The HeartMate 3 left ventricular assist device as a strategy to bridge to transplant.
Recent changes in the market for left ventricular assist devices have resulted in the HeartMate 3 (HM3) being the only commercially-available device. This study evaluates the outcomes of patients with a HM3 waitlisted for and undergoing orthotopic heart transplantation (OHT). Patients waitlisted for isolated OHT with a HM3 or undergoing OHT after bridge-to-transplant (BTT) with a HM3 between 2015 and 2021 were identified from the UNOS registry and included in this study. Propensity matching was used to compare outcomes of BTT-HM3 versus primary OHT. A total of 1321 patients supported with a HM3 underwent OHT during our study period. Unadjusted 30-day, 90-day, and 1-year survival following OHT in the BTT-HM3 cohort was 96.5%, 94.4%, and 90.7%, respectively. In propensity-matched analysis, 1103 BTT-HM3 patients were compared with 1103 primary OHT patients. Rates of post-OHT stroke were higher in the BTT-HM3 group (4.4% vs. 2.0%, p = .001). The BTT-HM3 group had lower 30-day survival (96.2% vs. 97.4%, p = .033) although 90-day (94.2% vs. 95.3%, p = .103) and 1-year survival (90.4% vs. 91.7%, p = .216) were comparable. A total of 1251 patients were supported with a HM3 at the time of OHT listing during the study period. At the time of this analysis, 60 (4.5%) remained on the waitlist, 991 (75.0%) underwent OHT, and 119 (9.0%) died or clinically deteriorated with waitlist removal. The HM3 is a viable method for BTT with acceptable waitlist outcomes. Although 1-year survival is comparable to primary OHT, early outcomes are worse, suggesting that refinement of patient selection and perioperative management is prudent to optimizing outcomes.


Changes in duration of action of rocuronium following decrease in hepatic blood flow during pneumoperitoneum for laparoscopic gynaecological surgery.
A moderate insufflation pressure and deep neuromuscular blockade (NMB) have been recommended in laparoscopic surgery in consideration of the possible reduction in splanchnic perfusion due to the CO2-pneumoperitoneum. Since the liver is the major organ for rocuronium metabolism, the question of whether NMB of rocuronium would change with the variation of liver perfusion during pneumoperitoneum during laparoscopic surgery merits investigation. In this prospective study, a total of sixty female patients scheduled for either selective laparoscopic gynaecological surgery (group laparoscopy) or laparotomy for gynaecological surgery (group control) were analyzed. Rocuronium was administered with closed-loop feedback infusion system, which was also applied to monitor NMB complied with good clinical research practice (GCRP). The onset time, clinical duration, and recovery index were measured. Hepatic blood flow was assessed by laparoscopic intraoperative ultrasonography before insufflation/after entering the abdominal cavity (T1), 5 min after insufflation in the Trendelenburg position/5 min after skin incision (T2), 15 min after insufflation in the Trendelenburg position/15 min after skin incision (T3), 30 min after insufflation in the Trendelenburg position/30 min after skin incision (T4), and 5 min after deflation/before closing the abdomen (T5) in group laparoscopy/group control respectively. The relationship between the clinical duration of rocuronium and portal venous blood flow was analyzed using linear or quadratic regression. The clinical duration and RI of rocuronium were both prolonged significantly in group laparoscopy (36.8 ± 8.3 min; 12.8 ± 5.5 min) compared to group control (29.0 ± 5.8 min; 9.8 ± 4.0 min) (P < 0.0001; P = 0.018). A significant decrease was found in portal venous blood flow during the entire pneumoperitoneum period in group laparoscopy compared with group control (P < 0.0001). There was a significant correlation between the clinical duration of rocuronium and portal venous blood flow (Y = 51.800-0.043X + (1.86E-005) X 2; r2 = 0.491; P < 0.0001). Rocuronium-induced NMB during laparoscopic gynaecological surgery might be prolonged due to the decrease in portal venous blood flow induced by CO2-pneumoperitoneum. Less rocuronium could be required to achieve a desirable NMB in laparoscopic gynaecological surgery. ChiCTR. Registry number: ChiCTR-OPN-15007524 . Date of registration: December 4, 2015.


Analysis of the brain-stem white-matter tracts with diffusion tensor imaging.
The authors have reviewed the diffusion tensor imaging (DTI) of the brain stem in 19 subjects, consisting of 15 normal volunteers and four multi-system atrophy patients. The study was performed with 1.5 T MRI scanners. DTI was correlated with an automated program allowing superposition of the structural anatomy. Axial, sagittal, and coronal images demonstrated major white-matter fibers within the brain stem, including cortico-spinal tracts, transverse pontine fibers, and medial lemniscus. Smaller fibers, such as medial longitudinal fascicles and central tegmental tracts are difficult to visualize. To identify the anatomical orientation of the brain stem, white-matter fibers will help us understand the different functional disease processes, and DTI will play an important role for the evaluation of the different white matter fibers in the brain stem.


The Use of Contrast-enhanced Ultrasonography for Imaging of Carotid Atherosclerotic Plaques: Current Evidence, Future Directions.
Contrast-enhanced ultrasonography (CEUS) is a rapidly evolving modality for imaging carotid artery disease and systemic atherosclerosis. CEUS coupled with diagnostic ultrasonography predicts the degree of carotid artery stenosis and is comparable with computed tomography and magnetic resonance angiography. This article reviews the literature on the evolving role of CEUS for the identification and characterization of carotid plaques with an emphasis on detection of intra-plaque neovascularization and related high-risk morphologic features notably present in symptomatic patients. CEUS carotid imaging may play a prominent additive role in risk stratifying patients and serve as a powerful tool for monitoring therapeutic interventions.


In vitro aldose reductase inhibitory activity of 5-benzyl-2,4-thiazolidinediones.
Several 5-benzyl-2,4-thiazolidinediones (5-7) were synthesised and tested as in vitro aldose reductase (ALR2) inhibitors. Most of them, particularly N-unsubstituted 5-benzyl-2,4-thiazolidinediones 5 and (5-benzyl-2,4-dioxothiazolidin-3-yl)acetic acids 7, displayed moderate to high inhibitory activity levels. In detail, the insertion of an acetic chain on N-3 significantly enhanced ALR2 inhibitory potency, leading to acids 7 which proved to be the most effective among the tested compounds. In addition, in N-unsubstituted derivatives 5 the presence of an additional aromatic ring on the 5-benzyl moiety was generally beneficial. In fact, the ALR2 inhibition results of compounds 5-7, compared to those of the previously assayed corresponding 5-arylidene-2,4-thiazolidinediones, indicated that N-unsubstituted derivatives 5b, c and d, which bore an additional aromatic group in the para position of the 5-benzyl residue, were significantly more effective than their 5-arylidene counterparts; in all other cases, the saturation of the exocyclic double bond CC in 5 brought about a moderate decrease in activity.


Postpartum health risks among women with hypertensive disorders of pregnancy, California 2008-2012.
The aim of this study was to understand the associations between hypertensive disorders of pregnancy (HDP) and postpartum complications throughout the newly defined 12-week postpartum transition. We conducted a retrospective cohort study of the associations of HDP (any/subtype) with postpartum complications among 2.5 million California births, 2008-2012. We identified complications from discharge diagnoses from maternal hospital encounters (emergency department visits and readmissions) in the 12 weeks after giving birth. We compared rates of complications, overall and by diagnostic category, between groups defined by HDP. In survival analyses, we calculated the adjusted hazard ratios of postpartum complications associated with HDP. We adjusted for maternal age, race/ethnicity, prepregnancy obesity, chronic diabetes, gestational diabetes, insurance, delivery mode, gestational age and birth outcome (term and size). Among women with and without HDP, 12.8 and 7.7%, respectively, had a hospital encounter within 12 weeks of giving birth [adjusted hazard ratio 1.5, 95% confidence interval (95% CI): 1.5-1.5]. HDP was associated with increased risk across all major categories of complications: hypertension-related, adjusted hazard ratio 11.8 (95% CI: 11.2-12.3); childbirth-related, 1.4 (1.3-1.4); and other, 1.4 (1.4-1.4). Risk of any complication differed by hypertensive subtype: chronic hypertension with super-imposed preeclampsia, adjusted hazard ratio 1.8 (95% CI: 1.7-1.8); chronic hypertension, 1.6 (1.6-1.7); preeclampsia/eclampsia, 1.3 (1.3-1.4); and gestational hypertension, 1.2 (1.2-1.3). Over a quarter (28.9%) of maternal hospital encounters occurred more than 6 weeks after giving birth; this did not differ substantially by HDP status. Women with HDP are at an increased risk for virtually all postpartum complications, including those not related to hypertension, and may benefit from enhanced and comprehensive postpartum care.


[Treatment of septic arthritis of the hand using temporary intermittent immobilization with an external fixator].
To evaluate the treatment of a bacterial infection of a finger joint with incision, drainage and intermittent immobilization using external fixation apparatus. Retrospective, descriptive. Department of Surgery, St Elisabeth Hospital, Tilburg. In eight males and two females (median age 37 years) with acute bacterial arthritis of a finger joint, this joint was opened surgically, washed out and then immobilized using mini-external fixation equipment, for about 3 weeks. The fixator was unscrewed daily so that the patient could move the finger in water, with the purpose of mechanical cleansing of the joint; the intermittent pressure that occurs in the cartilage during movement is supposed to promote the removal of debris. Subsequently, the finger was fixed in alternating positions to prevent adhesions. Mean duration of follow-up was 48 months (11-78). Arthrodesis had to be carried out in one patient because of persistent arthritis and tissue necrosis, while in one other, part of the finger was amputated. The other eight patients showed good final results, without symptoms. In bacterial arthritis of a finger joint, temporary intermittent immobilization using external fixation equipment is certainly worth consideration.


[Collagen- and total-vitamin c-content of humanplacentae (author's transl)].
The contents of collagen and total-vitamin C in human placentae of varying periods of gestation, specially in the period from 27 to 40 weeks, have been chemically determined. During this period a linear increase of the mentioned placenta-contents has been found.


[Good practice in health reporting-from the beginning to version 2.0].
In the context of public health, health reporting functions as a mediator between science and policy. The development of guidelines for good practice in health reporting took place in response to needs that were frequently expressed by experts in this public health area. The pilot version of the guidelines was drawn up in 2011 and discussed at a number of relevant conferences. After the publication of version 1.0 in 2017, another peer review process followed, which led to the extensively revised guidelines for good practice in health reporting as version 2.0. As health reporting is currently in a process of innovation and increasing in importance, it is foreseeable that the guidelines will have to be revised again in the not too distant future.


Efficacy and safety of butylphthalide in secondary prevention of stroke: study protocol for a multicenter, real world trial based on Internet.
As one of the leading causes of morbidity and mortality, stroke and its recurrence has attracted more and more attention. Dl-3-n-butylphthalidle(NBP) has been widely used for treating acute ischemic stroke in China and shows a great clinical effect. NBP plays a role in different pathophysiological processes in the treatment of ischemic stroke, including antioxidants, anti-inflammatory, anti-apoptotic, anti-thrombosis, and mitochondrial protection. Many randomized, double-blind, placebo-controlled, multicenter clinical trials suggest that NBP is a safe and effective treatment for ischemic stroke. To sum up, the current research is mainly focused on the short-term treatment of stroke patients with RCT (randomized controlled trial). Therefore, we designed this study to confirm the role of butylphthalide in secondary stroke prevention in the real world. This study will be a multicenter, prospective real-world trial. We would recruit 8000 patients with ischemic stroke from 78 public hospitals in China. All participants will be allocated to one of two parallel treatment groups according to their own wills: (1) butylphthalide group: 0.2 g of butylphthalide capsules three times daily plus routine treatment (aspirin 50-300 mg/d, clopidogrel 75 mg/d, etc.); (2) control group: routine treatment (aspirin 50-300 mg/d, clopidogrel 75 mg/d, etc.). Treatment duration is 90 consecutive days or more. The primary outcome is recurrence rate of stroke within 1 month, 3 months, 6 months and 1 year in butylphthalide group and control group. The secondary outcomes included NIHSS score, the mRS score, other clinical cardiovascular events within one year (sudden death / myocardial infarction / arrhythmia / heart failure, etc.), and adverse events of patients in groups. NIHSS will be captured in the first month after discharge, and the others will be captured at the same time points as the primary end point. This trial will be exploring the efficacy and safety of butylphthalide in secondary prevention of ischemic stroke to expand the scope of application of butylphthalide soft capsules and provide new ideas for enriching the secondary prevention of stroke. Chinese Clinical Trial Registry (ChiCTR). ChiCTR2000034481. Registered on 6 July 2020, http://www.chictr.org.cn/showproj.aspx?proj=55800.


Bioinformatics Approaches for Parkinson's Disease in Clinical Practice: Data-Driven Biomarkers and Pharmacological Treatment.
Parkinson's disease is a gradually progressive neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the midbrain area called the substantia nigra pars compacta and cytoplasmic alpha-synuclein-rich inclusions termed Lewy bodies. The etiology and pathogenesis remain incompletely understood. The development of reliable biomarkers for the early and accurate diagnosis, including biochemical, genetic, clinical, and neuroimaging markers, is crucial for unraveling the pathogenic processes of the disease as well as patients' progress surveillance. High-throughput technologies and system biology methodologies can support the identification of potent molecular fingerprints together with the establishment of dynamic network biomarkers. Emphasis is given on multi-omics datasets and dysregulated pathways associated with differentially expressed transcripts, modified protein motifs, and altered metabolic profiles. Although there is no therapy that terminates the neurodegenerative process and dopamine replacement strategy with L-DOPA represents the most effective treatment, numerous therapeutic protocols such as dopamine receptor agonists, MAO-B inhibitors, and cholinesterase inhibitors represent candidate treatments providing at the same time valuable network-based approaches to drug repositioning. Computational methodologies and bioinformatics platforms for visualization, clustering, and validating of molecular and clinical datasets provide important insights into diagnostic processing and therapeutic pipeline.


Recommendations on screening mammography in patients with ventriculoperitoneal shunts and deep brain stimulation.
Insertion of ventriculoperitoneal (VP) shunt and deep brain stimulation (DBS) are common neurosurgical procedures. Concerns have been raised regarding the safety of mammography in this patient cohort due to the risk of damaging the VP shunt tubing or DBS implantable pulse generator, and the degradation in mammography image quality secondary to the implanted devices. Based on a review of the current literature, the authors propose that mammography is safe in patients with VP shunts and DBS, and should be performed routinely as a part of population screening.


An overview of hemostasis.
The normal hemostatic system is complex yet exquisitely well regulated. Interrelationships exist between responses of the vasculature, circulating platelets, coagulation proteins, and fibrinolytic mechanism. These relationships serve to limit blood loss, preserve tissue perfusion, and stimulate local repair processes. Natural inhibitors of coagulation and fibrinolysis modulate these systems to prevent uncontrolled thrombosis or hemorrhage following pathologic stimuli. Vascular endothelial cells play an important role in the maintenance of a thromboresistant luminal interface with circulating cells and proteins. Normal hemostasis also requires the synthetic, metabolic, and repair processes of the vascular endothelium. The initial vascular response to injury produces brief vasoconstriction and exposes subendothelial substances that attract circulating platelets and activate coagulation proteins. Platelets respond by adherence and aggregation at the site of injury, with subsequent release of substances that mitigate blood loss. Platelet adherence to collagen requires von Willebrand's factor, fibrinogen, fibronectin, and specific glycoprotein receptors on platelet surfaces. Platelet-to-platelet interactions (aggregation) recruit additional platelets to the primary hemostatic plug. Aggregation requires fibrinogen, energy, and calcium. Release of ADP, serotonin, and the contents of intracellular granules as well as generation of prostaglandins prepares platelet surfaces for reactions with the coagulation proteins. Activation of the intrinsic or extrinsic coagulation pathway, or of both, causes formation of fibrin from fibrinogen by means of an elaborate and intricate system that also entraps platelets and activated coagulation proteins. The intrinsic system is activated by the contact of factor XII with a negatively charged surface, most likely collagen. Through a series of reactions with prekallikrein, HMWK, and factors XI, IX, and VIII, the common coagulation pathway is propagated. The extrinsic, or tissue factor, system stimulates both the common pathway and factor IX the intrinsic pathway. Discovery of this stimulation of the intrinsic pathway by factor VII in the extrinsic pathway has stimulated reassessment of the biologic importance of the extrinsic system. The common pathway includes factors X and V and causes thrombin to convert fibrinogen to fibrin. Calcium and platelet phospholipids are substances that have important roles in steps in the coagulation scheme. Once fibrin is formed, factor XIII interacts with the substance, providing a stabilizing effect.(ABSTRACT TRUNCATED AT 400 WORDS)


Significant response to immune therapies in a case of subacute necrotizing myopathy and FKRP mutations.
Necrotizing myopathies can be encountered in various conditions as acquired myopathies (toxic or autoimmune) or muscular dystrophies. We report a twenty-year-old Caucasian woman who presented with clinical findings suggestive of an inflammatory myopathy: subacute onset of lower limb muscle weakness, myalgia, weight loss and absence of family history. The serum creatine kinase level was elevated at 4738 IU/L (normal range, 25-175 IU/L). Muscle biopsy was consistent with necrotizing myopathy. The patient showed significant clinical improvement following corticosteroid, azathioprine and intravenous immunoglobulin treatments. Biological tests revealed no specific autoantibodies associated with necrotizing autoimmune myopathies. Immunohistochemical staining for sarcolemmal proteins in muscle biopsy samples finally led to a diagnosis of limb-girdle muscular dystrophy 2I (fukutin-related protein gene mutations). The response to immune therapies suggested a possible inflammatory component associated with the muscular dystrophy and highlighted the potential benefit of corticosteroid treatment in patients with LGMD2I and subacute onset.


Adenocarcinoma arising in a tailgut cyst: a case report.
Tailgut cyst (TGC), also called retrorectal hamartoma, is a rare congenital lesion arising from persistent remnants of the postanal gut. Malignant transformation of TGC is exceedingly uncommon. We report herein the clinicopathologic features and the follow-up of a new case of a TGC with adenocarcinomatous transformation occurring in a 61 year-old woman.


US-based indices of area-level deprivation: results from HealthCare for Communities.
In this analysis we create census-tract level indices of area deprivation for the US that parallel similar indices developed in Britain, and we determine whether these indices are related to physical and mental health outcomes. Data for the indices come from the 2000 Census Summary File Tapes and the 2001 Zip Code Business Patterns Files. These indices are then linked by census tract to cross-sectional data from the HealthCare for Communities (HCC) study, and equations are estimated using multi-level models with census-tract random effects. We find that area-level deprivation predicts poor mental and physical health outcomes, but different components of deprivation have different effects. When we measure deprivation using three factor scores that emerged from our analysis (rather than combining all measures of deprivation into a single index), we find that access to services has a more pronounced association with physical health, whereas racial composition and local language barriers are more strongly correlated with mental health. These findings suggest that grouping all variables into a single index may mask important heterogeneity in the ways in which area characteristics affect health outcomes.


Evaluating the resource implications of different service delivery models for offering additional genomic findings.
To evaluate the resource implications of different delivery models for the provision of additional findings (AF) in genomics from a health-care purchaser perspective. Data from the Additional Findings study were used to develop and validate a discrete event simulation model that represented the pathway of delivering AF. Resource implications were estimated by microcosting the consultations, sample verifications, bioinformatics, curation, and multidisciplinary case review meetings. A proof-of-concept model was used to generate costing, and then the simulation model was varied to assess the impact of an automated analysis pipeline, use of telehealth consultation, full automation with electronic decision support, and prioritizing case review for cases with pathogenic variants. For the proof-of-concept delivery model, the average total cost to report AF was US$430 per patient irrespective of result pathogenicity (95% confidence interval [CI] US$375-US$489). However, the cost of per AF diagnosis was US$4349 (95% CI US$3794-US$4953). Alternative approaches to genetic counseling (telehealth, decision support materials) and to multidisciplinary case review (pathogenic AF cases only) lowered the total per patient cost of AF analysis and reporting by 41-51%. Resources required to provide AF can be reduced substantially by implementing alternative approaches to counseling and multidisciplinary case review.


Medical Students' Perceptions on Research: Results from a Small European Island State.
A crucial aspect of medical education is research training. Many studies have been conducted targeting the publishing rate among medical students, but information is lacking about the perceptions of medical students towards research, especially of students studying in small island states. This study aims to investigate students' perceptions towards research and increase the insight on what motivates and hinders medical students to conduct research. An anonymous mixed-methods cross-sectional online questionnaire was distributed to five hundred and forty-nine medical students studying at the University of Malta. The data gathered was statistically analysed and consequently interpreted. A response rate of 25.05% was achieved, with 10.00% of students having already published their research. Despite 86.43% of students interested in conducting research, only 22.86% have pursued a research endeavour. The main reason for conducting research was 'out of students' own interest'. The main barrier hindering students from conducting research was perceived as the absence of research opportunities. Medical students have a positive attitude towards the conduction of research, to enhance their medical education. Hence, identification of potential barriers hindering medical students from conducting research should be sought out and hands-on research opportunities should be provided, on an elective basis, to pursue their research interest. The online version contains supplementary material available at 10.1007/s40670-021-01426-4.


Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release.
In this paper, a hollow mesoporous silica nanoparticles (HMSN) was used as the drug vehicle to develop the redox and pH dual stimuli-responsive delivery system, in which the chitosan (CS), a biodegradable cationic polymer, was grafted on the surface of HMSN via the cleavable disulfide bonds. CS was chosen as the gatekeeper mainly due to its appropriate molecular weight as well as possessing abundant amino groups which could be protonated in the acidic condition to achieve pH-responsive drug release. In addition, the PEG was further grafted on the surface of CS to increase the stability and biocompatibility under physiological conditions. The DOX loaded DOX/HMSN-SS-CS@PEG had a relatively high drug loading efficiency up to 32.8%. In vitro release results indicated that DOX was dramatically blocked within the mesopores of HMSN-SS-CS@PEG in pH 7.4 PBS without addition of GSH. However, the release rate of DOX was markedly increased after the addition of 10mM GSH or in pH5.0 release medium. Moreover, the release of DOX was further improved in pH5.0 PBS with 10mM GSH. The HMSN-SS-CS@PEG could markedly decrease the hemolysis percent and protein adsorption, and increase the biocompatibility and stability of HMSN compared with the HMSN-SS-CS and bare HMSN. This work suggested an exploration about HMSN based stimuli-responsive drug delivery and these results demonstrated that HMSN-SS-CS@PEG exhibited dual-responsive drug release property and could be used as a promising carrier for cancer therapy.


Zinc, future mono/adjunctive therapy for depression: Mechanisms of antidepressant action.
Affective disorders (depression) are considered as chronic illnesses leading to substantial disability, morbidity and mortality. While the etiology and pathophysiology of these diseases are still poorly recognized, the most important problems concerning them are low treatment response, treatment resistance and/or tolerance and risk of relapse. Recently published review articles have already demonstrated the important role of zinc in the pathophysiology and treatment of affective disorders, plus discussed the potential value of zinc as a marker of these diseases. This present concise review will update the experimental and clinical data on the antidepressant activity of zinc and focus on the mechanisms of its action. The mechanisms involving NMDA and AMPA glutamate, 5-HT1A serotonin and the GPR39 zinc-sensing receptor and intracellular pathways will be discussed.


Strain hardening and fracture of heat-set fractal globular protein gels.
Non-linear mechanical behavior at large shear deformation was been investigated for heat-set beta-lactoglobulin gels at pH 7 and 0.1 M NaCl using both oscillatory shear and shear flow. These gels have a self-similar structure at length scales smaller than the correlation length of the gel with fractal dimension d(f)=2. Strain hardening is observed that can be well described using the model proposed by Gisler et al. [T.C. Gisler, R.C. Ball, D.A. Weitz, Phys. Rev. Let. 82 (1999) 1064] for fractal colloidal gels. The increase of the shear modulus normalized by the low strain value (G(0)) is independent of G(0). For weak gels the elasticity increases up to a factor of ten, while for strong gels the increase is very small. At higher deformation irreversible fracture occurs, which leads eventually to macroscopic failure of the gel. For weak gels formed at low concentrations the deformation at failure is about 2, independent of the shear modulus. For strong gels fracture occurs at approximately constant stress (2 x 10(3) Pa).


Furosemide dynamics in conscious rabbits: modulation by angiotensin II.
The aim of this study was to investigate the effects of an infusion of angiotensin II (50 ng/kg/min) on furosemide pharmacodynamics and kinetics in the conscious rabbit. The protocol included a 90-minute phase to estimate the glomerular filtration rate and the renal plasma flow, followed by a 60-minute phase where 5 mg/kg (n = 12) or 10 mg/kg (n = 9) of furosemide were administered. During the pre-furosemide phase, compared to control rabbits, angiotensin II increased natriuresis and diuresis. In the presence of angiotensin II, the furosemide-induced natriuresis decreased, that is, it was 174 +/- 14 versus 95 +/- 25 mumol/min (p < 0.05) and 187 +/- 17 versus 89 +/- 21 mumol/min (p < 0.05) for the 5 and the 10 mg/kg doses, respectively. The infusion of angiotensin II decreased renal plasma flow without modifying the glomerular filtration rate, thus the filtration fraction was increased. Angiotensin II increased the area under the furosemide plasma concentrations as a function of time since it decreased its systemic clearance. However, furosemide urinary excretion rate was not altered and its renal clearance decreased slightly without reaching statistical significance. It is concluded that angiotensin II decreases the response to furosemide and the mechanism underlying this effect is related to the pharmacodynamics rather than the kinetics of the diuretic.


Adsorptive stripping voltammetric determination of cefetamet in human urine.
On the basis of previously established mechanism of cefetamet (CEF) reduction, two methods were suggested for CEF determination-differential pulse polarographic and differential pulse adsorptive stripping voltammetric method. Two pH values were chosen, 2.0 and 8.4, where the electrochemical process was defined as one four-electron and two two-electron processes, respectively. The methods were performed in Britton-Robinson (BR) buffer and the corresponding calibration graphs were constructed and statistical parameters were evaluated. Applying the AdSV method at pH 2.0 linearity was achieved from 2 x 10(-8) to 2 x 10(-7) M with limit detection and limit determination of 4 x 10(-9) and 1.4 x 10(-8) M, respectively. At pH 8.4, the linearity was obtained between 6 x 10(-8) and 6 x 10(-7) M, with limit detection and limit determination of 1.5 x 10(-8) and 5 x 10(-8) M, respectively. Since the AdSV method enabled lower concentrations of CEF to be determined, this method was tested for CEF determination in spiked urine samples, and DPP method was used as a comparative one.


Polydatin protects against gouty nephropathy by inhibiting renal tubular cell pyroptosis.
To investigate the protective effect and mechanism of polydatin (PD) against gouty nephropathy (GN) in mice. Twenty-four mice were randomly divided into three groups: the control group (no treatment), the GN group (300 mg/kg hypoxanthine + 150 mg/kg potassium oxonate), and the GN + PD group (300 mg/kg hypoxanthine + 150 mg/kg potassium oxonate + 50 mg/kg PD). Histological changes in the kidneys and the levels of uric acid (UA), blood urea nitrogen (BUN), and serum creatinine (SCr) in the sera were measured. In addition, the expression of gasdermin D (GSDMD) protein in renal tubular epithelial cells, and the expression of NOD-like receptor protein 3 (NLRP3), GSDMD, and caspase-1 proteins in the kidney tissues were determined by immunohistochemistry, immunofluorescence, and Western blot. In vitro, PD inhibited the expression of NLRP3, caspase-1, and GSDMD and protected the renal tubular epithelial cells from pyroptosis. In vivo, PD treatment significantly ameliorated the pathological changes in kidney tissue, and reversed the decrease of serum UA and BUN in GN model mice. The expression of NLRP3, GSDMD, and caspase-1 proteins was also decreased in the PD-treated GN mice. The results suggest that PD has a protective effect on mice with GN, which may be related to the downregulation of NLRP3, GSDMD, and caspase-1 proteins and the inhibition of renal tubular epithelial cells pyroptosis.


Everolimus plus endocrine vs endocrine therapy in treatment advanced ER+, HER2- breast cancer patients: A meta-analysis.
The purpose of this review was to compare the efficacy and safety of everolimus plus endocrine therapy with endocrine therapy for hormone receptor-positive, human epidermal growth factor 2 negative advanced breast cancer patients. We comprehensively searched the PubMed, the Cochrane Library, EMBASE, Web of Science, Chinese biomedicine literature database, WanFang Data, CNKI, and VIP database for relevant articles. The retrieval time limit is from building the database to July 2018. The computer search was supplemented with a manual search of reference lists for all available review articles. We scanned references of all included studies for additional studies. We included 7 randomized trials involving 1527 patients. Meta-analysis results are as follows: Everolimus plus endocrine therapy group is significantly better than endocrine therapy group in progression-free survival and clinical benefit rate, (hazard ratio [HR] = 0.48, 95% confidence interval [CI 0.42-0.55], P < 0.00001) and (risk ratio = 1.9, 95% CI [1.60-2.26], P < 0.00001). But there was no significant difference between the 2 groups in overall response rate and time to definitive deterioration (risk ratio = 4.37, 95% CI [0.79-24.27], P = 0.21) and (HR = 0.74, 95% CI [0.49-1.11], P = 0.15). In terms of safety, the incidence rate in everolimus plus endocrine therapy was higher than that in endocrine therapy group. Most frequently reported adverse events associated with everolimus treatment were stomatitis, rash, fatigue, diarrhea, decreased appetite, cough, dyspnea, and pneumonitis. The incidences of grade 3-4 adverse events were stomatitis, fatigue, diarrhea, pneumonitis, and hyperglycemia. Everolimus increased the efficacy of endocrine therapy in treatment advanced endocrine receptor-positive, human epidermal growth factor 2 negative breast cancer patients, and the safety profile of the combination is acceptable.


Modelling the mass adoption potentials of eBikes among Malaysian youth.
This study examined (1) the effect of environmental concern, environmental knowledge, and health consciousness on attitude towards eBikes; (2) the effect of eBikes attributes of interest and infrastructure on perceived behavioural control; and finally, (3) the effect of attitude towards eBikes, subjective norms, and perceived behavioural control on eBikes commuting intention and its usage among Malaysian youth. This study adopted a cross-sectional design and convenience sampling, and collected quantitative data from 699 Malaysian youth through an online survey. Findings revealed that (1) environmental concern, environmental knowledge, and health consciousness had a positive and significant impact on attitude towards eBikes; (2) eBikes attributes of interest and infrastructure were positively and significantly related to perceived behavioural control; (3) attitude towards eBikes, subjective norms, and perceived behavioural control had a positive and significant effect on eBikes commuting intention; (4) eBikes commuting intention was positively and significantly related to the usage of eBikes; (5) eBikes commuting intention significantly mediated the relationship between attitude towards eBikes and perceived behavioural control on the usage of eBikes among Malaysian youth; and (6) eBikes commuting intention did not mediate the relationship between social norm and usage of eBikes. Although environmental knowledge and social norm are proven to have a positive and significant relationship, this analysis demonstrated a relatively low effect size. To promote environmental and sustainable development in cities through the mass adoption of eBikes among Malaysian youth, policymakers should highlight the benefits of using eBikes, introduce proper policies, and involve the development of improved and connected cycling paths in the city sustainable infrastructure plans.


Fetal magnetoencephalography: a non-invasive method for the assessment of fetal neuronal maturation.
To assess the maturation of auditory evoked cortical responses in the human fetus using fetal magnetoencephalography. Prospective case series over a three-year period. Antenatal clinics, university hospital. Singleton pregnancies at 29-40 weeks of gestation. We used a 31-channel-SQUID-biomagnetometer in a magnetically-shielded room to perform fetal magnetoencephalography. To record auditory evoked fields from the fetal brain we applied 500 monotonal bursts generated by a computerised sound generator directly to the maternal abdominal wall near the fetal head. The continuously recorded data sets were analysed stepwise using a specially developed heart artefact rejection software, Fourier filtering, principle component analysis and half split analysis of the averaged data. In 36 of 64 examinations we detected signals of auditory evoked fields comparable to the P2m component in adults. The earliest recording succeeded in the 29th gestational week. The latencies of the auditory evoked responses declined during the third trimester from 300 ms to nearly 150 ms at term. The maturation of different components of the auditory evoked field could be demonstrated from the 31st gestational week onwards. The maturation of a fetal auditory cortical function using fetal magnetoencephalography could be assessed directly for the first time. We believe that this method will add information to current indirect methods of assessing the normal maturation of the human fetal brain.


[Current aspects on nutrition in hypercholesterolemia].
New European and American guidelines for nutrition in hypercholesterolemia coincided with a lowered target value for LDL(Low density lipoprotein)-cholesterol. Guidelines, their development and supporting meta-analyses were searched in Medline/PubMed and Cochrane database and analyzed for the influence of fat, carbohydrates and protein on reduction of LDL-cholesterol as well as the differences between European and American guidelines. In contrast to European guidelines, American guidelines increasingly refrain from controlling fat in nutrition, based on studies on the influence of nutrition on LDL-cholesterol and saturated fat; instead, monosaccharides and disaccharides are to be reduced from 15% to 10% of total calories for avoidance of high LDL-cholesterol and a non-alcoholic fatty liver. In predisposed persons the ratio of triglycerides to HDL-cholesterol should be checked when controlling LDL-cholesterol, an early indicator of type 2 diabetes mellitus and non-alcoholic fatty liver disease. Substituting animal fat with plant fat hardly influences LDL-cholesterol. Whole fat milk should be consumed as a source of protein. The nutritional pattern is more important than single components. Fat content in nutrition is increasingly less important in hypercholesterolemia but the reduction of monosaccharides and disaccharides gains importance.


Life-threatening unilateral hearing impairments. Review of the literature on the association between inner ear malformations and meningitis.
Bacterial meningitis is a life threatening disease that can be triggered by a CSF leak through an inner ear malformation. Early identification of the specific type of cochleovestibular dysplasia and the associated risk of meningitis is of vital importance. The objective of this review is to collect and discuss available data on the association between inner ear malformations and meningitis in children. Electronic databases were crosschecked for obtaining relevant papers published in the last 20 years, and further cases were identified by hand searching through the references. Demographic data were extracted from full texts, together with information on the severity of hearing impairment, the type of inner ear anomaly, the site of cerebrospinal fluid leak, the number of recurrent meningitis episodes. Sixty-seven cases of meningitis related to inner ear malformation have been identified among 45 papers. Mean age at presentation is 3.60±3.00 (range 0.1-14) years. Average diagnostic delay from the first episode of meningitis is 3.44±3.41 (range 0.00-10.00) years. The number of meningitis episodes that occurred before the correct diagnosis and definitive surgical treatment is 3.27±1.81 (range 1.00-10.00). Unilateral hearing impairment affects 70% of patients. Six patients had normal hearing at presentation. Two children are dead from inner-ear-malformation-related meningitis among reviewed reports. A high number of paediatric patients carrying inner ear malformations, especially when associated with unilateral hearing impairment, could be at risk to develop recurrent bacterial meningitis. Universal newborn hearing screening programs should prompt a diagnostic work-up even in the case of unilateral hearing impairment, in order to prevent inner ear malformation-related meningitis.


Delayed perforation: a hazardous complication of endoscopic resection for non-ampullary duodenal neoplasm.
Perforation is a major complication of endoscopic resection for gastrointestinal neoplasms. However, little is known about delayed perforation after endoscopic resection for non-ampullary duodenal neoplasm. The aim of the present study was to investigate the clinical features of delayed perforation after endoscopic resection for non-ampullary duodenal neoplasm. This was a retrospective cohort study conducted in a referral cancer center. A total of 63 patients (41 with adenomas and 22 with carcinomas) underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) from January 1993 to December 2011. Incidence, outcome, and factors associated with occurrence of delayed perforation were investigated. Delayed perforation occurred in four patients (6.3%). All lesions were located distal to Vater's ampulla. Three of four delayed perforations occurred within 36 h after endoscopic resection. All patients developed retroperitonitis, and two also had retroperitoneal abscesses. Although three patients were cured with conservative management, a long hospital stay was required (28-, 80-, and 81-day hospital stay, respectively). One patient required emergency surgery as a result of panperitonitis. There was, fortunately, no mortality in this series. The significant predictors of delayed perforation were location (distal to Vater's ampulla, P = 0.007) and resection method (ESD and piecemeal EMR, P = 0.003). Endoscopic resection for non-ampullary duodenal neoplasms has a possible risk of morbid complication i.e. delayed perforation, especially in patients with lesions located on the side distal from the ampulla and who are treated with piecemeal EMR or ESD.


Using tracer methods and experimental design approach for examination of hydrodynamic conditions in membrane separation modules.
The possibility of application of fluorescein and radioactive 99mTc as tracers for determination of residence time distribution of liquid phase and for diagnosing hydrodynamic conditions in apparatuses for membrane separation was studied. Two different ultrafiltration systems with diverse arrangement of liquid flow: the apparatus with helical flow generated by the movable element (inner cylinder) and the tubular module with cross flow filtration, were tested by the RTD technique. The tracer studies were supplemented with modelling. The optimal conditions enabling to handle the plug flow-like structure in the helical apparatus were determined. The minimum of dimensionless variance (vard) was obtained at P=0.765 bar, Q(R)=121.88 l/h and Ω=2887.5 rpm. In spite of higher linear velocities attained in the tubular cross-flow module, the flow structure in the helical apparatus was more similar to the ideal plug flow pattern that was demonstrated by higher Peclet numbers and lower values of the dimensionless variance. Application of movable part and Couette-Taylor flow in the membrane apparatus may balance the advantages coming from high flow rates applied in cross-flow filtration systems minimising formation of the deposit on the membrane surface and reducing membrane fouling.


Rupture of a previously bypassed popliteal aneurysm: a case report.
A case of rupture of a previously excluded popliteal aneurysm is reported and the pertinent literature reviewed. Symptoms of aneurysm expansion with nerve compression preceded the rupture. The need for continued follow-up after treatment of popliteal aneurysms is emphasized.


Filtering blebs at the site of sutured posterior chamber intraocular lenses.
A 78-year-old man with a traumatic giant retinal tear and phacodonesis had 3-port pars plana vitrectomy (3PPPV), lensectomy, and sutured posterior chamber intraocular lens (IOL) implantation. Two years after surgery, a filtration bleb was noted at 1 of the suture sites. In another case, a 32-year-old man with lens subluxation secondary to Marfan's syndrome had 3PPPV, lensectomy, and sutured posterior chamber IOL implantation. Two months after surgery, a filtration bleb was noted at 1 of the suture sites. Sutured posterior chamber IOL implantation is 1 of the few instances in which there is virtually a full-thickness suture through the sclera. We presume the filtering bleb formed as a direct result of the permanent passage created from the posterior chamber to the subconjunctiva due to presence of the suture. Presence of a filtering bleb can lead to complications including endophthalmitis.


Diphenylamine-induced renal lesions in the chicken.
Chronic intoxication with diphenylamine (DPA), which causes a cystic kidney disease in the rat and the guinea-pig, caused degeneration of the renal tubular epithelium in the chicken. This was similar to but much more serious than that preceding the formation of cysts in the rodents, but did not actually result in cyst formation, probably because of the high mortality rate observed in the birds even at this early stage. In the chicken until now it had been possible to obtain a pattern of renal cysts only with polychlorinated biphenyls (PCB) which also induce the "chick oedema" syndrome. The renal lesions due to DPA in the chicken were similar to those produced by PCB, but were not accompanied by oedema, which suggests that "chick oedema" caused by PCB is not due to renal insufficiency. The differences in the renal lesions noted in the various animal species give credit to the hypothesis that DPA may have two effects on the tubular epitelium, one stimulating cell proliferation and one leading to degeneration. Cysts may be formed only in those species in which there is cell proliferation.


Creation of a Prognostic Index for Spine Metastasis to Stratify Survival in Patients Treated With Spinal Stereotactic Radiosurgery: Secondary Analysis of Mature Prospective Trials.
There exists uncertainty in the prognosis of patients following spinal metastasis treatment. We sought to create a scoring system that stratifies patients based on overall survival. Patients enrolled in 2 prospective trials investigating stereotactic spine radiation surgery (SSRS) for spinal metastasis with ≥ 3-year follow-up were analyzed. A multivariate Cox regression model was used to create a survival model. Pretreatment variables included were race, sex, age, performance status, tumor histology, extent of vertebrae involvement, previous therapy at the SSRS site, disease burden, and timing of diagnosis and metastasis. Four survival groups were generated based on the model-derived survival score. Median follow-up in the 206 patients included in this analysis was 70 months (range: 37-133 months). Seven variables were selected: female sex (hazard ratio [HR] = 0.7, P=.02), Karnofsky performance score (HR = 0.8 per 10-point increase above 60, P = .007), previous surgery at the SSRS site (HR = 0.7, P=.02), previous radiation at the SSRS site (HR = 1.8, P=.001), the SSRS site as the only site of metastatic disease (HR = 0.5, P=.01), number of organ systems involved outside of bone (HR = 1.4 per involved system, P<.001), and >5 year interval from initial diagnosis to detection of spine metastasis (HR = 0.5, P < .001). The median survival among all patients was 25.5 months and was significantly different among survival groups (in group 1 [excellent prognosis], median survival was not reached; group 2 reached 32.4 months; group 3 reached 22.2 months; and group 4 [poor prognosis] reached 9.1 months; P < .001). Pretreatment symptom burden was significantly higher in the patient group with poor survival than in the group with excellent survival (all metrics, P < .05). We developed the prognostic index for spinal metastases (PRISM) model, a new model that identified patient subgroups with poor and excellent prognoses.


Novel missense mutation found in a Japanese patient with myeloperoxidase deficiency.
Myeloperoxidase (MPO; EC 22.214.171.124) plays an important role in the host defense mechanism against microbial diseases. The neutrophil disorder characterized by the lack of MPO activity, is speculated to be associated with a decreased level of immunity. A Japanese patient was identified with complete MPO deficiency through automated hematography. Neutrophil function analysis revealed that MPO activity was significantly diminished with slightly elevated superoxide production. Mutational analysis of the patient revealed a glycine to serine substitution (G501S) in the exon 9 region. This mutation was not detected in the 96 healthy controls analyzed. The amino acid substitution found may be responsible for the failure of mature MPO production in the patient. This is the first case of MPO deficiency of G501S missense mutation identified in a Japanese patient.


Simultaneous Vestibular Schwannoma Resection and Cochlear Implantation Using Electrically Evoked Auditory Brainstem Response Audiometry for Decision-making.
The aim of the study was to evaluate the predictive value regarding postoperative hearing benefit of electrically evoked auditory brainstem response audiometry in sporadic vestibular schwannoma patients undergoing simultaneous tumor resection and cochlear implantation. Patients were included in a prospective study conducted between October 2016 and January 2019. The study was conducted at a tertiary care center. Subjects with unilateral sporadic vestibular schwannoma were screened for study participation. Patients underwent translabyrinthine vestibular schwannoma resection and cochlear implantation simultaneously. Electrically evoked brainstem response audiometry was performed during surgery before and after tumor removal using an intracochlear test electrode to objectively evaluate nerve conduction. Electrically evoked brainstem response audiometry results were correlated with postoperative sound field audiometry, word recognition tests, and speech reception thresholds. Quality of life was assessed before and 12 months after translabyrinthine tumor removal and cochlear implantation. Five patients, three male and two female, were included in the study and followed for at least 1 year after implantation. Three of the five patients are daily cochlear implant users with open set speech recognition. Two individuals with negative intraoperative electrically evoked auditory brainstem response results showed no auditory perception with cochlear implant. Simultaneous translabyrinthine vestibular schwannoma resection and cochlear implantation with intraoperative electrically evoked auditory brainstem response measurements is a feasible and promising option for sporadic vestibular schwannoma patients. Preservation of electrically evoked auditory brainstem responses seems to predict good subsequent hearing outcomes.


Association of dietary inflammatory index and leukocyte telomere length with mild cognitive impairment in Chinese older adults.
There are minimal data on the relationship between DII and MCI in an elderly Chinese population and no research has assessed the potential effect of LTL. We investigated the association between DII and MCI while taking into account the potential effect of LTL. This cross-sectional study included 3,386 participants aged ≥ 60 years of age from the Tianjin Elderly Nutrition and Cognition Cohort study. DII score was constructed based on a validated self-administered food frequency questionnaire was calculated based on the method developed by Shivappa et al. LTL was measured by quantitative real-time polymerase chain reaction. Multivariable logistic regression analysis was used to analyze the association between DII, LTL and MCI. Moreover, mediation analysis was employed to test the mediation effect of LTL on the total effect of DII on MCI. Compared with the participants in the lowest tertiles of LTL and DII score, the odds ratios (ORs) of MCI in the highest tertiles were 0.386(95% CI: 0.281-0.529) and 1.650 (95% CI: 1.232-2.209), respectively. The significant association between DII score and MCI persisted after further adjusting for LTL (OR: 1.595; 95% CI: 1.189-2.140). The link between DII score and MCI was mediated partially by LTL (βindirect effect= -0.008, P<0.05). High DII score was positively associated with MCI prevalence in an elderly Chinese population and the link between DII scores and MCI seemed to be mediated partially by LTL.


Clearance and tissue distribution of functionalized polymeric liposomes from the blood stream of rats.
Polymeric liposomes containing a synthetic porphinato-iron-imidazole complex (hemoglobin or red blood cell model) were labeled by introducing 1,2-di[1-14C]palmitoyl-sn-glycero-3-phosphocholine into their polymerized bilayers. After intravenous injection into rats, their clearance from a blood stream was measured. The apparent half-life time (50% disappearance time) was about 14 +/- 2 h. Their tissue distribution was determined with time by whole autoradiographic measurement.


Chemical synthesis of two deoxyribododecanucleotides for the attachment of restriction termini to an artificial minigene.
In order to permit in vivo cloning of an artificial minigene designed to code for a modified S-peptide, the phosphodiester method for the chemical synthesis of two dodecadeoxyribonucleotides is described. Each of the latter possesses antiparallel complementarity to one of the two minigene strands and to the single-stranded EcoRI-generated end. They can thus serve as cohesive termini ("splints") for polynucleotide ligase joining.


The fine structure of large cell undifferentiated carcinoma of the lung. Evidence for its relation to squamous cell carcinomas and adenocarcinomas.
The light microscopic diagnosis of large cell undifferentiated carcinoma of the lung is known to be highly subjective and shows poor interobserver reproducibility; the very existence of this tumor as a separate entity has been challenged. The ultrastructure of seven large cell undifferentiated carcinomas was examined in an attempt to determine whether they were merely poorly differentiated adenocarcinomas and squamous cell carcinomas, or actually represented an entirely separate class of tumors. Four large cell undifferentiated carcinomas demonstrated intra- and intercellular lumina and were designated adenocarcinomas. In three cases there were well formed desmosomes with numerous tonofilaments and intercellular bridges. These tumors were classified as squamous cell carcinomas. An eighth tumor metastatic to the abdominal wall also showed the features of squamous carcinoma. In addition, all tumors contained a variable population of primitive cells without identifying features. The large cell undifferentiated carcinomas were compared ultrastructurally with eight cases of poorly differentiated adenocarcinomas and squamous cell carcinomas classified by light microscopy. These tumors were morphologically similar, but contained fewer primitive cells and greater numbers of differentiated cells. Cells with a clear cytoplasm as seen by light microscopy were present in both the large cell undifferentiated and poorly differentiated groups; these cells contained variable amounts of glycogen but were otherwise similar to the nonclear cells. It is suggested that most of the subcategories of large cell undifferentiated carcinoma represent very poorly differentiated adenocarcinomas and squamous carcinomas.


[Presence of 2 different epitopes on the human beta 2-microglobulin defined by monoclonal antibodies].
Two monoclonal antibodies recognizing monomorphic determinants on class I antigens of MHC were characterized. They were shown to recognize beta 2m by cytotoxicity inhibition studies. The epitopes recognized were different, as assayed by cross-inhibition and phylogenetical studies. One antibody recognized free as well as HLA-associated beta 2m. The other reacted with a conformational epitope which was well conserved during evolution.


Clinical next-generation sequencing assay combining full-length gene amplification and shotgun sequencing for the detection of CMV drug resistance mutations.
Cytomegalovirus (CMV) causes severe systemic and tissue-invasive disease in immunocompromised patients, particularly solid organ and hematopoietic stem cell transplant recipients. While antiviral drugs offer promising efficacy, clinical management is complicated by the high frequency of drug resistance-associated mutations. The most commonly encountered mutations occur in the genes encoding for the drug targets: UL54 (DNA polymerase), UL56 (terminase complex), and UL97 (phosphotransferase), conferring resistance to ganciclovir/cidofovir/foscarnet, letermovir, and ganciclovir/maribavir, respectively. Currently, standard practice for detecting drug resistance is sequencing-based genotypic analysis by commercial reference laboratories with strictly prescribed sample requirements and reporting parameters that can often restrict testing in a highly vulnerable population. In order to circumvent these limitations, we developed a dual-step next-generation sequencing (NGS)-based clinical assay that utilizes full-length gene amplification by long-range PCR followed by shotgun sequencing for mutation analysis. This laboratory-developed test (LDT) achieved satisfactory performance with 96.4% accuracy, 100% precision, and an analytical sensitivity of 300IU/mL with 20% allele frequency. Highlighted by two clinical cases, our NGS LDT was able to provide critical results from patient specimens with viral loads <500IU/mL and volumes <0.5 mL - conditions otherwise unacceptable by reference laboratories. Here, we describe the development and implementation of a robust NGS LDT that offers greater testing flexibility and sensitivity to accommodate a more diverse patient population.


Effects of renal impairment on the pharmacokinetics of orally administered deferiprone.
In light of the growing recognition of renal disease in thalassemia, it is important to understand the impact of renal impairment on the pharmacokinetics of iron chelators. This study evaluated the pharmacokinetics and safety of the iron chelator deferiprone (DFP) in subjects with renal impairment in comparison with healthy volunteers (HVs). Thirty-two subjects were categorized into four groups based on degree of renal impairment: none, mild, moderate or severe, as determined by estimated glomerular filtration rate (eGFR). All subjects received a single oral dose of 33 mg kg(-1) DFP, provided serum and urine samples for pharmacokinetic assessment over 24 h and were monitored for safety. Renal clearance of DFP decreased as renal impairment increased. However, based on Cmax , AUC(0,t) and AUC(0,∞), there were no significant group differences in systemic exposure, because less than 4% of the drug was excreted unchanged in the urine. DFP is extensively metabolized to a renally excreted, pharmacologically inactive metabolite, deferiprone 3-O-glucuronide (DFP-G), which exhibited higher Cmax , AUC(0,t), AUC(0,∞) and longer tmax and t1/2 in the renally impaired groups compared with HVs. The Cmax and AUCs of DFP-G increased as eGFR decreased. Overall, 75%-95% of the dose was retrieved in urine, either as DFP or DFP-G, regardless of severity of renal impairment. With respect to safety, DFP was well tolerated. These data suggest that no adjustment of the DFP dosage regimen in patients with renal impairment is necessary, as there were no significant changes in the systemic exposure to the drug.


Effects of glycosaminoglycans and proteinase inhibitors on astroglia-induced detachment of cultured rat cerebellar neurons.
Neurons in mixed primary embryonic CNS cultures degenerate secondary to their detachment from the substratum. The present study demonstrates that in primary cultures of postnatal cerebellum, detachment of neurons can be prevented by antiproliferative drugs which inhibit the growth of astroglia. Several types of proteinase inhibitors did not affect the process of detachment. However, among several types of glycosaminoglycans, heparan sulfate and to a lesser degree heparin, could reversibly inhibit neuron detachment without causing morphological changes of astroglia. The enzymes heparitinase and heparinase caused neuron detachment but only within the first 24-48 hr after plating and not in older cultures. We conclude: (1) cerebellar interneurons in culture are not dependent on astroglia for their survival; (2) astroglia are most probably responsible for neuron detachment via a membrane associated activity and (3) heparan sulfate-like glycosaminoglycans are important in neuron-substratum attachment.


The structure and position of mouse centromeric heterochromatin in BrdU-labelled chromosomes and diplochromosomes stained by the pH 10.4 method.
A mouse cell line of C57Bl/6J spontaneous melanoma (clone PG 19), and a C-type virus transformed cell line (G-8 clone 124) originating from normal Balb/c mice were used in a study of the centromeric heterochromatin region of BrdU-labelled chromosomes stained by the Giemsa pH 10.4 method. Three possible explanations for the generation of compound lateral asymmetry within the centromeric heterochromatin region of the laboratory mouse are discussed: 1) inverted translocation; 2) centric fusion followed by paracentromeric fission and 3) inversion of part of the centromeric satellite DNA. These processes could be of considerable genetic and evolutionary significance. The non-random spatial position of unstained and dark stained C-bands in BrdU-labelled diplochromosomes of endoreduplicated cells can be explained as being due to the localization of the old and new DNA chains in a unineme chromatid model. The late replicating regions are shown to be located on the inside of the half-chromatid close to the axial symmetry axis of the metaphase chromosome.


Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice.
The cardioprotection by ischemic preconditioning is lost in aged wild-type and in STAT3 (signal transducer and activator of transcription 3)-deficient mice. The aim of the present study was to analyze whether or not ischemic postconditioning (iPoco) was effective in aged mice hearts and whether iPoco was dependent on STAT3. Young (3 months) and aged (>13 months) C57Bl6/J mice underwent 30 minutes of ischemia and 2 hours of reperfusion without or with iPoco (3 cycles of 10 seconds of ischemia/10 seconds of reperfusion [3x10] or 5 cycles of 5 seconds of ischemia/5 seconds of reperfusion [5x5] at the beginning of reperfusion). In young mice, both iPoco3x10 and iPoco5x5 reduced infarct size (IS), whereas in aged mice, only iPoco5x5 was effective in reducing IS. In young mice, iPoco3x10 increased the phosphorylated over total STAT3 (phosphorylated STAT3/STAT3) ratio at 10 minutes of reperfusion in the postconditioned anterior wall compared with the control posterior wall. In aged mice hearts, total STAT3 and phosphorylated STAT3/STAT3 in the anterior wall at reperfusion were reduced compared with young mice hearts. In young mice hearts subjected to iPoco3x10 but pretreated with the JAK-2 inhibitor AG-490, phosphorylated STAT3/STAT3 was reduced in the anterior wall compared with untreated young mice hearts, and IS reduction by iPoco3x10 was abolished. Furthermore, in young mice with a cardiomyocyte-restricted deletion of STAT3, iPoco3x10 failed to reduce IS, whereas iPoco5x5 reduced IS. Thus, cardioprotection by iPoco is dependent on the postconditioning protocol in aged and STAT3-deficient hearts. The reduced levels of STAT3 with increasing age may contribute to the age-related loss of iPoco.


Linked-Color Imaging Detects More Colorectal Adenoma and Serrated Lesions: An International Randomized Controlled Trial.
Effects of linked-color imaging (LCI) on colorectal lesion detection and colonoscopy quality remain controversial. This study compared the detection rates of adenoma and other precursor lesions using LCI vs white-light imaging (WLI) during screening, diagnostic, and surveillance colonoscopies. This randomized controlled trial was performed at 11 institutions in 4 Asian countries/regions. Patients with abdominal symptoms, a primary screening colonoscopy, positive fecal immunochemical test results, or undergoing postpolypectomy surveillance were recruited and randomly assigned in a 1:1 ratio to either the LCI or high-definition WLI group. The primary outcome was adenoma detection rate (ADR). Secondary outcomes were polyp detection rate, advanced ADR, sessile serrated lesion (SSL) detection rate, and the mean number of adenomas per colonoscopy. The recommended surveillance schedule distribution after trial colonoscopy was analyzed. Between November 2020 and January 2022, there were 3050 participants (LCI, n = 1527; WLI, n = 1523) recruited. The LCI group ADR was significantly higher than the WLI group ADR using intention-to-treat (58.7% vs 46.7%; P < .01) and per-protocol analyses (59.6% vs 46.4%; P < .01). The LCI group polyp detection rates (68.6% vs 59.5%; P < .01), SSL detection rates (4.8% vs 2.8%; P < .01), and adenomas per colonoscopy (1.48 vs 1.02; P < .01) also were significantly higher. However, the advanced ADR was not significantly different (13.2% vs 11.0%; P = .06). Significantly more patients in the LCI group had shorter recommended surveillance schedules than the WLI group (P < .01). Compared with WLI, LCI improved adenoma and other polyp detection rates, including SSLs, resulting in alteration of the recommended surveillance schedule after screening, diagnostic, and postpolypectomy surveillance colonoscopies. UMIN000042432 (https://www.umin.ac.jp/ctr/index.htm).


Induction of input-specific spine shrinkage on dendrites of rodent hippocampal CA1 neurons using two-photon glutamate uncaging.
Shrinkage and loss of dendritic spines are vital components of the neuronal plasticity that supports learning. To investigate the mechanisms of spine shrinkage and loss, Oh and colleagues established a two-photon glutamate uncaging protocol that reliably induces input-specific spine shrinkage on dendrites of rodent hippocampal CA1 pyramidal neurons. Here, we provide a detailed description of that protocol and also an optimized version that can be used to induce input- and synapse-specific shrinkage of dendritic spines at physiological Ca2+ levels. For complete details on the use and execution of this protocol, please refer to Oh et al. (2013), Stein et al. (2015), Stein et al. (2020), and Stein et al. (2021).


Demonstration of spontaneous XX/XY chimerism by DNA fingerprinting.
The M13 bacteriophage probe, which makes possible the establishment of DNA fingerprints, was used to study a phenotypically normal woman with a 46XY karyotype and her twin brother. Identical fingerprints and positive hybridization with a series of Y-specific probes were obtained on blood samples from the siblings. DNA from a skin biopsy of the woman yielded a clearly different pattern and displayed no Y-specific hybridization, indicating that she is a spontaneous chimera. This study illustrates the use of DNA fingerprinting as a powerful and simple aid to the diagnosis of natural chimerism.


Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene.
The established mouse cell line NIH 3T3 has been used with considerable success over the past three years as the basis of an in vitro transformation assay for demonstrating the presence of transfectable transforming genes in the DNA of certain human and rodent tumour cells (for review see ref. 1). In the case of the human bladder carcinoma cell lines EJ and T24, this approach has led to the molecular cloning of a transforming gene which is closely related to the rat-derived Harvey sarcoma virus oncogene, v-Ha-ras. A single point mutation, which distinguishes these genes from their normal human homologue (c-Ha-ras1), is thought to be solely responsible for their transforming potential. However, carcinogenesis in both humans and laboratory rodents is a multi-stage process (reviewed in ref. 11) of which the NIH 3T3 cell, already partly transformed, may represent only the penultimate stage. We therefore chose to examine the transforming effects of the EJ oncogene in a hamster fibroblast system originally developed in our laboratory to study stages in carcinogen-induced malignant transformation of normal diploid cells. We show here that EJ c-Ha-ras-1 lacks complete transforming activity when transfected into normal fibroblasts which have a limited lifespan, but can fully transform fibroblasts that have been newly 'immortalized' by carcinogens.


Staphylococcal pyomyositis with idiopathic dermatomyositis.
We have described a patient with staphylococcal pyomyositis of the left pectoralis major muscle, complicating idiopathic dermatomyositis. Dermatomyositis and corticosteroids are possible predisposing factors. Patients with idiopathic muscle inflammation should be considered at risk for bacterial superinfection.


Functional and dynamic response characteristics of a custom composite ankle foot orthosis for Charcot-Marie-Tooth patients.
Custom carbon-fiber composite ankle foot orthoses (AFOs) have been anecdotally reported to improve gait of Charcot-Marie-Tooth (CMT) patients. The purpose of the study was to characterize the spatio-temporal, joint kinetic and mechanical responses of a custom carbon fiber AFO during locomotion for persons diagnosed with CMT. Eight volunteers were fitted with custom AFOs. Three of the devices were instrumented with eight strain gauges to measure surface deformation of the shell during dynamic function. Following a minimum 10 weeks accommodation period, plantar- and dorsiflexor strength was measured bilaterally. Volunteers then walked unbraced and braced, at their preferred pace over a force platform and instrumented walkway while being tracked with a 12-camera motion capture system. Strength, spatio-temporal and lower extremity joint kinetic parameters were evaluated between conditions (single subject) using the model statistic procedure. Mechanical loads were presented descriptively. All participants walked faster (89.4 ± 13.3 vs 115.6 ± 18.0 cm/s) in the braced condition with ankle strength negatively correlated to speed increase. As Δ velocity increased, maximum joint moments during loading response shifted from the hip joint to the ankle and knee joints. During propulsion, the hip joint moment dominated. Subjects exhibiting the greatest and least Δ velocity imposed an average load of 54.6% and 16.6% of body weight on the braces, respectively. Energy storage in the brace averaged 9.6 ± 6.6J/kg. Subject-specific effects of a custom AFO on gait for CMT patients were documented. The force-deflection properties of carbon-fiber composite braces may be important considerations in their design.


A simplified technique for fabricating esthetic cast metal occlusal surfaces for dentures.
This article describes a simplified method for making esthetic cast metal occlusal surfaces. Monoplane posterior acrylic resin block teeth, cast in a nickel-chrome alloy, are coated with silane and an esthetic composite resin veneer is applied to the buccal surface. These veneered posterior metal teeth are incorporated in the wax setup and the dentures are processed and finished. The dentist's routine technique for delivering dentures to the patient can be followed.


Sequential pulse defibrillation in humans: orthogonal sequential pulse defibrillation with epicardial electrodes.
A newly described sequential pulse technique, using four mesh electrodes positioned to approximate a true orthogonal system around the heart, was compared with a single pulse system using two of these same electrodes, which were located in positions that would be used for an automatic implantable defibrillator. The influence of electrode size was also assessed. The minimal energy necessary for defibrillation (defibrillation threshold) was determined intraoperatively in 21 volunteer patients undergoing accessory pathway ablation of Wolff-Parkinson-White syndrome. Ventricular fibrillation was induced with alternating current. Ten seconds after fibrillation onset defibrillation shocks were begun using either the single or the sequential pulse technique with stored voltage incremented until defibrillation was accomplished (defibrillation threshold). Selection of the use of a single or sequential pulse technique for the initial attempt was randomized. Defibrillation thresholds were determined in three groups of patients: 1) those with four small mesh electrodes (6 cm2), 2) those with two small and two large (13 cm2) mesh electrodes, and 3) those with four large mesh electrodes. In all cases, the average minimal energy needed for sequential pulse defibrillation was less than that required for single pulse defibrillation in the same patients with the same electrodes (four small, 24.8 +/- 24.7 J single versus 6.7 +/- 8.3 J sequential; two small plus two large, 11.4 +/- 15.0 J single versus 2.7 +/- 1.4 J sequential; four large, 8.1 +/- 5.3 J single versus 3.9 +/- 2.6 J sequential). Using the 6 cm2 electrodes for single pulse defibrillation energies delivered at greater than 45 J in two patients failed to defibrillate the heart.(ABSTRACT TRUNCATED AT 250 WORDS)


Predictors of poor health-related quality of life among hemodialysis patients with anemia in Jordan.
This study examined health-related quality of life (HRQoL) and factors associated with poor HRQoL among hemodialysis (HD) patients. A multicenter cross-sectional study was conducted on HD patients with anemia in Jordan (n = 168). Validated questionnaires were utilized to collect data on HRQoL using EQ-5D-5L, psychiatric symptoms using Hospital Anxiety and Depression Scale (HADS), and comorbidities score using the modified Charlson Comorbidity Index (mCCI). Multiple linear regression analysis was conducted to identify the variables which are independently associated with HRQoL among patients. The mean (± SD) age of study participants was 52.2 (± 14.6) years. The mean utility value of EQ-5D-5L was 0.44 (± 0.42). Participants reported extreme problems mostly in pain/discomfort domain (19.6%). Increased age, increased mCCI and patient complains, more years under dialysis, decreased exercise, and low family income were significantly associated with poor HRQoL (p < 0.05). The study findings revealed poor HRQoL among HD patients with anemia. Various dimensions of health were negatively affected among HD patients. Development and implementation of appropriate approaches with adequate education and psychosocial support to HD patients by healthcare professionals targeting improved HRQoL and clinical outcomes would be necessary.


Exacerbated inequalities: A scoping review of the experiences of older persons during conflict situations.
We conducted the first known comprehensive literature review to (1) identify, categorize, and summarize the existing knowledge about the experiences of older persons and their caregivers during conflict situations; (2) identify the support needs of older persons and their caregivers, and; (3) identify gaps in the literature and understanding that may inform future research. A scoping review methodology of academic peer-reviewed and gray English language literature was employed using six academic literature databases and one gray literature database. We further performed comprehensive searches of relevant search engines and organization websites and bibliographic hand searches to identify additional academic and gray literature. Two authors screened for eligibility of identified studies and documents. One reviewer extracted data regarding authors, article type, geographic origin, key participant characteristics, aims, study design and data collection method, results, conclusions and limitations. Data were analyzed thematically. 83 documents met this review's inclusion criteria, including 21 academic documents and 62 from the gray literature. Thematic analysis revealed that conflict situations exacerbate existing inequalities experienced by older persons. Within this overarching theme were three interconnected sub-themes: (1) Older adults are particularly vulnerable during conflict situations; (2) Older persons are inadequately supported in conflict situations; (3) In the face of great challenges, many older adults still manage to endure through conflict situations. We identified 15 recommendations from the reviewed documents to better support older adults in conflict situations. Existing inequalities, such as ageism and ableism, targeted discrimination, and poor health outcomes, become exacerbated during conflict situations, resulting in older persons being less able to flee and meet their daily needs with sufficient access to necessities and healthcare. Little is known of the experiences and needs of family caregivers during conflict situations. We identified several opportunities to improve the experience and support of older persons in conflict situations.


The contribution of cometary volatiles to the primitive Earth.
It has been estimated that during its early history the Earth captured a mass of cometary material of the order of 10(23) grams. Since carbon is supposed to be at least three times more abundant in comets than in carbonaceous chondrites (3.5% C in C 1 chondrites), it can be deduced that about 1 x 10(22) grams of carbon (as carbon compounds), was added by comets to the surface of the prebiotic Earth. This carbon value is of the same order of magnitude as the value of the organic carbon buried in the Earth's sedimentary shell, but approximately one order of magnitude lower than the Earth's surface total carbon (7 x 10(22) gm). The capture of comets by the Earth would also have contributed to generating the appropriate aqueous and reducing environmental conditions necessary for organic synthesis. Although it is possible that some of the cometary carbon compounds falling on the Earth survived, most of them were probably decomposed by the heat and shock waves of the cometary collision. Upon quenching to low temperatures, however, the reactive chemical species produced by the impact would have recombined, leading to the synthesis of a great variety of organic molecules. Laboratory experiments with radiation, heat and shock waves have demonstrated that some of the synthesized compounds are biochemical molecules: amino acids, sugars, purines, and pyrimidines. These are essential to all living systems.


Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death.
Radiotherapy is commonly used as a cytotoxic treatment of a wide variety of tumors. Interestingly, few case reports underlined its potential to induce immune-mediated abscopal effects, resulting in regression of metastases, distant from the irradiated site. These observations are rare, and apparently depend on the dose used, suggesting that dose-related cellular responses may be involved in the distant immunogenic responses. Ionizing radiation (IR) has been reported to elicit immunogenic apoptosis, necroptosis, mitotic catastrophe, and senescence. In order to link a cellular outcome with a particular dose of irradiation, we performed a systematic study in a panel of cell lines on the cellular responses at different doses of X-rays. Remarkably, we observed that all cell lines tested responded in a similar fashion to IR with characteristics of mitotic catastrophe, senescence, lipid peroxidation, and caspase activity. Iron chelators (but not Ferrostatin-1 or vitamin E) could prevent the formation of lipid peroxides and cell death induced by IR, suggesting a crucial role of iron-dependent cell death during high-dose irradiation. We also show that in K-Ras-mutated cells, IR can induce morphological features reminiscent of methuosis, a cell death modality that has been recently described following H-Ras or K-Ras mutation overexpression.


A pooled data analysis of injury incidence in rugby league football.
The aim of this study was to summarise the injury rates in professional rugby league football. Previously published studies were identified from database searches of the literature from Medline, Sports Discus and Web of Science. A total of 18 articles, which reported the prospective injury data collection for at least one playing season in professional rugby league worldwide, were included. The definition of injury adopted required an injured player to miss the subsequent game through injury. Ten studies satisfied the injury definition criteria for inclusion. A review of articles and extraction of relevant data were carried out independently by two authors. A total of 517 injuries were reported during 12819 hours of exposure (753 games), which resulted in an overall injury rate of 40.3 injuries per 1000 hours [95% confidence interval (CI) 36.9 to 43.8]. Most injuries were to the lower half of the body (20.7 per 1000 hours, 95% CI 17.7 to 24), with the trunk receiving the least (6.7 per 1000 hours, 95% CI 5 to 8.6). Injury rates in professional rugby league are higher than in some other contact sports, probably because of the large number of physical collisions that take place. This pooled data analysis provides more accurate estimates of injury incidence in the game of professional rugby league football.


The effect of Elymus nutans sowing density on soil reinforcement and slope stabilization properties of vegetation-concrete structures.
Elymus nutans is an herbaceous plant that can be used to restore degraded alpine and subalpine ecosystems. Here, we evaluated how sowing density affects soil reinforcement and slope stabilization properties of vegetation-concrete structures. To investigate the optimal sowing density of E. nutans in vegetation-concrete applications for slope protection, six experimental treatments were established with different plant densities: control, I (1100 seeds/m2), II (2200 seeds/m2), III (3300 seeds/m2), IV (4400 seeds/m2), and V (5500 seeds/m2). Several parameters of plant growth in addition to soil reinforcement and slope stabilization properties were measured in each treatment, as well as the associations among parameters. As density increased, aboveground biomass continually increased, and plant heights, root surface areas, root lengths, and underground biomass all first increased and then decreased. In contrast, tiller numbers and the average root diameter gradually decreased with increasing density. Increased density also resulted in increased maximum water interception levels by aboveground stems and leaves. The maximum water interception by the aboveground stems and leaves was 41.75% greater in the highest density treatment (V) compared to the lowest density treatment (I). However, the enhancement of erosion resistance and soil shear strength first increased and then decreased as density increased, with maximal values observed in the medium-high density treatment (IV). Sowing density was highly correlated with aboveground biomass, plant heights, tiller numbers, and the maximum level of water interception by stems and leaves. Thus, sowing density directly influenced soil reinforcement and slope stabilization properties of aboveground plant components. However, density was not significantly correlated with belowground biomass, root lengths, root surface areas, the enhancement of erosion resistance, and soil shear strengths. Therefore, sowing density indirectly influenced soil reinforcement and slope stabilization of belowground plant components. Following from these results, we suggest that the optimal sowing density of E. nutans is approximately 4400 plants/m2 in their application within vegetation-concrete structures used for slope protection.


Nitrous oxide and risk of surgical wound infection: a randomised trial.
Nitrous oxide inactivates vitamin B12 and methionine synthase, thereby impairing DNA formation and, consequently, new cell formation. The gas also inhibits methionine production, which can reduce scar formation and depresses chemotactic migration by monocytes. Therefore, we assessed whether nitrous oxide increases the incidence of surgical wound infection. We recruited 418 patients aged 18-80 years, scheduled for colon resection that was expected to last more than 2 h, at three hospitals in Austria and Hungary. Patients were randomly assigned 65% intraoperative nitrous oxide (n=208) or nitrogen (n=206), with remifentanil and isoflurane. The primary outcome was the incidence of clinical postoperative wound infection, analysed by intention to treat. 206 patients in the nitrous oxide group and 202 in the nitrogen group were included in the final analysis. Duration of surgery was longer in the nitrogen group (3.4 h [1.5]) than in the nitrous oxide group (3.0 h [SD 1.3]) and arterial pressure (84 mm Hg [10] vs 81 mm Hg [9]), bispectral index values (53 [9] vs 44 [8]), and end-tidal isoflurane concentration (0.64% [0.14] vs 0.56% [0.13]) were greater in patients given nitrogen than in those given nitrous oxide. Infection rate was 15% (31/206) in patients given nitrous oxide and 20% (40/202) in those given nitrogen (p=0.205). Additionally, the ASEPSIS wound healing score, wound collagen deposition, number of patients admitted to critical care unit, time to first food ingestion, duration of hospital stay, and mortality did not differ between treatment groups. Nitrous oxide does not increase the incidence of surgical wound infection.


Hyperresponsiveness to phencyclidine in animals lesioned in the amygdala on day 7 of life. Implications for an animal model of schizophrenia.
Phencyclidine (PCP) has been described to exacerbate psychotic symptoms in patients suffering from schizophrenia. In rats, PCP, dose-dependently, induces hyperactivity, stereotyped behaviour and social isolation, postulated to represent the positive (hyperactivity, stereotypy) and negative (social isolation) symptoms of schizophrenia. Based on previous studies, ibotenic acid lesions in the amygdala on day 7 of life have been proposed as an animal model of psychiatric neurodevelopmental disorders like schizophrenia. The purpose of the present study was to determine whether the responsiveness to PCP on locomotor activity in animals lesioned in the amygdala on day 7 of life is different from the response to this drug in sham-operated animals. The effect of graded doses of PCP on behaviour was assessed in a small open field. Animals lesioned in the amygdala on day 7 of life appeared to be hyperresponsive to PCP compared to sham-operated animals. The hyperresponsiveness to PCP in rats lesioned in the amygdala on day 7 of life further contributes to the validation of this putative animal model of schizophrenia.


Grief, alcohol dependence and women.
A comparison was made between similar age-grouped widows (N = 37) and non-widows (N = 85) who were admitted to an alcohol dependence unit for treatment. The widows reported excess drinking to have occurred less frequently in close relatives and more frequently in their late spouses as compared to the non-widowed females. Widows also had significantly different referral patterns. The findings suggest that the widows of alcoholics who had unresolved marital conflicts, or who become socially isolated are more vulnerable to abnormal grief responses. Prospective studies are required to verify this pilot survey.


Heparin cofactor II-thrombin complex in MPS I: a biomarker of MPS disease.
The mucopolysaccharidoses are a clinically heterogeneous group of lysosomal storage disorders presenting with broad multi-system disease and a continuous range of phenotypes. Currently, there are no objective biomarkers of MPS disease that clearly reflect disease severity or therapeutic responsiveness. Using proteomic studies in the murine MPS I model, we have identified the formation of the heparin cofactor II-thrombin (HCII-T) complex, a well-known serine protease inhibitor (serpin)-serine protease complex, as an informative biomarker for MPS I. MPS I patients showed a range of serum HCII-T concentrations from 46,000-208,600 pM, whereas the control values varied from 115.1-398.0 pM. HCII-T complex was also elevated in plasma from MPS I patients and mice. The degree of HCII-T complex formation appears to correlate with disease severity and is responsive to therapy. In addition to its role as a biomarker, the discovery of increased serpin-serine protease complex formation provides a valuable insight into possible pathophysiological mechanisms of MPS disease.


When people living with dementia say 'no': Negotiating refusal in the acute hospital setting.
A quarter of UK acute hospital beds are occupied by people living with dementia (PLWD). Concerns have been raised by both policy makers and carers about the quality of communication between hospital staff and PLWD. PLWD may experience communication impairments such as word finding difficulties, limited ability to construct coherent narratives and difficulties understanding others. Since much healthcare delivery occurs through talk, healthcare professionals (HCPs) and PLWD are likely to experience increased communication barriers. Consistent with this, HCPs report stress and reduced job satisfaction associated with difficulty communicating with PLWD. HCPs face these challenges whilst striving to deliver person-centred care, respecting the autonomy and wishes of the patient before them. However, best practice recommendations in the field tend not to be based on actual interactional evidence. This paper investigates recurring interactional difficulties around HCP requests to carry out health and social care tasks and subsequent reluctance or refusal on the part of PLWD. Using conversation analysis, we examined 41 video recordings of HCP/PLWD interactions collected across three acute inpatient wards. We identify both the nature of the refusals, and any mitigation offered, and explore the requests preceding them in terms of entitlement and contingency. We also explore the nature of HCP requests which precede PLWD agreement with a course of action. We conclude that several features of requests can be seen to precede acceptance, principally the use of higher entitlement requests, and the lowering of contingencies. Our findings underline the importance of examining the contextual interactional detail involved in the negotiation of healthcare, which here leads to an understanding of how design of HCP requests can impact on an important healthcare activity being carried out. They also emphasise the power of conversation analytic methods to identify areas of frequent interactional trouble in dementia care which have not previously been articulated.


How molecular diagnosis can change allergen-specific immunotherapy prescription in a complex pollen area.
The identification of disease-eliciting allergens is a prerequisite for accurate prescription of allergen-specific immunotherapy (SIT). The aim of this study was to determine whether molecular diagnosis (MD) may change indication and allergen prescription of SIT. A total of 141 patients with allergic rhinoconjunctivitis and/or asthma sensitized to pollen with or without concomitant food allergy were included. Skin prick testing with a panel of aeroallergens and a microarray-based panel of allergens (ISAC(®); Phadia, Sweden) was performed in all patients. Prior to learning the results of molecular diagnosis, three of the authors reached a consensus on the indication of SIT and use of allergens following EAACI recommendations, basing their judgment on clinical history and skin prick test results before and after obtaining the ISAC results. The agreement coefficient (kappa index) was used to analyze the results. Fifty-nine percent of the patients were women with a mean age of 31 ± 13.63. Agreement in SIT indication before and after ISAC(®) results was found in only 62 (46%) patients (kappa = 0.1057 ± 0.0413). Concerning allergens used in the most common prescriptions before and after MD results, we obtained the following results: κ = 0.117 ± 0.0825 for grass; κ = 0.1624 ± 0.0639 for olive; κ = 0.0505 ± 0.0548 for olive and grass; κ = 0.1711 ± 0.0471 for grass and cypress; κ = 0.1897 ± 0.0493 for grass and London plane; κ = 1 ± 0.0842 for olive and cypress, and κ = 0.3586 ± 0.0798 for other combinations. There was very low agreement concerning indication and use of allergens for SIT before and after performing MD. This discrepancy emphasizes the usefulness of MD, at least in areas of complex sensitization to pollen, in determining correct indication of SIT.


Mangifera indica L. extract protects T cells from activation-induced cell death.
The aqueous stem bark extract of Mangifera indica L. (Vimang) has been reported to have antioxidant properties. AIDS is characterized by up-regulation of CD95 ligand (CD95L) expression and enhancement of activation-induced cell death (AICD). Recent studies demonstrate oxidative signals combined with simultaneous calcium (Ca(2+)) influx into the cytosol are required for induction of CD95L expression. In this study we show that M. indica extract attenuated anti-CD3-induced accumulation of reactive oxygen species (ROS) and intracellular free Ca(2+) and consequently, downregulates CD95L mRNA expression and CD95-mediated AICD. In addition, TCR triggering caused an elevation in the antioxidant enzyme manganous superoxide dismutase (Mn-SOD) and the increase in c-Jun N-terminal kinase (JNK) phosphorylation, both effects being prevented by M. indica extract. We provide a number of evidences regarding how M. indica extract enhance T-cell survival by inhibiting AICD, a finding associated with a decrease in oxidative stress generated through the TCR signaling pathway in activated T cells.


Handling of impact forces in inverse dynamics.
In the standard inverse dynamic method, joint moments are assessed from ground reaction force data and position data, where segmental accelerations are calculated by numerical differentiation of position data after low-pass filtering. This method falls short in analyzing the impact phase, e.g. landing after a jump, by underestimating the contribution of the segmental accelerations to the joint moment assessment. This study tried to improve the inverse dynamics method for the assessment of knee moment by evaluating different cutoff frequencies in low-pass filtering of position data on the calculation of knee moment. Next to this, the effect of an inclusion of direct measurement of segmental acceleration using accelerometers to the inverse dynamics was evaluated. Evidence was obtained that during impact, the contribution of the ground reaction force to the sagittal knee moment was neutralized by the moments generated by very high segmental accelerations. Because the accelerometer-based method did not result in the expected improvement of the knee moment assessment during activities with high impacts, it is proposed to filter the ground reaction force with the same cutoff frequency as the calculated accelerations. When this precaution is not taken, the impact peaks in the moments can be considered as artifacts. On the basis of these findings, we recommend in the search to biomechanical explanations of chronic overuse injuries, like jumper's knee, not to consider the relation with impact peak force and impact peak moment.


The CTGF gene -945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes.
Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes. The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria). The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD. In Caucasians with type 2 diabetes, genetic variation in the CTGF -945 G/C polymorphism is not associated with cardiac or kidney complications.