, Cabernet Sauvignon variety (trial CS), or an ethanol solution (trial E), or water (trial W). Blood samples were collected before and after meal consumption and at several time points during the next 6 h. Platelet aggregation against PAF (EC50 values) and several blood biomarkers were measured, and incremental areas under the curve (iAUC) were calculated. A significant trial effect was found in platelet sensitivity against PAF (p trial = 0.01). Moreover, the iAUC-PAF EC50 of CS trial was higher compared to both iAUC-PAF EC50 of E and W trials (P = 0.04, P = 0.02). Plasminogen activator inhibitor-1 iAUC was higher in all alcoholic beverages compare with the one of W trial (P E = 0.05, P R = 0.01, P CS = 0.01). Triacylglycerol iAUC increased significantly only in E compared to W trial (P = 0.04) and were significantly lower at 60-120 min in wine trials compared to the one of E (P < 0.05). Wine consumption improved platelet sensitivity independently of alcohol, kept triacylglycerols at lower levels during their postprandial elevation, and did not affect plasminogen activator inhibitor-1 levels more adversely than ethanol per se.


Regulation of non-muscle myosin assembly by calmodulin-dependent light chain kinase.
The presence of actin and myosin in non-muscle cells suggests that they may be involved in a wide range of cellular contractile activities. The generally accepted view is that interaction between actin and myosin in these cells and in vertebrate smooth muscle, is regulated by the level of phosphorylation of the 20,000-molecular weight (MW) light chain. In the absence of calcium, this light chain is not phosphorylated and the myosin cannot interact with actin. Calcium activates a specific calmodulin-dependent kinase which phosphorylates the light chain, initiating actin-myosin interaction. Although most studies on the role of phosphorylation have concentration on the regulation of actin-activated myosin Mg-ATPase activity, phosphorylation of the light chain also seems to control the assembly of smooth muscle myosin into filaments. Using purified smooth muscle light chain kinase, we have confirmed this observation. We report here studies of myosins isolated from the two non-muscle sources, thymus cells and platelets. We observed that these myosins are assembled into filaments at physiological ionic strength and Mg-ATP concentrations, only when the 20,000-MW light chain is phosphorylated.


[Superior labrum-biceps anchor complex].
The focus in overhead sport injuries of the shoulder has been directed on lesions of the superior labrum-biceps complex during the last few years. This is due to improved imaging modalities as well as a better understanding of the anatomy and biomechanics. Arthroscopy is capable of diagnosing and treating these lesions. The anatomy, biomechanics, and operative treatment strategies and techniques are described in detail. The superior labrum anterior-posterior (SLAP) lesion is found in young active overhead athletes. Based on their classification and concomitant lesions, the unstable SLAP lesions (types II and IV) have to be repaired in order to restore stability to the superior labrum-biceps complex for stabilizing the glenohumeral joint. According to our own results and after review of the current literature, SLAP repair yields good results in overhead athletes enabling them to return to pain-free participation in their sport.


Usefulness of combined NGS and QF-PCR analysis for product of conception karyotyping.
Since chromosomal abnormalities can be detected in more than half of miscarriages, cytogenetic testing of the product of conception (POC) can provide important information when preparing for a subsequent pregnancy. Conventional karyotyping is the common diagnostic method for a POC but can be problematic due to the need for cell culture. We here conducted shallow whole-genome sequencing (sWGS) using next-generation sequencing (NGS) for alternative POC cytogenomic analysis. Since female euploidy samples can include 69,XXX triploidy, additional QF-PCR was performed in these cases. We here analyzed POC samples from miscarriages in 300 assisted reproductive technology (ART) pregnancies and detected chromosomal abnormalities in 201 instances (67.0%). Autosomal aneuploidy (151 cases, 50.3%) was the most frequent abnormality, consistent with prior conventional karyotyping data. Mosaic aneuploidy was detected in seven cases (2.0%). Notably, the frequency of triploidy was 2.3%, 10-fold lower than the reported frequency in non-ART pregnancies. Structural rearrangements were identified in nine samples (3%), but there was no case of segmental mosaicism. These data suggest that NGS-based sWGS, with the aid of QF-PCR, is a viable alternative karyotyping procedure that does not require cell culture. This method could also assist with genetic counseling for couples who undergoes embryo selection based on PGT-A data.


A case of pegylated interferon alpha-related diabetic ketoacidosis: can this complication be avoided?
We report the case of a 42-year-old woman with chronic hepatitis C (genotype 1), who in June 2004 started therapy with pegylated interferon alpha (PEG-IFNalpha) plus ribavirin. Two months later, she discontinued treatment because of polydipsia, polyuria and vomiting leading to a marked dehydration. Biochemical data showed type 1 diabetes mellitus with ketoacidosis, and insulin therapy was started. The patient, who before starting PEG-IFN alpha plus ribavirin therapy tested negative for glutamic acid decarboxylase antibodies (GADAb) and islet cell (ICAb) antibodies, became strongly positive for both autoimmune markers. This case confirms that patients with chronic hepatitis C who do not have baseline markers of pancreatic autoimmunity may develop severe ketoacidosis during treatment with PEG-IFNalpha, as well as with standard IFNalpha. In order to avoid this complication, as no guidelines are available and the pancreatic autoimmunity markers are not routinely analysed, we suggest frequent monitoring (e.g., every one to two weeks) of glycaemic values: e.g., every one to two weeks during the first 3 months (when this complication occurs most frequently) and monthly thereafter so as to identify diabetes at an early stage and before the onset of the appearance of severe ketoacidosis, which is life-threatening.


The myelin brake: when enough is enough.
Myelination by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system is tightly regulated by interactions with axons. Various investigations have shed light on the signaling pathways that mediate the production of myelin, but an important question remains; that is, which signals determine when the cell stops myelinating. New studies demonstrate that in Schwann cells, this is controlled by the abundance of Dlg1, which acts to stop active myelination.


Serologic Evidence of Severe Fever with Thrombocytopenia Syndrome Virus and Related Viruses in Pakistan.
We describe the seroprevalence of severe fever with thrombocytopenia syndrome virus (SFTSV) and the association of antibody occurrence with location, sex, and age among the human population in Pakistan. Our results indicate substantial activity of SFTSV and SFTSV-related viruses in this country.


Effects of the carbamates fenoxycarb, propamocarb and propoxur on energy supply, glucose utilization and SH-groups in neurons.
Carbamates belonged to an older insecticide group, with propoxur being representative of this group. However, today carbamates with hormonal effects on insects, like fenoxycarb, or with fungicide properties, like propamocarb, are also used. The goal was a comparison of three structurally and functional different carbamates with a possibly common toxicological mechanism. Primary neuronal cell cultures of the rat are a well established model to identify neurotoxic compounds like n-hexane or acrylamide. In this cell culture model endpoints such as viability, energy supply, glucose consumption, glutathione (GSH) levels and cytoskeleton elements were determined. Added to cultured rat cortical neurons for 1 week, fenoxycarb, propamocarb and propoxur considerably decreased ATP levels, mitochondrial membrane potential and glucose consumption. Besides this, fenoxycarb and propamocarb had an impact on neurofilaments. After recovery for 1 week, propoxur also showed effects on neurofilaments, whereas with the other carbamates no tendency for a recovery was seen. These effects were prevented completely by pyruvate for propoxur and propamocarb, and partly so for fenoxycarb. In contrast to the main experimental design, GSH was determined after 1-h treatment with the test substances. Surprisingly, the compounds had only slight or no effect on the GSH level within this time. Further mechanistic studies indicated that carbamates primarily interacted with SH-groups, most likely by interfering with glycolysis and the construction of fibrillary proteins like neurofilaments. The prevention by pyruvate and acetylcysteine pointed to these biochemical endpoints.


The ReFOLD assay for protein formulation studies and prediction of protein aggregation during long-term storage.
The formulation of novel therapeutic proteins is a challenging task which aims at finding formulation conditions that will minimize protein degradation during long-term storage. One particularly important and difficult-to-predict protein degradation pathway is the so-called non-native aggregation. The qualitative and quantitative prediction of the latter has been a subject of extensive research over the past two decades. An increasing body of evidence shows that the widely-used short-term biophysical techniques cannot accurately rank formulation conditions in order of their effect on the aggregation during long-term storage of some therapeutic proteins, e.g. monoclonal antibodies. Here we suggest a novel approach for the selection of formulation conditions that will suppress the formation of protein aggregates during long-term storage. We postulate that conditions (i.e. pH, buffer type, ionic strength) that reduce the isothermal aggregation of various denaturant-induced partially folded protein species will be conditions that impede protein aggregation during long-term storage. To test our hypothesis, we developed an isothermal microdialysis-based unfolding/refolding assay, named ReFOLD, which we use to induce moderate aggregation of partially folded proteins. Next, we assessed the relative monomer yield after isothermal unfolding/refolding of two monoclonal antibodies, each formulated in 12 different conditions. Using the proposed approach, we were able to accurately rank the formulations in order of their effect on the amount of protein aggregates detected after storage for 12 months at 4 °C and 25 °C, while widely-used stability-indicating parameters like protein melting and aggregation onset temperatures failed to provide accurate predictive formulation rankings.


A comparison of fixation methods in adolescent patients with diaphyseal forearm fractures.
The purpose of this study was to compare both bone diaphyseal forearm fractures in adolescent patients treated with plate fixation to patients treated with intramedullary fixation to identify differences in complications and outcomes. A retrospective study was performed on all adolescent patients with age between 10 and16 year and treated with intramedullary fixation or plate fixation for a diaphyseal both bone forearm fracture between 2005 and 2014. Demographic information and clinical data was collected. Radiographs were reviewed to evaluate post-operative radial bow magnitude and location, time to union, and residual angulation. Complications were graded using the modified Clavien-Dindo Classification system. A total of 102 patients met the inclusion criteria. Of these, 32 were treated with plate fixation and 70 with intramedullary fixation. The intramedullary nail group had 55% of complications classified as major. There were no major complications in the plate fixation group (P = 0.1). The radial bow was significantly more distal and smaller in magnitude in the intramedullary fixation group (P < 0.01). Of the patients who underwent intramedullary fixation, 76% required an open reduction of at least one forearm bone. There was increased time to radiographic union in patients treated with intramedullary fixation when compared to those treated with plates, 68 days versus 58 days (P = 0.03). A second operation was necessary for 91% of patients treated with intramedullary fixation compared to only 3% of patients treated with a plate (P < 0.01). Diaphyseal forearm fractures in adolescent patients remain challenging injuries to treat. Forearm bony anatomy is not completely restored with intramedullary fixation. Results suggested an association towards increased complication rates and complication severity with intramedullary fixation. Level 3 retrospective comparative study.


Retrograde cerebral perfusion using pulsatile flow under conditions of profound hypothermia.
We investigated the effects of pulsatile flow for retrograde cerebral perfusion under profound hypothermia. Total cardiopulmonary bypass was carried out in adult mongrel dogs to induce hypothermia. One hour of total circulatory arrest was then performed at 20 degrees C in the control group of 6 dogs. In another group of 6 dogs, after cardiac arrest was obtained at 20 degrees C, retrograde cerebral perfusion with nonpulsatile flow was performed through both sides of the internal maxillary vein for 60 minutes; in a third group of 6 dogs, retrograde pulsatile perfusion was continued for 60 minutes. At the end of either retrograde perfusion or total circulatory arrest for 60 minutes, cerebrospinal fluid pressure and blood flow in the cerebral tissues were measured, and cerebral tissues were collected to measure water and adenosine triphosphate content. A significant difference was found for water content between the group undergoing retrograde perfusion with pulsatile flow as opposed to nonpulsatile flow. Cerebral tissues in the group perfused retrogradely with nonpulsatile flow contained more water than in the group perfused with pulsatile flow. Cerebrospinal fluid pressure was lower in the group perfused retrogradely with pulsatile flow when compared with nonpulsatile flow, but no significant difference could be found. As for cerebral flow and adenosine triphosphate content, no significant differences could be found between the groups perfused retrogradely with pulsatile or with non-pulsatile flow. Values were always higher, nonetheless, in the groups perfused with pulsatile flow. We conclude that retrograde cerebral perfusion with pulsatile flow, when used under conditions of profound hypothermia, possesses more cerebroprotective effects than does non-pulsatile perfusion or circulatory arrest.


Broadband reconfigurable logic gates in phonon waveguides.
The high-quality-factor mechanical resonator in electromechanical systems has facilitated dynamic control of phonons via parametric nonlinear processes and paved the development of mechanical logic-elements. However, the narrow spectral bandwidth of the resonating element constrains the available nonlinear phenomena thus limiting the functionality of the device as well as the switching speeds. Here we have developed phonon waveguides, with a two-octave-wide phonon transmission band, in which mechanical four-wave-like mixing is demonstrated that enables the frequency of phonon waves to be converted over 1 MHz. We harness this platform to execute multiple binary mechanical logic gates in parallel, via frequency division multiplexing in this broadband, where each gate can be independently reconfigured. The fidelity of the binary gates is verified via temporal measurements yielding eye diagrams which confirm the availability of high speed logic operations. The phonon waveguide architecture thus offers the broadband functionality that is essential to realising mechanical signal processors.


Pathophysiological findings in a model of persistent atrial fibrillation and severe congestive heart failure.
Develop and evaluate a model of persistent atrial fibrillation (AF) and severe congestive heart failure (CHF). A single-chamber atrial pacemaker was implanted in pigs (20-30 kg). Burst atrial pacing at 42 Hz led to development of persistent AF. Immediately and 20 days after activation of the burst pacing protocol, animals underwent echocardiography. Heart rate, rhythm and general condition were monitored on a daily basis. After 20 days of atrial fibrillation, the animals were sacrificed. Conventional histological methods were used to evaluate microscopic structural changes. In the pig model, persistent atrial fibrillation developed 5 +/- 0.7 days after initiation of the burst protocol. Ventricular response rate was 274 +/- 5 bpm during atrial fibrillation, leading to a tachycardiomyopathy. Heart failure symptoms occurred approximately 15 days after initiation of burst pacing. Increases in QT interval on electrocardiogram, heart weight-to-body weight ratio, and laboratory values suggestive of a hypercatecholaminergic state, as well as liver and kidney dysfunction occurred during the 20-day duration of the study. Microstructural changes consistent with cellular hypertrophy, variable fibrosis, myolysis and apoptosis were found in the atria and ventricles of the study animals. The combined entity of atrial fibrillation and severe congestive heart failure leads to multiple organ dysfunction, ultrastructural and microscopic cardiac changes. Cellular hypertrophy, fibrosis and apoptosis are more prominent in this combined entity than previously reported models of lone atrial fibrillation or heart failure. This model can be used for further investigation into the pathophysiology and treatment of atrial fibrillation and advanced heart failure.


Morphological changes in chest radiographs of patients with acute respiratory distress syndrome (ARDS).
To determine whether the quality of infiltrations in chest radiographs can accurately predict the histological extent of fibrotic change in patients with acute respiratory distress syndrome (ARDS). Retrospective clinical investigation. Intensive care unit (ICU) of a university teaching hospital. Of 47 patients treated with extracorporeal membrane oxygenation (ECMO) for severe ARDS over a 5-year period, 23 patients underwent open lung biopsy at thoracotomy for treatment, mostly of pneumothorax. Chest films obtained by portable chest roentgenography preceding the operation were reviewed retrospectively and compared to the histomorphological results of the lung specimen. Chest radiographs displayed mixed alveolar-reticular opacification in 60.2%, alveolar patterns in 22.9% and reticular opacities in 10.5%. In 0.4% there were no infiltrates, 6% could not be evaluated because of insufficient quality. There was no relevant difference between the right and left lungs. Subdividing patients into two groups according to the histological results of either absent or mild (1) or severe (2) lung fibrosis, we found an alveolar haziness in 12.3% in group 1 compared with 28.2% in group 2, while reticular characteristics were identified in 13% and 11%, respectively. The most common opacity in chest radiographs of patients with severe ARDS treated with ECMO is mixed alveolar-reticular opacification. Severe lung fibrosis is not positively correlated with a reticular radiographic pattern. ECMO does not lead to specific radiological changes in conventional radiograms, contrary to clinical findings that treatment with ECMO might induce pleural or pulmonic haemorrhage, especially in the earlier days when systemic heparinization had to be used instead of the heparin-coated tube-surfacing.


Advances in chemotherapy for pancreatic cancer.
Pancreatic cancer remains challenging to treat. Over the past decade, there have been some major improvements in systemic therapy. Gemcitabine remains the key drug for both early and advanced cancer but combination chemotherapy is emerging as a new paradigm for patients with good performance status. This review focuses on current chemotherapy status for patients with pancreatic cancer.


Threshold functions for electrical stimulation of the human cochlear nucleus.
Thresholds to sinusoidal and biphasic pulsatile electrical stimuli were measured in two patients with electrodes positioned on the cochlear nucleus. The threshold functions differ from those observed in patients with scala tympani electrodes, primarily at low sinusoidal frequencies and long pulse widths. This difference is probably due to differences in the biophysical properties of the stimulated neural tissues in the two regions.


A study of a normoxic polymer gel dosimeter comprising methacrylic acid, gelatin and tetrakis (hydroxymethyl) phosphonium chloride (MAGAT).
In this study, the response to ionsing radiation of the normoxic polymer gel dosimeter comprising tetrakis (hydroxymethyl) phosphonium chloride (THPC) with methacrylic acid (MAA) and gelatin, named MAGAT, has been investigated. Using magnetic resonance imaging (MRI), the R2-dose response or change in R2 (DeltaR2) is evaluated for different concentrations of the component chemicals: THPC, MAA, gelatin and hydroquinone (HQ). The formulation for which the MAGAT polymer gel dosimeter had a maximum response was determined, and the spatial and temporal stability for this formulation analyzed. It was found that the formulation that provided the greatest change in R2 was 10 mM THPC, 0-0.05 mM HQ, 6-7% gelatin and 4-6% MAA (evaluated one day post-irradiation). MAGAT polymer gel dosimeters comprising 10mM THPC, 0.05 mM HQ, 6-9% MAA and 4-6% gelatin have shown potential for use in radiation therapy dosimetry.


Newborn Screening for Mucopolysaccharidoses: Results of a Pilot Study with 100 000 Dried Blood Spots.
To test, in a newborn screening (NBS) laboratory, the performance of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assay 5 enzymatic activities in dried blood spots (DBS) for NBS of 5 lysosomal storage diseases (mucopolysaccharidosis [MPS]-II, MPS-IIIB, MPS-IVA, MPS-VI, and MPS-VII). Three mm punches from de-identified DBS were obtained from the Washington NBS laboratory and submitted to the 5-plex LC-MS/MS assay. Screen cut-offs were established by analyzing the enzymatic activity in patients confirmed to have the MPS disorder. DNA sequencing of the relevant gene was performed on a second DBS punch for all samples with enzyme activity below 10% of the mean daily activity. (1) For MPS-II, 18 below cut-off samples, 1 pathogenic genotype, and 2 "high risk" genotypes; (2) For MPS-IIIB, no below cut-off samples; (3) For MPS-IVA, 8 below cut-off samples, 4 non-pathogenic genotypes, 4 genotypes unobtainable; (4) For MPS-VI, 4 below cut-off samples and no high-risk genotypes; (5) For MPS-VII, 1 below cut-off sample confirmed by genotype and clinical report to be affected. These results establish that the number of initial screen positive samples is low and manageable. Thus, population newborn screening for these conditions is feasible in a state newborn screening laboratory.


Solubility analysis and disposal options of combustion residues from plants grown on contaminated mining area.
Biomass, as a renewable energy source, is an excellent alternative for the partial replacement of fossil fuels in thermal and electric energy production. A new fuel type as biomass for energy utilisation includes ligneous plants with considerable heavy metal content. The combustion process must be controlled during the firing of significant quantities of contaminated biomass grown on brownfield lands. By implementing these measures, air pollution and further soil contamination caused by the disposal of the solid burning residue, the ash, can be prevented. For the test samples from ligneous plants grown on heavy metal-contaminated fields, an ore mine (already closed for 25 years) was chosen. With our focus on the determination of the heavy metal content, we have examined the composition of the soil, the biomass and the combustion by-products (ash, fly ash). Our results confirm that ash resulting from the combustion must be treated as toxic waste and its deposition must take place on hazardous waste disposal sites. Biomass of these characteristics can be burnt in special combustion facility that was equipped with means for the disposal of solid burning residues as well as air pollutants.


Receiving, decoding and noise limiting systems for a new pressure-sensitive ingestible radio telemetric capsule.
A new pressure-sensitive radiotelemetric capsule for recording intraluminal pressures within the human gastrointestinal tract has been developed; this capsule employs a pulsed mode of operation. Data recording as a pulse train greatly simplifies problems encountered hitherto in this field, but has produced the requirement for a decoding system which, on tape replay, will reproduce the original pressure change. A system is described here which, in addition to producing an analogue signal from the recorded pulse train, will also eliminate artefacts due to either spurious radio signals or variations in magnetic tape transport speed; it also provides a sensitive and accurate indication of transient signal loss.


Crystal structure and Hirshfeld surface analysis of di-chlorido-(methanol-κO)bis-(2-methyl-pyridine-κN)copper(II).
In the title complex, [CuCl2(C6H7N)2(CH3OH)], the copper atom is five-coordinated by two nitro-gen atoms of 2-methyl-pyridine ligands, two chloro ligands and an oxygen atom of the methanol mol-ecule, being in a tetra-gonal-pyramidal environment with N and Cl atoms forming the basal plane. In the crystal, complex mol-ecules related by the twofold rotation axis are joined into dimeric units by pairs of O-H⋯Cl hydrogen bonds. These dimeric units are assembled through C-H⋯Cl inter-actions into layers parallel to (001).


Subclinical elevated B-type Natriuretic Peptide (BNP) indicates endothelial dysfunction contributing to hypoxia susceptibility in healthy individuals.
Baseline elevated B-type Natriuretic Peptide (BNP) has been found in high altitude pulmonary edema susceptible population. Exaggerated pulmonary vascular response to hypoxia may be related to endothelial dysfunction in hypoxia susceptible. We hypothesize that baseline BNP levels can predict hypoxia susceptibility in healthy individuals. The pulmonary vascular response to hypoxia was compared in 35 male healthy individuals divided into two groups based on BNP levels (Group 1 ≤ 15 and Group 2 > 15 pg/ml). Acute normobaric hypoxia was administered to both the groups, to confirm hypoxia susceptibility in Group 2. Unlike Group 1, Group 2 had elevated post hypoxia BNP levels (26 vs 33.5 pg/ml, p = 0.002) while pulmonary artery pressure was comparable. A negative correlation with tissue oxygen consumption (delta pO2) and compartmental fluid shift was seen in Group 1 only. Endothelial dysfunction in Group 2 resulted in reduced vascular compliance leading to elevation of mean blood pressure on acute hypoxia exposure. BNP showed a positive correlation with endothelial dysfunction in Group 2 and has been linked to pre-diabetic disorder (HbA1c 6 ± 0.44%) and may additionally represent a lower cross-sectional area of vascular bed related to vascular remodeling mediated by chronic hypoxia. Hypoxia susceptibility in healthy individuals may be related to endothelial dysfunction that limits vascular compliance during hypoxic stress. BNP level showed positive correlation with HbA1c (r = 0.49, p = 0.04) and negative correlation with delta pO2 (r = -0.52, p = 0.04) can predict reduced microvascular compliance due to endothelial dysfunction contributing to hypoxia susceptibility in healthy individuals. BNP levels≤15 pg/ml at sea level is indicative of hypoxia resistance.


The Association of Obstructive Sleep Apnea With Breast Cancer Incidence and Mortality: A Systematic Review and Meta-analysis.
Emerging evidence from animal models suggests that intermittent hypoxia due to obstructive sleep apnea (OSA) is a risk factor for breast cancer. Despite their biological plausibility, human epidemiological studies have reported conflicting results. Therefore, we conducted a meta-analysis to delineate this relationship. We searched the PubMed, Embase, Scopus, and Cochrane Library databases for eligible studies from inception until June 6, 2021. Two reviewers selected randomized trials or observational studies reporting the association between OSA and breast cancer incidence compared with those without OSA. Two reviewers extracted relevant data and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and Newcastle-Ottawa Scale (NOS). We pooled the maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse variance-weighted meta-analysis and performed pre-specified subgroup analyses. We included six studies out of 1,707 records, comprising a combined cohort of 5,165,200 patients. All studies used the International Classification of Diseases codes to classify OSA and breast cancer. OSA patients had a 36% increased breast cancer risk (HR, 1.36; 95% confidence interval [CI], 1.03-1.80; N = 6, I² = 96%) compared to those without OSA. Most studies adjusted for confounders, such as age, sex, obesity, diabetes mellitus, alcohol use, and hypertension. Subgroup analyses for studies with (1) multivariate adjustment and (2) at least five years of follow-up yielded HRs of 1.35 (95% CI, 0.98-1.87; N = 5, I² = 96%) and 1.57 (95% CI, 1.14-2.18; N = 4; I² = 90%), respectively. One Mendelian randomization study suggested a causal relationship, with a two-fold increase in the odds of breast cancer in patients with OSA. This meta-analysis suggested that OSA is a risk factor for breast cancer. Future studies should explore the dose-response relationship between OSA and breast cancer, and whether treatment may mitigate breast cancer risk or progression.


Noise removal in magnetic resonance diffusion tensor imaging.
Although promising for visualizing the structure of ordered tissues, MR diffusion tensor imaging (DTI) has been hampered by long acquisition time and low spatial resolution associated with its inherently low signal-to-noise ratio (SNR). Moreover, the uncertainty in the DTI measurements has a direct impact on the accuracy of structural renderings such as fiber streamline tracking. Noise removal techniques can be used to improve the SNR of DTI without requiring additional acquisitions, albeit most low-pass filtering methods are accompanied by undesirable image blurring. In the present study, a modified vector-based partial-differential-equation (PDE) filtering formalism was implemented for smoothing DTI vector fields. Using an image residual-energy criterion to equate the degree of smoothing and error metrics empirically derived from DTI data to quantify the relative performances, the effectiveness in denoising DTI data is compared among image-based and vector-based PDE and fixed and adaptive low-pass k-space filtering. The results demonstrate that the edge-preservation feature of the PDE approach can be highly advantageous in enhancing DTI measurements, particularly for vector-based PDE filtering in applications relying on DTI directional information. These findings suggest a potential role for the postprocessing enhancement technique to improve the practical utility of DTI.


Outcomes of Mixed Pathologic Response in Patients with Multiple Colorectal Liver Metastases Treated with Neoadjuvant Chemotherapy and Liver Resection.
Pathologic response to preoperative chemotherapy predicts survival in patients with colorectal liver metastases (CLMs) who undergo hepatectomy. In multiple CLMs, mixed pathologic response, wherein tumors exhibit different degrees of treatment response, is possible. We sought to evaluate survival outcomes of mixed response in patients with multiple CLMs. We conducted a retrospective cohort study using a single-institution database of patients with two or more CLMs who underwent preoperative chemotherapy and hepatectomy (2010-2018). Pathologic response of each tumor was measured on pathology. Patients were stratified by pathologic response as complete (pCR) = 0-1% viability; major (pMajR) = 2-49% viability; minor (pMinR) = 50-99% viability; or mixed (pMixR) = at least one pCR/MajR tumor and one pMinR. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adjusted risk of death was evaluated using Cox regression. Among 444 patients, 6% had pCR, 34% had pMajR, 36% had pMinR, and 24% had pMixR. Median and 5-year RFS for patients with pMixR was 10.4 months and 16%, respectively, compared with pMajR (11.3 months and 18%, respectively), pMinR (7.7 months and 13%, respectively), and pCR (23.1 months and 38%, respectively) [log-rank p < 0.001]. Median and 5-year OS for patients with pMixR was 77.4 months and 60%, respectively, compared with pMajR (80.5 months and 63%, respectively), pMinR (49.9 months and 39%, respectively), and pCR (median OS not reached; median follow-up of 37.1 months and 5-year OS of 65%) [log-rank p = 0.002]. pMixR was associated with a 52% risk of death reduction (hazard ratio 0.48, 95% confidence interval 0.30-0.78 vs. pMinR). One-quarter of patients with multiple CLMs have pMixR following preoperative chemotherapy and hepatectomy. OS and RFS for patients with pMixR mirror those of pMajR rather than pMinR, suggesting the greatest response achieved in any metastasis best predicts survival.


A histone deacetylase inhibitor, azelaic bishydroxamic acid, shows cytotoxicity on Epstein-Barr virus transformed B-cell lines: a potential therapy for posttransplant lymphoproliferative disease.
Posttransplant lymphoproliferative disease (PTLD), driven by the presence of Epstein-Barr virus (EBV), is becoming an increasingly important clinical problem after solid organ transplantation. The use of immunosuppressive therapy leads to the inhibition of the cytotoxic T cells that normally control the EBV latently infected B cells. The prognosis for many patients with PTLD is poor, and the optimal treatment strategy is not well defined. This study investigates the use of a histone deacetylase inhibitor, azelaic bishydroxamic acid (ABHA), for its ability to effectively kill EBV-transformed lymphoblastoid cell lines. In vitro treatment of lymphoblastoid cell lines with ABHA showed that they were effectively killed by low doses of the drug (ID50 2-5 microg/ml) within 48 hr. As well as being effective against polyclonal B-cell lines, ABHA was also shown to be toxic to seven of eight clonal Burkitt's lymphoma cell lines, indicating that the drug may also be useful in the treatment of late-occurring clonal PTLD. In addition, ABHA treatment did not induce EBV replication or affect EBV latent gene expression. These studies suggest that ABHA effectively kills both polyclonal and clonal B-cell lines and has potential in the treatment of PTLD.


Use of the sodium borohydride reduction technique to identify a gamma-glutamyl phosphate intermediary in the Escherichia coli glutamine synthetase reaction.
Incubation of unadenylylated Escherichia coli glutamine synthetase with ATP, L-[14C]glutamate and metal ion results in the formation of gamma-glutamyl-P which can under appropriate conditions be reduced by sodium borohydride. The acyl-P compound is formed catalytically as judged by the quantity of radioactive alpha-amino-delta-hydroxyvalerate produced compared to the concentration of enzyme subunits. Formation of the glutamyl-P compound occurs in the presence of magnesium or manganous ions, and the relation of this apparent lack of metal ion specificity with regard to the highly specific Mg2+-supported biosynthetic activity of the unadenylylated form is discussed.


The Use of Electrotherapeutics in Ophthalmology.
To present a perspective on the use of electrotherapeutics in the history of ophthalmology along with the development of novel contemporary ophthalmic instrumentation. Perspective study. We reviewed historical journals, articles, and books discussing the use of electricity and electrotherapeutics in ophthalmology. Electrotherapeutic applications have been researched and used to treat ocular diseases as far back as the 18th century. By the 20th century, research in electrotherapeutics in ophthalmology had caught the eye of Edward Jackson, the first president of the American Academy of Ophthalmology and Otolaryngology and first editor of the present (third) series American Journal of Ophthalmology. Edward Jackson published an extensive review on this topic and reported a variety of modalities used to treat ocular diseases. While many early therapeutic uses of electricity did not produce effective and replicable results, studies on electrical stimulation of the eye provided the foundation for the development of clinically significant vision enhancing and restoring instrumentation.


MicroRNAs: something important between the genes.
Non-coding small endogenous RNAs, of 21-24 nucleotides in length, have recently emerged as important regulators of gene expression in both plants and animals. At least three categories of small RNAs exist in plants: short interfering RNAs (siRNAs) deriving from viruses or transgenes and mediating virus resistance or transgene silencing via RNA degradation; siRNAs deriving from transposons or transgene promoters and controlling transposon and transgene silencing probably via chromatin changes; and microRNAs (miRNAs) deriving from intergenic regions of the genome and regulating the expression of endogenous genes either by mRNA cleavage or translational repression. The disruption of miRNA-mediated regulation causes developmental abnormalities in plants, demonstrating that miRNAs play an important role in the regulation of developmental decisions.


Possible involvement of D2/D3 receptor activation in ischemic preconditioning mediated protection of the brain.
Ischemic stroke is a medical condition that arises because of poor blood supply to the brain. Reperfusion being salvage to the brain further causes, exacerbation of tissue injury, known as reperfusion injury. Ischemic preconditioning (IPC) has been known to provide benefits against ischemia reperfusion (I/R) injury. Dopamine D2/D3 receptor mediated several pathways are also reported as mediators in the IPC mediated neuroprotection. This study investigates the possible involvement of D2/D3 receptor activation in IPC mediated neuroprotection in the I/R brain. Global cerebral ischemia/reperfusion (GCI/R) injury in swiss albino mice was induced by occluding the common carotid arteries for 17 min, followed by 24 h reperfusion. IPC was provided by giving 3 episodes of I/R prior to Ischemia (17 min). Morris water maze (MWM) was used to assess the spatial learning, memory and Rota rod, lateral push test as well as inclined beam test were conducted to assess the motor functions in animals. Cerebral oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-α, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE, infarct size (% weight and % volume), and histopathological changes were also assessed. Haloperidol (0.05 mg/kg, i.p) was used to antagonize the effects of D2/D3 receptor activation. I/R animals showed reduction in memory, motor function, increase in cerebral oxidative stress, inflammation, AChE activity, infarct size and histopathological changes. Episodes of IPC prior to ischemia, attenuated the deleterious effects of I/R injury. Administration of haloperidol abolished the protective effects of IPC. Hence, it may be concluded that IPC mediated neuroprotection may involves dopamine D2/D3 receptor activation in mice.


Differences in tissue degeneration between preoperative chemotherapy and preoperative chemoradiotherapy for colorectal cancer.
Preoperative chemoradiotherapy (CRT) for rectal cancer is administered to improve local control, but can also induce severe anal dysfunction after surgery, while preoperative chemotherapy that significantly reduces the primary lesion in rectal cancer has recently been developed. The aim of the study was to examine differences in the effects of preoperative CRT and chemotherapy on tissue degeneration of patients with colorectal cancer. The subjects were 91 patients, including 68 with rectal cancer who underwent internal sphincteric resection with (n = 47, CRT group) or without (n = 21, control group) preoperative CRT, and 23 with colorectal cancer who received preoperative FOLFOX treatment. Peripheral nerve degeneration was evaluated histopathologically using H&E-stained sections, based on karyopyknosis, disparity of the nucleus, denucleation, vacuolar or acidophilic degeneration of the cytoplasm, and adventitial neuronal changes. The incidence of neural degeneration was significantly higher in the CRT group than in the control group and FOLFOX group. There were no differences in any items of neural degeneration between the FOLFOX and control groups. CRT induced marked neural degeneration around the rectal tumor. FOLFOX treatment produced mild neural degeneration similar to that in the control group.


Off-pump coronary artery bypass grafting using in situ bilateral skeletonized internal thoracic arteries.
All arterial off-pump coronary artery bypass grafting (OPCAB) with in situ bilateral skeletonized internal thoracic arteries (ITAs) may become a standard procedure that would provide better long-term results without affecting early results. Our study included 404 consecutive patients who underwent OPCAB with one or two ITAs. We compared the clinical results of 135 patients who underwent OPCAB using unilateral ITA (UITA group) to those of 269 patients using bilateral ITAs (BITA group). The average number of distal anastomoses was 3.07 in the UITA group and 3.47 in the BITA group (P < 0.01). Four operative mortalities occurred in the UITA group and two in the BITA group. There were no significant differences in morbidity between the two groups. OPCAB using bilateral skeletonized ITAs is technically feasible, with good early results. Arterial OPCAB using in situ bilateral skeletonized ITAs may become a standard procedure in the future.


Lateral hypothalamic-induced antinociception may be mediated by a substance P connection with the rostral ventromedial medulla.
Stimulation of the lateral hypothalamus (LH) produces antinociception modified by intrathecal serotonergic receptor antagonists. Spinally-projecting serotonergic neurons in the LH have not been identified, suggesting that the LH innervates brainstem serotonergic neurons in the rostral ventromedial medulla (RVM), known to modify nociception in the spinal cord dorsal horn. To determine whether substance P (SP) plays a role in LH-induced antinociception mediated by the RVM, we conducted an anatomical experiment using retrograde tract tracing combined with double label immunocytochemistry and found that neuron profiles immunoreactive for SP in the LH project to the RVM. To further identify a functional connection between SP neurons in the LH and the RVM, the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of female Sprague-Dawley rats (250-350 g) and antinociception was obtained on the tail flick or foot withdrawal tests. Cobalt chloride (100 nM) was then microinjected in the RVM to block synaptic activation of spinally-projecting RVM neurons. Within 5 min of the cobalt chloride injection, the antinociceptive effect of carbachol stimulation was blocked. In another set of experiments, the specific NK1 receptor antagonist L-703,606 (5 microg) was microinjected in the RVM following LH stimulation with carbachol and abolished LH-induced antinociception as well. Microinjection of cobalt chloride or L-703,606 in the absence of LH stimulation had no effect. These anatomical and behavioral experiments provide converging evidence to support the hypothesis that antinociception produced by activating neurons in the LH is mediated in part by the subsequent activation of spinally-projecting neurons in the RVM.


A novel near infrared spectroscopy analytical strategy for meat and bone meal species discrimination based on the insight of fraction composition complexity.
This study analyzed the meat and bone meal (MBM) matrix complexity from the perspective of fraction composition diversity and a classification strategy was proposed to accurately and rapidly identify the MBM species based on near infrared spectroscopy (NIRS). Partial Least Squares-Discrimination Analysis (PLS-DA) based on full samples, meat meal (MM), MBM and bone meal (BM) performed with decreasing classification errors of 0.115, 0.079, 0.044 and 0.039 which were partly caused by wide sample range; bone fraction content had positive correlation with most of MBM species differences reflected by principal component scores; and PLS-DA classification errors among MM, MBM and BM were lower than 0.013. To take fully advantage of the above results, a sequential classification strategy was proposed; near infrared spectra were selected (belong to MM, MBM or BM) and then species discrimination analysis was conducted based on the specific PLS-DA model.


DLNLF-net: Denoised local and non-local deep features fusion network for malignancy characterization of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a primary liver cancer with high mortality rate. The degree of HCC malignancy is an important prognostic factor for predicting recurrence and survival after surgical resection or liver transplantation in clinical practice. Currently, deep features obtained from data-driven machine learning algorithms have demonstrated superior performance in characterising lesion features in medical imaging processing. However, previous convolutional neural network (CNN)-based studies on HCC lesion characterisation were based on traditional local deep features. The aim of this study was to propose a denoised local and non-local deep features fusion network (DLNLF-net) for grading HCC. Gadolinium-diethylenetriaminepentaacetic-acid-enhanced magnetic resonance imaging data of 117 histopathologically proven HCCs were collected from 112 patients with resected HCC between October 2012 and October 2018. The proposed DLNLF-net primarily consists of three modules: feature denoising, non-local feature extraction, and bilinear kernel fusion. First, local feature maps were extracted from the original tumour images using convolution operations, followed by a feature denoising block to generate denoised local features. Simultaneously, a non-local feature extraction block was employed on the local feature maps to generate non-local features. Finally, the two generated features were fused using a bilinear kernel model to output the classification results. The dataset was divided into a training set (77 HCC images) and an independent test set (40 HCC images). Training and independent testing were repeated five times to reduce measurement errors. Accuracy, sensitivity, specificity, and area under the curve (AUC) values in the five repetitive tests were calculated to evaluate the performance of the proposed method. Denoised local features (AUC 89.19%) and non-local features (AUC 88.28%) showed better performance than local features (AUC 86.21%) and global average pooling features (AUC 87.1%) that were derived from a CNN for malignancy characterisation of HCC. Furthermore, the proposed DLNFL-net yielded superior performance (AUC 94.89%) than a typical 3D CNN (AUC 86.21%), bilinear CNN (AUC 90.46%), recently proposed local and global diffusion method (AUC 93.94%), and convolutional block attention module method (AUC 93.62%) for malignancy characterisation of HCC. The non-local operation demonstrated a better capability of yielding global representation, and feature denoising based on the non-local operation achieved performance gains for lesion characterisation. The proposed DLNLF-net, which integrates denoised local and non-local deep features, evidently outperforms conventional CNN-based methods in the malignancy characterisation of HCC.


Microscopic distribution of misonidazole in mouse tissues.
Mice were injected with tritiated misonidazole (750 mg/kg-1), killed after 24h and the excised tissues prepared for autoradiography (ARG) to identify sites of accumulation. The previously reported high grain count associated with bound misonidazole metabolite(s) was observed in the liver. The ratio of grain count in the emulsion above the centrilobular hepatocytes to the count over connective tissue (stroma) was 12. A higher count ratio for 'target' cells to stroma was observed in the following cells/tissues: meibomian gland (ducts 110, acini 65), oesophagus (keratinised layer 60), incisor (enamel organ 17), nasal septum (subepithelial glands 13). For some of these tissues the explanation might appear to lie with localised hypoxia, but for others which were probably normoxic there is as yet no obvious reason for these findings.


Tislelizumab for Relapsed/Refractory Classical Hodgkin Lymphoma: 3-Year Follow-up and Correlative Biomarker Analysis.
Tislelizumab is an anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody specifically designed to minimize binding to Fcγ receptors (FcγR). Here, we present the extended 3-year follow-up of a phase II study of tislelizumab in 70 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) who failed or were ineligible for autologous stem cell transplantation. With a median follow-up of 33.8 months, the overall response rate by the independent review committee was 87.1%, and the complete response (CR) rate was 67.1%. Responses were durable as shown by a median duration of response of 31.3 months, and median progression-free survival (PFS) of 31.5 months. The 3-year PFS and overall survival rates were 40.8% and 84.8%, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 97.1% of patients; the grade ≥3 TRAE rate was low (31.4%), and only 8.6% of patients experienced adverse events leading to treatment discontinuation. Correlative biomarker analysis showed that FcγRΙ-expressing macrophages had no observed impact on either the CR rate or PFS achieved with tislelizumab, which may be potentially related to its engineered Fc region. With extended follow-up, tislelizumab yielded long-term benefits and demonstrated a favorable safety profile for patients with relapsed/refractory cHL. This trial was registered at clinicaltrials.gov as NCT03209973.


Content Validity of Assessment Instrument for High-Performance Work Systems in Healthcare Industry.
Background and Purpose: The main purpose of this article is to content validate and evaluate a measuring instrument of high-performance work systems (HPWS) in healthcare organizations that capture the nurses' perception of HPWS present in their working organization. Methods: A panel of six experts participated to validate the HPWS instrument through their feedback. Later, coding and recoding of expert feedback were performed to calculate the item content validity index (I-CVI), scale content validity index (S-CVI), and Kappa statistic coefficient (K*) to rate its content validity. Results: For 50 out of 52 items of the measuring instrument, I-CVI is well above the recommended minimum acceptable value of 0.78. The S-CVI value is observed as 0.94, and the K* value is above 0.74 for 50 items. Conclusion: The results indicated excellent content validity for all the domains indicating evidence that the HPWS scale and the items on it are content valid and can be used for nursing research in the healthcare industry.


When the times get tough the toughs get funny: Means by which humor buffers against death anxiety emerged during COVID-19 outbreak.
According to Terror Management Theory (TMT), there are three common buffers that minimize the anxiety of mortality salience: affirmation of a) one's cultural worldview, b) the self and one's personal values, and c) one's significance in the context of close personal relationships. The current study aimed at examining the contents of memes, which were distributed on social media during the COVID-19 outbreak, to explore the means by which humor buffers against death anxiety. A deductive and inductive thematic analysis captured three means by which humor buffers against death anxiety, a) humor as a means for connecting to cultural worldviews; b) humor as a means for inclusion in group; c) humor as a means to gain a sense of control. These findings are discussed through the theoretical lens of TMT.


Quality of life and health-related utility after trans-oral surgery for head and neck cancers.
The purpose of this study was to assess utility coefficients of health states following two minimally invasive surgical approaches for head and neck cancer, namely trans-oral robotic surgery and trans-oral laser microsurgery. Those utility coefficients will be later exploited in an economic evaluation study comparing the two approaches. The above cited economic evaluation will be done from the Swiss healthcare system perspective and, as such, Swiss healthcare professionals were interviewed to elicit utility coefficients. Health states, ranging from remission to palliative care, were described using clinical vignettes. A computerized tool (UceWeb) implementing standard gamble and rating scale methods was used. Utility coefficients for 18 different health states were elicited with the two methods from 47 individuals, for a total of 1692 values. Elicited values varied from 0.980 to 0.213. Comparison with values elicited in previous studies show the need for population-specific elicitation, mainly for the worst health states. Herein we report health utility coefficients for the Swiss population for health states following minimally invasive trans-oral surgery. This study provides utility values that can be used not only for a specific cost-utility analysis, but also for future studies involving the same health states.


Highly Conformal Craniospinal Radiotherapy Techniques Can Underdose the Cranial Clinical Target Volume if Leptomeningeal Extension through Skull Base Exit Foramina is not Contoured.
Craniospinal irradiation (CSI) remains a crucial treatment for patients with medulloblastoma. There is uncertainty about how to manage meningeal surfaces and cerebrospinal fluid (CSF) that follows cranial nerves exiting skull base foramina. The purpose of this study was to assess plan quality and dose coverage of posterior cranial fossa foramina with both photon and proton therapy. We analysed the radiotherapy plans of seven patients treated with CSI for medulloblastoma and primitive neuro-ectodermal tumours and three with ependymoma (total n = 10). Four had been treated with a field-based technique and six with TomoTherapy™. The internal acoustic meatus (IAM), jugular foramen (JF) and hypoglossal canal (HC) were contoured and added to the original treatment clinical target volume (Plan_CTV) to create a Test_CTV. This was grown to a test planning target volume (Test_PTV) for comparison with a Plan_PTV. Using Plan_CTV and Plan_PTV, proton plans were generated for all 10 cases. The following dosimetry data were recorded: conformity (dice similarity coefficient) and homogeneity index (D2 - D98/D50) as well as median and maximum dose (D2%) to Plan_PTV, V95% and minimum dose (D99.9%) to Plan_CTV and Test_CTV and Plan_PTV and Test_PTV, V95% and minimum dose (D98%) to foramina PTVs. Proton and TomoTherapy™ plans were more conformal (0.87, 0.86) and homogeneous (0.07, 0.04) than field-photon plans (0.79, 0.17). However, field-photon plans covered the IAM, JF and HC PTVs better than proton plans (P = 0.002, 0.004, 0.003, respectively). TomoTherapy™ plans covered the IAM and JF better than proton plans (P = 0.000, 0.002, respectively) but the result for the HC was not significant. Adding foramen CTVs/PTVs made no difference for field plans. The mean Dmin dropped 3.4% from Plan_PTV to Test_PTV for TomoTherapy™ (not significant) and 14.8% for protons (P = 0.001). Highly conformal CSI techniques may underdose meninges and CSF in the dural reflections of posterior fossa cranial nerves unless these structures are specifically included in the CTV.


Development of a digital biomarker and intervention for subclinical depression: study protocol for a longitudinal waitlist control study.
Depression remains a global health problem, with its prevalence rising worldwide. Digital biomarkers are increasingly investigated to initiate and tailor scalable interventions targeting depression. Due to the steady influx of new cases, focusing on treatment alone will not suffice; academics and practitioners need to focus on the prevention of depression (i.e., addressing subclinical depression). With our study, we aim to (i) develop digital biomarkers for subclinical symptoms of depression, (ii) develop digital biomarkers for severity of subclinical depression, and (iii) investigate the efficacy of a digital intervention in reducing symptoms and severity of subclinical depression. Participants will interact with the digital intervention BEDDA consisting of a scripted conversational agent, the slow-paced breathing training Breeze, and actionable advice for different symptoms. The intervention comprises 30 daily interactions to be completed in less than 45 days. We will collect self-reports regarding mood, agitation, anhedonia (proximal outcomes; first objective), self-reports regarding depression severity (primary distal outcome; second and third objective), anxiety severity (secondary distal outcome; second and third objective), stress (secondary distal outcome; second and third objective), voice, and breathing. A subsample of 25% of the participants will use smartwatches to record physiological data (e.g., heart-rate, heart-rate variability), which will be used in the analyses for all three objectives. Digital voice- and breathing-based biomarkers may improve diagnosis, prevention, and care by enabling an unobtrusive and either complementary or alternative assessment to self-reports. Furthermore, our results may advance our understanding of underlying psychophysiological changes in subclinical depression. Our study also provides further evidence regarding the efficacy of standalone digital health interventions to prevent depression. Trial registration Ethics approval was provided by the Ethics Commission of ETH Zurich (EK-2022-N-31) and the study was registered in the ISRCTN registry (Reference number: ISRCTN38841716, Submission date: 20/08/2022).


Thoracoscopic Correction of Post-traumatic Kyphosis with an Expandable Cage: Radiologic and Patient-Reported Outcomes.
Retrospective cohort study. To determine the long-term functional and radiological outcomes after thoracoscopic post-traumatic kyphosis (PTK) correction (PTKC). PTK after insufficient treatment of unstable fractures usually presents with pain and decreased back function. The results of PTKC using a minimally invasive thoracoscopic approach with an anterior titanium cage have not previously been reported. Data in this study were collected from all patients who underwent thoracoscopic PTKC with an expandable cage between 2007 and 2017. Kyphosis and intervertebral body height were assessed on radiographic material. Quality of life (QOL) and functional outcome scores were determined by the Euroquol 5 dimensions (EQ5D) and the Oswestry Disability Index (ODI). Additionally, satisfaction and subjective symptom improvement were determined. Fourteen patients were treated for symptomatic PTK using a combined thoracoscopic anterior and posterior approach. Nine patients received initial conservative fracture treatment and five patients underwent initial posterior fracture fixation. All patients presented with pain and without neurologic injury. The mean time between injury and PTKC was 15.4 months. Cobb angle (CA) improved with 10.6° immediately after PTKC. During the first follow-up, 4.8° kyphosis correction was lost, but CAs remained stable at longer follow-up. Bony fusion was achieved in 92% of the patients after 16 months. The majority of patients reported an improvement of symptoms 85 months after surgery, satisfaction with and willingness to undergo the procedure again. The mean EQ5D index score was 0.71 and the mean ODI score was 22.3. The results of minimally invasive thoracoscopic PTKC using an expandable cage were satisfactory. The majority of the patients were satisfied after treatment and no neurological complications occurred. Functional and QOL scores were fairly good. Whereas some postoperative kyphosis correction was lost over time, bony fusion was achieved in the majority of the patients. The thoracoscopic approach minimizes surgical morbidity, does not lead to serious complications, and provides a good option for PTKC.


[Cutaneous squamous cell carcinoma and human papillomavirus].
The relationship between mucosal human papillomavirus (HPV) and cervical carcinoma or anogenital squamous cell carcinoma (SCC) is becoming increasingly evident, whereas a link between HPV and other cutaneous SCCs is less clear. Recent studies have reported links between epidermodysplasia-verruciformis-associated HPV and extragenital cutaneous SCC, particularly in immunosuppressed patients, although immunocompetent patients have also been affected. Mucosal HPV could also be linked to some types of Bowen disease and certain SCCs of the fingers, oropharyngeal mucosa, etc. We review the possible oncogenic mechanisms involving mucosal HPV and epidermodysplasia-verruciformis-associated HPV. Most SCCs could be explained by the combined action of HPV, immunosuppression, and the oncogenic and immunosuppressive effect of UV radiation. HPV might be associated with worse prognosis of SCC, with implications for clinical practice including greater risk of metastasis.


Clinical and electrophysiologic attributes as predictors of results of autonomic function tests.
Autonomic dysfunction is a feature of some neuropathies and not others. It has been suggested that some clinical and electrophysiologic attributes are predictable of autonomic impairment detected using laboratory testing; however, dear guidelines are unavailable. We evaluated 138 relatively unselected patients with peripheral neuropathy who underwent neurologic evaluation, electromyography (EMG), nerve conduction studies, and autonomic function tests to determine which variables were predictive of laboratory findings of autonomic failure. The variables evaluated were 1) clinical somatic neuropathic findings, 2) clinical autonomic symptoms, and 3) electrophysiologic findings. Autonomic symptoms were strongly predictive (Rs = 0.40, p < 0.001) of autonomic failure. Among the non-autonomic indices, absent ankle reflexes were mildly predictive (Rs = 0.19, p = 0.022) of autonomic impairment, but all others were not (duration, clinical pattern, severity, weakness, sensory loss). Electrophysiologic changes of an axonal neuropathy predicted autonomic impairment while demyelinating neuropathy did not. We conclude that autonomic studies will most likely be abnormal in patients who have symptoms of autonomic involvement and those who have an axonal neuropathy.


Spatial patterns of goldenrod aphids and the response of enemies to patch density.
The two aphid species feeding on goldenrod (Solidago altissima) in northern Florida (U.S.A.) exhibited behavioral differences that resulted in characteristic spatial patterns. Uroleucon nigrotuberculatum alates (winged forms) aggregated when colonizing stems and subsequent non-winged generations were relatively sedentary, resulting in a clumped spatial pattern. U. tissoti colonized stems singly and was more mobile; these behaviors resulted in its more random spatial pattern within fields of goldenrod.Manipulations of aphid density in the field revealed that although patches with high densities of aphids accumulated more predators than patches with few aphids, predation pressure (measured as number of predators per aphid) was lower in dense patches. As a result, aphids in dense patches had a higher per capita change in density than aphids in sparse patches. However, when the fungal pathogen, Neozygites fresenii, became the dominant mortality agent, the influence of aphid density on mortality was reversed; aphids in dense patches were then more vulnerable than aphids in sparse patches. Thus the spatial patterns exhibited by the U. nigrotuberculatum and U. tissoti resulted in differences in their relative vulnerability to different natural enemies.


Parosteal chondrosarcoma, a very rare condition of the mandibular condyle.
We present a rare case of parosteal chondrosarcoma of the madibular condyle. The patient was referred for a functional limitation of the left temporo-mandibular joint. CT and MRI examinations demonstrated a 3.5-cm cystic mass with a peripheral rim of contrast enhancement located in the left pterygo-maxillary space. The mass had partial intraarticular spread causing deformation and focal cortical erosion of the medial aspect of the condylar head. The lesion was surgically removed; the histological diagnosis was of low-grade chondrosarcoma.


Effect of iron deficiency anaemia on HbA1c levels is dependent on the degree of anaemia.
Studies suggest that iron deficiency anaemia (IDA) is associated with higher HbA1c levels. We conducted a control–case study to investigate the effect of IDA on HbA1c levels, measured by two commonly used methods, in non-diabetic individuals. A total of 122 patients were included, 61 patients with IDA and 61 patients without anaemia. HbA1c was measured by both ion exchange HPLC Variant II Turbo BioRad and immunoturbidimetry (IT) Tina Quant II Roche Diagnostics in each sample. HbA1c results were compared between groups. For correlation analysis, patients were considered altogether. There was a significant difference between the results of HbA1c in patients with IDA [HPLC 5.6 ± 0.4% (38 ± 4.4 mmol/mol) and IT 5.7 ± 0.4% (39 ± 4.4 mmol/mol)] and those measured in patients without anaemia [HPLC 5.3 ± 0.4% (34 ± 4.4 mmol/mol) and IT 5.3 ± 0.3% (34 ± 3.3 mmol/mol)], (p < 0.001). Significant negative correlations were observed between total haemoglobin (Hb), haematocrit, mean corpuscular volume (MCV) and ferritin with HbA1c values measured by IT (r = − 0.557; r = − 0.539; r = − 0.488; r = − 0.499; p < 0.01; respectively). These negative correlations were weaker with HbA1c measured by HPLC (r = − 0.272; r = − 0.250; r = − 0.273; r = − 0.229 for Hb, haematocrit, MCV and ferritin; p < 0.05; respectively). HbA1c results were higher in patients with moderate and severe anaemia. However mild anaemia did not show significant effects on HbA1c results measured by both methods. IDA affects HbA1c results and this effect is dependent on anaemia degree. These upward changes are statistically significant but they may be not clinically relevant when the overall variability of the HbA1c test is considered. The presence of slight anaemia is likely to have a minor effect on HbA1c levels favouring its use to diagnose diabetes in patients with mild anaemia.


The Jekyll and Hyde of Senescence in Cancer: TIMP1 Controls the Switch from Tumor-Controlling to Tumor-Promoting Senescence.
Cellular senescence is a response with two faces in cancer: it restricts tumor proliferation, but it can also promote cancer progression and metastasis. In this issue of Cancer Cell, Guccini et al. uncover the role of TIMP1 in prostate cancer allowing a switch from tumor-controlling to tumor-promoting senescence.


Neurocognitive function in users of MDMA: the importance of clinically significant patterns of use.
Use of MDMA (ecstasy), a serotonin neurotoxin, has been associated with memory impairment and psychological dysfunction. This study examined cognitive functioning in abstinent MDMA users and MDMA-naive controls. Participants completed measures of intelligence, motor function, attention, memory span, verbal fluency, immediate and delayed verbal memory, and working memory. They were also assessed for the presence of psychopathology. In addition to comparing cognitive function in MDMA users relative to controls, the possibility that clinically dysfunctional MDMA use increases the risk of cognitive impairment was examined. MDMA users exhibited relative deficits in mnemonic and executive functions. Additionally, users that met DSM-IV substance use disorder criteria for lifetime MDMA abuse or dependence exhibited a number of additional deficits relative to those who did not meet these criteria. These findings suggest that clinically dysfunctional, rather than purely recreational, MDMA use is associated with cognitive impairment. Future research studies of diverse samples of users may shed light on the mechanisms that underlie these differences.


Differential expression of GABA(A) receptor subunits in the distinct nuclei of the rat amygdala.
Detailed knowledge of the anatomical distribution of different GABA(A) receptor subunits is crucial for understanding the physiological actions of GABA in individual brain areas and for developing drugs acting through the individual GABA receptor subtypes. Since the amygdala is a key brain structure in the processing of emotional information with distinct functions in each nucleus, GABA(A) receptors in the amygdala are an important target of treatment for emotional disorders. In this study, we analyzed by quantitative RT-PCR the expression levels of all GABA(A) receptor subunits in distinct nuclei of the amygdala, the central (Ce) and the lateral/basolateral (LA/BLA) amygdala. We found the strongest expression of the gamma(2) subunit mRNA in both the Ce and LA/BLA, modest expressions of alpha(1), alpha(2) and alpha(3) mRNAs in the LA/BLA and alpha(2) and gamma(1) mRNAs in the Ce, and weak expressions of alpha(6), rho(2) and rho(3) mRNAs in both regions. We further revealed the significantly different expressions of alpha(1), alpha(3), alpha(5), gamma(1), gamma(2), delta, epsilon and theta subunit mRNAs in the Ce and LA/BLA. Differences in the expression levels of GABA(A) receptor subunits suggest different sensitivity to a variety of drugs including benzodiazepines and anesthetics in amygdala nuclei with distinct functions.


The use of vesical irrigation system dual pump Endo FMS urology in the endoscopic therapy of benign prostatic hyperplasia.
Transurethral resection of the prostate (TURP) remains the reference standard treatment in the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). The objective of this study was to determine whether vesical irrigation during TURP with the dual pump system Endo FMS Urology is more efficient than standard gravity irrigation. A group of 30 patients who underwent TURP using the Endo FMS Urology was compared to a group of 30 patients treated with standard vesical irrigation. A 40% decrease of fluid irrigated, a 10% decrease of time for procedure and a 10% increase in the volume of the resected tissue was observed in patients treated with the Endo FMS Urology compared to controls treated with standard vesical irrigation.


Genetic polymorphisms of microsomal epoxide hydrolase and UDP-glucuronosyltransferase (UGT) and its effects on plasma carbamazepine levels and metabolic ratio in persons with epilepsy of South India: A cross-sectional genetic association study.
Carbamazepine (CBZ), an anti-seizure drug, is widely prescribed for the management of focal seizures. At a given therapeutic dose, CBZ exhibits marked interindividual variation in the plasma CBZ levels. The aim wasto study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on plasma carbamazepine (CBZ) levels in persons with epilepsy (PWE) from South India. 115 PWE belong to South India origin who are on carbamazepine monotherapy were recruited. Genotyping of the two variants weredone using RT-PCR method. PWE who had seizure freedom for one year and their last dose which was not changed for one year duration were included and their plasma levels of CBZ and its active metabolite CBZ 10,11 epoxide were analysed by reverse phase HPLC. In EPHX1 c. 337 (T>C) polymorphism, the PWE carrying CC had lower plasma CBZ levels when compared to CT genotype (2.45 μg/ml vs 3.15 μg/ml. In UGT2B7*2, PWE carrying homozygous mutant TT had higher levels when compared with CT (3.09 μg/ml vs 2.74 μg/ml) genotype but found no statistical significance. Mutant genotype of EPHX1 (CC) had higher metabolic ratio compared to TT genotype (1.33 vs 1.17) but not found to be statistically significant. Mutant genotype of UGT2B7*2 (TT) was found to be having lower metabolic ratio when compared with CC genotype (1.18 vs 1.35; p value =0.08). PWE carrying EPHX1 c.337 T>C (rs1051740) and UGT2B7*2 (rs7439366) genetic polymorphisms did not affect the plasma CBZ levels and metabolic ratio of PWE of South Indian origin. However, this finding should be confirmed in a larger sample size which may help in optimization and personalized CBZ therapy in South Indians.


Excitatory influence of the accessory olfactory bulb on tuberoinfundibular arcuate neurons of female mice and its modulation by oestrogen.
The role of the accessory olfactory bulb in conveying pheromonal information to tuberoinfundibular arcuate neurons was examined electrophysiologically in chloral hydrate-anaesthetized, oestrogen (0.5 micrograms in silastic capsules)-treated and untreated ovariectomized Balb/c female mice. Electrical stimulation of the accessory olfactory bulb orthodromically excited part of tuberoinfundibular neurons which were antidromically stimulated from the median eminence and histologically verified as being located within the arcuate nucleus. No inhibitions followed accessory bulb stimulation. The excitatory response to accessory bulb stimulation was reversibly blocked by the local anaesthetic lignocaine infused into the amygdala. The percentage of tuberoinfundibular arcuate neurons responding to accessory bulb stimulation was significantly higher in oestrogen-treated than in untreated animals. There was no difference between the two groups for the antidromic activation threshold, spontaneous firing rate, absolute refractory period or frequency of successful antidromic propagation into the soma of tuberoinfundibular arcuate neurons. In oestrogen-treated preparations, tuberoinfundibular arcuate neurons responsive and unresponsive to accessory bulb stimulation could be distinguished by the frequency of successful antidromic propagation into the soma. These studies demonstrate that olfactory relay neurons in the accessory olfactory bulb act to enhance the activity of a subpopulation of tuberoinfundibular arcuate neurons via the amygdala and that this neural transmission is modulated by oestrogen.


Simultaneous and selective electrochemical sensing of methotrexate and folic acid in biological fluids and pharmaceutical samples using Fe3O4/ppy/Pd nanocomposite modified screen printed graphite electrode.
The purpose of this study was to fabricate an electrochemical sensor for the detection of methotrexate and folic acid based on a screen-printed graphite electrode (SPGE) modified with prepared iron oxide (Fe3O4)/polypyrrole (ppy)/Palladium (Pd) nanocomposite. Transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR) techniques were employed to characterize the Fe3O4/ppy/Pd nanocomposite. The produced modifier was used to induce a remarkable electrocatalytic impact relative to the oxidation of methotrexate, which caused the potential peak shift to a less positive amount (from 800 mV to about 500 mV) and improved the peak current (from 5.3 μA to about 16 μA). Methotrexate peak current was linearly dependent on its concentration from 0.03100.0 μM and the limit of detection (LOD) was estimated at 7.0 nM. The methotrexate and folic acid were co-detected by the proposed sensor. The experimental results indicated that the oxidation peaks of methotrexate and folic acid were separated about 200 mV in phosphate buffer solution (PBS) at pH 7.0. Fe3O4/ppy/Pd/SPGE was successfully able to detect methotrexate and folic acid in pharmaceutical and biological samples with excellent recovery.


Process in psychotherapy as decreasing asymmetry between patient and therapist: evidence from the verbal interaction.
Transcripts of over half the sessions of a psychodynamically oriented psychotherapy were coded to show amount of speech by patient and therapist, and role dimensions derived from Stiles' Verbal Response Mode system. Results indicate the process of psychotherapy as one of decreasing asymmetry between participants, in both activity and status.


Detectable radio flares following gravitational waves from mergers of binary neutron stars.
Mergers of neutron-star/neutron-star binaries are strong sources of gravitational waves. They can also launch subrelativistic and mildly relativistic outflows and are often assumed to be the sources of short γ-ray bursts. An electromagnetic signature that persisted for weeks to months after the event would strengthen any future claim of a detection of gravitational waves. Here we present results of calculations showing that the interaction of mildly relativistic outflows with the surrounding medium produces radio flares with peak emission at 1.4 gigahertz that persist at detectable (submillijansky) levels for weeks, out to a redshift of 0.1. Slower subrelativistic outflows produce flares detectable for years at 150 megahertz, as well as at 1.4 gigahertz, from slightly shorter distances. The radio transient RT 19870422 (ref. 11) has the properties predicted by our model, and its most probable origin is the merger of a compact neutron-star/neutron-star binary. The lack of radio detections usually associated with short γ-ray bursts does not constrain the radio transients that we discuss here (from mildly relativistic and subrelativistic outflows) because short γ-ray burst redshifts are typically >0.1 and the appropriate timescales (longer than weeks) have not been sampled.


Detection and characterization of lipid hydroperoxides at picomole levels by high-performance liquid chromatography.
A new method for the detection of various lipid hydroperoxides and hydrogen peroxide at the picomole level has been developed by combining an HPLC system with an ultrasensitive analytical system based on the detection of chemiluminescence emitted by isoluminol in the presence of hydroperoxide and microperoxidase. This HPLC separation removes interfering antioxidants so that the method can be applied to biological samples such as blood plasma lipids. Several HPLC conditions are described which allow simple identification of different lipid hydroperoxides.


Arterial transit artifacts on arterial spin labeling MRI can predict cerebral hyperperfusion after carotid endarterectomy: an initial study.
To investigate whether preoperative arterial spin labeling (ASL) MRI can predict cerebral hyperperfusion after carotid endarterectomy (CEA) in patients with carotid stenosis. Consecutive patients with carotid stenosis who underwent CEA between May 2015 and July 2021 were included. For each patient, a cerebral blood flow ratio (rCBF) map was obtained by dividing postoperative CBF with preoperative CBF images from two pseudo-continuous ASL scans. Hyperperfusion regions with rCBF > 2 were extracted and weighted with rCBF to calculate the hyperperfusion index. According to the distribution of the hyperperfusion index, patients were divided into hyperperfusion and non-hyperperfusion groups. Preoperative ASL images were scored based on the presence of arterial transit artifacts (ATAs) in 10 regions of interest corresponding to the Alberta Stroke Programme Early Computed Tomography Score methodology. The degree of stenosis and primary and secondary collaterals were evaluated to correlate with the ASL score. Logistic regression and receiver operating characteristic curve analyses were performed to assess the predictive ability of the ASL score for cerebral hyperperfusion. Of 86 patients included, cerebral hyperperfusion was present in 17 (19.8%) patients. Carotid near occlusion, opening of posterior communicating arteries with incomplete anterior semicircle, and leptomeningeal collaterals were associated with lower ASL scores (p < 0.05). The preoperative ASL score was an independent predictor of cerebral hyperperfusion (OR = 0.48 [95% CI [0.33-0.71]], p < 0.001) with the optimal cutoff value of 25 points (AUC = 0.98, 94.1% sensitivity, 88.4% specificity). Based on the presence of ATAs, ASL can non-invasively predict cerebral hyperperfusion after CEA in patients with carotid stenosis. • Carotid near occlusion, opening of posterior communicating arteries with incomplete anterior semicircle, and leptomeningeal collaterals were associated with lower ASL scores. • The ASL score performed better than the degree of stenosis, type of CoW, and leptomeningeal collaterals, as well as the combination of the three factors for the prediction of cerebral hyperperfusion. • For patients with carotid stenosis, preoperative ASL can non-invasively identify patients at high risk of cerebral hyperperfusion after carotid endarterectomy without complex post-processing steps.


The accuracy of suicide statistics: are true suicide deaths misclassified?
Official suicide statistics often produce an inaccurate view of suicide populations, since some deaths endorsed as being of uncertain manner are in fact suicides; it is common, therefore, in suicide research, to account for these deaths. We aimed to test the hypothesis that non-suicide death categories contain a large potential reservoir of misclassified suicides. Data on undetermined intent and ill-defined death causes, and official suicide deaths recorded in the district of Tel Aviv for the years 2005 and 2008 were extracted. Based on supplementary data, cases regarded as probable suicides ("suicide probable") were then compared with official suicides ("suicide verdicts") on a number of socio-demographic variables, and also in relation to the mechanism of death. Suicide rates were 42 % higher than those officially reported after accounting for 75 probable suicides (erroneously certified under other cause-of-death categories). Both death classifications ("suicide probable" and "suicide verdicts") had many similarities, significantly differing only with respect to method used. Logistic regression confirmed that the most powerful discriminator was whether the mechanism of death was considered "less active" or "more active" (p < 0.001). Indeed, deaths among the less active group were 4.9 times as likely to be classified as "suicide probable" than were deaths among the more active group. Caution is needed when interpreting local area data on suicide rates, and undetermined and ill-defined deaths should be included in suicide research after excluding cases unlikely to be suicides. Improving suicide case ascertainment, using multiple sources of information, and uniform reporting practices, is advised.


Opa1-mediated mitochondrial dynamics is important for osteoclast differentiation.
Opatic atrophy 1 (Opa1) is a mitochondrial GTPase that regulates mitochondrial fusion and maintenance of cristae architecture. Osteoclasts are mitochondrial rich-cells. However, the role of Opa1 in osteoclasts remains unclear. Here, we demonstrate that Opa1- deficient osteoclast precursor cells do not undergo efficient osteoclast differentiation and exhibit abnormal cristae morphology. Thus, Opa1 is a key factor in osteoclast differentiation through regulation of mitochondrial dynamics.