Efficacy of strength training on tension-type headache: A randomised controlled study.
Background Strength training has shown effects in reducing neck pain. As neck pain is highly prevalent in tension-type headache (TTH), it is relevant to examine the effect of strength training of the shoulder muscles on TTH patients. Aim To examine the effect of strength training of the shoulder/neck muscles on TTH frequency and duration. Methods Sixty patients with TTH were randomised into strength training or a control group. The strength training group trained ten weeks with elastic resistance bands. The control group performed ergonomic and posture correction. Efficacy was evaluated at follow-up after 19-22 weeks. Results Twenty-three patients completed strength training and 21 completed ergonomic and posture correction (per-protocol). No between-group effect was detected, but within groups numerical reductions were noted in both groups from baseline to follow-up. Frequency of TTH in the strength training group decreased by 11% ( P = 0.041) and duration decreased by10% ( P = 0.036), while the ergonomic and posture correction group showed a significant reduction in frequency of 24% ( P = 0.0033) and a decrease in duration of 27% ( P = 0.041). Conclusion No significant difference between the groups was found and the within-group effects did not reach clinical significance. Combining all the elements into a multifaceted intervention could prove more useful and should be further explored in future studies. Clinical trials registration number NCT02984826.


Canadian nurses under a single-payer system: advantage or disadvantage?
The American nursing community has not wholeheartedly endorsed comprehensive health care system reform because of fear that nursing salaries, wage compression, direct reimbursement, and political power will be negatively affected in a single-payer system. These issues are evaluated under the Canadian health care system (a single-payer system). The source of payment does not appreciably affect these issues.


Phosphorus removal by steel slag filters: modeling dissolution and precipitation kinetics to predict longevity.
This article presents an original numerical model suitable for longevity prediction of alkaline steel slag filters used for phosphorus removal. The model includes kinetic rates for slag dissolution, hydroxyapatite and monetite precipitation and for the transformation of monetite into hydroxyapatite. The model includes equations for slag exhaustion. Short-term batch tests using slag and continuous pH monitoring were conducted. The model parameters were calibrated on these batch tests and experimental results were correctly reproduced. The model was then transposed to long-term continuous flow simulations using the software PHREEQC. Column simulations were run to test the effect of influent P concentration, influent inorganic C concentration and void hydraulic retention time on filter longevity and P retention capacity. High influent concentration of P and inorganic C, and low hydraulic retention time of voids reduced the filter longevity. The model provided realistic P breakthrough at the column outlet. Results were comparable to previous column experiments with the same slag regarding longevity and P retention capacity. A filter design methodology based on a simple batch test and numerical simulations is proposed.


Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors.
Part C of the guideline is preceded by Part B General Pharmacology IJCPT. 2008; 46: 600 - 617. Included in Part C are practical guidelines for improving the therapy of some age-specific diseases and problems commonly encountered in general practice. The article in this issue is dedicated to the therapy of Dementia and M. Parkinson. Further guidelines for the other age specific diseases and problems named above will be published in the following issues of IJCPT. An important feature of these guidelines are the inclusion of Levels of Evidence and of the Strength of Recommendations for the therapy which are shown when reliable studies are available. (For both see levels of evidence at the end of this article.).


Post-transplantation lymphoproliferative disorders in renal vs. simultaneous renal-pancreas allograft recipients: a survey and analysis of data from the literature.
The epidemiology and other aspects of post-transplantation lymphoproliferative disorders (PTLD) are different in different transplant populations. In this study, we sought to determine the clinical, histopathological and various other features of PTLD in recipients of pancreas-renal allografts and to compare their data with renal-only transplant patients, based on the current available literature. We conducted a comprehensive search for the available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders after renal and simultaneous pancreas-renal (SPR) transplantations. A total of 229 recipients of renal and pancreas-renal allografts were included in the analysis. Localizations for SPR recipients were significantly higher than renal recipients in the pancreas (P <0.0001), skin (P = 0.035), liver (P = 0.043) and bone marrow (P = 0.022). Involvement of lymph nodes was more prevalent in renal recipients (P = 0.046). The occurrence of metastasis was more common among SPR recipients (P = 0.005). Hodgkin's and Hodgkin's-like PTLD were also more prevalent among SPR transplant patients (P <0.0001). Time to development of PTLD was significantly shorter among recipients of SPR (P <0.0001). In this study of international data, we found that PTLD in SPR transplant recipients have various characteristics in their site of involvement, disease presentation time and histopathological features. However, no difference in outcome was detected in these groups of PTLD patients. Future studies with larger study populations are needed for confirming and extending our study results.


The relationship of p53 protein in meninigioma grading and their various influencing factors amongst neurosurgical patients in Hospital Kuala Lumpur.
Meningioma, is the second most frequent intracranial tumor in Malaysia and are classified according to the World Health Organization classification. The relationship of p53 protein in the determination of meningioma grading and their influencing factors were studied via immunohistochemistry studies on 77 intracranial meningiomas (67 benign, 10 atypical). The higher the p53 reaction was correlated to the poorer the histological grade (19.4% in benign and 90% in atypical meningioma) (p < 0.001). Other variables like age, sex, ethnicity, demographic location, surgical clearance, midline shift and contrast enhancement of CT Scan Brain and clinical features were found not to be significant.


Discovery of small molecule degraders for modulating cell cycle.
The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.


Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy attributable to elastin deficiency.
Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency. As previously reported, Eln(-/-) mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln(+/-) mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln(-/-) pups and prevented medial hyperlamellation in Eln(+/-) weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln(-/-) pups, and it retarded the somatic growth of juvenile Eln(+/-) and Eln(+/+) mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome. mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.


lpla (lipoprotein lipase a) is a marker of early adipogenesis rather than late adipogenesis in grass carp (Ctenopharyngodon idellus).
Lipoprotein lipase (LPL) functions as a marker of adipocyte differentiation in mammals, but little is known about its role in fish adipogenesis. The aim of this research is to investigate the function of Lpl in adipocyte differentiation in fish. In this paper, we isolated and characterized lipoprotein lipase a (lpla) and lipoprotein lipase b (lplb) from grass carp (Ctenopharyngodon idellus). The complete coding sequence of lpla and lplb was 1524 bp and 1503 bp in length, coding for 507 amino acids and 500 amino acids, respectively. Both lpla and lplb mRNA were expressed in a great number of tissues. During adipogenesis, the level of lpla mRNA reached its maximum at day 2 and then dropped gradually, while the level of lplb mRNA had no significant changes, indicating that lpla and lplb may have different function in the differentiation of grass carp adipocyte. Furthermore, inhibition of lpla by inhibitor of LPL(GSK264220A) at early time points most clearly reduced adipogenesis, whereas these effects were less pronounced at later stages, suggesting that lpla predominantly affects early adipogenesis rather than late adipogenesis. Based on these findings, it can be inferred that lpla and lplb in grass carp may have distinct roles in the differentiation of grass carp adipocyte, and lpla may play an important role in the early adipogenesis rather than late adipogenesis in grass carp.


Treatment of binge-eating disorder with topiramate: a clinical case series.
Reduced appetite and weight loss were found in clinical trials of topiramate for epilepsy. Binge-eating disorder is characterized by recurrent episodes of binge eating that are not associated with regular use of inappropriate compensatory behaviors. Overweight and obesity may be common complications. To explore the effectiveness and tolerability of topiramate in binge-eating disorder, we describe the response of 13 consecutive outpatients with binge-eating disorder to naturalistic, open-label treatment with topiramate. The response of 13 female outpatients with binge-eating disorder by DSM-IV criteria to naturalistic, open-label treatment with topiramate (100-1400 mg/day) was reviewed. Response of binge-eating disorder symptoms was clinically assessed as none, mild, moderate, marked, or remission. Weight and side effects were also evaluated. All 13 patients had comorbid Axis I psychiatric disorders along with binge-eating disorder and were receiving psychotropic medications at the time of topiramate administration. After beginning topiramate treatment, 9 patients displayed a moderate or better response of binge-eating disorder symptoms that was maintained for periods ranging from 3 to 30 months (mean +/- SD = 18.7+/-8.0 months). Two other patients displayed moderate or marked responses that subsequently diminished. The remaining 2 patients had a mild or no response. The mean +/- SD weight of the 13 patients decreased from 99.3+/-26.4 kg to 87.5+/-20.4 kg (z = -2.4, df = 1, p = .02), but only 7 patients lost > or = 5 kg of weight. The mean topiramate treatment dose was 492.3+/-467.8 mg/day for all 13 patients. The mean topiramate dose was higher in patients who lost > or = 5 kg than in patients who lost < 5 kg. Also, topiramate dose correlated significantly with weight loss (p < .01). In general, topiramate was well tolerated, with neurologic side effects the most common. Of 3 patients who discontinued topiramate because of side effects, 2 resumed the drug at a later date without significant recurrence of these effects. Topiramate may be an effective treatment for binge-eating disorder. Controlled studies of topiramate in binge-eating disorder appear warranted.


Assessing county-level water footprints of different cellulosic-biofuel feedstock pathways.
While agricultural residue is considered as a near-term feedstock option for cellulosic biofuels, its sustainability must be evaluated by taking water into account. This study aims to analyze the county-level water footprint for four biofuel pathways in the United States, including bioethanol generated from corn grain, stover, wheat straw, and biodiesel from soybean. The county-level blue water footprint of ethanol from corn grain, stover, and wheat straw shows extremely wide variances with a national average of 31, 132, and 139 L of water per liter biofuel (L(w)/L(bf)), and standard deviation of 133, 323, and 297 L(w)/L(bf), respectively. Soybean biodiesel production results in a blue water footprint of 313 L(w)/L(bf) on the national average with standard deviation of 894 L(w)/L(bf). All biofuels show a greater green water footprint than the blue one. This work elucidates how diverse spatial resolutions affect biofuel water footprints, which can provide detailed insights into biofuels' implications on local water sustainability.


The multifaceted role of ischemia/reperfusion in sickle cell anemia.
Sickle cell anemia is a unique disease dominated by hemolytic anemia and vaso-occlusive events. The latter trigger a version of ischemia/reperfusion (I/R) pathobiology that is singular in its origin, cyclicity, complexity, instability, perpetuity, and breadth of clinical consequences. Specific clinical features are probably attributable to local I/R injury (e.g., stroke syndromes) or remote organ injury (e.g., acute chest syndrome) or the systematization of inflammation (e.g., multifocal arteriopathy). Indeed, by fashioning an underlying template of endothelial dysfunction and vulnerability, the robust inflammatory systematization no doubt contributes to all sickle pathology. In this Review, we highlight I/R-targeting therapeutics shown to improve microvascular blood flow in sickle transgenic mice undergoing I/R, and we suggest how such insights might be translated into human therapeutic strategies.


Randomized controlled trial on hemifield eye patching and optokinetic stimulation in acute spatial neglect.
Right hemisphere stroke patients frequently experience spatial neglect, a severe lack of awareness for contralesional hemispace. Although neglect counts among the strongest predictors for poor functional outcome after stroke, there is no established therapy, particularly not for the acute stage. In a randomized controlled trial, we compared the combined treatment of hemifield eye patching and repetitive optokinetic stimulation in acute stroke patients with neglect to the spontaneous course. Outcome measures were a neuropsychological test battery for neglect as well as scales of functional independence and clinical impairment. Outcomes were assessed at baseline (day 1), post treatment (day 8), and at 1-month follow-up (day 30). Final analysis included 21 acute right hemisphere stroke patients with neglect (23 enrolled, 2 lost to follow-up) allocated either to the treatment (1 week hemifield eye patching and daily sessions of optokinetic stimulation, n=11) or the control group (no neglect-specific treatment, n=10). At baseline, both groups did not differ in neuropsychological test performance, clinical impairment, or functional disability. At the post treatment session, both groups had improved in all these measures, and results were stable or further improved at follow-up. However, there was no significant difference in this change between the treatment and the control group. An early intervention of combined hemifield eye patching and optokinetic stimulation in acute stroke patients with spatial neglect has no additive effect to the spontaneous remitting course of the disorder. http://www.clinicaltrials.gov. Unique identifier: NCT01617343.


Patient-specific 3D scanned and 3D printed antimicrobial polycaprolactone wound dressings.
The increasing prevalence of wound infections caused by antibiotic resistant bacteria is an urgent challenge facing modern medicine. To address this issue the expedient use of antimicrobial metals such as zinc, copper and silver were incorporated into an FDA-approved polymer (polycaprolactone - PCL) to produce filaments for 3D printing. These metals have broad-spectrum antimicrobial properties, and moreover, copper and zinc can enhance the wound healing process. 3D scanning was used to construct 3D models of a nose and ear to provide the opportunity to customize shape and size of a wound dressing to an individual patient. Hot melt extrusion was used to extrude pellets obtained by vacuum-drying of solutions of PCL and the different metals in order to manufacture metal-homogeneously-loaded filaments. Wound dressings with different shapes were produced with the filaments containing different concentrations of metals. Release of the metals from the dressings was determined by inductively coupled plasma atomic emission spectroscopy. All the different metal dressings show fast release (up to 24h) followed by slow release (up to 72h). The antibacterial efficacy of the wound dressings was tested using a thermal activity monitor system, revealing that silver and copper wound dressings had the most potent bactericidal properties. This study shows that 3D scanning and 3D printing, which are becoming simpler and more affordable, have the potential to offer solutions to produce personalised wound dressings.


The C-terminal V5 domain of Protein Kinase Cα is intrinsically disordered, with propensity to associate with a membrane mimetic.
The C-terminal V5 domain is one of the most variable domains in Protein Kinase C isoforms (PKCs). V5 confers isoform specificity on its parent enzyme through interactions with isoform-specific adaptor proteins and possibly through specific intra-molecular interactions with other PKC domains. The structural information about V5 domains in solution is sparse. The objective of this work was to determine the conformational preferences of the V5 domain from the α isoform of PKC (V5α) and evaluate its ability to associate with membrane mimetics. We show that V5α and its phosphorylation-mimicking variant, dmV5α, are intrinsically disordered protein domains. Phosphorylation-mimicking mutations do not alter the overall conformation of the polypeptide backbone, as evidenced by the local nature of chemical shift perturbations and the secondary structure propensity scores. However, the population of the "cis-trans" conformer of the Thr(638)-Pro(639)-Pro(640) turn motif, which has been implicated in the down-regulation of PKCα via peptidyl-prolyl isomerase Pin1, increases in dmV5α, along with the conformational flexibility of the region between the turn and hydrophobic motifs. Both wild type and dmV5α associate with micelles made of a zwitterionic detergent, n-dodecylphosphocholine. Upon micelle binding, V5α acquires a higher propensity to form helical structures at the conserved "NFD" motif and the entire C-terminal third of the domain. The ability of V5α to partition into the hydrophobic micellar environment suggests that it may serve as a membrane anchor during the PKC maturation process.


Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.
Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ní Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.


A Dual Role of Type I Interferons in Antitumor Immunity.
Type I interferons (IFN-Is) are a family of cytokines that exert direct antiviral effects and regulate innate and adaptive immune responses through direct and indirect mechanisms. It is generally believed that IFN-Is repress tumor development via restricting tumor proliferation and inducing antitumor immune responses. However, recent emerging evidence suggests that IFN-Is play a dual role in antitumor immunity. That is, in the early stage of tumorigenesis, IFN-Is promote the antitumor immune response by enhancing antigen presentation in antigen-presenting cells and activating CD8+ T cells. However, in the late stage of tumor progression, persistent expression of IFN-Is induces the expression of immunosuppressive factors (PD-L1, IDO, and IL-10) on the surface of dendritic cells and other bone marrow cells and inhibits their antitumor immunity. This review outlines these dual functions of IFN-Is in antitumor immunity and elucidates the involved mechanisms, as well as their applications in tumor therapy.


A qualitative investigation of the barriers to help-seeking among members of the public presented with symptoms of new-onset rheumatoid arthritis.
Treating patients with rheumatoid arthritis (RA) within 3 months of symptom onset leads to significantly improved clinical outcomes. However, many people with RA symptoms wait a long time before seeking medical attention. To develop effective health interventions to encourage people to seek help early, it is important to understand what the general public knows about RA, how they would react to the symptoms of RA, and what might delay help-seeking. Qualitative interviews were conducted with 38 members of the general public (32 women) without any form of inflammatory arthritis about their perceptions of RA symptoms and decisions to seek help were they to experience such symptoms. The interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis. A number of barriers and drivers to help-seeking were identified and grouped into 5 themes: perceived causes of symptoms; factors related to presentation, location, and experience of symptoms; perceived effect of symptoms on daily life; self-management of symptoms; and general practitioner-related drivers and barriers. To our knowledge, our study is the first to investigate barriers to and drivers of help-seeking in response to the onset of RA symptoms in individuals without a diagnosis of RA. It has revealed a number of additional factors (e.g., the importance of the location of the symptoms) besides those previously identified in retrospective studies of patients with RA. Together with the data from previous research, these findings will help inform future health interventions aimed at increasing knowledge of RA and encouraging help-seeking.


PredCSO: an ensemble method for the prediction of S-sulfenylation sites in proteins.
Protein S-sulfenylation is a type of reversible post-translational modification (PTM) through which cysteine (CYS) thiols of proteins are reversibly oxidized to cysteine sulfenic acids (CSO). Recent studies have shown that this event plays an essential role in cell signaling, transcriptional regulation and protein functions. Therefore, the identification of S-sulfenylation sites is important to understand the functions of S-sulfenylated proteins. In this study, we proposed PredCSO, a computational method for predicting S-sulfenylation sites in proteins. PredCSO is built on four kinds of features, including position-specific scoring matrix, position-specific amino acid propensity, the absolute solvent accessibility and four-body statistical pseudo-potential. In particular, 21 crucial features were refined out using a two-step feature selection procedure consisting of a max-relevance algorithm and a sequential backward elimination algorithm. To overcome the problem of imbalanced sample sizes, we adopt an ensemble method, which combines bootstrap resampling, gradient tree boosting and majority voting. Our performance evaluation shows that PredCSO achieves state-of-the-art performance in identifying S-sulfenylation sites in proteins.


Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer.
Pancreatic cancer (PC) has an extremely poor prognosis due to the expansion of immunosuppressive myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the inflammatory tumor microenvironment (TME), which halts the recruitment of effector immune cells and renders immunotherapy ineffective. Thus, the identification of new molecular targets that can modulate the immunosuppressive TME is warranted for PC intervention. Src Homology-2 (SH2) domain-containing Inositol 5'-Phosphatase-1 (SHIP-1) is a lipid signaling protein and a regulator of myeloid cell development and function. Herein, we used the bioflavonoid apigenin (API) to reduce inflammation in different PC models. Wild type mice harboring heterotopic or orthotopic PC were treated with API, which induced SHIP-1 expression, reduced inflammatory tumor-derived factors (TDF), increased the proportion of tumoricidal macrophages and enhanced anti-tumor immune responses, resulting in a reduction in tumor burden compared to vehicle-treated PC mice. In contrast, SHIP-1-deficient mice exhibited an increased tumor burden and displayed augmented proportions of pro-tumor macrophages. These results provide further support for the importance of SHIP-1 expression in promoting pro-tumor macrophage development in the pancreatic TME. Our findings suggest that agents augmenting SHIP-1 expression may provide novel therapeutic options for the treatment of PC.


Pomegranate seed oil reduces intestinal damage in a rat model of necrotizing enterocolitis.
Pomegranate seed oil (PSO), which is the major source of conjugated linolenic acids such as punicic acid (PuA), exhibits strong anti-inflammatory properties. Necrotizing enterocolitis (NEC) is a devastating disease associated with severe and excessive intestinal inflammation. The aim of this study was to evaluate the effects of orally administered PSO on the development of NEC, intestinal epithelial proliferation, and cytokine regulation in a rat model of NEC. Premature rats were divided into three groups: dam fed (DF), formula-fed rats (FF), or rats fed with formula supplemented with 1.5% of PSO (FF + PSO). All groups were exposed to asphyxia/cold stress to induce NEC. Intestinal injury, epithelial cell proliferation, cytokine production, and trefoil factor 3 (Tff3) production were evaluated in the terminal ileum. Oral administration of PSO (FF+PSO) decreased the incidence of NEC from 61 to 26%. Feeding formula with PSO improved enterocyte proliferation in the site of injury. Increased levels of proinflammatory IL-6, IL-8, IL-12, IL-23, and TNF-α in the ileum of FF rats were normalized in PSO-treated animals. Tff3 production in the FF rats was reduced compared with DF but not further affected by the PSO. In conclusion, administration of PSO protects against NEC in the neonatal rat model. This protective effect is associated with an improvement of intestinal epithelial homeostasis and a strong anti-inflammatory effect of PSO on the developing intestinal mucosa.


Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity.
Two landmark intervention studies, the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes mellitus and the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes mellitus, have unequivocally demonstrated that intensive diabetes therapy reduces the risk of long-term diabetic complications. As a result, the commonly accepted treatment goal for most patients with diabetes is the achievement and maintenance of glycemic control that is as close to the normal range as safely possible. Important adverse effects of intensive diabetes therapy, particularly when the treatment includes insulin or several of the oral antihyperglycemic agents, are an increased risk of hypoglycemia and undesired weight gain. Improvement of glycemic control with insulin, insulin secretagogues (sulfonylureas, meglitinides), and insulin sensitizers (thiazolidinediones) is often accompanied by weight gain. The etiology of this weight gain is likely multifaceted, including a reduction of glucosuria, increased caloric intake to prevent hypoglycemia, and anabolic effects on adipose tissue. Biguanides and alpha-glucosidase inhibitors have a neutral or even positive effect (decrease) on weight, which may partly be attributable to their non-insulinotropic mechanism of action, a modest effect on satiety, and to their gastrointestinal adverse effect profile. Several antihyperglycemic agents that are currently in clinical development may improve glycemic control in conjunction with weight reduction. These include an analog of the pancreatic beta-cell hormone amylin (pramlintide), as well as glucagon-like peptide-1 (GLP-1) and exendin, and their analogs. Pharmacological agents with antihyperglycemic and positive weight effects have the potential to become important additions to our therapeutic armamentarium, in that they may help to achieve glycemic targets while addressing the long-standing clinical problem of weight gain as an adverse effect of intensive diabetes therapy.


Physical and chemical characteristics of meat from broilers raised in 4 different rearing systems, stored under freezing for up to 12 months.
This study evaluated the effects of freezing (-18°C) for 12 mo on attributes related to the texture of breast, drumstick, and thigh from broilers raised in 4 different rearing systems. Five-hundred carcasses of male broilers raised in 4 rearing systems (Antibiotic-free, Cobb 500, n = 125; Free-range, Hubbard ISA, n = 125; Conventional, Cobb 500, n = 125; Organic, Cobb 500, n = 125) were divided into breast, drumstick, and thigh and stored under freezing (-18°C) for 3, 6, 9, and 12 months. Breast, drumstick, and thigh meat from broilers raised in all studied rearing systems showed reduction (P < 0.001) of water-holding capacity (WHC) during freezing for up 12 months. It was observed an increase (P < 0.001) of cooking loss in breast samples from antibiotic-free, conventional, and organic broilers, and in thigh samples from broilers raised in all rearing systems studied. Breast meat from alternative broilers showed an increase in shear force values, while breast meat from conventional broilers became tenderer during the freezing storage. In general, alternative broilers had harder thigh meat than conventional broilers. A reduction (P < 0.001) in myofibrillar fragmentation index and total collagen concentration was verified in breast, drumstick, and thigh samples throughout the experiment. The freezing for up to 12 mo affects characteristics related to the succulence of chicken meat. Freezing chicken meat cuts for long periods, regardless of the rearing system, may interfere with the meat texture during preparation and consumption and, consequently, influence the consumer decision in a next purchase.


Alcohol consumption and cigarette smoking in combination: A predictor of contralateral breast cancer risk in the WECARE study.
Alcohol drinking and, to a lesser extent, cigarette smoking are risk factors for a first primary breast cancer. Information on these behaviours at diagnosis may contribute to risk prediction of contralateral breast cancer (CBC) and they are potentially modifiable. The WECARE Study is a large population-based case-control study of women with breast cancer where cases (N = 1,521) had asynchronous CBC and controls (N = 2,212), matched on survival time and other factors, had unilateral breast cancer (UBC). Using multivariable conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CI), we examined the risk of CBC in relation to drinking and smoking history at and following first diagnosis. We adjusted for treatment, disease characteristics and other factors. There was some evidence for an association between CBC risk and current drinking or current smoking at the time of first breast cancer diagnosis, but the increased risk occurred primarily among women exposed to both (RR = 1.62, 95% CI 1.24-2.11). CBC risk was also elevated in women who both smoked and drank alcohol after diagnosis (RR = 1.54, 95% CI 1.18-1.99). In the subset of women with detailed information on amount consumed, smoking an average of ≥10 cigarettes per day following diagnosis was also associated with increased CBC risk (RR = 1.50, 95% CI 1.08-2.08; p-trend = 0.03). Among women with a diagnosis of breast cancer, information on current drinking and smoking could contribute to the prediction of CBC risk. Women who both drink and smoke may represent a group who merit targeted lifestyle intervention to modify their risk of CBC.


Bioactive Compounds Isolated from Marine-Derived Microbes in China: 2009-2018.
This review outlines the research that was carried out regarding the isolation of bioactive compounds from marine-derived bacteria and fungi by China-based research groups from 2009-2018, with 897 publications being surveyed. Endophytic organisms featured heavily, with endophytes from mangroves, marine invertebrates, and marine algae making up more than 60% of the microbial strains investigated. There was also a strong focus on fungi as a source of active compounds, with 80% of publications focusing on this area. The rapid increase in the number of publications in the field is perhaps most notable, which have increased more than sevenfold over the past decade, and suggests that China-based researchers will play a major role in marine microbial natural products drug discovery in years to come.


Trapping as an alternative method of eradicating classical swine fever in a wild boar population in Bulgaria.
Between August and November 2009, eight cases of classical swine fever (CSF) occurred in young wild boar in a 25-km2 oak forest3 km south of the river Danube in the north-eastern part of Bulgaria. The wild boar population within the affected area was estimated to be 156 animals, or approximately six boar per km2. To control and eradicate the disease, and in addition to vaccination and hunting, trapping was used to reduce the boar population to below two animals per km2. In total, 124 wild boar were removed from the infected area within three months. Of these, 119 were trapped. In this paper, the authors present trapping as a successful tool to eradicate CSF from an area where hunting and vaccination alone might not be sufficient. Up to seven wild boar could be trapped in a single trap. Furthermore, the spread of CSF virus to the local domestic pig population and to wild boar in neighbouring areas was prevented. By decreasing the wild boar population to fewer than two animals per km2, it was assumed that the virus would no longer circulate and the disease would fade out. In fact, no further CSF cases were diagnosed afterwards. Under Bulgarian and similar conditions, trapping seems to be a more reliable method than hunting for reducing a wild boar population within a short period of time. Furthermore, trapping may be used alone or in combination with hunting, depending on the situation.


[Oogenesis of Mozambique tilapia. IV. Yolk formation].
Yolk globules in developing oocytes of Tilapia mosambique are formed by two processes: 1) biosynthetical activity of oocyte organoides; 2) vitellogenin migration by micropinocytosis and its further transformation. Undoubtedly, yolk globules of endogenic and exogenic origin are fused. The primary yolk globules are spherical, and the secondary ones are lobular. The latter originate by incorporating the former. The fast growth of the late vitellogenic stage oocytes occurs as a result of active migration of primary yolk globules into the central part of the oocyte and as their association with the secondary yolk globules. In vitellogenic oocytes of T. mosambique no yolk vesicles (cortical granules), were found by any existing methods.


Ripk3 mediates cardiomyocyte necrosis through targeting mitochondria and the JNK-Bnip3 pathway under hypoxia-reoxygenation injury.
Context: Cardiomyocyte necrosis following myocardial infarction drastically the progression of heart failure.Objective: In the current study, we explored the upstream mediator for cardiomyocytes necrosis induced by hypoxia-reoxygenation (HR) injury with a focus on mitochondrial function and JNK-Bnip3 pathway.Materials and methods: Cell necrosis was determined via MTT assay, TUNEL staining and PI staining. siRNA transfection was performed to inhibit Ripk3 activation in response to HR injury. Pathway blocker was applied to prevent JNK activation.Results: Ripk3 was rapidly increased in HR-treated cardiomyocytes and correlated with the necrosis of cardiomyocytes. Interestingly, silencing of Ripk3 attenuated HR-mediated cardiomyocytes necrosis. At the molecular levels, Ripk3 deletion sustained mitochondrial bioenergetics and stabilized mitochondrial glucose metabolism. Besides, Ripk3 deletion also reduced mitochondrial oxidative stress and inhibited mPTP opening. To the end, we found Ripk3 activation was along with JNK pathway activation and Bnip3 upregulation. Interestingly, blockade of JNK pathway abolished the harmful effects of HR injury on mitochondrial function, energy metabolism and redox balance. Moreover, overexpression of Bnip3 abrogated the protection action played by Ripk3 deletion on cardiomyocytes survival.Conclusions: Taken together, these data may identify Ripk3 upregulation, mitochondrial dysfunction and JNK-Bnip3 axis activation as the novel mechanisms underlying cardiomyocytes necrosis achieved by HR injury. Thereby, approaches targeted to the Ripk3-JNK-Bnip3-mitochondria cascade have the potential to ameliorate the progression of HR-related cardiomyocytes necrosis in the clinical practice.


[Rationale for an early treatment of multiple sclerosis].
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of unknown etiology. Its pathological hallmark is the presence within the CNS of inflammatory infiltrates containing few autoreactive T cells and a multitude of pathogenic nonspecific lymphocytes. Based on that, various non-specific immunosuppressive agents have been tested with marginal benefits on the natural evolution of the disease and frequent short- and long-term adverse effects. Moreover, due to their unfavourable profile, these therapies have been usually limited to patients with progressive courses or high clinical activity. The recent approval of IFN beta and Copolymer 1, as therapies able to modify the disease course in relapsing-remitting and secondary progressive, as well as the available immunopathological and clinical data suggesting that the early treatment of MS with safe profile immunomodulatory drugs could be advantageous compared to late treatments, supports the 'putative' relevance of these new drugs in the early treatment of MS patients. However we must wait for the results of ongoing clinical trials to define if such an early treatment has substantial advantages compared to late treatment.


Acetylated Trivalent Mannobioses: Chemical Modification, Structural Elucidation, and Biological Evaluation.
People suffering from allergies can be treated with repeated injections of increasing amounts of a specific allergen. This type of specific immunotherapy is currently the only way to treat the underlying pathological immune response associated with an allergy. The approach can afford long-lasting protection, but the process takes 3-5 years, can produce allergic reactions, and in severe cases treatment is often aborted due to anaphylaxis. However, treatment can be optimized with the use of specific adjuvants that modify the immune response, its duration, and that increase the production of the correct type of antibodies. In the pursuit of such adjuvants, two new trivalent acetylated β-(1→2)-linked mannobioses based on a previously discovered lead molecule were prepared. The new molecules, along with the previously developed lead, were investigated by rigorous NMR and molecular modeling experiments in order to elucidate their behavior and preferred conformations in solution. Furthermore, the molecules were subjected to a biological investigation in which their immunostimulatory properties were evaluated by assessing their effect on the production of TH 2-type cytokine interleukin-4 (IL-4) and Treg pro-inflammatory cytokine tumor necrosis factor (TNF). Treatment of peripheral mononuclear blood cell cultures from patients suffering from birch allergy with birch allergen Bet v induced a strong IL-4 response, whereas the same treatment together with the trivalent acetylated mannobioses caused significant suppression of the induced IL-4.


Research Trends in the Effect of Caffeine Intake on Fat Oxidation: A Bibliometric and Visual Analysis.
In the last few decades, numerous studies pertaining to research groups worldwide have investigated the effects of oral caffeine intake on fat oxidation at rest, during exercise, and after exercise. However, there is no bibliometric analysis to assess the large volume of scientific output associated with this topic. A bibliometric analysis of this topic may be used by researchers to assess the current scientific interest in the application of caffeine as a nutritional strategy to augment fat oxidation, the journals with more interest in this type of publication, and to draw international collaborations between groups working in the same area. For these reasons, the purpose of this study was to assess the research activity regarding oral caffeine intake and fat oxidation rate in the last few decades by conducting a bibliometric and visual analysis. Relevant publications from 1992 to 2022 were retrieved from the Web of Science (WoS) Core Collection database. Quantitative and qualitative variables were collected, including the number of publications and citations, H-indexes, journals of citation reports, co-authorship, co-citation, and the co-occurrence of keywords. There were 182 total publications, while the number of annual publications is saw-shaped with a modest increase of 11.3% from 2000 to 2009 to 2010 to 2019. The United States was the country with the highest number of publications (24.17% of the total number of articles), followed by the Netherlands (17.03%). According to citation analyses, the average number of citations per document is 130, although there are 21 documents that have received more than 100 citations; the most cited document reached 644 citations. These citation data support the overall relevance of this topic in the fields of nutrition and dietetics and sport sciences that when combined harbored 85.71% of all articles published in the WoS. The most productive author was Westerterp-Plantenga with 16 articles (8.79% of the total number of articles). Nutrients was the journal that published the largest number of articles on this topic (6.59% of the total number of articles). Last, there is a tendency to include keywords such as "performance", "carbohydrate", and "ergogenic aid" in the newer articles, while "obesity", "thermogenic", and "tea" are the keywords more commonly included in older documents. Although research into the role of caffeine on fat oxidation has existed since the 1970s, our analysis suggests that the scientific output associated with this topic has progressively increased since 1992, demonstrating that this is a nutritional research area with a strong foundational base of scientific evidence. Based on the findings of this bibliometric analysis, future investigation may consider focusing on the effects of sex and tolerance to caffeine to widen the assessment of the effectiveness of oral caffeine intake as a nutritional strategy to augment the use of fat as a fuel, as these terms rarely appear in the studies included in this analysis. Additionally, more translational research is necessary as the studies that investigate the effect of oral caffeine intake in ecologically valid contexts (i.e., exercise training programs for individuals with excessive adiposity) are only a minor part of the studies on this topic.


Beneficial Effects of Galectin-3 Blockade in Vascular and Aortic Valve Alterations in an Experimental Pressure Overload Model.
Galectin-3 (Gal-3) is involved in cardiovascular fibrosis and aortic valve (AV) calcification. We hypothesized that Gal-3 pharmacological inhibition with modified citrus pectin (MCP) could reduce aortic and AV remodeling in normotensive rats with pressure overload (PO). Six weeks after aortic constriction, vascular Gal-3 expression was up-regulated in male Wistar rats. Gal-3 overexpression was accompanied by an increase in the aortic media layer thickness, enhanced total collagen, and augmented expression of fibrotic mediators. Further, vascular inflammatory markers as well as inflammatory cells content were greater in aorta from PO rats. MCP treatment (100 mg/kg/day) prevented the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of PO rats. Gal-3 levels were higher in AVs from PO rats. This paralleled enhanced AV fibrosis, inflammation, as well as greater expression of calcification markers. MCP treatment prevented the increase in Gal-3 as well as fibrosis, inflammation, and calcification in AVs. Overall, Gal-3 is overexpressed in aorta and AVs from PO rats. Gal-3 pharmacological inhibition blocks aortic and AV remodeling in experimental PO. Gal-3 could be a new therapeutic approach to delay the progression and the development of aortic remodeling and AV calcification in PO.


[Caries prevalence in primary teeth of German and foreign children within the scope of the 1995/96 school entrance examination in Dusseldorf].
900 children of 6 years of age were examined and interviewed by dentists of the Board of Health before they started school. 29.77% of these prospective pupils were children of foreign workers, i.e., the amount of foreign pupils within the examined group was approximately twice as high as it actually is in the population of Düsseldorf (15.21%). The caries prevalence dmf-t (ratio of decayed, missing and filled teeth to the total number of teeth) of these foreign pupils shows an evident need for dental treatment, which is higher than among German pupils. This fact correlates with the low percentage of foreign children with no tooth decay at all. Dental health programmes do not seem to reach this group of the population. Improvement might be possible with the help of foreign organisations or groups in Germany who know the respective foreign cultures and habits of personal hygiene and so could enable their transfer into programmes to promote the oral health of foreigners living here.


Evaluating the Association of Common Variants of the SLC44A4 Gene with Ulcerative Colitis Susceptibility in the Han Chinese Population.
The SLC44A4 gene was recently reported to be associated with ulcerative colitis (UC) susceptibility in the Indian and Japanese populations. The aim of our study was to investigate the association of common variants within the SLC44A4 gene and the susceptibility to UC among the Han Chinese. We examined 16 tag single nucleotide polymorphisms (SNPs) within the SLC44A4 gene in a Han Chinese population that consisted of 311 UC patients and 675 healthy controls; both SNP and haplotypic association analyses were performed. We found that rs2736428 was significantly associated with UC risk (allelic p = 0.0004), and the CT and TT genotypes of rs2736428 had a higher distribution compared with the CC genotypes (genotypic p = 0.001), suggesting that the T allele was a risk allele (odds ratio = 1.45, 95% confidence interval = 1.18-1.78). Moreover, one haplotype block that included rs2736428 was found to be strongly associated with UC risk as well (global p < 0.001). Our results provide further supportive evidence for an important role of the SLC44A4 gene in the pathogenesis of UC.


Changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate.
To determine the temporal relationship between changes in contractile performance and flux through the citric acid cycle in hearts oxidizing acetoacetate, we perfused isolated working rat hearts with either glucose or acetoacetate (both 5 mM) and freeze-clamped the tissue at defined times. After 60 min of perfusion, hearts utilizing acetoacetate exhibited lower systolic and diastolic pressures and lower cardiac outputs. The oxidation of acetoacetate increased the tissue content of 2-oxoglutarate and glutamate and decreased the content of succinyl-CoA suggesting inhibition of citric acid cycle flux through 2-oxoglutarate dehydrogenase. Whereas hearts perfused with either acetoacetate or glucose were similar with respect to their function for the first 20 min, changes in tissue metabolites were already observed within 5 min of perfusion at near-physiological workloads. The addition of lactate or propionate, but not acetate, to hearts oxidizing acetoacetate improved contractile performance, although inhibition of 2-oxoglutarate dehydrogenase was probably not diminished. If lactate or propionate were added, malate and citrate accumulated indicating utilization of anaplerotic pathways for the citric acid cycle. We conclude that a decreased rate of flux through 2-oxoglutarate dehydrogenase in hearts oxidizing acetoacetate precedes, and may be responsible for, contractile failure and is not the result of decreased cardiac work. Further, anaplerosis play an important role in the maintenance of contractile function in hearts utilizing acetoacetate.


Donepezil in Alzheimer's disease: what to expect after 3 years of treatment in a routine clinical setting.
Clinical short-term trails have shown positive effects of donepezil treatment in patients with Alzheimer's disease. The outcome of continuous long-term treatment in the routine clinical settings remains to be investigated. The Swedish Alzheimer Treatment Study (SATS) is a descriptive, prospective, longitudinal, multicentre study. Four hundred and thirty-five outpatients with the clinical diagnosis of Alzheimer's disease, received treatment with donepezil. Patients were assessed with Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), global rating (CIBIC) and Instrumental Activities of Daily Living (IADL) at baseline and every 6 months for a total period of 3 years. The mean MMSE change from baseline was positive for more than 6 months and in subgroups of patients for 12 months. After 3 years of treatment the mean change from baseline in MMSE-score was 3.8 points (95% CI, 3.0-4.7) and the ADAS-cog rise was 8.2 points (95% CI, 6.4-10.1). This is better than expected in untreated historical cohorts, and better than the ADAS-cog rise calculated by the Stern equation (15.6 points; 95% CI, 14.5-16.6). After 3 years with 38% of the patients remaining, 30% of the them were unchanged or improved in the global assessment. Three-year donepezil treatment showed a positive global and cognitive outcome in the routine clinical setting.


Experimental investigation of Brillouin and Raman scattering in a 2SG sulfide glass microstructured chalcogenide fiber.
In this work, we investigate the Brillouin and Raman scattering properties of a Ge15Sb20S65 chalcogenide glass microstructured single mode fiber around 1.55 microm. Through a fair comparison between a 2-m long chalcogenide fiber and a 7.9-km long classical single mode silica fiber, we have found a Brillouin and Raman gain coefficients 100 and 180 larger than fused silica, respectively.


Fundamental study on diagnostic reference level quantities for endoscopic retrograde cholangiopancreatography using a C-arm fluoroscopy system.
The diagnostic reference level (DRL) is an effective tool for optimising protection in medical exposures to patients. However regarding air kerma at the patient entrance reference point (Ka,r), one of the DRL quantities for endoscopic retrograde cholangiopancreatography (ERCP), manufacturers use a variety of the International Electrotechnical Commission and their own specific definitions of the reference point. The research question for this study was whetherKa,ris appropriate as a DRL quantity for ERCP. The purpose of this study was to evaluate the difference betweenKa,rand air kerma incident on the patient's skin surface (Ka,e) at the different height of the patient couch for a C-arm system. Fluoroscopy and radiography were performed using a C-arm system (Ultimax-i, Canon Medical Systems, Japan) and a over-couch tube system (CUREVISTA Open, Fujifilm Healthcare, Japan).Ka,ewas measured by an ion chamber placed on the entrance surface of the phantom. Kerma-area product (PKA) andKa,rwere measured by a built-inPKAmeter and displayed on the fluoroscopy system.Ka,edecreased whileKa,rincreased as the patient couch moved away from the focal spot. The uncertainty of theKa,e/Ka,rratio due to the different height of the patient couch was estimated to be 75%-94%.Ka,rmay not accurately representKa,e.PKAwas a robust DRL quantity that was independent of the patient couch height. We cautioned against optimising patient doses in ERCP with DRLs set in terms ofKa,rwithout considering the patient couch height of the C-arm system. Therefore, we recommend thatKa,ris an inappropriate DRL quantity in ERCP using the C-arm system.


Changes of microvascular architecture, ultrastructure and permeability of rat jejunal villi at different ages.
To investigate the changes of microvascular architecture, ultrastructure and permeability of rat jejunal villi at different ages. Microvascular corrosion casting, scanning electron microscopy, transmission electron microscopy and Evans blue infiltration technique were used in this study. The intestinal villous plexus of adult rats consisted of arterioles, capillary network and venules. The marginal capillary extended to the base part of the villi and connected to the capillary networks of adjacent villi. In newborn rats, the villous plexus was rather simple, and capillary network was not formed. The villous plexus became cone-shaped and was closely arrayed in ablactation rats. In adult rats, the villous plexus became tongue-shaped and was enlarged both in height and width. In aged rats, the villous plexus shrank in volume and became shorter and narrower. The diametral ratio of villous arteriole to villous venule increased as animals became older. The number of endothelial holes, the thickness of basal membrane and the permeability of microvasculature were increased over the entire course of development from newborn period to aged period. The digestive and absorptive functions of the rat jejunum at different ages are highly dependent upon the state of villous microvascular architecture and permeability, and blood circulation is enhanced by collateral branches such as marginal capillary, through which blood is drained to the capillary networks of adjacent villi.


The effects of membrane potential and lanthanides on the conformation of the Ca2+-transport ATPase in sarcoplasmic reticulum.
The effects of Ca2+, lanthanide ions (Gd3+, La3+ and Pr3+) and membrane potential on the fluorescence of tryptophan and covalently bound fluorescein were analysed in native and fluorescein isothiocyanate (FITC)-labelled sarcoplasmic reticulum vesicles. The binding of Ca2+ and lanthanides to the Ca2+-ATPase increases the fluorescence intensity of tryptophan and decreases the fluorescence intensity of FITC; the dependence of these effects on cation concentration is consistent with the involvement of the high-affinity Ca2+-binding sites of the Ca2+-ATPase in the cation-induced fluorescence changes. The fluorescence of FITC-labelled sarcoplasmic reticulum vesicles is also influenced by membrane potential changes induced by ion substitution. Inside positive potential increases, while inside negative potential decreases, the fluorescence of bound FITC. Smaller potential-dependent changes in tryptophan fluorescence were also observed. The effects of Ca2+, lanthanides and membrane potential on the fluorescence of tryptophan and FITC are discussed in terms of the two major conformations of the Ca2+-ATPase (E1 and E2), that are assumed to alternate during Ca2+ transport. The observations support the suggestion [Dux, Taylor, Ting-Beall & Martonosi (1985) J. Biol. Chem. 260, 11730-11743] that the vanadate-induced crystals of Ca2+-ATPase represent the E2, while the Ca2+ and lanthanide-induced crystals the E1, conformation of the enzyme.


Somatic genetic rescue of a germline ribosome assembly defect.
Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.


The assembly mode of the pseudopilus: a hallmark to distinguish a novel secretion system subtype.
In gram-negative bacteria, type II secretion systems assemble a piston-like structure, called pseudopilus, which expels exoproteins out of the cell. The pseudopilus is constituted by a major pseudopilin that when overproduced multimerizes into a long cell surface structure named hyper-pseudopilus. Pseudomonas aeruginosa possesses two type II secretion systems, Xcp and Hxc. Although major pseudopilins are exchangeable among type II secretion systems, we show that XcpT and HxcT are not. We demonstrate that HxcT does not form a hyper-pseudopilus and is different in amino acid sequence and multimerization properties. Using structure-based mutagenesis, we observe that five mutations are sufficient to revert HxcT into a functional XcpT-like protein, which also becomes capable of forming a hyper-pseudopilus. Phylogenetic and experimental analysis showed that the whole Hxc system was acquired by P. aeruginosa PAO1 and other Pseudomonas species through horizontal gene transfer. We thus identified a new type II secretion subfamily, of which the P. aeruginosa Hxc system is the archetype. This finding demonstrates how similar bacterial machineries evolve toward distinct mechanisms that may contribute specific functions.


Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study.
Negative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs. To identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs. No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10-8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors. Our findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.


Self-assembly of miktoarm star-like ABn block copolymers: from wet to dry brushes.
Self-assembly of miktoarm star-like ABn block copolymer in both selective solvent (A- or B-selective) and miscible homopolymer matrix (A or B homopolymer), that is, formation of micelles, was for the first time investigated by theoretical calculations based on self-consistent mean field theory. Interestingly, the calculation revealed that the size of micelles in solvent was smaller than that in homopolymer under the same conditions. In B-selective solvent, with increasing number of B blocks n in miktoarm star-like ABn block copolymer at a fixed volume fraction of A block, the micellar size decreased gradually. In stark contrast, when miktoarm star-like ABn block copolymer dissolved in B homopolymer matrix at molecular weight ratio of B homopolymer to ABn block copolymer fH = 0.30, the overall micellar size decreased nonmonotonically as the number of B blocks n in ABn block copolymer increased. The largest micelle was formed in AB2 (i.e., n = 2). This intriguing finding can be attributed to a wet-to-dry brush transition that occurred from n = 1 to n = 2 in the micellization of miktoarm star-like ABn block copolymer. Moreover, the micellization behaviors of miktoarm star-like ABn block copolymer in A-selective solvent and A homopolymer matrix were also explored, where the overall micellar size in both scenarios was found to decrease monotonically as n in ABn block copolymer increased. These self-assembled nanostructures composed of miktoarm star-like ABn block copolymers may promise a wide range of applications in size-dependent drug delivery and bionanotechnology.


Role of PBP1 in cell division of Staphylococcus aureus.
We constructed a conditional mutant of pbpA in which transcription of the gene was placed under the control of an IPTG (isopropyl-beta-D-thiogalactopyranoside)-inducible promoter in order to explore the role of PBP1 in growth, cell wall structure, and cell division. A methicillin-resistant strain and an isogenic methicillin-susceptible strain, each carrying the pbpA mutation, were unable to grow in the absence of the inducer. Conditional mutants of pbpA transferred into IPTG-free medium underwent a four- to fivefold increase in cell mass, which was not accompanied by a proportional increase in viable titer. Examination of thin sections of such cells by transmission electron microscopy or fluorescence microscopy of intact cells with Nile red-stained membranes showed a morphologically heterogeneous population of bacteria with abnormally increased sizes, distorted axial ratios, and a deficit in the number of cells with completed septa. Immunofluorescence with an antibody specific for PBP1 localized the protein to sites of cell division. No alteration in the composition of peptidoglycan was detectable in pbpA conditional mutants grown in the presence of a suboptimal concentration of IPTG, which severely restricted the rate of growth, and the essential function of PBP1 could not be replaced by PBP2A present in methicillin-resistant cells. These observations suggest that PBP1 is not a major contributor to the cross-linking of peptidoglycan and that its essential function must be intimately integrated into the mechanism of cell division.


Designing image segmentation studies: Statistical power, sample size and reference standard quality.
Segmentation algorithms are typically evaluated by comparison to an accepted reference standard. The cost of generating accurate reference standards for medical image segmentation can be substantial. Since the study cost and the likelihood of detecting a clinically meaningful difference in accuracy both depend on the size and on the quality of the study reference standard, balancing these trade-offs supports the efficient use of research resources. In this work, we derive a statistical power calculation that enables researchers to estimate the appropriate sample size to detect clinically meaningful differences in segmentation accuracy (i.e. the proportion of voxels matching the reference standard) between two algorithms. Furthermore, we derive a formula to relate reference standard errors to their effect on the sample sizes of studies using lower-quality (but potentially more affordable and practically available) reference standards. The accuracy of the derived sample size formula was estimated through Monte Carlo simulation, demonstrating, with 95% confidence, a predicted statistical power within 4% of simulated values across a range of model parameters. This corresponds to sample size errors of less than 4 subjects and errors in the detectable accuracy difference less than 0.6%. The applicability of the formula to real-world data was assessed using bootstrap resampling simulations for pairs of algorithms from the PROMISE12 prostate MR segmentation challenge data set. The model predicted the simulated power for the majority of algorithm pairs within 4% for simulated experiments using a high-quality reference standard and within 6% for simulated experiments using a low-quality reference standard. A case study, also based on the PROMISE12 data, illustrates using the formulae to evaluate whether to use a lower-quality reference standard in a prostate segmentation study.


<FONT COLOR=#0E3193>Triplet deciphers genomes
particularly up to date features, Gerald Karp's book includes a section in the Cancer chapter on angiogenesis, as does Lodish et al., but in Karp the information imparted extends to a scheme showing the effect of endostatin on mouse tumours, replete with photographs of mice from such an experiment. All of this has resulted in a book that is focused but highly informative and a delight to browse through. If it appears by now that your reviewer is suggesting you should dash out and buy all three of these books, I can only admit that I am delighted to have them on my shelf. If you have to choose, for fundamental biochemical science with a fair degree of breadth thrown in it has to be Lehninger. For a comprehensive molecular biology course Lodish et al. is the equal of anything else on the market. For a broad grounding in cell and molecular biology that will appeal especially to medical students go for Karp.


Patients' views and experiences on the supported self-management/patient-initiated follow up pathway for breast cancer.
To explore patients' expectations and experience of Supportive Self-Management (SSM)/ Patient Initiated Follow Up (PIFU) following breast cancer treatments over a 12-month period. In total, 32/110 (29%) patient participants in the PRAGMATIC (Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer) study were interviewed at baseline, 3, 6, 9 and 12 months. Interviews in this sub-study used a mix-methods approach to explore understanding of the pathway, confidence in self-management, triggers to seek help and/or re-engage with the clinical breast team and impact of the COVID-19 pandemic. Responses to pre-assigned categories were summarised as counts/ percentages and collated in tabular or graphic format. Free responses were recorded verbatim and reviewed using framework analysis. Participants regarded the SSM/PIFU pathway as a way to save time and money for them and the National Health Service (NHS) (14/32; 44%) and as a means of assuming responsibility for their own follow-up (18/32; 56%). Most maintained (very/somewhat) confidence in managing their BC follow-up care (baseline 31/32, 97%; 12 months 29/31, 93%). During the year, 19% (5/26) stopped endocrine therapy altogether because of side effects. Qualitative analysis revealed general satisfaction with SSM/PIFU and described the breast care nurses as reassuring and empathic. However, there was a lingering anxiety about identifying signs and symptoms correctly, particularly for those with screen-detected cancers. There was also uncertainty about who to contact for psychological support. The COVID-19 pandemic discouraged some participants from contacting the helpline as they did not want to overburden the NHS. The results show that during the first year on the SSM/PIFU pathway, most patients felt confident managing their own care. Clinical teams should benefit from understanding patients' expectations and experiences and potentially modify the service for men with BC and/or those with screen-detected breast cancers.


Challenges and needs in experimental therapies for multiple sclerosis.
Despite dramatic advances in the treatment of people with multiple sclerosis over the last decade, several unmet medical needs still remain and should be approached with new compounds in experimental clinical trials. The prerequisites for successful clinical trials in multiple sclerosis have changed considerably over time and activities have started to improve clinical development of new drugs in several aspects including trial designs, patient selection and outcome parameters. This review will address some of the challenges in early experimental trials in multiple sclerosis and recent approaches in the field. Highly intensive treatment regimens like autologous hematopoietic stem cell transplantation provide evidence for sustained long-term treatment effects in multiple sclerosis patients. Several different approaches towards neuroprotection and remyelination have entered the clinical phase and demonstrated that stabilization, even improvement of disability is achievable in short-term studies. New therapeutic strategies have entered the clinic with the prospects of long-term efficacy and enduring effects on disability progression.


Survey of general practice--1971.
In this survey an attempt has been made to document a profile of certain aspects of the work carried out by a general practitioner in Australia. This includes the type of practice, and especially the range and frequency of the procedures he carries out. It is realised that, as this survey was conducted in 1971, some of the facts may have become dated. However, a proportion of the information given is unobtainable elsewhere, and it is believed that through publishing the survey, interested readers may be prompted to seek additional information from the author.


Multi-population stochastic modeling of Ebola in Sierra Leone: Investigation of spatial heterogeneity.
A major outbreak of the Ebola virus occurred in 2014 in Sierra Leone. We investigate the spatial heterogeneity of the outbreak among districts in Sierra Leone. The stochastic discrete-time susceptible-exposed-infectious-removed (SEIR) model is used, allowing for probabilistic movements from one compartment to another. Our model accounts for heterogeneity among districts by making use of a hierarchical approach. The transmission rates are considered time-varying. It is investigated whether or not incubation period, infectious period and transmission rates are different among districts. Estimation is done using the Bayesian formalism. The posterior estimates of the effective reproductive number were substantially different across the districts, with pronounced variability in districts with few cases of Ebola. The posterior estimates of the reproductive number at the district level varied between below 1.0 and 4.5, whereas at nationwide level it varied between below 1.0 and 2.5. The posterior estimate of the effective reproductive number reached a value below 1.0 around December. In some districts, the effective reproductive number pointed out for the persistence of the outbreak or for a likely resurgence of new cases of Ebola virus disease (EVD). The posterior estimates have shown to be highly sensitive to prior elicitation, mainly the incubation period and infectious period.


The image of you: constructing nursing identities in YouTube.
This article is a report on a descriptive study of nursing identity as constructed in the Web 2.0 site YouTube. Public images of the nurse carry stereotypes that rely on the taken for granted gender category of the nurse as woman. Nursing images represent a form of public discourse that has the capacity to construct nursing identity. Critical discourse analysis was used to describe, analyse and explain how nurse and nursing identity were constructed in a purposive sample of ten video clips accessed on 17 and 18 July 2010. The ten most-viewed videos depicting the nurse and nursing on YouTube offered narratives that constructed three distinct nursing identity types, namely nurse as 'a skilled knower and doer', nurse as 'a sexual plaything' and nurse as 'a witless incompetent' individual. Nursing identities recoverable from the texts of YouTube images propagate both favourable and derogatory nursing stereotypes. To mitigate the effects of unfavourable nursing stereotypes in such areas as interprofessional working and clinical decision-making, nursing professional bodies need to act to protect the profession from unduly immoderate representations of the nurse and to support nurses in their efforts to maximize opportunities afforded by YouTube to promote a counter discourse.


Neosporosis in cattle.
During the past decade, Neospora caninum infection has emerged as an important reproductive disease in cattle throughout the world. Abortion, occurring during the middle of gestation, is the primary clinical sign of the infection in cattle. Surveys in several countries from three continents have identified N. caninum infection as the major diagnosed cause of bovine abortion. Both endemic and epidemic patterns of abortion may occur in herds. An important feature of this disease is that the protozoan parasite is maintained in cattle as a chronic infection which can be passed on to the fetus during pregnancy. Two methods for the transmission of the infection in cattle have been proposed and are the subject of current investigations. Horizontal transmission utilizes a two-host life cycle whereby the cow is infected from ingestion of coccidial oocyst stages shed by the definitive host. Experimental infections have confirmed that the dog is a definitive host for the parasite. There is epidemiological evidence that the dog has a role in the prevalence of the infection but, as yet, no confirmation that the dog is the source for natural infections in cattle. Vertical transplacental transmission of the infection is an important route of infection in many herds. Vertical transmission occurs because fetal infection frequently does not result in abortion but rather the fetus survives to be a persistently infected animal. A heifer calf that is born congenitally infected is capable of transmitting the infection to the next generation when she becomes pregnant, thus maintaining the infection in the herd. The clinical outcome of transplacental fetal infection with N. caninum is likely determined by maternal and fetal immune responses which involve humoral, and most importantly, cell-mediated immune factors. The diagnosis of the infection is assisted through histopathology and immunohistochemical examination of aborted fetuses and serologic testing of cattle for evidence of infection. Several types of serologic tests, based on the use of culture-derived organisms or recombinant N. caninum antigens are available. There are no proven control methods for the prevention or treatment of neosporosis. Suggested control measures focus on programs to reduce the number of congenitally infected animals retained in the herd and to minimize the opportunity for postnatal transmission from the environment.


Emerging treatments and combinations in the management of NSCLC: clinical potential of nintedanib.
There remains an unmet need for effective, well-tolerated treatment options in advanced non-small cell lung cancer (NSCLC) to alleviate the disease burden for a broad selection of patients. Nintedanib is a potent, oral, triple angiokinase inhibitor of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, and was recently approved in Europe for use in combination with docetaxel for the treatment of adults with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma tumor histology, following first-line chemotherapy. Nintedanib has been investigated extensively in preclinical research and in a number of clinical studies, the most important of which was the Phase III LUME-Lung 1 study, which investigated nintedanib in combination with docetaxel in patients with advanced NSCLC after failure of first-line chemotherapy. In this study, which led to the approval of nintedanib, addition of nintedanib to docetaxel significantly improved overall survival in patients with adenocarcinoma histology. Nintedanib demonstrated a manageable safety profile in combination with docetaxel. This review focuses on the clinical experience with nintedanib in NSCLC and discusses the clinical potential of this agent for use in combination with chemotherapy.


Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation.
The proliferation of genetically modified mouse models has exposed phenotypic variation between investigators and institutions that has been challenging to control. In many cases, the microbiota is the presumed cause of the variation. Current solutions to account for phenotypic variability include littermate and maternal controls or defined microbial consortia in gnotobiotic mice. In conventionally raised mice, the microbiome is transmitted from the dam. Here we show that microbially driven dichotomous faecal immunoglobulin-A (IgA) levels in wild-type mice within the same facility mimic the effects of chromosomal mutations. We observe in multiple facilities that vertically transmissible bacteria in IgA-low mice dominantly lower faecal IgA levels in IgA-high mice after co-housing or faecal transplantation. In response to injury, IgA-low mice show increased damage that is transferable by faecal transplantation and driven by faecal IgA differences. We find that bacteria from IgA-low mice degrade the secretory component of secretory IgA as well as IgA itself. These data indicate that phenotypic comparisons between mice must take into account the non-chromosomal hereditary variation between different breeders. We propose faecal IgA as one marker of microbial variability and conclude that co-housing and/or faecal transplantation enables analysis of progeny from different dams.


[The practice guideline 'Thyroid disorders' (first revision) from the Dutch College of General Practitioners; a response from the perspective of internal medicine].
The revised practice guideline from the Dutch College of General Practitioners offers straightforward instruction on the diagnosis and treatment of thyroid dysfunction. Most cases of hypothyroidism can indeed be managed by general practitioners, and indications for referral to specialists are made clear. For substitution therapy with levothyroxine in otherwise healthy subjects the guidelines advocate the 'start low, go slow'-principle under the adage 'better safe than sorry'. The guidelines recommend referral of thyrotoxic patients to an internist for treatment, unless the general practitioner has sufficient expertise in this area. Self-limiting thyrotoxicosis (e.g. subacute and postpartum thyroiditis), however, can generally be managed in a primary care setting. The guidelines recommend no intervention for subclinical thyroid dysfunction. Most internists believe that treatment is warranted for subclinical hyperthyroidism in patients with a multinodular goitre, especially in postmenopausal women. Assessment of thyroid peroxidase antibodies is not mentioned in the guidelines, but this may help inform treatment decisions, especially in patients with subclinical hypothyroidism and pregnant women. The recommendation to request thyroid ultrasound for patients with a solitary thyroid nodule or a dominant nodule in a multinodular goitre before referral seems superfluous, since specialists are also likely to request an ultrasound in these patients for the purpose of guiding fine-needle aspiration therapy.


Suppression of 7,12-dimethylbenz(alpha) anthracene-induced breast carcinoma by coumarin in the rat.
The effect of oral administration of coumarin on the induction of breast tumors brought about by DMBA has been studied in female Wistar rats. Coumarin given before DMBA caused a significant dose-related suppression of the incidence of adenocarcinomas, although no histologic difference was found in the tumor between untreated and coumarin-treated rats. The growth rate, size and multiplicity were also reduced and tumor occurrence was delayed. Parallel with the suppression, hepatic drug metabolizing activity was decreased and serum prolactin level increased. Coumarin given after DMBA elicited no effect on the carcinogenic potency of DMBA. In contrast to the action on mammary tumorigenesis, coumarin provided no protection against hemopoietic and adrenocortical necrosis brought about by DMBA.


The donation and sale of blood by intravenous drug users.
In spite of efforts to dissuade intravenous drug users (IVDUs) from donating or selling blood, some continue to do so. As part of a longitudinal study, 915 IVDUs in South Florida were interviewed concerning their history of donation or sale of blood and tested for antibodies to HIV-1 and HTLV-I/II. Approximately 17 percent had either donated or sold blood during 1985 through 1988; most contributors (80.4 percent) sold to commercial blood services. IVDUs who had donated/sold blood were more likely to be male and not in drug treatment than were those who had not contributed blood. IVDUs not in treatment at the time of interview were more likely than IVDUs in treatment to have sold blood. Of those who had donated/sold blood since 1985, 19.6 percent subsequently tested positive for antibodies to HIV-1 and 5.7 percent were positive for antibodies to HTLV-I/II. Increased effort is required to screen prospective donors and sellers, particularly at commercial blood banks.


First report of cerebellar abiotrophy in an Arabian foal from Argentina.
Evidence of cerebellar abiotrophy (CA) was found in a six-month-old Arabian filly with signs of incoordination, head tremor, wobbling, loss of balance and falling over, consistent with a cerebellar lesion. Normal hematology profile blood test and cerebrospinal fluid analysis excluded infectious encephalitis, and serological testing for Sarcocystis neurona was negative. The filly was euthanized. Postmortem X-ray radiography of the cervical cephalic region identified not abnormalities, discounting spinal trauma. The histopathological analysis of serial transverse cerebellar sections by electron microscopy revealed morphological characteristics of apoptotic cells with pyknotic nuclei and degenerate mitochondria, cytoplasmic condensation and areas with absence of Purkinje cells, matching with CA histopathological characteristics. The indirect DNA test for CA was positive in the filly, and DNA test confirmed the CA carrier state in the parents and the recessive inheritance of the disease. To our knowledge this is the first report of a CA case in Argentina.


Rapid analysis of cell-generated forces within a multicellular aggregate using microsphere-based traction force microscopy.
We present a new approach to measuring cell-generated forces from the deformations of elastic microspheres embedded within multicellular aggregates. By directly fitting the measured sensor deformation to an analytical model based on experimental observations and invoking linear elasticity, we dramatically reduce the computational complexity of the problem, and directly obtain the full 3D mapping of surface stresses. Our approach imparts extraordinary computational efficiency, allowing tractions to be estimated within minutes and enabling rapid analysis of microsphere-based traction force microscopy data.


Iridium-catalyzed anti-diastereo- and enantioselective carbonyl (trimethylsilyl)allylation from the alcohol or aldehyde oxidation level.
Using the ortho-cyclometalated pi-allyl iridium precatalyst (R)-I derived from [Ir(cod)Cl](2), 4-cyano-3-nitrobenzoic acid, (R)-SEGPHOS, and allyl acetate, enantioselective transfer hydrogenation of alpha-(trimethylsilyl)allyl acetate in the presence of aldehydes 2a-i mediated by 2-propanol delivers products of (trimethylsilyl)allylation 4a-i in good isolated yields and with exceptional levels of anti-diastereoselectivity and enantioselectivity (90-99% ee). In the absence of 2-propanol, but under otherwise identical reaction conditions, carbonyl (trimethylsilyl)allylation is achieved directly from the alcohol oxidation level to furnish an equivalent set of adducts 4a-i with roughly equivalent isolated yields and stereoselectivities. To evaluate the synthetic utility of the reaction products 4a-i, adduct 4g was converted to the 1,4-ene-diol 5g via dioxirane-mediated oxidative desilylation with allylic transposition, the allylic alcohol 6g via protodesilylation with allylic transposition, and the gamma-lactam 7g via chlorosulfonyl isocyanate-mediated cycloaddition.


Comparison of effects of nitrendipine, lacidipine and mibefradil on postischaemic myocardial damage in isolated rat hearts.
During ischaemia and reperfusion increased cytosolic Ca2+ is one of the important causes for ischaemic-reperfusion myocardial injury. In the present study we compared effects of preferentially L-type Ca2+ antagonists nitrendipine (NT) and lacidipine (LP), and of mibefradil (MB) a Ca2+ antagonist with higher affinity to T- than to L-type channels on myocardial function during reperfusion. Coronary flow (CF), heart rate (HR), left ventricular pressure (LVP), lactate dehydrogenase (LDH) release rate and ECG were registered during 40 min of reperfusion following 30 min of global zero flow ischaemia in Langendorff's isolated rat hearts. Either NT (100 nmol/L) or LP (10 nmol/L) or MB (100 nmol/L) was added to Krebs-Henseleit solution 10 min before ischaemia till the end of experiments. All three drugs influenced CF, HR and LVP. All of them decreased LDH release rate (P < 0.05, in microkat/g x min) when compared with control hearts (53.2 +/- 5.1): MB (19.4 +/- 4.3) > LP (30.7 +/- 6.6) > NT (43.3 +/- 2.8). NT reduced the duration of continuous arrhythmias at the beginning of reperfusion (to 59.1 +/- 6.1% of ischaemic controls) as well as the number of single arrhythmic events arising during the whole period of reperfusion (to 26.1 +/- 6.0% of ischaemic controls). MB diminished only single arrhythmic events during reperfusion to 39.1 +/- 17.3% of ischaemic controls. LP did not affect the onset of arrhythmias. Results of our experiments indicate a relatively greater importance of T-type than of L-type Ca2+ channels in the arising of postischaemic myocardial damage.


Cost-effectiveness analysis of ceritinib vs. crizotinib in previously untreated anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in Hong Kong.
Lower-dose ceritinib (450 mg) once-daily with food was approved in 2018 in Hong Kong (HK) for first-line treatment of patients with anaplastic lymphoma kinase-positive (ALK +) advanced non-small cell lung cancer (NSCLC). This study examined the cost-effectiveness of ceritinib vs. crizotinib in the first-line treatment of ALK + NSCLC from a HK healthcare service provider's or government's perspective. Costs and effectiveness of first-line ceritinib vs. crizotinib over a 20-year time horizon was evaluated using a partitioned survival model with three health states (stable disease, progressed disease, and death). The efficacy data for ceritinib were obtained from a phase 3 trial comparing ceritinib with chemotherapy for advanced non-small cell lung cancer (ASCEND-4) and extrapolated using parametric survival models. Long-term survival associated with crizotinib were estimated using hazard ratio of crizotinib vs. ceritinib obtained from matching-adjusted indirect comparison based on ASCEND-4 and PROFILE 1014 trials. Drug acquisition, administration, adverse events costs, and medical costs associated with each health state were obtained from public sources and converted to 2018 US Dollars. Incremental costs per quality-adjusted-life-year (QALY) and life-year (LY) gained were estimated for ceritinib vs. crizotinib. The base case results showed that ceritinib was associated with 3.22 QALYs, 4.51 LYs, and total costs of $157,581 over 20 years. Patients receiving crizotinib had 2.68 QALYs, 3.85 LYs, and $150,424 total costs over the same time horizon. The incremental cost per QALY gained for ceritinib vs crizotinib was $13,343. Results were robust to deterministic sensitivity analyses in most scenarios. Ceritinib offers a cost-effective option compared to crizotinib for previously untreated ALK + advanced NCSLC in HK.


[Enzymatic methods for quantitative determination of total cholesterol in blood serum].
Advantages and disadvantages of enzymatic assays of total cholesterol content in human blood serum are reviewed. Factors, affecting these assays are discussed: specificity of the enzymes used (cholesterol esterase and cholesterol oxidase), conditions of analysis and composition of the reaction mixture, interference with components of blood serum. Adaptation of the enzymatic assays of total cholesterol estimation for various types of biochemical analyzers, including systems containing immobilized enzymes, is considered.


Detection of intestinal metaplasia after successful eradication of Barrett's Esophagus with radiofrequency ablation.
Radiofrequency ablation (RFA) is an effective means of eradicating Barrett's esophagus (BE), both with and without associated dysplasia. Several studies have documented high initial success rates with RFA. However, there is limited data on IM detection rates after eradication. To determine the rate of detection of intestinal metaplasia (IM) after successful eradication of Barrett's esophagus. BE patients with and without dysplasia who had undergone RFA were retrospectively identified. Only those who had complete eradication as documented on the initial post-ablation endoscopy, and had minimum two surveillance endoscopies, were included in the analyses. Clinical, demographic, and endoscopic data were collected. Cumulative incidence of IM detection was calculated by the Kaplan-Meier method. Forty-seven patients underwent RFA and had complete eradication of Barrett's epithelium. The majority of patients were male (76.6%), and the mean age was 64.2 years. The cumulative incidence of newly detected IM at 1 year was 25.9% (95% CI 15.1-42.1%). Dysplasia was detected at the time of recurrence in four patients, and all cases were detected at the GE junction in the absence of visible BE. Patients with recurrent IM had longer baseline segments of BE (median, 4 cm vs. 2 cm, p = 0.03). The rate of detection of new IM is high in patients who have undergone successful eradication of BE by RFA. Additionally, dysplasia can recur at the GE junction in the absence of visible BE. Future studies are warranted to identify those patients at increased risk for the development of recurrent intestinal metaplasia.


Evaluating the accuracy and economic value of a new test in the absence of a perfect reference test.
Streptococcus pneumoniae (SP) pneumonia is often treated empirically as diagnosis is challenging because of the lack of a perfect test. Using BinaxNOW-SP, a urinary antigen test, as an add-on to standard cultures may not only increase diagnostic yield but also increase costs. To estimate the sensitivity and specificity of BinaxNOW-SP and subsequently estimate the cost-effectiveness of adding BinaxNOW-SP to the diagnostic work-up. We fit a Bayesian latent-class meta-analysis model to obtain estimates of BinaxNOW-SP accuracy that adjust for the imperfect accuracy of culture. Meta-analysis results were combined with information on prevalence of SP pneumonia to estimate the number of patients who are correctly classified under competing diagnostic strategies. Taking into consideration the cost of antibiotics, we determined the incremental cost of adding BinaxNOW-SP to the work-up per case correctly diagnosed. The BinaxNOW-SP test had a pooled sensitivity of 0.74 (95% credible interval [CrI], 0.67-0.83) and a pooled specificity of 0.96 (95% CrI, 0.92-0.99). An overall increase in diagnostic accuracy of 6.2% due to the addition of BinaxNOW-SP corresponded to an incremental cost per case correctly classified of $582 Canadian dollars. The methods we have described allow us to evaluate the accuracy and economic value of a new test in the absence of a perfect reference test using an evidence-based approach.


Kinetics of adenosine 3':5'-monophosphate-dependent protein kinase activation and inhibition of thymidine incorporation into DNA in P1798 lymphosarcoma cells.
The kinetics for activation of the cyclic adenosine 3':5'-monophosphate (cyclic AMP)-dependent protein kinase (PKA) and thymidine incorporation into DNA was investigated in epinephrine- and prostaglandin E1 (PGE1)-treated murine P1798 lymphosarcoma cells. A positive correlation between the duration and extent of PKA activation and accumulation of cyclic AMP and inhibition of thymidine incorporation into DNA was observed with both hormones. Epinephrine and PGE1 elevated intracellular cyclic AMP 34- and 14-fold, respectively. All hormone concentrations which increased cyclic AMP accumulation also promoted inhibition of thymidine incorporation into DNA. In addition, dibutyryl cyclic AMP (50 microM) inhibited thymidine incorporation. No difference in the kinetics for activation of PKA was observed when cells were treated with microM epinephrine or PGE1. With both agents, 50% PKA activation was observed when intracellular cyclic AMP concentrations were elevated 6.5-fold, or to 9 pmol/10(6) cells. In the presence of microM epinephrine, the cyclic AMP concentration was approximately 3-fold greater than that required for maximal PKA activation. In this case, the duration of the activation time for PKA was also 3- to 4-fold longer than that observed with 0.1 microM epinephrine. The data are consistent with a mechanism wherein both epinephrine and PGE1 suppress DNA synthesis by a cyclic AMP-mediated cascade of protein phosphorylation. No evidence for independent cyclic AMP or PKA pools which respond independently to either epinephrine or PGE1 could be detected.