Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response.
We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.


Predictors of exercise induced myocardial ischemia in patients with isolated coronary artery ectasia.
The aim of this study was to investigate the angiographic predictors of exercise induced ischemia in patients with isolated coronary ectasia. We have prospectively analysed coronary angiograms of 1521 consecutive patients undergoing cardiac catheterisation. The overall incidence of coronary ectasia was 6.7% (102 patients). Forty-six patients (3%) with non-obstructive, diffuse or segmental coronary ectasia (i.e. isolated coronary ectasia) constituted the main study group. Coronary angiograms were reviewed for stigmata of an impaired coronary blood flow such as 'slow flow', 'segmental backflow phenomenon' and stasis. 'Slow flow' was quantified with frame counting. An ectasia-jeopardy score was also described in order to assess the effect of the extent of coronary ectasia on exercise induced ischemia. Exercise induced ischemia was observed in 24 patients (52%). Exercise test was abnormal in 70% of the patients with diffuse ectasia and 26% of patients with segmental ectasia (p = 0.003). The frame count of the arteries of the study group was higher than the control group but the correlation between the frame count of the ectatic vessels and exercise induced ischemia was not significant. Stasis of the dye also did not correlate with ischemia. There was a significant correlation between exercise induced ischemia and backflow phenomenon in left anterior descending artery (LAD) (r = 0.56, p = 0.0001). Exercise induced ischemia was best correlated with the ectasia-jeopardy score (r = 0.77, p = 0.0001) and a score of > or =4 identified the patients at risk with 90% sensitivity and 80% specificity. In conclusion, the extent of the ectasia within the coronary tree, diffuse ectasia and backflow-phenomenon in LAD were identified as the most important predictors of exercise induced ischemia.


The chaotic milling behaviors of interacting swarms after collision.
We consider the problem of characterizing the dynamics of interacting swarms after they collide and form a stationary center of mass. Modeling efforts have shown that the collision of near head-on interacting swarms can produce a variety of post-collision dynamics including coherent milling, coherent flocking, and scattering behaviors. In particular, recent analysis of the transient dynamics of two colliding swarms has revealed the existence of a critical transition whereby the collision results in a combined milling state about a stationary center of mass. In the present work, we show that the collision dynamics of two swarms that form a milling state transitions from periodic to chaotic motion as a function of the repulsive force strength and its length scale. We used two existing methods as well as one new technique: Karhunen-Loeve decomposition to show the effective modal dimension chaos lives in, the 0-1 test to identify chaos, and then constrained correlation embedding to show how each swarm is embedded in the other when both swarms combine to form a single milling state after collision. We expect our analysis to impact new swarm experiments which examine the interaction of multiple swarms.


Genomic analysis of insulin-like growth factor-I gene transfer in thermally injured rats.
Thermal trauma causes tissue damage by membrane destabilization and energy depletion at the cellular level, resulting in tissue necrosis and inflammation leading to delayed cell death. One therapeutic approach is to block the immediate triggering of the inflammatory cascade that results in prolonged hypermetabolic responses and immune dysfunction while promoting the expression of growth factors. In the present study, we determined hepatic gene expression responses to insulin-like growth factors-i (IGF-I) gene transfer to burned rats using high-density DNA microarray assays. The expression of 123 out of approximately 8,800 genes assayed (1.4% of total) were significantly altered. Of these, 42 genes were altered irrespective of treatment by burn trauma (p < 0.05). Changes in gene expression were confirmed by measuring mRNA levels using reverse transcription-polymerase chain reaction and protein levels by Western blot assays. DNA microarray analyses showed two major mechanisms that mediated beneficial outcomes after IGF-I gene transfer in the burned rat livers. These mechanisms were the stimulation of IGF binding protein potentiation of peripheral IGF-I and the inhibition of the burn-augmented pro-apoptotic and oxidative mitochondrial metabolites stimulated by thermal trauma.


Doctor won't see you now: changing paradigms in mountain medicine.
The evolution in communication and digital technologies is revolutionising the practice of medicine. A physician is now able to oversee provision of healthcare at a distance. In this paper, we argue that practice of telemedicine is an essential and evolving aspect of high altitude and expedition medicine. We acknowledge the lack of international consensus, limited legislation as well as possible reservations towards telemedical practice. Given some unique social and medical aspects of participation in remote, high altitude expeditions we propose a number of guiding principles for those involved in provision of telemedical services for such endeavours.


Practice variations in antibiotic administration for the management of peritonitis in patients on automated peritoneal dialysis in Australia and New Zealand.
In the absence of guidelines on the management of peritoneal dialysis (PD)-associated peritonitis in patients on automated peritoneal dialysis (APD), variations in clinical practice potentially exist between PD units that could affect clinical outcomes. This study aimed to document the current practices of treating PD-associated peritonitis in patients on APD across Australia and New Zealand and the reasons for practice variations using a cross-sectional online survey. Of the 62 PD units, 34 medical leads (55%) responded to the survey. When treating APD-associated peritonitis, 21 units (62%) continued patients on APD and administered intraperitoneal (IP) antibiotics in manual daytime exchanges; of these, 17 (81%) considered allowing at least 6 h dwell time for adequate absorption of the IP antibiotics as an important reason for adding manual daytime exchange. Nine units (26%) temporarily switched patients from APD to continuous ambulatory peritoneal dialysis (CAPD); of these, five (55%) reported a lack of pharmacokinetic (PK) data for IP antibiotics in APD, four (44%) reported a shortage of APD-trained nursing staff to perform APD exchanges during hospitalisation and three (33%) reported inadequate time for absorption of IP antibiotics on APD as important reasons for their practice. Four units (12%) continued patients on APD and administered IP antibiotics during APD exchanges; of these, three (75%) believed that PK data available in CAPD could be extrapolated to APD. This study demonstrates wide variations in the management of APD-associated peritonitis in Australia and New Zealand; it points towards the lack of PK on antibiotics used to treat peritonitis as an important reason underpinning practice variations.


E-selectin-mediated rolling facilitates pancreatic cancer cell adhesion to hyaluronic acid.
Tumor cell extravasation is a multistep process preceded by cell rolling and arrest on the vessel wall via the formation of specific receptor-ligand bonds. The strength, availability, and number of receptor-ligand bonds regulate the rate by which tumor cells tether, roll, and adhere to vascular walls. Although the mechanics of selectin-mediated rolling have been extensively studied, little is known regarding how tumor cell rolling on selectins facilitates adhesion to a distinct substrate-bound protein with different kinetic properties. By using multicomponent protein patterning and a microfluidic system, we evaluated how E-selectin-dependent rolling modulates hyaluronic acid (HA) adhesion as a function of fluid shear, contact time, and the spacing between E-selectin and HA regions patterned on the substrate. We show that tumor cells rolling on E-selectin were ∼40-fold more likely to bind to HA than nonrolling cells in shear flow. Furthermore, E-selectin-dependent rolling promotes adhesion to HA by both physically slowing cells and enabling them to position proximal to the surface, thereby increasing the on rate of adhesion. A better understanding of tumor cell adhesion under physiologic shear would lead to the development of new diagnostic assays and pave the way to clinical approaches aimed ultimately to halt metastasis.-Shea, D. J., Li, Y. W., Stebe, K. J., Konstantopoulos, K. E-selectin-mediated rolling facilitates pancreatic cancer cell adhesion to hyaluronic acid.


[Experience with surgical treatment of newborns with necrotizing enterocolitis].
At the period from 1984 through 2010 there were 306 patients with necrotizing enterocolitis aged from 1 to 13 days. Conservative therapy in 214 (70%) cases resulted in favorable outcome of the disease. Operative treatment was necessary in 92 (30%) neonates. In 26 of them double entero-, colostomies were performed, in 7 patients ulcer defects were sutured, in 6 patients parts of intestinal necroses were resected with applying primary end-to-end anastomoses, in 15 patients--laparostomas in combination with intestinal stomas, in 13 patients isolated laparostomas, in 8 patients diagnostic laparotomies.


Imaging and Endovascular Treatment of Bleeding Pelvic Fractures: Review Article.
Pelvic fractures are potentially life-threatening injuries with high mortality rates, mainly due to intractable pelvic arterial bleeding. However, concomitant injuries are frequent and may also be the cause of significant blood loss. As treatment varies depending on location and type of hemorrhage, timely imaging is of critical importance. Contrast-enhanced CT offers fast and detailed information on location and type of bleeding. Angiography with embolization for pelvic fracture hemorrhage, particularly when performed early, has shown high success rates as well as low complication rates and is currently accepted as the first method of bleeding control in pelvic fracture-related arterial hemorrhage. In the current review imaging workup, patient selection, technique, results and complications of pelvic embolization are described.


Serum biochemical changes in dogs with experimental Leptospira interrogans serovar icterohaemorrhagiae infection.
Inoculation of 2 groups of dogs with 1 X 10(9) and 4 X 10(9) Leptospira interrogans serovar icterohaemorrhagiae produced disease varying from transient fever to uremia and death. Clinical signs of disease in the severely affected dogs were fever, dehydration, depression, and icterus. Laboratory changes in serum of infected dogs included increased urea nitrogen, creatinine, phosphorus, alkaline phosphatase, total bilirubin, aspartate aminotransferase, and alanine aminotransferase. Chloride concentration decreased in the serum of dogs with severe disease. The icterus in the infected dogs did not appear to be related to hemolytic anemia.


Discovery of a beta-MSH-derived MC-4R selective agonist.
A series of novel, disulfide-constrained human beta-melanocyte stimulating hormone (beta-MSH)-derived peptides were optimized for in vitro melanocortin-4 receptor (MC-4R) binding affinity, agonist efficacy, and selectivity. The most promising of these, analogue 18, was further studied in vivo using chronic rat food intake and body weight models.


Fiber-optic strain-displacement sensor employing nonlinear buckling.
A new class of intrinsic fiber-optic strain-displacement sensors based on the precisely controlled nonlinear buckling of optical fibers and the resulting optical bend loss is introduced. A multimode fiber version of the sensor is described that exhibits a sensing range convenient for many structural monitoring applications (<100 nm to several millimeters), linear response over a wide range of displacements, and excellent repeatability. It is extremely simple to fabricate and employs inexpensive optoelectronics. A high-temperature version of the sensor is capable of operation at temperatures as high as 600 degrees C.


HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment.
HLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet-derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell-replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT.


Does understanding endotypes translate to better asthma management options for all?
Despite the development of novel treatments, improvement in the design of delivery devices, and new technologies for monitoring and improving adherence, the burden of asthma is not decreasing. Predicting an individual patient's response to asthma drugs remains challenging, and the provision of personalized treatment remains elusive. Although biomarkers, such as allergic sensitization and blood eosinophilia, might be important predictors of response to inhaled corticosteroids in preschool children, these relatively cheap and available investigations are seldom used in clinical practice to select patients for corticosteroid prescription. However, for the majority of patients, response to different treatments cannot be accurately predicted. One of the key factors preventing further advances is the reductionist view of asthma as a single disease, which is forcing patients with different asthma subtypes into a single group for empiric treatment. This inevitably results in treatment failures and, for some, an unacceptable risk/benefit ratio. The approach to asthma today is an example of the traditional symptom (diagnosis)-based, one-size-fits-all approach rather than a stratified approach, and our guidelines-driven management based on a unitary diagnosis might not be the optimal way to deliver care. The only way to deliver stratified medicine and find a cure is through the understanding of asthma endotypes. We propose that the way to discover endotypes, biomarkers, and personalized treatments is through the iterative process based on interpretation of big data analytics from birth and patient cohorts, responses to treatments in randomized controlled trials, and in vitro mechanistic studies using human samples and experimental animal models, with technological and methodological advances at its core.


Antimicrobial Resistance in the Environment.
This review su mmarizes selected publications from 2017 highlighting the occurrence of antimicrobial resistance (AMR) genes in the environment with emphasis on the aquatic environment. The review also covers different treatment technologies being developed for AMR genes as an environmental contaminant. The progress made in the area of AMR gene databases and tools is also reviewed. Besides a brief introduction, the content is categorized into three main sections: i) Occurrence of AMR in the Environment, ii) Treatment technologies for AMR, and iii) AMR databases and tools.


KRN8602 (MX2-hydrochloride): an active new agent for the treatment of recurrent high-grade glioma.
To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma. Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score < or = 2) were treated with an intravenous bolus of 40 mg/m(2) KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles. A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting. KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.


Spindle Position Checkpoint Kinase Kin4 Regulates Organelle Transport in Saccharomyces cerevisiae.
Membrane-bound organelles play important, frequently essential, roles in cellular metabolism in eukaryotes. Hence, cells have evolved molecular mechanisms to closely monitor organelle dynamics and maintenance. The actin cytoskeleton plays a vital role in organelle transport and positioning across all eukaryotes. Studies in the budding yeast Saccharomyces cerevisiae (S. cerevisiae) revealed that a block in actomyosin-dependent transport affects organelle inheritance to daughter cells. Indeed, class V Myosins, Myo2, and Myo4, and many of their organelle receptors, have been identified as key factors in organelle inheritance. However, the spatiotemporal regulation of yeast organelle transport remains poorly understood. Using peroxisome inheritance as a proxy to study actomyosin-based organelle transport, we performed an automated genome-wide genetic screen in S. cerevisiae. We report that the spindle position checkpoint (SPOC) kinase Kin4 and, to a lesser extent, its paralog Frk1, regulates peroxisome transport, independent of their role in the SPOC. We show that Kin4 requires its kinase activity to function and that both Kin4 and Frk1 protect Inp2, the peroxisomal Myo2 receptor, from degradation in mother cells. In addition, vacuole inheritance is also affected in kin4/frk1-deficient cells, suggesting a common regulatory mechanism for actin-based transport for these two organelles in yeast. More broadly our findings have implications for understanding actomyosin-based transport in cells.


Transverse-mode-selectable microlens vertical-cavity surface-emitting laser.
A new vertical-cavity surface-emitting laser structure employing a thin microlens is suggested and numerically investigated. The laser can be made to emit in either a high-power Gaussian-shaped single-fundamental mode or a high-power doughnut-shaped higher-order mode. The physical origin of the mode selection properties of the new structure is rigorously analyzed and compared to other structures reported in the literature. The possibility of engineering the emission shape while retaining strong single mode operation is highly desirable for low-cost mid-range optical interconnects applications as well as the compact optical trapping of high-refractive-index dielectric particles and low-refractive-index, absorbing, or metallic particles.


Adolescent substance use: Latent class and transition analysis.
The prevention and intervention of adolescent substance use is a public health priority. Most adolescents will engage in some form of substance use, and a sizeable minority will transition to using multiple substances. An emerging body of research takes a person-centered approach to model adolescent substance use over time; however, the findings have been equivocal. Our study modeled adolescent substance use transition patterns over three years based on a comprehensive list of substances and examined gender as a moderator. We used three annual waves of data (Time 2, Time 3, and Time 4) from an ongoing longitudinal study of an ethnically diverse sample of 1042 adolescents originally recruited from multiple high schools in southeast Texas. Participants were 56% female, 32% Hispanics, 30% Whites, 29% African Americans, and 9% other with an average of 16.1years (SD=0.79) at Time 2. Data were analyzed using latent transition analyses. The study identified three substance use statuses (Mild Alcohol Use, Alcohol and Moderate Marijuana Use, and Polysubstance Use) and suggested that adolescents generally remained in the same statuses over time. When they did transition, it was typically to a more harmful substance use status. Further, males were more likely than females to be polysubstance users and had higher probabilities of transiting to and remaining in a more harmful drug use status. The study identifies overall and gender specific adolescent substance use transition patterns, which are vital to informing intervention development.


Presence of temporal gray-white matter abnormalities does not influence epilepsy surgery outcome in temporal lobe epilepsy with hippocampal sclerosis.
Temporal lobe gray-white matter abnormalities (GWMA) are frequent morphological aberrances observed on MRI in patients with temporal lobe epilepsy (TLE) in addition to hippocampal sclerosis (HS). To study the influence of temporal pole GWMA on clinical characteristics and seizure outcome in patients with HS operated on for TLE. A cohort of 370 patients undergoing surgery for intractable TLE was prospectively collected in an epilepsy surgery data base. Clinical characteristics and seizure outcome of all 58 TLE patients with identified HS and GWMA (group 1) were compared with those of a matched control group of 58 HS patients without GWMA (group 2). Both groups were further subdivided into patients undergoing transsylvian selective amygdalohippocampectomy (sAH) and anterior temporal lobectomy with amygdalohippocampectomy (ATL). The HS plus GWMA patients were significantly younger at epilepsy onset than those without GWMA. In the HS plus GWMA group, 41% of patients were younger than 2 years when they experienced their first seizure in contrast to only 17% of patients with pure HS (P = .004). Seizure outcome was not statistically different between the 2 groups: 75.9% of the patients in group 1 were seizure free (Engel class I) compared with 81% of patients in group 2. Seizure outcome in both groups was about equally successful with selective amygdalohippocampectomy and anterior temporal lobectomy (ns). Limited and standard resections in TLE patients with HS are equally successful regardless of the presence of GWMA.


Mobilizing store Ca(2+) in the presence of La(3+) evokes exocytosis in bovine chromaffin cells.
The effect on exocytosis of La(3+), a known inhibitor of plasma membrane Ca(2+)-ATPases and Na(+)/Ca(2+) exchangers, was studied using cultured bovine adrenal chromaffin cells. At high concentrations (0.3-3 mM), La(3+) substantially increased histamine-induced catecholamine secretion. This action was mimicked by other lanthanide ions (Nd(3+), Eu(3+), Gd(3+), and Tb(3+)), but not several divalent cations. In the presence of La(3+), the secretory response to histamine became independent of extracellular Ca(2+). La(3+) enhanced secretion evoked by other agents that mobilize intracellular Ca(2+) stores (angiotensin II, bradykinin, caffeine, and thapsigargin), but not that due to passive depolarization with 20 mM K(+). La(3+) still enhanced histamine-induced secretion in the presence of the nonselective inhibitors of Ca(2+)-permeant channels SKF96365 and Cd(2+), but the enhancement was abolished by prior depletion of intracellular Ca(2+) stores with thapsigargin. La(3+) inhibited (45)Ca(2+) efflux from preloaded chromaffin cells in the presence or absence of Na(+). It also enhanced and prolonged the rise in cytosolic [Ca(2+)] measured with fura-2 during mobilization of intracellular Ca(2+) stores with histamine in Ca(2+)-free buffer. The results suggest that the efficacy of intracellular Ca(2+) stores in evoking exocytosis is enhanced dramatically by inhibiting Ca(2+) efflux from the cell.


99mTc(V)DMSA quantitatively predicts 188Re(V)DMSA distribution in patients with prostate cancer metastatic to bone.
Rhenium-188 dimercaptosuccinic acid complex [188Re(V)DMSA], a potential therapeutic analogue of the tumour imaging agent 99mTc(V)DMSA, is selectively taken up in bone metastases in patients with prostate cancer. It would be helpful in planning palliative radionuclide therapy if 99mTc(V)DMSA could be used to predict tumour and kidney retention of 188Re(V)DMSA. The aim of this study was to determine the correlation between tumour-to-normal tissue ratios and kidney-to-soft tissue ratios of 99mTc(V)DMSA and 188Re(V)DMSA. This would determine whether a scan with 99mTc(V) DMSA could be used to identify patients for whom 188Re(V)DMSA treatment would be contra-indicated, and enable prediction of relative kidney and tumour radiation absorbed dose in 188Re(V)DMSA treatment. Ten patients with prostate carcinoma were recruited following observation of disseminated bone metastases on a recent 99mTc-hydroxydiphosphonate bone scan. Whole-body planar scans were obtained at ca. 4 h and 24 h after hydration and injection of 600 MBq 99mTc(V)DMSA, and a week later, at similar times after hydration and injection of 370 MBq 188Re(V)DMSA. A triple-energy window (TEW) scatter correction was applied to the 188Re scans. Counts per pixel were determined in regions of interest drawn over metastatic sites, kidneys and normal soft tissue. Tumour-to-soft tissue ratios were significantly lower (by a factor of approximately 0.8 after the TEW was applied) on 188Re scans than on 99mTc scans, but the two were highly linearly correlated both in all individual patients and in tumours pooled from all patients together both at 4 h and at 24 h. Kidney-to-soft tissue ratios were similarly correlated and were lower for 188Re than for 99mTc by a similar factor. Both tumour- and kidney-to-soft tissue ratios increased between 4 and 24 h but the latter increased more. In conclusion, only minor differences were seen between 99mTc and 188Re scans, and kidney-to-background ratios on 188Re scans were not higher than on 99mTc scans. These differences are insufficient to infer that they are due to a real difference in biodistribution, and they may be due only to different physical imaging characteristics. Thus 99mTc(V)DMSA scans are predictive of 188Re(V)DMSA biodistribution and could be used to estimate tumour and renal dosimetry and assess suitability of patients for 188Re(V)DMSA treatment.


Intracellular study of recurrent facilitation.
Recurrent facilitation in the cat's spinal cord has been studied in deep peroneal and quadriceps motoneurons with the use of intracellular recording. The presence of facilitation was indicated by several criteria, among them increased firing index of the cells or decreased latency of firing. In many, but not all, facilitated cells the conditioning volley caused a small visible depolarization. Subthreshold synaptic potentials were frequently increased in magnitude by the conditioning volley, which also increased the effectiveness of a stimulus applied through the microelectrode. Facilitation was found in a large percentage of the motoneurons investigated and was clearly able to bring about pronounced changes in the excitability and firing behavior of these cells.


Multicolor 4D printing of shape-memory polymers for light-induced selective heating and remote actuation.
Four-dimensional (4D) printing can add active and responsive functions to three-dimensional (3D) printed objects in response to various external stimuli. Light, among others, has a unique advantage of remotely controlling structural changes to obtain predesigned shapes. In this study, we demonstrate multicolor 4D printing of shape-memory polymers (SMPs). Using color-dependent selective light absorption and heating in multicolor SMP composites, we realize remote actuation with light illumination. We experimentally investigate the temperature changes in colored SMPs and observe a clear difference between the different colors. We also present simulations and analytical calculations to theoretically model the structural variations in multicolor composites. Finally, we consider a multicolor hinged structure and demonstrate the multistep actuation by changing the color of light and duration of illumination. 4D printing can allow complex, multicolor geometries with predesigned responses. Moreover, SMPs can be reused multiple times for thermal actuation by simply conducting thermomechanical programming again. Therefore, 4D printing of multicolor SMP composites have unique merits for light-induced structural changes. Our study indicates that multicolor 4D printing of SMPs are promising for various structural changes and remote actuation.


N-terminal pro B-type natriuretic peptide is an independent predictor of postoperative myocardial injury in patients undergoing major vascular surgery.
Myocardial ischemia and infarction after surgery remain leading causes of morbidity and mortality in patients undergoing major vascular surgery. B-type natriuretic peptide has been shown to predict early postoperative cardiac events in patients undergoing major noncardiac surgery. We aimed to determine if N-terminal pro B-type natriuretic peptide (NT-pro-BNP), with its longer half-life and greater plasma stability, can predict postoperative myocardial injury in vascular patients. Recruited were 136 patients undergoing elective surgery for subcritical limb ischemia or abdominal aortic aneurysm (AAA) repair. Plasma NT-pro-BNP was measured preoperatively, and troponin-I was measured immediately after surgery and on postoperative days 1, 2, 3, and 5. Twenty-eight patients (20%) sustained postoperative myocardial injury (troponin-I rise of >0.1 ng/mL). The median NT-pro-BNP level of those with myocardial injury was significantly higher than those who did not (380 pg/mL [interquartile range (IQR), 223-967] vs 209 pg/mL [109-363]; P = .003). NT-pro-BNP predicted this outcome with an area under the receiver operating characteristic (ROC) curve of 68% (95% confidence interval [CI] 0.56%-0.78%). In a multivariate analysis, a NT-pro-BNP value of >/=308 pg/mL (the optimal ROC curve-derived cutoff) was associated with an increased incidence of myocardial injury (odds ratio, 3.4; 95% CI, 1.41-9.09, P =.01). Elevated preoperative plasma NT-pro-BNP levels independently predict postoperative myocardial injury, which is associated with adverse outcome in the short- and long-term regardless of the presence of symptoms of acute coronary syndrome.


Improvement of the embalming perfusion method: the innovation and the results by light and scanning electron microscopy.
Embalming is a chemical process that aims the preservation and sanitization of the human body indefinitely. The technique of embalming is an important tool in teaching and research in anatomy enabling the preservation of cadaveric material in good conditions (lessening any significant structural changes and maintaining the natural appearance). This article presents the results of embalmed cadavers in the course of arterial perfusion, through the use of a perfusion machine, particularly designed to this objective, and which allows the control of the embalming fluid injection process. The influence of this technique and the optimization of its parameters on the final quality of embalming were evaluated by sequential histological analysis of the cadaveric tissues using an original method of classification of samples collected from 17 deceased corpses of the Corpses Donation Office of the Department of Anatomy of Faculdade de Ciências Médicas from Universidade Nova de Lisboa, subject to the embalming technique developed in the Department. We concluded that, with this method, there is a decrease of the decomposition process at the time of embalming, which is effective at long term (over a year), requiring merely the maintenance of the body at low temperatures (4° C) and it is possible to observe that the tissue best preserved over time is muscle, showing a conservation considered optimal.


DNA electron transfer mechanism and dynamics.
The dynamics and efficiency of photoinduced charge separation in synthetic DNA hairpins and dumbbells possessing stilbenedicarboxamide (Sa) and stilbene-diether (Sd) linkers separated by short poly(dA)-poly(dT) base pair sequences have been investigated by means of time resolved fluorescence and transient absorption spectroscopy. Charge separation occurs via a single step superexchange mechanism at short distances and by a multistep hole transport mechanism when the linkers are separated by two or more base pairs. The dynamics and efficiency of hole transport are strongly distance dependent over the first few base pairs, but are relatively insensitive to distance at larger separations. The distance dependence is attributed to a Coulomb cage effect. Hole transport across alternating AT base sequences is less efficient than across poly(dA) sequences. Introduction of guanine into the poly(dA) sequence can either enhance or diminish the efficiency of charge separation, depending upon the location of G. Our experimental results are interpreted using several theoretical models.


Resident continuity of care experience in a Canadian general surgery training program.
To provide baseline data on resident continuity of care experience, to describe the effect of ambulatory centre surgery on continuity of care, to analyse continuity of care by level of resident training and to assess a resident-run preadmission clinic's effect on continuity of care. Data were prospectively collected for 4 weeks. All patients who underwent a general surgical procedure were included if a resident was present at operation. The Division of General Surgery, Queen's University, Kingston, Ont. Preoperative, operative and inhospital postoperative involvement of each resident with each case was recorded. Residents assessed preoperatively (before entering the operating room) 52% of patients overall, 20% of patients at the ambulatory centre and 83% of patients who required emergency surgery. Of patients assessed by the chief resident, 94% were assessed preoperatively compared with 32% of patients assessed by other residents (p < 0.001). Of the admitted patients, 40% had complete resident continuity of care (preoperative, operative and postoperative). There was no statistical difference between this rate and that for emergency, chief-resident and non-chief-resident subgroups. Of the eligible patients, 58% were seen preoperatively by the resident on the preadmission clinic service compared with 54% on other services (p < 0.1). This study serves as a reference for the continuity of care experience in Canadian surgical programs. Residents assessed only 52% of patients preoperatively, and only 40% of patients had complete continuity of care. Factors such as ambulatory surgery and junior level of training negatively affected continuity experience. Such factors must be taken into account in planning surgical education.


Genome-wide association study reveals loci and candidate genes of flowering time in jute (Corchorus L.).
Suitable flowering time can improve fiber yield and quality, which is of great significance for jute biological breeding. In this study, 242 jute accessions were planted in Fujian for 2 consecutive years, and 244,593 SNPs distributed in jute genome were used for genome-wide association analysis of flowering time. A total of 19 candidate intervals (P < 0.0001) were identified by using GLM and FaST-LMM and were significantly associated with flowering time, with phenotypic variation explained (PVE) ranging from 5.8 to 18.61%. Six stable intervals that were repeatedly detected in different environments were further identified by the linkage disequilibrium heatmap. The most likely 7 candidate genes involved to flowering time were further predicted according to the gene functional annotations. Notably, functional analysis of the candidate gene CcPRR7 of the major loci qFT-3-1, a key factor in circadian rhythm in the photoperiodic pathway, was evaluated by linkage, haplotype, and transgenic analysis. β-glucuronidase (GUS) and luciferase (LUC) activity assay of the promoters with two specific haplotypes confirmed that the flowering time can be controlled by regulating the expression of CcPRR7. The model of CcPRR7 involved in the photoperiod regulation pathway under different photoperiods was proposed. These findings provide insights into genetic loci and genes for molecular marker-assisted selection in jute and valuable information for genetically engineering PRR7 homologs in plants. The online version contains supplementary material available at 10.1007/s11032-023-01435-8.


NF-κB/RelA-PKM2 mediates inhibition of glycolysis by fenofibrate in glioblastoma cells.
Aerobic glycolysis (production of lactate from glucose in the presence of oxygen) is a hallmark of cancer. Fenofibrate is a lipid-lowering drug and an agonist of the peroxisome proliferator-activated receptor alpha (PPARα). We found that FF inhibited glycolysis in a PPARα-dependent manner in glioblastoma cells. Fenofibrate inhibited the transcriptional activity of NF-κB/RelA and also disrupted its association with hypoxia inducible factor1 alpha (HIF1α), which is required for the binding of NF-κB/RelA to the PKM promoter and PKM2 expression. High ratios of PKM2/PKM1 promote glycolysis and inhibit oxidative phosphorylation, thus favoring aerobic glycolysis. Fenofibrate decreased the PKM2/PKM1 ratio and caused mitochondrial damage. Given that fenofibrate is a widely used non-toxic drug, we suggest its use in patients with glioblastoma multiforme (GBM).


Increasing tryptophan synthesis in a forage legume Astragalus sinicus by expressing the tobacco feedback-insensitive anthranilate synthase (ASA2) gene.
A cDNA clone that encodes a feedback-insensitive anthranilate synthase (AS), ASA2, isolated from a 5-methyl-tryptophan (Trp) (5MT)-resistant tobacco cell line under the control of the constitutive cauliflower mosaic virus 35S promoter, was introduced into the forage legume Astragalus sinicus by Agrobacterium rhizogenes with kanamycin selection. The 35S-ASA2 gene was expressed constitutively as demonstrated by northern-blot hybridization analyses and the presence of feedback-insensitive AS. Hairy root lines transformed with 35S-ASA2 grew in concentrations of up to 100 microM 5MT, whereas the controls were completely inhibited by 15 microM 5MT. Expression of the feedback-insensitive ASA2 resulted in a 1.3- to 5.5-fold increase in free Trp. Kinetic studies of the AS activity demonstrate the Trp feedback alterations and indicate that the ASA2 alpha-subunit can interact with the native A. sinicus beta-subunit to form an active enzyme. The ASA2 transcript and high free Trp were also detected in the leaves, stems, and roots of plants regenerated from the transformed hairy roots. Thus, we show for the first time that ASA2 can be used to transform plants of a different species to increase the levels of the essential amino acid Trp and impart 5MT resistance.


Progress toward improving animal models for idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) remains a disease with an unknown cause and a poor prognosis. Among attempts to define disease pathogenesis, animal models of experimental lung fibrosis have a prominent role. Commonly used models include exposure to bleomycin, silica, fluorescein isothiocyanate; irradiation; or expression of specific genes through a viral vector or transgenic system. These all have been instrumental in the study of lung fibrosis, but all have limitations and fall short of recapitulating a pattern of usual interstitial pneumonia, the pathologic correlate to IPF. A model of repetitive bleomycin lung injury has recently been reported that results in marked lung fibrosis, prominent alveolar epithelial cell hyperplasia, a pattern of temporal heterogeneity and persistence of aberrant remodeling well after stimulus removal, representing a significant addition to the collection of animal lung fibrosis models. Taken together, animal models remain a key component in research strategies to better define IPF pathogenesis.


Fast determination of saturation intensity and maximum emission rate by single-emitter imaging.
We investigate the dependence of the spot size in single-emitter confocal imaging on the degree of saturation. We show that single-emitter spots are broadened and flattened significantly already at excitation intensities well below saturation. The resulting single-emitter spot shapes thus deviate significantly from the excitation point spread function.We show and support by Monte Carlo simulations that fitting of a single spot is sufficient to extract the saturation intensity and the maximum emission rate of a single emitter with high accuracy. Our results will be of interest in all areas of single-emitter studies.


Phase I study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies.
This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine. Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m(2) intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m(2)/day which was escalated by 250 mg/m(2)/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy. Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m(2), two DLT of prolonged neutropenia of grade > or =3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m(2)/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past. A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts.


Low Control and High Demands at Work as Risk Factors for Suicide: An Australian National Population-Level Case-Control Study.
Previous research suggests that psychosocial job stressors may be plausible risk factors for suicide. This study assessed the relationship between psychosocial job stressors and suicide mortality across the Australian population. We developed a job exposure matrix to objectively measure job stressors across the working population. Suicide data came from a nationwide coronial register. Living controls were selected from a nationally representative cohort study. Incidence density sampling was used to ensure that controls were sampled at the time of death of each case. The period of observation for both cases and controls was 2001 to 2012. We used multilevel logistic regression to assess the odds of suicide in relation to 2 psychosocial job stressors (job control and job demands), after matching for age, sex, and year of death/survey and adjusting for socioeconomic status. Across 9,010 cases and 14,007 matched controls, our results suggest that low job control (odds ratio [OR], 1.35; 95% confidence interval [CI], 1.26-1.44; p < .001) and high job demands (OR, 1.36; 95% CI, 1.26-1.46; p < .001) were associated with increased odds of male suicide after adjusting for socioeconomic status. High demands were associated with lower odds of female suicide (OR, 0.81; 95% CI, 0.72-0.92; p = .002). It seems that adverse experiences at work are a risk factor for male suicide while not being associated with an elevated risk among females. Future studies on job stressors and suicide are needed, both to further understand the biobehavioral mechanisms explaining the link between job stress and suicide, and to inform targeted prevention initiatives.


Equity of access to renal transplant waiting list and renal transplantation in Scotland: cohort study.
To examine the access to the renal transplant waiting list and renal transplantation in Scotland. Cohort study. Renal and transplant units in Scotland. 4523 adults starting renal replacement therapy in Scotland between 1 January 1989 and 31 December 1999. Impact of age, sex, social deprivation, primary renal disease, renal or transplant unit, and geography on access to the waiting list and renal transplantation. 1736 of 4523 (38.4%) patients were placed on the waiting list for renal transplantation and 1095 (24.2%) underwent transplantation up to 31 December 2000, the end of the study period. Patients were less likely to be placed on the list if they were female, older, had diabetes, were in a high deprivation category, and were treated in a renal unit in a hospital with no transplant unit. Patients living furthest away from the transplant centre were listed more quickly. The only factors governing access to transplantation once on the list were age, primary renal disease, and year of listing. A significant centre effect was found in access to the waiting list and renal transplantation. A major disparity exists in access to the renal transplant waiting list and renal transplantation in Scotland. Comorbidity may be an important factor.


Computed tomography of anorexia nervosa.
Computed tomographic studies were performed in patients with anorexia nervosa to confirm the observations of other authors on so-called reversible cerebral atrophy. In 21 of 23 cases a marked enlargement of the cortical sulci and the interhemispheric fissures was observed, which was reversed in a second computed tomographic study in 11 patients 4 weeks after they had reached normal weight. Psychological tests were carried out at the same time as the computed tomographic studies to correlate the changes in the brain tissue with cerebral function. Data obtained in each group of tests for both the initial and the follow-up studies were analyzed using the Student t-test. The differences were found to be statistically significant (p = 0.01 in most cases). The results indicate that anorexia nervosa is not only a psychodynamic problem, but also one in which an organic brain lesion plays an important role during the course of the illness.


Surface properties of sludge and their role in bioflocculation and settleability.
The influence of sludge retention time (SRT) on the extracellular polymeric substances (EPS) and physicochemical properties (hydrophobicity and surface charge) of sludge was studied using laboratory-scale sequencing batch reactors (SBRs) fed a synthetic wastewater containing glucose and inorganic salts. Sludge surfaces were more hydrophobic (larger contact angle) and less negatively charged at higher SRTs (16 and 20 d) than at lower SRTs (4 and 9 d). The ratio of proteins to carbohydrates within the EPS of the sludges increased as the SRT increased from 4 to 12 d corresponding to the changes in the physicochemical properties of the sludge. The protein:carbohydrate ratio remained constant at SRTs of 16 and 20 d. A transition in sludge properties appeared to occur between the upper range of low- (9 d) and lower range of high-SRTs. The total EPS content, however, was independent of the SRT. A higher sludge volume index (SVI), an indication of poorer settleability or compression, was associated with a larger amount of total EPS but no significant correlation between SVI and the surface properties of sludge was observed. A more hydrophobic and less negatively charged surface corresponded to lower levels of ESS. These results indicate that it is the surface properties, hydrophobicity, surface charge and composition of EPS, of sludge, rather than the quantity of EPS, that govern bioflocculation. In contrast, the EPS content is more important in controlling the settleability of sludge.


Habitat complexity mediates the predator-prey space race.
The spatial relationship between predator and prey is often conceptualized as a behavioral response race, in which prey avoid predators while predators track prey. Limiting habitat types can create spatial anchors for prey or predators, influencing the likelihood that the predator or prey response will dominate. Joint spatial anchors emerge when predator and prey occupy similar feeding habitat domains and risk and reward become spatially conflated, confusing predictions of which player will win the space race. These spatial dynamics of risk-foraging trade-offs are often obscured by habitat heterogeneity and community complexity in large vertebrate systems, fueling ambiguity regarding the generality of predictions from predator-prey theory. To test how habitat distribution influences the predator-prey space race, we examine correlation in puma and vicuña habitat selection and space use at two sites, one of which generates a distinct risk-foraging trade-off at a joint spatial anchor. The distribution of vegetation, which serves as both forage for vicuñas and stalking cover for pumas, differs between the sites; the llano contains a single central meadow that acts as a joint spatial anchor, while the canyon is characterized by more heterogeneous vegetation. Puma-vicuña habitat selection correlation was positive in the llano and negative in the canyon, and similarly, utilization distributions were more strongly correlated in the llano than the canyon. Vicuña locations occurred at higher values of puma habitat selection and utilization in the llano than in the canyon. Similarly, puma locations in the llano occurred at higher values of vicuña habitat selection and utilization than in the canyon. Although pumas consistently selected for and utilized vegetative and topographic cover regardless of habitat distribution, vicuñas only selected against vegetation in the heterogeneous canyon site, reducing spatial correlation with pumas. Our work suggests a joint spatial anchor favors pumas in the space race due to the inability for vicuñas to avoid crucial foraging habitat. The outcome of the predator-prey space race appears to be strongly informed by the distribution of habitat, whereby corresponding predictability of predator and prey favors predators in the spatial game.


The safety and efficacy of the use of the flexible laryngeal mask airway with positive pressure ventilation in elective ENT surgery: a 15-year retrospective single-center study.
The use of flexible laryngeal mask airway (FLMA) in elective ear, nose and throat (ENT) surgery offers significant advantages, but is frequently considered inferior to tracheal intubation (TI) for ventilation and airway protection. We investigated the safety and success rate of intraoperative FLMA use with positive pressure ventilation (PPV), and the factors responsible for FLMA failure. A 15-year single center retrospective study. FLMA failure was defined as the need for FLMA removal and TI, either during induction (primary failure), or after turning the patient over to the surgeon (secondary failure). Strict failure criteria included the inability to achieve and/or maintain all 3 essential FLMA functions, such as ventilation (tidal volume ≥6 mL/kg), airway protection from above the cuff (airway sealing pressure [ASP] >12 cm H2O), and separation of the respiratory and gastrointestinal tracts (absent gastric insufflation during PPV). In 685 patients, FLMA was successfully inserted in 94%. Secondary failure rate was 1.5%, with half of failures observed intraoperatively. The inability to seat FLMA during induction or FLMA dislodgment were the most common reasons for failures. The number of FLMA insertion attempts and low ASP were associated with FLMA primary failure and the need for TI. There were no complications. The results suggest an acceptably low failure rate of use of FLMA with PPV in selected ENT surgical procedures. True intraoperative FLMA failure is uncommon. We advocate observing strict criteria for adequacy of FLMA placement, and close monitoring of FLMA function intraoperatively at all times.


[Corrected Transposition of the Great Arteries, Ventricular Septal Defect, Tricuspid Regurgitation and Pulmonary Hypertension Operated at Middle Age: Report of a Case].
A 45-year-old male with corrected transposition of great arteries and the ventricular septal defect (VSD) was considered to have no indication for the total repair because of severe pulmonary hypertension in his young age. He was suffered from heart failure with absence at the age of 44. Detail examinations revealed the severe tricuspid valve regurgitation with VSD. We reevaluated him for the operative indication by the aspect of pulmonary hypertension. His pulmonary vascular resistance decreased with the administration of 100% oxygen, and no pulmonary vascular obstructions were detected in the lung specimen. As a result, he underwent VSD patch closure and tricuspid valve replacement. His postoperative course was uneventful and he was discharged from our hospital at day 16 postoperatively. Our data suggested that reevaluation including lung biopsy should be important to determine operative indication for adult congenital heart disease.


Apolipoprotein(a), through its strong lysine-binding site in KIV(10'), mediates increased endothelial cell contraction and permeability via a Rho/Rho kinase/MYPT1-dependent pathway.
Substantial evidence indicates that endothelial dysfunction plays a critical role in atherogenesis. We previously demonstrated that apolipoprotein(a) (apo(a); the distinguishing protein component of the atherothrombotic risk factor lipoprotein(a)) elicits rearrangement of the actin cytoskeleton in human umbilical vein endothelial cells, characterized by increased myosin light chain (MLC) phosphorylation via a Rho/Rho kinase-dependent signaling pathway. Apo(a) contains kringle (K)IV and KV domains similar to those in plasminogen: apo(a) contains 10 types of plasminogen KIV-like sequences, followed by sequences homologous to the plasminogen KV and protease domains. Several of the apo(a) kringles contain lysine-binding sites (LBS) that have been proposed to contribute to the pathogenicity of Lp(a). Here we demonstrate that apo(a)-induced endothelial barrier dysfunction is mediated via a Rho/Rho kinase-dependent signaling pathway that results in increased MYPT1 phosphorylation and hence decreased MLC phosphatase activity, thus leading to an increase in MLC phosphorylation, stress fiber formation, cell contraction, and permeability. In addition, studies using recombinant apo(a) variants indicated that these effects of apo(a) are dependent on sequences within the C-terminal half of the apo(a) molecule, specifically, the strong LBS in KIV(10). In parallel experiments, the apo(a)-induced effects were completely abolished by treatment of the cells with the lysine analogue epsilon-aminocaproic acid and the Rho kinase inhibitor Y27632. Taken together, our findings indicate that the strong LBS in apo(a) KIV(10) mediates all of our observed effects of apo(a) on human umbilical vein endothelial cell barrier dysfunction. Studies are ongoing to further dissect the molecular basis of these findings.


Significance of Pathologic T3a Upstaging in Clinical T1 Renal Masses Undergoing Nephrectomy.
The objectives of the present study were to report the incidence of pathologic T3a upstaging in a contemporary cohort of patients with clinical stage T1 (cT1) renal tumors treated with partial or radical nephrectomy; investigate the clinical outcomes; and identify the predictors associated with pathologic upstaging. From a single-institution, institutional review board-approved renal tumor database of 945 patients, we identified 610 patients who had undergone surgery for a cT1 renal mass. Data for 494 patients were available for analysis. Of these, 66 lesions had been pathologically upstaged to T3a after surgery and 428 had not. The oncologic follow-up data and clinical and pathologic features were recorded, and multivariable logistic regression analysis was performed to identify the risk factors for pT3a upstaging, controlling for age, gender, body mass index, and nephrectomy type. The cT1 tumors of 66 patients (13.3%) were upstaged to pT3a after surgery. Of these 66 patients, 44 (66.7%) had undergone partial and 22 (33.3%) radical nephrectomy. The median follow-up period was 50 months. No patient with upstaging developed recurrence, and all were disease free at their last follow-up visit. On multivariable analysis, tumor size > 4 cm (odds ratio [OR], 3.766; 95% confidence interval [CI], 1.417-10.011; P < .008), clear cell histologic features (OR, 4.461; 95% CI, 1.498-13.461; P < .007), and positive surgical margins (hazard ratio, 5.118; 95% CI, 2.088-12.547; P < .0001) were associated with upstaging. Of the cT1 lesions in 66 patients, 13% were pathologically upstaged after surgery. The patients with larger tumors, clear cell histologic features, and positive surgical margins were at the greatest risk of upstaging. However, after an intermediate follow-up period, pathologic upstaging did not appear to result in worsened oncologic outcomes.


Identification of an alpha subunit of dihydropyridine-sensitive brain calcium channels.
Voltage-sensitive calcium channels in different tissues have diverse functional properties. Polyclonal antibodies (PAC-2) against the alpha subunits of purified rabbit skeletal muscle calcium channels immunoprecipitated calcium channels labeled with the dihydropyridine PN200-110 from both skeletal muscle and brain. The immunoreactivity of PAC-2 with the skeletal muscle channel was greater than that with the brain calcium channel and was absorbed only partially by prior treatment with the brain channel. PAC-2 specifically recognized a large peptide in synaptic plasma membranes of rabbit brain with an apparent molecular size of 169,000 daltons. This protein resembles an alpha subunit of the skeletal muscle calcium channel in apparent molecular weight, antigenic properties, and electrophoretic behavior after reduction of disulfide bonds. Thus, the dihydropyridine-sensitive calcium channel of rabbit brain has an alpha subunit that is homologous, but not identical, to those of the skeletal muscle calcium channel. The different functional properties of these two calcium channels may result from minor variations in structurally similar components.


Bisphosphonates in lung cancer: more than a palliative therapy?
Bone metastases are a common complication in patients with advanced lung cancer, and most patients with bone metastases from lung cancer develop skeletal-related events (SREs). Skeletal-related events adversely impact patient quality of life and clinical outcome and are associated with increased costs of clinical management, underscoring the need for SRE prevention. Because current practice guidelines do not recommend pretreatment bone scans for all patients at initial presentation, skeletal involvement is not detected in a proportion of patients with early stage asymptomatic bone metastases. In addition, there are no uniform guidelines outlining treatment for patients with bone metastases. Although many bisphosphonates have not been investigated in this setting, zoledronic acid has proven efficacy in delaying the onset and reducing the risk of SREs in patients with bone metastases from lung cancer. Further, recent exploratory analyses in patients with bone metastases from solid tumors suggest that, in addition to normalizing biochemical markers of bone metabolism, zoledronic acid may improve survival in specific patient subsets, including those with lung cancer. Accordingly, several prospectively designed clinical trials assessing anticancer activity of zoledronic acid in the adjuvant setting are ongoing. New insights into the clinical relevance of bone-conserving therapy in patients with lung cancer are discussed.


Adapting Project RED to Skilled Nursing Facilities.
This article describes our recommendation for adapting hospital-based RED (Reengineered Discharge) processes to skilled nursing facilities (SNFs). Using focus groups, the SNFs' discharge processes were assessed twice additionally, research staff then recorded field notes documenting discussions about facility discharge processes as they related to RED processes. Data were systematically analyzed using thematic analysis to identify recommendations for adapting RED to the SNF setting including (a) rapidly identifying, involving, and preparing family/caregivers to implement a patient focused SNF discharge plan; (b) reconnecting patients quickly to primary care providers; and (c) educating patients at discharge about their target health condition, medications, and impact of changes on other chronic health needs. Limited SNF staff capacity and corporate-level policies limited adoption of some key RED components. Transitional care processes such as RED, developed to avoid discharge problems, can be adapted for SNFs to improve their discharges.


p53 Immunostaining guided laser capture microdissection (p53-LCM) defines the presence of p53 gene mutations in focal regions of primary prostate cancer positive for p53 protein.
A wide range of p53 mutations (5-65%), detected by various methods, has been reported in primary prostate cancers (CaP). IHC staining of radical prostatectomy specimens shows marked heterogeneity of focally distributed p53-positive cells. However, a significant relationship between the focal staining of p53 and cancer recurrence after radical prostatectomy has been noted. Increased frequency of p53 mutations has been generally observed in advanced stage CaP and metastatic prostate cancer cell lines. The significance of focal p53 immunostaining in primary CaP remains uncertain with respect to the p53 gene mutation or tumor progression. The goal of this study was to evaluate p53 gene mutations in focal regions of primary prostate cancers positive by p53 immunostaining. Whole-mount prostates from men with clinically organ-confined prostate cancer were immunostained for p53 protein. Laser capture microdissection (LCM) was used to harvest p53 positive cells from areas of tumor and prostatic intraepithelial neoplasia and benign gland. DNA from microdissected cells were amplified for p53 exons 5-8 by polymerase chain reaction (PCR) and analyzed for mutations by single strand conformation polymorphism and DNA sequencing. Mutation analysis of the p53 gene exons 5-8 was performed in the p53 immunostaining positive focal regions (1+ to 4+) of whole-mount prostate sections from 16 patients. Of 16 patients with p53 IHC positive tumors, 11 (69%) had p53 gene mutations as determined by DNA sequence analysis. However, randomly microdissected tumor cells from 4 of 18 patients (22%) negative for p53 IHC also demonstrated mutations in the p53 gene. A significant fraction of prostate tumors with focally positive immunostaining for p53 have been confirmed to contain mutations in the p53 gene. p53 immunostaining guided LCM combined with DNA-based analyses emphasizes the presence of focal p53 mutations in primary prostate cancers and underscores the significance of previous observations showing a correlation between focal p53 immunostaining in primary CaP and cancer recurrence after radical prostatectomy.


A new highly toxic protein isolated from the death cap Amanita phalloides is an L-amino acid oxidase.
A new highly cytotoxic protein, toxophallin, was recently isolated from the fruit body of the death cap Amanita phalloides mushroom [Stasyk et al. (2008) Studia Biologica 2, 21-32]. The physico-chemical, chemical and biological characteristics of toxophallin differ distinctly from those of another death cap toxic protein, namely phallolysin. The interaction of toxophallin with target cells is not mediated by a specific cell surface receptor. It induces chromatin condensation, as well as DNA and nucleus fragmentation, which are typical for apoptosis. However, caspase III inhibitor [benzyloxycarbonyl-Asp(OMe)-fluoromethylketone] did not stop toxophallin-induced DNA fragmentation. Thus, toxophallin uses a caspase-independent pathway of apoptosis induction. In the present study, we applied a complementary approach based on a combination of proteomics and molecular biology tools for the protein identification of toxophallin. The primary structure of toxophallin was partially studied via direct sequencing of its tryptic peptides, followed by PCR-based cloning of the corresponding cDNA. A subsequent bioinformatic search revealed a structural homology of toxophallin with the l-amino acid oxidase of the Laccaria bicolor mushroom. This demonstrates the usefulness of our approach for the identification of proteins in organisms with unknown genomes. We also found a broad substrate specificity of toxophallin with respect to oxidizing selected amino acids. Ascorbic acid inhibited the cytotoxic effect of toxophallin, most likely as a result of scavenging hydrogen peroxide, which is the product of oxidase catalysis. Thus, in addition to highly toxic cyclopeptides and toxic lectin phallolysin, the death cap fruit body contains another cytotoxic protein in the form of an enzyme, namely l-amino acid oxidase.


Minimally Invasive Sacroiliac Joint Fusion Using Triangular Titanium versus Cylindrical Threaded Implants: A Comparison of Patient-Reported Outcomes.
Minimally invasive fusion of the sacroiliac (SI) joint has gained popularity for the treatment of refractory dysfunction. The purpose of this study was to compare the clinical outcomes of minimally invasive SI joint fusion between cylindrical threaded implants (CTIs) and triangular dowel implants (TDIs). We retrospectively reviewed consecutive patients who underwent SI joint fusions with either CTIs or TDIs. Data collected included patient demographics, perioperative data, and all patient-reported outcomes (PROs) including postoperative visual analog scale (VAS), Oswestry Disability Index, and Short Form-12 at 6 months and 1 year. The change from baseline PROs between the cohorts was analyzed as the primary outcome. Secondary outcomes included revision rates and time to revision between the two cohorts. A P value <0.05 was considered significant. One hundred fifty-six consecutive patients underwent SI joint fusion, 74 patients with CTIs and 82 with TDIs. There was a significant difference in procedure length with CTI averaging 60.0 minutes (confidence interval: 55.7-64.3) and TDI averaging 41.2 minutes (confidence interval: 38.4-43.9, P < 0.0005). In both cohorts, there was a significant improvement in all PROs at 6 months when compared with preoperative values. However, when compared, there was no significant difference between the cohorts at 6-month follow-up or 1-year follow-up for either VAS-back, VAS-leg, Oswestry Disability Index, or Short Form-12. A 6.1% revision rate in the CTI cohort was observed compared with a 2.4% revision rate in the TDI cohort (P = 0.11). SI joint fusions with TDI or CTI offer a significant improvement in pain, disability, and quality of life. However, no difference was observed between devices to suggest superior clinical outcomes. Increased revision rates in the Rialto group warrants further investigation.


Strict glycemic targets need not be so strict: a more permissive glycemic range for critically ill children.
The goal was to determine whether a more permissive glycemic target would be associated with a decreased incidence of hypoglycemia but not increased mortality rates in critically ill pediatric patients. This retrospective study evaluated clinical and laboratory data for 177 patients who underwent 211 consecutive surgical procedures for repair or palliation of congenital heart defects at Driscoll Children's Hospital. To establish the relationship between postoperative glycemia and subsequent morbidity and mortality rates, patients were stratified into 4 groups according to their median glucose levels, that is, euglycemia (60-125 mg/dL, 3.3-6.9 mmol/L), mild hyperglycemia (126-139 mg/dL, 6.9-7.7 mmol/L), moderate hyperglycemia (140-179 mg/dL, 7.7-9.9 mmol/L), or severe hyperglycemia (>or=180 mg/dL, >or=9.9 mmol/L). Postoperative outcomes for those groups also were compared with outcomes for a more permissive glycemic target group (90-140 mg/dL, 5-7.7 mmol/L). The peak and mean blood glucose measurements and duration of hyperglycemia were not different for survivors and nonsurvivors in the first 24 hours after surgery. Nonsurvivors had higher peak glucose levels (389.3 +/- 162 mg/dL vs 274.4 +/- 106.3 mg/dL, 21.4 +/- 8.9 mmol/L vs 15.1 +/- 5.9 mmol/L) and longer duration of hyperglycemia (3.06 +/- 1.67 days vs 2.11 +/- 0.92 days) during the first 5 postoperative days, compared with survivors. Mortality rates were significantly higher for the moderate (38.8%) and severe (58.3%) hyperglycemia groups, compared with the euglycemia (6.02%) and permissive target (4.69%) groups. The incidence of hypoglycemia was significantly higher in the euglycemia group (31.8%), compared with the permissive target group (17.18%). Postoperative hyperglycemia is associated with increased morbidity and mortality rates in children after surgical repair of congenital heart defects. A more permissive glycemic target is associated with a lower incidence of hypoglycemia but not increased mortality rates in these patients.


Relapse prevention in bipolar disorder: a critical review of current guidelines.
Bipolar disorder is an important and serious mental illness associated with significant morbidity and mortality. However, unfortunately, the evidence base regarding treatment is less than satisfactory. In such circumstances clinicians often resort to reputable sets of guidelines. A number of these currently exist; in the United Kingdom the most prominent being that produced by the British Association of Psychopharmacology (BAP). This paper reviews the methodology of this guideline and its recommendations regarding the long-term treatment of bipolar disorder and compares this with guidelines produced by the American Psychiatric Association (APA), the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the Texas Implementation of Medication Algorithms (TIMA) for bipolar I disorder. It is concluded that the BAP guidelines continue to be a reasonable set of recommendations, though there are new data available since their publication. All the guidelines reviewed place lithium and valproate at the top of the list of options for long-term treatment. There is a trend to increasingly recognize atypical antipsychotics, particularly olanzapine, as an additional alternative and an increasing prominence of lamotrigine for prevention of depressive relapses. All other treatment options currently have an extremely limited evidence base and do not feature consistently in the published guidelines.


Modifying factors in urinary bladder carcinogenesis.
N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is a potent carcinogen in the urinary bladder of animals. The BBN model of bladder cancer is an excellent model of human urinary bladder cancer and has already led to a greater knowledge of its pathogenesis. In our studies, histogenesis and morphological characteristics of BBN urinary bladder cancer were analyzed in different animal species such as rats, mice, hamsters and guinea pigs and also in different rat strains. Papillary or nodular hyperplasia (PN hyperplasia) is found to be a preneoplastic lesion of the rat urinary bladder. Therefore, the promoting and inhibitory effects of various chemicals in two-stage urinary bladder carcinogenesis were judged by measuring PN hyperplasia in rats. Dose-dependent and organ-specific effects of the urinary bladder promoter, saccharin, in the induction of PN hyperplasia were shown in rats after initiation by BBN. The promoting effect of saccharin was seen more clearly in the urinary bladder of rats after potent initiation. A strain difference in susceptibility of the urinary bladder to the promoter was also shown. These results suggest that the above various factors may also have modifying activities on urinary bladder carcinogenesis in man.


HLA-G-treated tolerogenic dendritic cells induce tolerogenic potential by increasing expression of B7-1 (CD80) molecules.
By consensus, HLA-G has a role in the induction of tolerance via interaction with dendritic cells and manipulation of co-stimulatory molecule expression. The purpose of this study was to demonstrate that HLA-G modified dendritic cells exhibit a decreased ability to stimulate T-cells in vitro due to increased expression of B7-1, which provides regulatory signalling to T-cells as a consequence of binding CD28 and CD152 ligands. Bone-marrow cells were cultured from Brown Norway (BN) rat femurs and sorted with anti-rat dendritic cell Ab (OX62) microbeads. Isolated dendritic cells (DCs) were treated with HLA-G tetramer for 3 days. Initially, cells were plated with media, alloantigenic splenocytes, and T-cells and then observed in mixed lymphocyte reaction for thymidine uptake. Also, the cells were analyzed by flow cytometry using antibodies for MHC-II (IA), CD80, and CD86. This study displays that HLA-G-modified DCs decrease induction of an alloproliferative response. In addition, this study demonstrated that HLA-G tetramer treatment decreases CD86 and permits expression of CD80 without altering MHC-II expression. This study specifically investigated the role of B7-1 (CD80), showing that HLA-G treatment of immature DCs allows expression of B7-1 (CD80) without altering MHC-II expression and simultaneously decreases B7-2 (CD86) expression. Therefore, a low level of B7-2 (CD86) allows attenuation of T-cell response after activation, both of which are beneficial to immune tolerance. The selective expression of B7-1 (CD80) is important and may serve as a guide for future therapies aimed at transplant tolerance.


Whole-cell-based biosensors for environmental biomonitoring and application.
A variety of whole-cell-based biosensors has been developed using numerous native and recombinant biosensing cells. The use of reporter genes, for example bacterial luciferase and gfp, to monitor gene expression is discussed in terms of each reporters' benefits and disadvantages, including their possible use on-line, their sensitivity, the need for extra substrate, etc. All biosensing cells in use can be classified into two groups in terms of their biosensing mechanisms--constitutive expression and stress- or chemical-specific inducible expression. In this review several examples of each are presented and discussed. The use of recombinant whole-cell biosensors in the field requires three components--biosensing cells, a measurement device, and a signal-transducing apparatus, the last two depending on the first and the final applications of the system. The use of different immobilization techniques in several studies to maintain the cells and their viability is also discussed, in particular their use in the development of both high-throughput and chip-based biosensing systems. Finally the application of whole-cell-based biosensors to different environmental media, such as water, soil, and atmospheric monitoring is discussed; particular attention is given to their use for detection of various stressors, including dioxins, endocrine-disrupting chemicals, and ionizing radiation.


Mitotic History Reveals Distinct Stem Cell Populations and Their Contributions to Hematopoiesis.
Homeostasis of short-lived blood cells is dependent on rapid proliferation of immature precursors. Using a conditional histone 2B-mCherry-labeling mouse model, we characterize hematopoietic stem cell (HSC) and progenitor proliferation dynamics in steady state and following several types of induced stress. HSC proliferation following HSC transplantation into lethally irradiated mice is fundamentally different not only from native hematopoiesis but also from other stress contexts. Whereas transplantation promoted sustained, long-term proliferation of HSCs, both cytokine-induced mobilization and acute depletion of selected blood cell lineages elicited very limited recruitment of HSCs to the proliferative pool. By coupling mCherry-based analysis of proliferation history with multiplex gene expression analyses on single cells, we have found that HSCs can be stratified into four distinct subtypes. These subtypes have distinct molecular signatures and differ significantly in their reconstitution potentials, showcasing the power of tracking proliferation history when resolving functional heterogeneity of HSCs.


Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis.
Several lines of evidence have suggested that oxidative stress plays an important role for the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, by using immunohistochemical staining of liver biopsy samples, we measured hepatic 7,8-dihydro-8-oxo-2' deoxyguanosine (8-oxodG), a DNA base-modified product generated by hydroxyl radicals, of 38 NASH patients and compared with 24 simple steatosis and 10 healthy subjects. Relation of hepatic 8-oxodG with clinical, biochemical, and histologic variables and changes after iron reduction therapy (phlebotomy plus iron-restricted diet) were also examined. Hepatic 8-oxodG levels were significantly higher in NASH compared with simple steatosis (17.5 versus 2.0 8-oxodG-positive cells/10(5) microm(2); P < 0.0001). 8-oxodG was significantly related to iron overload condition, glucose-insulin metabolic abnormality, and severities of hepatic steatosis in NASH patients. Logistic regression analysis also showed that hepatic iron deposit and insulin resistance were independent variables associated with elevated hepatic 8-oxodG. After the iron reduction therapy, hepatic 8-oxodG levels were significantly decreased (from 20.7 to 13.8 positive cells/10(5) microm(2); P < 0.01) with concomitant reductions of serum transaminase levels in NASH patients. In conclusion, iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH.


Sphere-rod morphogenesis of Escherichia coli.
The morphogenetic capacity of E. coli was studied by converting the rod-shaped cells into spheres and then determining whether these spheres could revert to rods. The morphogenesis of cells was followed by immobilizing them in a viscous Methocel-containing medium. Two different types of spheres were prepared: cells which retained a mechanically intact sacculus, and osmotically sensitive sphaeroplasts lacking a sacculus. The sphaeroplasts were not able to revert to rods although they were able to synthesize a new sacculus. In contrast, spheres which had retained an intact sacculus were able to reshape themselves into rods. The were also able to form new ends at (or near) the sites of the ends on the original rods.


A taxonomy of hospitals based on partnerships for population health management.
Hospitals face growing pressures and opportunities to engage with partner organizations in efforts to improve population health at the community level. Variation has been observed in the degree to which hospitals develop such partnerships. The aim of this study was to generate a taxonomy of hospitals based on their partnerships with external organizations, employing the theoretical notion of organizations' focus on exploration versus exploitation. With 1,238 valid cases from the 2015 American Hospital Association Population Health Survey, our study uses items asking about the level of partnership strength for 36 named partner types. Excluding three variables with low reliability, 33 variables are classified into six partner groups by factor analysis. Then, cluster analysis is conducted to generate a taxonomy of hospitals based on their partnerships with the six partner groups. Of 1,238 hospitals, 26.1% are classified as exploratory hospitals that develop more collaborative relationships with partners outside the medical sector. Exploitative hospitals (18.3%) focus on relationships with traditional medical sector partners. Ambidextrous hospitals (27.0%) develop partnerships both in and outside the medical sector. Finally, independent hospitals (28.6%) do not establish strong partnerships. Larger hospitals, not-for-profit hospitals, and teaching hospitals are more likely to be classified as exploratory. The four-cluster taxonomy can provide hospital and health system leaders and managers with a better understanding of the wide variation in partnerships that hospitals establish and insights into their different strategic options with regard to partnership development.


[Effects of ultraviolet irradiation on structural and functional condition of T- and B-lymphocytes of human blood].
The influence of ultraviolet (UV) radiation on structural and functional condition of membranes T- and B-lymphocytes of human blood is investigated. It is shown, that intergral flow of UV-light (240-390 nm) in doses 151-1359 J/m2 leads to the increase of the expression of some HLA-antigen (DR1, DR2, DR5, DR7) and Fc-receptors on membranes of B-lymphocytes. The level of HLA-antigen was increased by 20-500% from the initial state after exposure to different doses. The growth of the expression of Fc-receprots was registered in 80% of the donors in the range from 20 up to 540%. The minimum dose of UV-light (151 J/m2) caused the maximum effect. The reduction of the level of Fc-receptors by 10-90% relatively to the native condition was registered for T-cells in 80% of the donors. Groups of the donors were revealed, T-lymphocytes of which differed by the sensitivity to UV-radiation. The effect of "strengthening--weakening", resulting to the reduction of the initially high parameters and to increase in the initially low ones was found.


Risk factors for patellar tendinopathy: a systematic review of the literature.
Patellar tendinopathy (PT) is an injury with a high prevalence in sports. Knowledge of risk factors is essential for developing preventive measures and rehabilitation programmes. However, risk factors associated with PT have not yet been systematically studied. This review was undertaken to identify risk factors associated with PT. The literature was systematically searched to identify articles that investigated risk factors for PT. There was no strong or moderate evidence that any investigated risk factor was associated with PT. For nine risk factors there was some evidence: weight, body mass index, waist-to-hip ratio, leg-length difference, arch height of the foot, quadriceps flexibility, hamstring flexibility, quadriceps strength and vertical jump performance. Based on the present evidence, reducing body weight, increasing upper-leg flexibility and quadriceps strength and the use of orthotics may be beneficial treatment options. However, it should be stressed that the evidence for the nine identified risk factors was only limited. Therefore, there is a clear need for high-quality studies in order to identify the exact risk factors associated with PT.


Chronic pain in people with HIV: a common comorbidity and threat to quality of life.
Evidence indicates that over half of all people with HIV (PWH) will experience nonmalignant chronic pain throughout their lifetimes, with increasing prevalence as they age. Peripheral neuropathy resulting from the neurotoxic effects of HIV itself and the medications used to treat HIV were widely considered the primary cause of acute and chronic pain early on in the antiretroviral treatment era. However, recent studies suggest a predominance of non-neuropathic (e.g., musculoskeletal) pain in PWH with uncertain etiology. Chronic pain is often widespread in PWH, affecting multiple body locations. Additional research is needed to better understand contributors to chronic pain in PWH, which is likely to include biological (e.g., immune dysregulation), psychological (e.g., substance abuse) and social (e.g., stigma) factors.


Improving osteoarthritis care by digital means - Effects of a digital self-management program after 24- or 48-weeks of treatment.
Osteoarthritis (OA) is highly prevalent in older adults and a growing cause of disability. Easily accessible first-line treatment of OA is increasingly important. Digital self-management programs have in recent years become available. Evidence of short-term effects of such programs are abundant, yet reports on long-term benefits and adherence to treatment are scarce. The current study's objective was to investigate the long-term pain and function outcomes of people with hip or knee OA participating in a digital self-management programme. In this longitudinal cohort study, individuals with hip and knee OA, from the register of a digital self-management program and with 0-24-week (n = 499) or 0-48-week adherence (n = 138), were included. The treatment effect in terms of monthly pain (NRS, 0-10 worst to best) and physical function (30-second chair stand test (30CST), number of repetitions) change were investigated using a mixed model, controlling for the effect of age, body mass index (BMI), gender and index joint. For the 24-week sub-sample, pain NRS decreased monthly by -0.43 units (95% CI -0.51, -0.35, mean knee pain from 5.6 to 3.1, and hip pain from 5.9 to 3.8) and 30CST repetitions increased monthly by 0.76 repetitions (95% CI 0.64, 0.89 mean for knee from 10.0 to 14.3, and for hip from 10.9 to 14.8). For the 48-week sub-sample, pain decreased monthly by -0.39 units (95% CI -0.43, -0.36, mean knee pain from 5.7 to 3.2, and hip pain from 5.8 to 3.8), and repetitions increased by 0.72 repetitions (95% CI 0.65, 0.79, mean repetitions for knee from 10.3 to 14.4, and for hip from 11.1 to 14.9). There were no clinically relevant effects on the improvement of pain or function by any covariate (age, sex, index joint). The lack of a control group and randomization limit our ability to explain the mechanisms of the observed results. Continuously participating in a digital OA treatment program for 6 or 12 months was associated with a clinically important decrease in joint pain and increased physical function, in hip and knee OA. Future research should follow OA-related outcomes in participants that end their treatment to explore when and why that decision was made.


Edward George Gray, 11 January 1924 - 14 August 1999.
George Gray was an early contributor to our knowledge of the electron microscopic appearance of the central nervous system. He was skillful with the difficult techniques for preparing the tissues, worked rapidly, and was an astute observer. Sitting with him in the dark, staring at a dim image that George was moving rapidly as he searched for significant detail, could be an exciting experience. He had clear ideas about features that mattered and could quickly relate the two-dimensional electron microscopic images to the three-dimensional neural structures under investigation. He is best known for his detailed and perspective description of synaptic junctions in the mammalian neocortex, and his name is still linked to two distinct junctional types (Gray's type 1 and Gray's type 2), now recognized as generally distinguishing excitatory from inhibitory junctions. He studied a wide range of neural tissues, played a significant role in the early isolation of 'synaptosomes', contributed greatly to the rapid advance of knowledge that accompanied the early application of the electron microscope to neural tissues, and influenced a great many later fine-structural studies of the nervous system.


Breast cancer detection using double reading of unenhanced MRI including T1-weighted, T2-weighted STIR, and diffusion-weighted imaging: a proof of concept study.
The purpose of this study was to investigate the diagnostic performance of unenhanced MRI in detecting breast cancer and to assess the impact of double reading. A total of 116 breasts of 67 women who were 36-89 years old were studied at 1.5 T using an unenhanced protocol including axial T1-weighted gradient-echo, T2-weighted STIR, and echo-planar diffusion-weighted imaging (DWI). Two blinded readers (R1 and R2) independently evaluated unenhanced images using the BIRADS scale. A combination of pathology and negative follow-up served as the reference standard. McNemar and kappa statistics were used. Per-breast cancer prevalence was 37 of 116 (32%): 30 of 37 (81%) invasive ductal carcinoma, five of 37 (13%) ductal carcinoma in situ, and two of 37 (6%) invasive lobular carcinoma. Per-breast sensitivity of unenhanced MRI was 29 of 37 (78%) for R1, 28 of 37 (76%) for R2, and 29 of 37 (78%) for double reading. Specificity was 71 of 79 (90%) for both R1 and R2 and 69 of 79 (87%) for double reading. Double reading did not provide a significant increase in sensitivity. Interobserver agreement was almost perfect (Cohen κ = 0.873). An unenhanced breast MRI protocol composed of T1-weighted gradient echo, T2-weighted STIR, and echo-planar DWI enabled breast cancer detection with sensitivity of 76-78% and specificity of 90% without a gain in sensitivity from double reading.


Comparison of muscle force production using the Smith machine and free weights for bench press and squat exercises.
The Smith machine (SM) (vertical motion of bar on fixed path; fixed-form exercise) and free weights (FWs) (free-form path) are commonly used strength training modes. Exercisers may need to alternate between types of equipment, depending on testing, training, rehabilitation, and/or the exercisers' goals. The purposes of this study were to compare muscle force production for SM and FWs using a 1 repetition maximum (1RM) for the parallel back squat and supine bench press exercises and to predict the 1RM for one mode from 1RM on the other mode. Men (n = 16) and women (n = 16) alternately completed 1RM testing for squat and bench press using SM and FWs. Analyses of variance (type of equipment x sex) and linear regression models were calculated. A significant difference was found between bench press and squat 1RMs for each mode of equipment for all participants. The squat 1RM was greater for the SM than the FWs; conversely, the bench 1RM was greater for FWs than the SM. When sex was considered, bench 1RM for FWs was greater than SM for men and women. The squat 1RM was greater for SM than FWs for women only. The 1RM on one mode of equipment was the best predictor of 1RM for the other mode. For both sexes, the equation SM bench 1RM (in kilograms) = -6.76 + 0.95 (FW bench 1RM) can be used. For women only, SM squat 1RM (in kilograms) = 28.3 + 0.73 (FW squat 1RM). These findings provide equations for converting between SM and FW equipment for training.


Associations of American Indian children's screen-time behavior with parental television behavior, parental perceptions of children's screen time, and media-related resources in the home.
American Indian children have high rates of overweight and obesity, which may be partially attributable to screen-time behavior. Young children's screen-time behavior is strongly influenced by their environment and their parents' behavior. We explored whether parental television watching time, parental perceptions of children's screen time, and media-related resources in the home are related to screen time (ie, television, DVD/video, video game, and computer use) among Oglala Lakota youth residing on or near the Pine Ridge Reservation in South Dakota. We collected baseline data from 431 child and parent/caregiver pairs who participated in Bright Start, a group-randomized, controlled, school-based obesity prevention trial to reduce excess weight gain. Controlling for demographic characteristics, we used linear regression analysis to assess associations between children's screen time and parental television watching time, parental perceptions of children's screen time, and availability of media-related household resources. The most parsimonious model for explaining child screen time included the children's sex, parental body mass index, parental television watching time, how often the child watched television after school or in the evening, parental perception that the child spent too much time playing video games, how often the parent limited the child's television time, and the presence of a VCR/DVD player or video game player in the home (F(7,367) = 14.67; P < .001; adjusted R(2) = .37). The presence of a television in the bedroom did not contribute significantly to the model. Changes in parental television watching time, parental influence over children's screen-time behavior, and availability of media-related resources in the home could decrease screen time and may be used as a strategy for reducing overweight and obesity in American Indian children.


What adults with intellectual and developmental disabilities say they need to access annual health examinations: System navigation support and person-centred care.
To gain an understanding of the support needs of adults with intellectual and developmental disabilities (IDD) when scheduling, traveling to, and attending annual health examinations (AHEs). Qualitative study that is part of a large population-level intervention aiming to increase uptake of AHEs among adults with IDD. Ontario. A total of 8 men and 5 women with IDD took part in semistructured interviews about their personal experiences related to AHEs. Thematic analysis was used to examine experiences relating to scheduling, traveling to, and attending AHEs. Support emerged as the overarching theme. Support included assistance navigating the health care system (assistance scheduling AHEs, reminders to book AHEs, financial assistance, transportation) and person-centred care (respect of privacy and autonomy, communication style, kindness, compassion, rapport with physician, health advocacy, and collaboration). Barriers to this support were also identified (lack of rapport, perception of unfriendliness, perception that the physician is too busy to tend to needs, and perception that the physician did not want to perform AHEs). For adults with IDD, system navigation support and person-centred care were central to accessing AHEs. In collaboration with informal caregivers, physicians have an important role in reducing barriers to patients accessing this valuable preventive care opportunity. Physicians can fulfil some of the needs disclosed by adults with IDD related to attending AHEs by offering support for scheduling appointments, by linking patients with IDD to resources that facilitate appointment attendance, and by increasing consultation duration.


Alzheimer's beta-amyloid peptide as a source of neurotoxic free radicals: the role of structural effects.
This mini review gives a brief overview over the oxidation mechanism of methionine (Met), relevant for processes which may lead to the oxidation of amyloid beta-peptide (betaAP), involved in the pathogenesis of Alzheimer's disease. The Cu(II) -catalysed oxidation of C-terminal Met35 in betaAP depends on the secondary structure of the peptide. That seems to be the key to the known propensities of this peptide to form reactive oxygen species and free radicals. The pro-oxidant character of betaPAP is not associated with its beta-sheet insoluble form. On the contrary, the alpha-helically organised structure is responsible for betaAP redox-related cytotoxicity.