Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia.
Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM.


[Sonographic features of lymphoma in the abdominal lymph nodes].
To summarize the sonographic features of the lymphoma in the abdominal lymph nodes. The clinical data and sonographic findings of 41 lymphoma patients with original appearance of abdominal mass or lymphadenectasis were retrospectively analyzed. Among these 41 cases, the retroperitoneal and mesenteric lymph nodes were most commonly involved.These patients were divided into two types according to sonographic appearances:solitary mass(n=14) and multiple nodules(n=27) .Solitary hypoechoic mass in abdomen was found in the former type, mostly with irregular or lobular shape, and the inner echo was often heterogenous.The typical appearances of the latter type were multiple enlarged lymph nodes, mostly round or oval, with homogeneous inner echo and clear margins.Some other sonographic characteristics were also helpful for the diagnosis of lymphoma, such as cobblestone sign, intranodular reticulation, vessels-embedded sign, and hilar vascularity. Ultrasonography can provide useful information in the diagnosis of the lymphoma in the abdominal lymph nodes.


Cell cycle-dependent phosphorylation of p27 cyclin-dependent kinase (Cdk) inhibitor by cyclin E/Cdk2.
The cyclin-dependent kinase (Cdk) inhibitor p27 interrupts progression of the cell cycle by inhibiting various cyclin/Cdk activities. Since the protein level of p27 does not correlate with its mRNA level or protein synthesis rate in most cases, it is suggested that degradation of the protein may be regulated via an unidentified mechanism(s) involving a post-translational modification(s). We present evidence here that p27 phosphorylation is cell cycle-dependent and peaks in the late G1 phase and that the level of p27 protein is inversely correlated with its phosphorylation. Although both cyclin D1- and cyclin-E-dependent kinases are active in the late G1 phase in human fibroblasts, cyclin E/Cdk2 specifically phosphorylates p27 on threonine-187 in vitro. Interestingly, ectopic expression of T187A revealed that it was far more stable in vivo than wild type p27. Thus, phosphorylation of p27 by cyclin E/ Cdk2 may affect the stability of its protein and play a role in how the protein functions.


Hypocomplementaemia due to a genetic deficiency of beta 1H globulin.
An 8-month-old Asian boy who presented with the haemolytic uraemic syndrome was found to have a low haemolytic complement, and in particular a very low C3 level, with a normal C4 level. These abnormalities persisted after recovery and were not associated with the presence of circulating C3 nephritic factor. A clinically healthy 3-year-old brother was found to have an identical complement profile, which indicated increased alternative pathway activation. Both brothers had normal levels of the C3b inactivator, but very low levels of beta 1H globulin (less than 10% of a reference standard serum). The parents, who were first cousins, had half-normal levels of beta 1H globulin, and low levels were found in other members of the family, indicating that the defect was inherited.


Modelling the Influence of Task Constraints on Goal Kicking Performance in Australian Rules Football.
The primary aim of this study was to determine the influence of task constraints, from an ecological perspective, on goal kicking performance in Australian football. The secondary aim was to compare the applicability of three analysis techniques; logistic regression, a rule induction approach and conditional inference trees to achieve the primary aim. In this study, an ecological perspective has been applied to explore the impact of task constraints on shots on goal in the Australian Football League, such as shot type, field location and pressure. Analytical techniques can increase the understanding of competition environments and the influence of constraints on skilled events. Differing analytical techniques can produce varying outputs styles which can impact the applicability of the technique. Logistic regression, Classification Based on Associations rules and conditional inference trees were conducted to determine constraint interaction and their influence on goal kicking, with both the accuracy and applicability of each approach assessed. Each analysis technique had similar accuracy, ranging between 63.5% and 65.4%. For general play shots, the type of pressure and location particularly affected the likelihood of a shot being successful. Location was also a major influence on goal kicking performance from set shots. When different analytical methods display similar performance on a given problem, those should be prioritised which show the highest interpretability and an ability to guide decision-making in a manner similar to what is currently observed in the organisation.


Hyperhomocysteinemia and neurologic disorders: a review.
Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. It has a physiologic role in DNA metabolism via methylation, a process governed by the presentation of folate, and vitamins B6 and B12. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy (eHcy) can be caused by deficiency of either vitamin B12 or folate, or a combination thereof. Certain genetic factors also cause eHcy, such as C667T substitution of the gene encoding methylenetetrahydrofolate reductase. eHcy has been observed in several medical conditions, such as cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and eclampsia. There is evidence from laboratory and clinical studies that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. This article provides a review of the current literature on the possible roles of eHcy relevant to various neurologic disorders.


[Differential diagnostic value of clinical symptoms of aortic dissection].
Acute aortic dissection is a relatively common catastrophic illness, in which the circulation of any major artery arising from the aorta may be compromised and any organ or organ system may become ischemic. Hereby a protean clinical picture may be developed. This disease is characterized by migration of symptoms which may be difficult to evaluate. It is expedient to range the various symptoms produced by aortic dissection among cardiac, pulmonary, cerebral and neurologic, abdominal and renal groups. This may be especially helpful diagnostically if more than one system has been involved. An accurate differential diagnosis can be made if the history and presented signs are carefully evaluated.


Second harmonic generation in Janus MoSSe a monolayer and stacked bulk with vertical asymmetry.
A recently synchronized Janus TMD material with broken out-of-plane symmetry offers a vertical dipole to enhance nonlinear optical behavior. Here, by comparing the second harmonic generation properties of MoS2 and MoSSe monolayers, we investigated the nonzero out-of-plane SHG susceptibilities of a Janus MoSSe 2D material. A three-fold enhancement of out-of-plane SHG susceptibilities exists in three stacked bulks of Janus MoSSe compared to that in the monolayer. A sensitivity to their stack pattern is also found. The broken out-of-plane symmetry, vertical dipole, and intrinsic tunable electronic properties of Janus two-dimensional materials make MoSSe a promising nanomaterial for nonlinear optical devices.


Adaptation of the hydrocarbonoclastic bacterium Alcanivorax borkumensis SK2 to alkanes and toxic organic compounds: a physiological and transcriptomic approach.
The marine hydrocarbonoclastic bacterium Alcanivorax borkumensis is able to degrade mixtures of n-alkanes as they occur in marine oil spills. However, investigations of growth behavior and physiology of these bacteria when cultivated with n-alkanes of different chain lengths (C6 to C30) as the substrates are still lacking. Growth rates increased with increasing alkane chain length up to a maximum between C12 and C19, with no evident difference between even- and odd-numbered chain lengths, before decreasing with chain lengths greater than C19. Surface hydrophobicity of alkane-grown cells, assessed by determination of the water contact angles, showed a similar pattern, with maximum values associated with growth rates on alkanes with chain lengths between C11 and C19 and significantly lower values for cells grown on pyruvate. A. borkumensis was found to incorporate and modify the fatty acid intermediates generated by the corresponding n-alkane degradation pathway. Cells grown on distinct n-alkanes proved that A. borkumensis is able to not only incorporate but also modify fatty acid intermediates derived from the alkane degradation pathway. Comparing cells grown on pyruvate with those cultivated on hexadecane in terms of their tolerance toward two groups of toxic organic compounds, chlorophenols and alkanols, representing intensely studied organic compounds, revealed similar tolerances toward chlorophenols, whereas the toxicities of different n-alkanols were significantly reduced when hexadecane was used as a carbon source. As one adaptive mechanism of A. borkumensis to these toxic organic solvents, the activity of cis-trans isomerization of unsaturated fatty acids was proven. These findings could be verified by a detailed transcriptomic comparison between cultures grown on hexadecane and pyruvate and including solvent stress caused by the addition of 1-octanol as the most toxic intermediate of n-alkane degradation.


The DD genotype of the angiotensin-converting enzyme gene occurs in very low frequency in Australian Aboriginals.
The DD genotype of the angiotensin-converting enzyme (ACE) gene appears to be an independent risk factor for myocardial infarction, left ventricular hypertrophy and an increased incidence and rate of progression of renal disease. The high incidence of renal disease and end-stage renal failure in the Australian Aboriginal population has prompted investigation of ACE genotypes in these people. ACE genotypes were determined in four groups: (i) normal Australian Caucasian blood donors (n = 100), (ii) Caucasian renal transplant recipients (n = 173), (iii) normal Australian Aboriginals from a single tribe (n = 184), and (iv) Australian Aboriginals included in the renal-transplant programme (n = 94). The D allele frequency in the normal Australian Caucasian (54.5%) and renal transplant groups (57.2%) was similar. However, the D allele frequency in the normal Australian Aboriginal (3%) and Aboriginal renal patient group (14.4%) was significantly lower than both Caucasian groups. The D allele of the ACE gene has little or no influence on the renal disease of Australian Aboriginals.


Vercirnon for the treatment of Crohn's disease.
CCR9 antagonism is a promising new therapeutic approach for the treatment of Crohn's disease. CCR9 is expressed on the cell surface of memory/effector CD4(+) T cells and selectively binds to the small intestinal lymphocyte chemoattractant CCL25 (TECK). Blockade of the CCR9/CCL25 interaction inhibits lymphocyte homing to the intestinal mucosa, thereby limiting inflammation and disease at this site. This review details the current research on CCR9 antagonism and summarizes available clinical trial data for vercirnon , a selective CCR9 antagonist currently under development. If the results of ongoing large-scale clinical trials of vercirnon are in line with preliminary reports, CCR9 antagonism may have comparable efficacy to anti-TNF therapies and a potentially superior safety profile, making it the latest addition to the growing arsenal of immunomodulatory drug therapies available to combat Crohn's disease. Moreover, since vercirnon is an oral drug, its associated costs will likely be much lower than expensive infusion-based anti-TNF therapies, providing further economic benefits.


Validity of diagnostic and treatment decisions of fissure caries.
The purpose of this in vitro study was to test the accuracy and the reproducibility of diagnostic and treatment decisions of fissure caries with and without explorer. 34 dentists were asked to diagnose 61 teeth and decide upon possible treatment. The teeth were then histologically prepared and diagnosed. The agreement between histological and clinical diagnoses was assessed. The results showed no difference in diagnostic accuracy between explorer and visual technique only. Sensitivity (62%) and specificity (84%) showed that the dentists were more likely not to treat decayed teeth than to restore sound teeth. The percentage 'correctly diagnosed teeth' was approximately 42%. As there was an inherent possibility of a correct diagnosis by chance, this value had to be corrected to 23% (kappa statistics). The percentage of 'clinically' correct treatment decisions, however, was 73%. The reproducibility test gave kappa values of 0.47 for diagnostic and 0.44 for treatment decisions. It was concluded that the use of an explorer does not improve the validity of the diagnosis of fissure caries when compared to that of a visual inspection alone.


Mitochondria, sex and variation in routine metabolic rate.
Variation in the metabolic costs associated with organismal maintenance may play a key role in determining fitness, and thus these differences among individuals are likely to be subject to natural selection. Although the evolvability of maintenance metabolism depends on its underlying genetic architecture, relatively little is known about the nature of genetic variation that underlies this trait. To address this, we measured variation in routine metabolic rate (ṀO2routine ), an index of maintenance metabolism, within and among three populations of Atlantic killifish, Fundulus heteroclitus, including a population from a region of genetic admixture between two subspecies. Polygenic association tests among individuals from the admixed population identified 54 single nucleotide polymorphisms (SNPs) that were associated with ṀO2routine , and these SNPs accounted for 43% of interindividual variation in this trait. However, genetic associations with ṀO2routine involved different SNPs if females and males were analysed separately, and there was a sex-dependent effect of mitochondrial genotype on variation in routine metabolism. These results imply that there are sex-specific genetic mechanisms, and potential mitonuclear interactions, that underlie variation in ṀO2routine . Additionally, there was evidence for epistatic interactions between 17% of the possible pairs of trait-associated SNPs, suggesting that epistatic effects on ṀO2routine are common. These data demonstrate not only that phenotypic variation in this ecologically important trait has a polygenic basis with considerable epistasis among loci, but also that these underlying genetic mechanisms, and particularly the role of mitochondrial genotype, may be sex-specific.


Safety, acceptability, and pharmacokinetics of a monoclonal antibody-based vaginal multipurpose prevention film (MB66): A Phase I randomized trial.
MB66 film is a multipurpose prevention technology (MPT) product with monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N). The mAbs were produced by transient expression in Nicotiana benthamiana (N). We conducted a Phase I clinical trial to assess the safety, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66 when used intravaginally. The clinical trial enrolled healthy reproductive-aged, sexually abstinent women. In Segment A, 9 women received a single MB66 film which was inserted into the vaginal posterior fornix by a clinician. In Segment B, 29 women were randomly assigned to MB66 (Active) or Placebo film groups and were instructed to insert 1 film vaginally for 7 consecutive days. Visits and clinical sampling occurred predose and at various time points after single and repeated film doses. The primary endpoint was number of adverse events (AEs) Grade 2 or higher related to product use. Secondary endpoints included film dissolution rate, Nugent score (a Gram stain scoring system to diagnose bacterial vaginosis), vaginal pH, post-use survey results, cytokine concentrations in cervicovaginal lavage (CVL) specimens (assessed by Luminex assay), mAb concentrations in vaginal fluid collected from 4 sites (assessed by ELISA), and HIV and HSV neutralization activity of CVL samples ex vivo (assessed by TZM-bl and plaque reduction assay, respectively). The product was generally safe and well tolerated, with no serious AEs recorded in either segment. The AEs in this study were primarily genitourinary in nature with the most commonly reported AE being asymptomatic microscopic hematuria. There were no differences in vaginal pH or Nugent scores or significant increases in levels of proinflammatory cytokines for up to 7 days after film insertion in either segment or between Active and Placebo groups. Acceptability and willingness to use the product were judged to be high by post-use surveys. Concentrations of VRC01-N and HSV8-N in vaginal secretions were assessed over time to generate pharmacokinetic curves. Antibody levels peaked 1 hour postdosing with Active film (median: 35 μg/mL) and remained significantly elevated at 24 hours post first and seventh film (median: 1.8 μg/mL). Correcting for sample dilution (1:20), VRC01-N concentrations ranged from 36 to 700 μg/mL at the 24-hour time point, greater than 100-fold the IC50 for VRC01 (0.32 μg/mL); HSV8-N concentrations ranged from 80 to 601 μg/mL, well above the IC50 of 0.1 μg/m. CVL samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo. Study limitations include the small size of the study cohort, and the fact that no samples were collected between 24 hours and 7 days for pharmacokinetic evaluation. Single and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable. Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were significantly elevated and thus could provide protection for at least 24 hours postdose. However, further research is needed to evaluate the efficacy of MB66 film in women at risk for HIV and HSV infection. Additional antibodies could be added to this platform to provide protection against other sexually transmitted infections (STIs) and contraception. ClinicalTrials.gov NCT02579083.


Review on Disasters and Lower Limb Venous Disease.
As per the World Health Organization, a disaster is defined as "an event that occurs in most cases suddenly and unexpectedly, causing severe disturbances to people or objects affected by it, resulting in the loss of life and harm to the health of the population." A number of health issues are often reported following disasters, such as physical and psychological trauma, infections, malnutrition, and cardiovascular events. Among these, venous thromboembolism is deemed serious and thus should be taken into consideration. Indeed, its risk has been demonstrated to increase following earthquakes, floods, burns, and intoxications. The recent coronavirus pandemic summarizes some of the main triggering factors involved in acute and chronic venous disease development in a disaster setting: inflammation, infection, lockdown-induced reduced mobility, potential malnutrition, and overweight. Proper venous risk assessment and guideline application have been determined to be essential in disaster management, particularly in the current time in which sheltering could lead to a potential exacerbation of the pandemic, which can only increase the risk for venous thrombotic diseases. Global scientific teamwork is needed to make the recommendations as evidence-based and as homogeneous as possible among continents. In this present review, we focus on how earthquakes impact venous thromboembolism, including an analysis of other disaster-related conditions, such as burns and intoxication. (This is a review article based on the informative seminar of the 40th Annual Meeting of Japanese Society of Phlebology.).


A Lewis acid-promoted cyclization of ethenetricarboxylate derivative aromatic compounds. Novel syntheses of oxindoles and benzofuranones via Friedel-Crafts intramolecular Michael addition.
A novel cyclization reaction of ethenetricarboxylate derivative aromatic compounds in the presence of various Lewis acids gave benzo-annulated cyclic compounds such as oxindole and benzofuran derivatives via Friedel-Crafts intramolecular Michael addition in high yields. For example, the reaction of diethyl 2-[(N-methyl-N-phenylcarbamoyl)methylene]malonate (1a) in the presence of ZnCl2 at room temperature gave diethyl 2-(1-methyl-2-oxoindolin-3-yl)malonate (2a) in 98% yield. The reactions also proceeded with a catalytic amount of a Lewis acid such as AlCl3, ZnCl2, ZnBr2, Sc(OTf)3, or InBr3.


Monoclonal Antibodies to Plant Growth Regulators: III. Zeatinriboside and Dihydrozeatinriboside.
Four high affinity monoclonal antibodies, which recognize two plant growth regulators from the cytokinin group, namely trans-zeatin riboside and dihydrozeatin riboside and their derivatives are reported. Six hybridomas were produced from three independent fusions of Balb/c spleen cells with P3-NS1-Ag 4-1 (abbreviated NS1) or X63-Ag 8.653 (X63) myeloma cells. The mice had been hyperimmunized with zeatin riboside-bovine serum albumin conjugate or dihydrozeatin riboside-bovine serum albumin conjugate for 3 months. The hybridomas secrete antibodies of the IgG 1 or IgG 2b subclass and allow the detection of femtomole amounts of the free cytokinins, their ribosides, and ribotides in plant extracts. The use of these monoclonals in radio- and enzyme-linked immunosorbent assay is also discussed.


Glucagon-like peptide-1 protects beta-cells against apoptosis by increasing the activity of an IGF-2/IGF-1 receptor autocrine loop.
The gluco-incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) protect beta-cells against cytokine-induced apoptosis. Their action is initiated by binding to specific receptors that activate the cAMP signaling pathway, but the downstream events are not fully elucidated. Here we searched for mechanisms that may underlie this protective effect. We performed comparative transcriptomic analysis of islets from control and GipR(-/-);Glp-1-R(-/-) mice, which have increased sensitivity to cytokine-induced apoptosis. We found that IGF-1 receptor expression was markedly reduced in the mutant islets. Because the IGF-1 receptor signaling pathway is known for its antiapoptotic effect, we explored the relationship between gluco-incretin action, IGF-1 receptor expression and signaling, and apoptosis. We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression. We demonstrated that GLP-1-induced Akt phosphorylation required active secretion, indicating the presence of an autocrine activation mechanism; we showed that activation of IGF-1 receptor signaling was dependent on the secretion of IGF-2. We demonstrated, both in MIN6 cell line and primary beta-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1-induced protection against apoptosis. An IGF-2/IGF-1 receptor autocrine loop operates in beta-cells. GLP-1 increases its activity by augmenting IGF-1 receptor expression and by stimulating secretion; this mechanism is required for GLP-1-induced protection against apoptosis. These findings may lead to novel ways of preventing beta-cell loss in the pathogenesis of diabetes.


Giant sacral schwannoma: a case report and review of the literature.
Intraspinal schwannomas localized in the sacrum are relatively infrequent, accounting for 1-5% of all spinal axis schwannomas. They frequently grow to considerable size before detection; hence, the term giant sacral schwannoma. Sacral schwannomas arise from the sacral nerve roots. The diagnosis of schwannomas in the spinal canal is difficult because of their slow growth, often resulting in extensive bony destruction. This case report documents the management of a 48-year-old male with a giant sacral schwannoma. We performed a two-stage surgery with intralesional tumour resection. The patient is now free of any complaint, complications and there is no recurrence two years after resection of the schwannoma. Intralesional excision of a sacral schwannoma is a less invasive procedure than total or partial sacrectomy. Using a combined anterior and posterior approach, satisfactory tumour excision and stabilization can be achieved, while avoiding the high morbidity related with total sacrectomy.


Binding model for nonpeptide antagonists of alpha(v)beta(3) integrin.
A binding model for nonpeptide antagonists of integrin alpha(v)beta(3) has been developed through docking analyses utilizing the MMFFs force field and the recently published crystal structure, 1JV2. Results of this docking study have led to the identification of a novel binding model for selective antagonists of alpha(v)beta(3) over alpha(IIb)beta(3) integrins. Four different chemical classes are shown to bind in a similar fashion providing a measure of confidence in the proposed model. All alpha(v)beta(3) and alpha(IIb)beta(3) antagonists have a basic nitrogen separated some distance from a carboxylic acid to mimic RGD. For the alpha(v)beta(3) antagonists under present consideration, these charged ends are separated by twelve bonds. The basic nitrogen of the active alpha(v)beta(3) ligands are shown to interact with D150 of alpha(v) and the ligands' carboxylic acid interact with R214 of beta(3) while adopting an extended conformation with minimal protein induced internal strain. In addition, an energetically favorable interaction is found with all of the active alpha(v)beta(3) molecules with Y178 of alpha(v) when docked to the crystallographically determined structure. This novel interaction may be characterized as pi-pi stacking for the most active of the alpha(v)beta(3) selective antagonists. The proposed model is consistent with observed activity as well as mutagenicity and photoaffinity cross-linking studies of the alpha(v)beta(3) integrin.


Tandem structure of porous silicon film on single-walled carbon nanotube macrofilms for lithium-ion battery applications.
Development of materials and structures leading to high energy and power density lithium-ion batteries is a major challenge to the power needs of the electronic and automobile industries. Silicon is an attractive anode material being closely scrutinized for use in lithium-ion batteries but suffers from a poor cyclability and early capacity fading. In this work, we present a tandem structure of porous silicon film on single-walled carbon nanotube (SWNT) film to significantly improve the cycling stability of silicon as lithium-ion battery anode material. With this new structure configuration of the silicon films, a reversible specific capacity of 2221 mAh/g was retained after 40 charge-discharge cycles at 0.1 C rate, which is 3.6 times that of silicon film on a regular copper substrate and more than 11 times that of the SWNT film. The facile method is efficient and effective in improving specific capacity and stability of silicon anode lithium-ion batteries and will provide a powerful means for the development of lithium-ion batteries.


Tiagabine: a new therapeutic option for people with intellectual disability and partial epilepsy.
Tiagabine exerts its antiepileptic drug (AED) activity by selectively inhibiting the uptake of gamma-aminobutyric acid (GABA) onto the transporter molecules, and thus, increasing extracellular concentrations of GABA in the brain. The absorption and elimination of tiagabine follow linear pharmacokinetics. Tiagabine is metabolized by hepatic cytochrome P450 enzymes and enzyme-inducing AEDs increase tiagabine clearance by 50-65%. Tiagabine has shown no clinically important interactions with other drugs, including oral contraceptives. In the perforant pathway stimulation model of status epilepticus, tiagabine reduced the seizure number and severity, and also prevented the loss of pyramidal cells in the hippocampus as well as alleviated impairment of the spatial memory impairment associated with hippocampal damage. Tiagabine has both antiepileptogenic and anticonvulsant effects in the kindling model of epilepsy. Based on the data from the short- and long-term add-on studies, tiagabine is effective adjunctive therapy for all partial seizure types in adolescents and adults. Conversion to tiagabine monotherapy has been also possible in substantial amount of patients with partial seizures in three trials. Tiagabine is generally well-tolerated. The most common adverse events in controlled studies involve the central nervous system; for example, dizziness, asthenia, nervousness, tremor, depressed mood and emotional lability. Special safety analyses with formal neuropsychological testing suggest that tiagabine does not adversely affect cognition or mood. Tiagabine represents an important new therapeutic option for patients with treatment-refractory partial seizures. The role of tiagabine in the management of partial epilepsy of patients with intellectual disability is especially emphasized since tiagabine has a low side-effect profile in the cognitive area.


[Portasystemic shunt--our twenty years experience].
It was the aim of this study to demonstrate our experiences over twenty years with portasystemic shunt surgery in patients with chronic liver disease and variceal bleeding. From January 1 st, 1980 to December 31 st, 2000 we performed 90 portasystemic shunt operations (PSO). The patients were divided in two groups. The patients of the first group were operated upon between 1980-1988 (n = 58), patients of the second group (n = 32) between 1988-1998. Both groups did not differ in age, gender and cause of hepatic disease. In the first group the most performed type of shunt was the portacaval shunt, in group II the splenorenal shunt. We observed an improved early and late mortality rate, encephalopathy rate and reduction of recurrent variceal bleeding in the second group: the early mortality rate decreased from 16 to 9 % (p < 0.01), the late mortality rate from 35 to 6 % (p < 0.05), the encephalopathy rate from 43 to 12 % and the variceal rebleeding rate from 10 to 6 %. Selective shunts, such as the distal splenorenal shunt are significantly superior to the standard (end-to-side or side-to-side) portasystemic shunt. In countries where acute treatment of recurrent variceal hemorrhage with sclerotherapy is not available in remote areas or in countries where transplantation procedures are in the very beginning and where TIPPS operations are too expensive, portasystemic shunt operations are the only possibility to save the patients life when sclerotherapy fails.


Response of carbon dioxide fixation to water stress: parallel measurements on isolated chloroplasts and intact spinach leaves.
Application of water stress to isolated spinach (Spinacia oleracea) chloroplasts by redutcion of the osmotic potentials of CO(2) fixation media below -6 to -8 bars resulted in decreased rates of fixation regardless of solute composition. A decrease in CO(2) fixation rate of isolated chloroplasts was also found when leaves were dehydrated in air prior to chloroplast isolation. An inverse response of CO(2) fixation to osmotic potential of the fixation medium was found with chloroplasts isolated from dehydrated leaves-namely, fixation rate was inhibited at -8 bars, compared with -16 or -24 bars.Low leaf water potentials were found to inhibit CO(2) fixation of intact leaf discs to almost the same degree as they did CO(2) fixation by chloroplasts isolated from those leaves. CO(2) fixation by intact leaves was decreased by 50 and 80% when water potentials were reduced from -7.1 to -9.6 and from -7.1 to -17.6 bars, respectively. Transpiration was decreased by only 40 and 60%, under the same conditions. However, correction for the increase in leaf temperature indicated transpiration decreases of 57 and 80%, similar to the relative decreases in CO(2) fixation.Despite the 4-fold increase in leaf resistance to CO(2) diffusion in the gas phase when the water potential of leaves was reduced from -6.5 to -14.0 bars, an additional increase of about 50% in mesophyll resistance was obtained. CO(2) concentration at compensation also increased when leaf water potential was reduced.


Percutaneous CT-guided biopsy of osseous lesion of the spine in patients with known or suspected malignancy.
CT-guided spinal biopsy (CTGSB) is considered a safe and accurate procedure. Our goal was to determine the accuracy of a CTGSB of osseous spinal lesions in patients with known or suspected underlying malignancy in reference to major variables such as the radiographic appearance of the biopsied lesion and its location within the spinal column. We retrospectively reviewed results of 410 consecutive percutaneous CTGSB procedures of osseous spinal lesions. Biopsy was determined to be adequate if diagnostic tissue was obtained (n = 401) or unsatisfactory (n = 9) if only blood without cellular elements was present on final pathologic-cytologic examination. The level of spinal biopsy was cervical in nine patients (2%), thoracic in 123 (31%), lumbar in 164 (42%), and sacral in 96 (25%). The overall diagnostic accuracy of CTGSB was 89%, with a false-negative rate of 11%. Biopsy of lytic lesions yielded an accurate diagnosis in 93% (220 of 236). Despite technical challenges inherent to biopsy of sclerotic lesions, diagnostic accuracy was 76% (63 of 83), although more importantly, 24% (20 of 83) of the results in sclerotic lesions were falsely negative. CTGSB of osseous spinal lesions is an important tool in the workup of patients with known or suspected underlying neoplastic disease. However, a negative result must be confirmed with either close follow-up or, preferably, open biopsy, especially in cases of sclerotic lesions for which diagnostic accuracy is decreased and the false-negative rate is high.


Integrated chemical profiling, network pharmacology and pharmacological evaluation to explore the potential mechanism of Xinbao pill against myocardial ischaemia-reperfusion injury.
Xinbao pill (XBW), a traditional Chinese herbal formula, is widely used in clinical treatment for cardiovascular diseases; however, the therapeutic effect of XBW on myocardial ischaemia-reperfusion injury (MI/RI) is unclear. This study evaluates the cardioprotective effect and molecular mechanism of XBW against MI/RI. A phytochemistry-based network pharmacology analysis was used to uncover the mechanism of XBW against MI/RI. Ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry method was used to identify chemicals. MI/RI-related targets of XBW were predicted using TargetNet database, OMIC database, etc. Sprague-Dawley (SD) rats under anterior descending artery ligation model were divided into Sham, MI/RI and XBW (180 mg/kg, intragastric administration). After 30 min ischaemia and 24 h reperfusion, heart tissues were collected for measurement of myocardial infarct size. After oxygen glucose deprivation for 6 h, H9c2 cells were treated with XBW (60, 240 and 720 μg/mL) and diazoxide (100 μM) for 18 h of reperfusion. Thirty-seven chemicals were identified in XBW; 50 MI/RI-related targets of XBW were predicted using indicated databases. XBW significantly reduced infarct size and creatine kinase MB (CK-MB) level after MI/RI; XBW protected H9c2 cells against OGD/R injury. Gene ontology (GO) and KEGG pathway enrichment analyses by String database showed that the cardioprotective effect of XBW was associated with autophagy and apoptosis signalling pathways. Experimental investigation also verified that XBW suppressed apoptosis, autophagy and endoplasmic reticulum (ER) stress. XBW showed therapeutic effects against MI/RI mainly via attenuating apoptosis though suppressing excessive autophagy and ER stress.


Predicting the success of endoscopic transpapillary gallbladder drainage for patients with acute cholecystitis during pretreatment evaluation.
Although endoscopic transpapillary gallbladder drainage (ETGBD) has been reported to be an effective treatment for acute cholecystitis, technical difficulties have precluded more widespread use of this technique. Case evaluations that can predict the occurrence of such difficulties should increase the acceptance of ETGBD for acute cholecystitis treatment. To establish a pretreatment evaluation protocol for patients with acute cholecystitis. Eleven patients with acute cholecystitis who received ETGBD in 2003 or 2004 were enrolled in the present retrospective study. The frequency of success, complications and overall effectiveness of ETGBD for treatment of cholecystitis were measured. Factors that could affect ETGBD success, including clinical and laboratory parameters, and gallbladder ultrasonograms, were also evaluated. ETGBD was successful in seven of 11 patients (success rate 63.6%). All seven patients who underwent ETGBD successfully were afebrile and asymptomatic within a few days. No clinical or laboratory variables were significantly associated with the success of ETGBD. In contrast, ultrasonographic measures of gallbladder minor-axis length and wall thickness in successful cases were significantly shorter (27.4 mm versus 38.0 mm; P=0.008) and thinner (4.2 mm versus 9.0 mm; P=0.041) relative to unsuccessful cases. Ultrasonographic measures of gallbladder minor-axis length and wall thickness can serve as important predictors of ETGBD technical difficulties during pretreatment evaluation of patients with acute cholecystitis.


Nasal eosinophilia: an indicator of eosinophilic inflammation in asthma.
It is noteworthy that there is a clear clinical, epidemiological and pathophysiological association between upper and lower airway inflammation in rhinitis and asthma. The aim of this study was to compare the eosinophil counts in induced sputum and nasal lavage fluids in asthma, checking their association and the accuracy of nasal eosinophilia as a predictor of sputum eosinophilia by a cross-sectional study. The clinical evaluation, asthma control questionnaire (ACQ), pre- and post-bronchodilator spirometry, nasal and sputum sample was performed. The nasal eosinophilia was analysed by a receiver operating curve and logistic regression model. In 140 adults, the post-bronchodilator forced expiratory volume in 1 s (FEV(1)) did not differ between patients with or without sputum eosinophilia (0.18). After adjusted for upper airway symptoms, age, ACQ score and post-bronchodilator FEV(1), sputum eosinophilia was associated with 52 times increase in odds of nasal eosinophilia, whereas each 1% increase in bronchodilator response was associated with 7% increase in odds of nasal eosinophilia. This study brings further evidence that upper airway diseases are an important component of the asthma syndrome. Furthermore, monitoring of nasal eosinophilia by quantitative cytology may be useful as a surrogate of sputum cytology in as a component of composite measurement for determining airway inflammation.


Management Of Penetrating Injury To Thoracic Inlet And Lower Neck With Retained Foreign Body Using Video Assisted Thoracoscopic Surgery.
Penetrating neck and chest injuries are a common form of occupational injuries. We hereby report a unique case in which a metallic rod had penetrated the left chest and neck of a plastic factory worker. The patient was vitally stable when he presented to Emergency Room. Chest X-ray was performed and the patient was rushed to the operating room. VATS (video assisted thoracoscopic surgery) and neck dissection was done for retrieval of the metallic rod. On table, endoscopy was also done to rule out injury to oesophagus. No injury to vital structures was found and the subsequent recovery was uneventful.


Comparison of strategies for substantiating freedom from scrapie in a sheep flock.
The public health threat represented by a potential circulation of bovine spongiform encephalopathy agent in sheep population has led European animal health authorities to launch large screening and genetic selection programmes. If demonstrated, such a circulation would have dramatic economic consequences for sheep breeding sector. In this context, it is important to evaluate the feasibility of qualification procedures that would allow sheep breeders demonstrating their flock is free from scrapie. Classical approaches, based on surveys designed to detect disease presence, do not account for scrapie specificities: the genetic variations of susceptibility and the absence of live diagnostic test routinely available. Adapting these approaches leads to a paradoxical situation in which a greater amount of testing is needed to substantiate disease freedom in genetically resistant flocks than in susceptible flocks, whereas probability of disease freedom is a priori higher in the former than in the latter. The goal of this study was to propose, evaluate and compare several qualification strategies for demonstrating a flock is free from scrapie. A probabilistic framework was defined that accounts for scrapie specificities and allows solving the preceding paradox. Six qualification strategies were defined that combine genotyping data, diagnostic tests results and flock pedigree. These were compared in two types of simulated flocks: resistant and susceptible flocks. Two strategies allowed demonstrating disease freedom in several years, for the majority of simulated flocks: a strategy in which all the flock animals are genotyped, and a strategy in which only founders animals are genotyped, the flock pedigree being known. In both cases, diagnostic tests are performed on culled animals. The less costly strategy varied according to the genetic context (resistant or susceptible) and to the relative costs of a genotyping exam and of a diagnostic test. This work demonstrates that combining data sources allows substantiating a flock is free from scrapie within a reasonable time frame. Qualification schemes could thus be a useful tool for voluntary or mandatory scrapie control programmes. However, there is no general strategy that would always minimize the costs and choice of the strategy should be adapted to local genetic conditions.


Fluorescence Study of Chemical Modification of Phosphoenolpyruvate Carboxylase from Crassula argentea.
The chemical modification of phosphoenolpyruvate carboxylase purified from Crassula argentea leaves was studied using the fluorescence of the extrinsic probe 8-anilino-1-naphalenesulfonate. The effects of ligands on kinetic parameters of phosphoenolpyruvate carboxylase activity, and its response to pH and metal cations, were associated with the binding of the ligands to the enzyme as measured by fluorescence. Binding of the ligands phosphoenolpyruvate, malate, and glucose-6-phosphate revealed by fluorescence measurements corresponds to competitive phenomena observed in kinetic studies. The fluorescence measurements also suggest the involvement of specific amino acids in the binding of a given ligand. Arginyl residues modified by 2,3-butanedione appear to be directly involved in the binding of phosphoenolpyruvate and malate to the active and the inhibition sites, respectively. A histidyl residue was involved in the binding of malate, accounting for the lack of inhibition by malate in kinetic studies of the enzyme treated with diethylpyrocarbonate. Although activity was lost, there was no decrease in the ability of the treated enzyme to bind phosphoenolpyruvate, suggesting that additional histidyl residues are essential for activity although not directly involved in the binding of phosphoenolpyruvate. The lysine reagent trinitrobenzenesulfonate caused a loss of activity and a reduction in malate inhibition and glucose-6-phosphate activation, but these modifications were not related to changes in the ability of the enzyme to bind any of the three ligands. This suggests that lysine residues were not directly involved in the binding of these ligands.


Aonchotheca musimon n. sp. (Nematoda : Capillariinae) from the mouflon Ovis musimon in the sub-antarctic Kerguelen archipelago, with comments on the relationships with A. bilobata (Bhalerao, 1933) Moravec, 1982 and other species of the genus.
An intestinal capillariid nematode, Aonchotheca musimon n. sp., is described from Ovis musimon imported into the Kerguelen archipelago (Terres Australes et Antarctiques Françaises). The comparison of this new material with other Aonchotheca spp. is based on the usual characters, i.e. spicule, caudal bursa, number of papillae, stichosome, bacillary bands, shape of the cirrus, and on the length of the ejaculatory duct which appears to be of some phylogenetic value. A. musimon, of which the spicule is 208-230 microm long, is close to A. bilobata, another parasite of bovids, which is redescribed here. It is distinct from this species because the posterior region of the female worm is cylindrical instead of conical, the lateral alae of the male worm are longer, quadrangular and vesicular instead of triangular and smooth, the caudal bursa has a folded dorso-lateral edge, there is a recurrent ventral fold of the cirrus, the slender distal part of the spicule is longer, the oesophagus is shorter in both sexes and the slightly larger eggs have a thicker shell. These two species from bovids and A. murissylvatici from murid rodents, of which the main characters are similar, represent a small group with a very elongate ejaculatory duct (1.9-2.5 mm). This is in contrast to a larger group of species with a short ejaculatory duct (350-600 microm), which are parasites of Chiroptera (A. brosseti, A. chabaudi, A. landauae, A. gabonensis), Insectivora (A. erinacei), mustelid Carnivora (A. putorii, A. mustelorum) and glirid rodents (A. myoxinitelae, A. legerae). A. bovis and A. dessetae, respectively parasites of bovids and lagomorphs, present an ejaculatory duct of intermediary length and do not belong to these groups. Several species are transferred to the genus Aonchotheca: A. kashmirensis (Raina & Kaul, 1982) n. comb., A. legerae (Justine, Ferté & Bain, 1987) n. comb., A. forresteri (Kinsella & Pence, 1987) n. comb., A. chabaudi (Justine, 1989) n. comb., A. landauae (Justine, 1989) n. comb., A. brosseti (Justine, 1989) n. comb., A. gabonensis (Justine, 1989) n. comb. and A. dessetae (Justine, 1990) n. comb.


Further investigations of the role of acetylation in sulphonamide hypersensitivity reactions.
Abstract Sulphonamide hypersensitivity reactions are believed to be mediated through reactive intermediates derived from oxidation of the paraamino group to form sulphonamide hydroxylamines. Sulphamethoxazole hydroxylamine (SMX-HA) can be acetylated by N-acetyltransferase (NAT) enzymes to form an acetoxy metabolite (acetoxySMX). In the current studies, acetoxySMX was found to be not toxic over the concentration range of 0 to 500 μM towards a human lymphoblastoid cell line (RPMI 1788) or a human hepatoma cell line (HepG2). Further, transient expression of NAT1 in COS-1 cells or stable transfection of NAT1 andNAT2 in HepG2 cells did not alter the toxicity of SMX-HA in vitro. The activity of NAT1 in isolated mononuclear leucocytes (a reflection of systemic NAT1 activity) determined with paraaminobenzoic acid as a substrate was not different between controls (n = 11) or patients with a known hypersensitivity reaction (n = 5) (4.1 ±1.2 nmol min(-1)mg(-1) vs 5.7 ± 1.4 nmol min(-1) mg(-1)). Thus, acetoxy SMX is unlikely to play a significant role in mediating SMX hypersensitivity reactions anda constitutive deficiency in NAT1 activity is not a common finding in patients susceptible to SMX hypersensitivity reactions.


Parsing the 100% calculated panel reactive antibody kidney transplant candidates: Who gets transplanted?
The new kidney allocation system in the United States has improved deceased donor transplant rates among candidates with high calculated panel reactive antibodies (CPRAs). Probability analysis predicts a very low transplant rate as the CPRA approaches 100%. This study sought to determine if the rate of deceased donor kidney transplant based on the actual CPRA in the cohort of 100% qualifying candidates behaved as predicted by probability analysis. Nine thousand two hundred and twenty eight patients were identified on the waiting list on or after December 2014 that had at least one CPRA greater than or equal to 99.5%. The distribution of the 100% CPRA group was highly skewed toward 100% (Median CPRA 99.98%). The decile group within the 100% CPRA qualifying population was by far the most important factor determining kidney transplantation. The highest two deciles of CPRA had a very low rate of transplantation. Options to improve the prospects of deceased donor transplant include intelligently lowering the CPRA by reducing unacceptable antigens, expanding the donor pool by listing candidates for higher risk donors, or through desensitization. The CPRA calculator should display the non-integer CPRA out to several decimal points so that informed decisions can be made for these candidates regarding their prospects of receiving a deceased donor offer.


Expression of the E-cadherin/β-catenin/tcf-4 pathway in gastric diseases with relation to Helicobacter pylori infection: clinical and pathological implications.
To determine the expression of E-cadherin, β-catenin, and transcription factor 4 (TCF4) proteins in gastric diseases with relation to Helicobacter pylori infection. A total of 309 patients including 60 with superficial gastritis (SG), 57 with atrophic gastritis (AG) and 192 with gastric cancer (GC), were enrolled. The expression of E-cadherin, β-catenin, TCF4 proteins in the gastric mucosa was detected by immunohistochemistry and H. pylori infection by immunohistochemistry and PCR. The expression rates of E-cadherin were significantly higher in SG and AG than in GC (P<0.01), while those of β-catenin in the nucleus were significantly lower in SG and AG than in GC (P<0.05). In GC cases, the expression rates of E-cadherin, β-catenin and TCF4 were significantly higher in the intestinal type than in the diffuse type (P<0.05). In GC patients, the expression rate of E-cadherin was significantly higher in the presence of H. pylori than in the absence of infection (P=0.011). Moreover, the expression level of TCF4 and β-catenin protein was significantly higher in the nucleus and cytoplasm in H. pylori positive than in H. pylori negative GC patients, especially in those with the intestinal type (all P < 0.05). The expression of E-cadherin and β-catenin progressively decreases during the process of GC tumorigenesis, while overexpression of TCF4 occurs. H. pylori infection is associated with a significant increase in the expression of E-cadherin and β-catenin in the cytoplasm and nucleus in GC patients, especially those with the intestinal type.


Tarsal tunnel syndrome: review of the literature.
Tarsal tunnel syndrome is defined as entrapment of the posterior tibial nerve at the level of the ankle. The syndrome has been associated with traumatic inflammatory etiologies. The diagnosis is made clinically by the presence of dysesthesia in the distribution of the medial and lateral plantar nerves, a positive Tinel's sign, paresthesias with compression of the nerve at the tarsal tunnel, tenderness of the nerve along its course (Valleix Phenomenon), and sensory or motor changes. Most authors suggest surgical decompression for the treatment of tarsal tunnel syndrome. The purpose of this review is to summarize the etiologies of tarsal tunnel found in the literature, to evaluate the current role of electrodiagnosis in the diagnosis of tarsal tunnel syndrome and to examine the results of treatment modalities presented.


Molecular-level insight in supported olefin metathesis catalysts by combining surface organometallic chemistry, high throughput experimentation, and data analysis.
A combination of high-throughput experimentation (HTE), surface organometallic chemistry (SOMC) and statistical data analysis provided the platform to analyze in situ silica-grafted Mo imido alkylidene catalysts based on a library of 35 phenols. Overall, these tools allowed for the identification of σ-donor electronic effects and dispersive interactions and as key drivers in a prototypical metathesis reaction, homodimerization of 1-nonene. Univariate and multivariate correlation analysis confirmed the categorization of the catalytic data into two groups, depending on the presence of aryl groups in ortho position of the phenol ligand. The initial activity (TOFin) was predominantly correlated to the σ-donor ability of the aryloxy ligands, while the overall catalytic performance (TON1 h) was mainly dependent on attractive dispersive interactions with the used phenol ligands featuring aryl ortho substituents and, in sharp contrast, repulsive dispersive interactions with phenol free of aryl ortho substituents. This work outlines a fast and efficient workflow of gaining molecular-level insight into supported metathesis catalysts and highlights σ-donor ability and noncovalent interactions as crucial properties for designing active d0 supported metathesis catalysts.


Optimisation of the operational conditions of trichloroethylene degradation using Trametes versicolor under quinone redox cycling conditions using central composite design methodology.
Extracellular radicals produced by Trametes versicolor under quinone redox cycling conditions can degrade a large variety of pollutant compounds, including trichloroethylene (TCE). This study investigated the effect of the agitation speed and the gas-liquid phase volume ratio on TCE degradation using central composite design (CCD) methodology for a future scale-up to a reactor system. The agitation speed ranged from 90 to 200 rpm, and the volume ratio ranged from 0.5 to 4.4. The results demonstrated the important and positive effect of the agitation speed and an interaction between the two factors on TCE degradation. Although the volume ratio did not have a significant effect if the agitation speed value was between 160 and 200 rpm, at lower speed values, the specific pollutant degradation was clearly more extensive at low volume ratios than at high volume ratios. The fitted response surface was validated by performing an experiment using the parameter combination in the model that maximised TCE degradation. The results of the experiments carried out using different biomass concentrations demonstrated that the biomass concentration had a positive effect on pollutant degradation if the amount of biomass present was lower than 1.6 g dry weight l(-1). The results show that the maximum TCE degradation was obtained at the highest speed (200 rpm), gas-liquid phase volume ratio (4.4), and a biomass concentration of 1.6 g dry weight l(-1).


Hydrogen-bonding-induced complexation of polydimethylsiloxane-graft-poly(ethylene oxide) and poly(acrylic acid)-block-polyacrylonitrile micelles in water.
Polydimethylsiloxane-graft-poly(ethylene oxide) (PDMS-g-PEO) copolymers form micelles in water with PDMS as the core and PEO as the corona. The introduction of poly(acrylic acid)-block-polyacrylonitrile (PAA-b-PAN) block copolymers in water leads to the formation of micellar complexes due to the hydrogen bonding between carboxyl groups and ether oxygens among the PAA and PEO chains in the corona of the micelles. The effects of pH, molar ratios (r) of PAA/PEO, and the standing time on the directly mixing these two micelles in water have been investigated using laser light scattering (LLS) and transmission electron microscopy (TEM). Our results showed that the complexation between PAA and PEO in the corona was greatly enhanced at a pH below 3.5. For a fixed pH value, the interactions between these two micelles in water were governed by the value of r. At r < ∼0.6, mixing the two micelles in water resulted in a large floccule because the smaller PAA-b-PAN micelles act as physical cross-links, which are absorbed onto one PDMS-g-PEO micelle and simultaneously bonded to PEO chains on the other micelles, forming bridges and causing flocculation. At ∼0.6 < r < ∼1.2, the mixing led to stable micellar complexes with a layer of PAA-b-PAN micelles absorbed onto the initial PDMS-g-PEO micelles. At r > ∼1.2, the resultant micellar complexes first remained stable, but they precipitated from solution after a long time standing.


Viral infection and the inner ear.
The work of Japanese research committees on the relation of viral infection to sudden deafness and acute profound deafness is briefly introduced. The criteria for making a diagnosis of sudden deafness and mumps deafness are described. A new method of detecting IgM antibody to mumps virus was developed in research done for one of the committees. Use of this method revealed that sudden deafness in 1 out of 39 patients was due to mumps virus. Experimental viral labyrinthitis was produced in guinea pigs using herpes simplex virus (types 1 and 2) and guinea pig cytomegalovirus (GPCMV). Histopathological studies were conducted, and the results are discussed and compared with those for human viral labyrinthitis. Anomaly of the cochlea was found in the offspring of a guinea pig which became pregnant just after GPCMV was inoculated into its cochlea.


Is cardiomegaly on chest radiograph representative of true cardiomegaly: a cross-sectional observational study comparing cardiac size on chest radiograph to that on echocardiography.
To determine whether or not cardiomegaly identified on chest radiograph (CXR) is indicative of true cardiomegaly as determined using echocardiography (echo) as the gold standard tool, and therefore whether or not cardiomegaly on CXR should be investigated further. CXR and echocardiogram reports were reviewed for the presence of cardiomegaly in a population following non-ST segment elevation myocardial infarction (NSTEMI). Data was evaluated to determine whether cardiomegaly reported on CXR did indeed represent true cardiomegaly. Exploratory analysis was undertaken to determine whether or not Body Surface Area (BSA) was a significant explanatory variable. Data was collected for 244 patients. Thirty-nine were reported to have cardiomegaly on CXR, 22 of those also had cardiomegaly on echo, giving a true positive rate of 56% and a false positive rate of 44%. Fifty-five were reported to have cardiomegaly on echo, of which 33 (60%) did not have cardiomegaly identified on CXR. Sensitivity of CXR to identify cardiomegaly was 40% and specificity was 91% with a positive predictive value of 56% and negative predictive value of 84%. BSA does not appear to be a significant explanatory variable for the discrepancy between the CXR and echo estimates of cardiomegaly. In patients following an NSTEMI, the true positive rate of cardiomegaly identified on CXR is not too dissimilar to the false positive rate, thereby suggesting that reporting "cardiomegaly" based on CXR findings is inaccurate and rather reporting should simply focus on the cardiothoracic ratio and defining this as an enlarged cardiac silhouette rather than true cardiomegaly. In clinical practice the data indicates that the number needed to investigate to identify true cardiomegaly on echo is only two, thereby concluding that all patients post-NSTEMI with cardiomegaly on CXR should go on to have an echo, consistent with current national guidelines. As the study population were all post-MI, further study is necessary to evaluate whether this association holds true in a wider population.


Insight into Biomass Upgrade: A Review on Hydrogenation of 5-Hydroxymethylfurfural (HMF) to 2,5-Dimethylfuran (DMF).
Recent developments in the transformation of biobased 5-hydroxymethylfurfural (HMF) into a potential liquid fuel, 2,5-dimethylfuran (DMF), are summarised. This review focuses briefly on the history of HMF conversion to DMF in terms of the feedstock used and emphasises the ideal requirements in terms of the catalytic properties needed in HMF transformation into DMF. The recent state of the art and works on HMF transformation into DMF are discussed in comparison to noble metals and non-noble metals as well as bimetallic catalysts. The effect of the support used and the reaction conditions are also discussed. The recommendations for future work and challenges faced are specified.


COVID-19 pandemic dynamics in India, the SARS-CoV-2 Delta variant, and implications for vaccination.
The COVID-19 Delta pandemic wave in India surged and declined within 3 months; cases then remained low despite the continued spread of Delta elsewhere. Here we aim to estimate key epidemiological characteristics of the Delta variant based on data from India and examine the underpinnings of its dynamics. We utilize multiple datasets and model-inference methods to reconstruct COVID-19 pandemic dynamics in India during March 2020 - June 2021. We further use model estimates to retrospectively predict cases and deaths during July - mid-Oct 2021, under various vaccination and vaccine effectiveness (VE) settings to estimate the impact of vaccination and VE for non-Delta-infection recoverees. We estimate that Delta escaped immunity in 34.6% (95% CI: 0 - 64.2%) of individuals with prior wildtype infection and was 57.0% (95% CI: 37.9 - 75.6%) more infectious than wildtype SARS-CoV-2. Models assuming higher VE among those with prior non-Delta infection, particularly after the 1 st dose, generated more accurate predictions than those assuming no such increases (best-performing VE setting: 90/95% vs. 30/67% baseline for the 1 st /2 nd dose). Counterfactual modeling indicates that high vaccination coverage for 1 st vaccine-dose in India (∼50% by mid-Oct 2021) combined with the boosting of VE among recoverees averted around 60% of infections during July - mid-Oct 2021. Non-pharmaceutical interventions, infection seasonality, and high coverage of 1-dose vaccination likely all contributed to pandemic dynamics in India during 2021. Given the shortage of COVID-19 vaccines globally and boosting of VE, for populations with high prior infection rates, prioritizing the first vaccine-dose may protect more people. Evidence before this study: We searched PubMed for studies published through Nov 3, 2021 on the Delta (B.1.617.2) SARS-CoV-2 variant that focused on three areas: 1) transmissibility [search terms: ("Delta variant" OR "B.1.617") AND ("transmission rate" OR "growth rate" OR "secondary attack rate" OR "transmissibility")]; 2) immune response ([search terms: ("Delta variant" OR "B.1.617") AND ("immune evas" OR "immune escape")]; and 3) vaccine effectiveness ([search terms: ("Delta variant" OR "B.1.617") AND ("vaccine effectiveness" OR "vaccine efficacy" OR "vaccination")]. Our search returned 256 papers, from which we read the abstracts and identified 54 relevant studies.Forty-two studies addressed immune evasion and/or vaccine effectiveness. Around half (n=19) of these studies measured the neutralizing ability of convalescent sera and/or vaccine sera against Delta and most reported some reduction (around 2-to 8-fold) compared to ancestral variants. The remainder (n=23) used field observations (often with a test-negative or cohort-design) and reported lower VE against infection but similar VE against hospitalization or death. Together, these laboratory and field observations consistently indicate that Delta can evade preexisting immunity. In addition, five studies reported higher B-cell and/or T-cell vaccine-induced immune response among recovered vaccinees than naïve vaccinees, suggesting potential boosting of pre-existing immunity; however, all studies were based on small samples (n = 10 to 198 individuals).Sixteen studies examined transmissibility, including 1) laboratory experiments (n=6) showing that Delta has higher affinity to the cell receptor, fuses membranes more efficiently, and/or replicates faster than other SARS-CoV-2 variants, providing biological mechanisms for its higher transmissibility; 2) field studies (n=5) showing higher rates of breakthrough infections by Delta and/or higher viral load among Delta infections than other variants; and 3) modeling/mixed studies (n=5) using genomic or case data to estimate the growth rate or reproduction number, reporting a 60-120% increase. Only one study jointly estimated the increase in transmissibility (1.3-1.7-fold, 50% CI) and immune evasion (10-50%, 50% CI); this study also reported a 27.5% (25/91) reinfection rate by Delta.Added value of this study: We utilize observed pandemic dynamics and the differential vaccination coverage for two vaccine doses in India, where the Delta variant was first identified, to estimate the epidemiological properties of Delta and examine the impact of prior non-Delta infection on immune boosting at the population level. We estimate that Delta variant can escape immunity from prior wildtype infection roughly one-third of the time and is around 60% more infectious than wildtype SARS-CoV-2. In addition, our analysis suggests the large increase in population receiving their first vaccine dose (∼50% by end of Oct 2021) combined with the boosting effect of vaccination for non-Delta infection recoverees likely mitigated epidemic intensity in India during July - Oct 2021.Implications of all the available evidence: Our analysis reconstructs the interplay and effects of non-pharmaceutical interventions, infection seasonality, Delta variant emergence, and vaccination on COVID-19 pandemic dynamics in India. Modeling findings support prioritizing the first vaccine dose in populations with high prior infection rates, given vaccine shortages.


Intolerance to administered lipids in tumor-bearing animals.
Cancer cachexia is a poorly understood phenomenon that contributes to patient intolerance of operations, radiation, and chemotherapy. Reversal of this dysmetabolic state has been attempted by administration of carbohydrates, proteins, and lipids, with little demonstrated clinical benefit. Identification of elevated serum triglycerides (TG) in two tumor-bearing (TB) animal models and recently reported in humans with cancer may be a part of this dysfunctional state. Because lipids makeup energy repletion in patients receiving TPN, the question of how exogenous lipids affect these TB animals needed to be resolved. Intralipid administered by intravenous or gastrointestinal routes raised serum levels in TB animals to greater than 600 mg/dl, even when their baseline TG levels were comparable to nontumor-bearing control animals. The addition of glucose concomitantly with Intralipid failed to prevent TG levels from rising abruptly. Increased lipolytic activity in TB sera was demonstrated and that was not due solely to hypoglycemia or hypoinsulinemia. Administration of lipids to TB animals results in excessively high serum TG levels that appear to be due, in part, to the demonstrated lipolytic activity in TB animal sera.


Analysis of SI-Related BoGAPDH Family Genes and Response of BoGAPC to SI Signal in Brassica oleracea L.
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is not only involved in carbohydrate metabolism, but also plays an important role in stress resistance. However, it has not been reported in Brassica oleracea. In this study, we performed a genome-wide identification of BoGAPDH in B. oleracea and performed cloning and expression analysis of one of the differentially expressed genes, BoGAPC. A total of 16 members of the BoGAPDH family were identified in B. oleracea, which were conserved, distributed unevenly on chromosomes and had tandem repeat genes. Most of the genes were down-regulated during self-pollination, and the highest expression was found in stigmas and sepals. Different transcriptome data showed that BoGAPDH genes were differentially expressed under stress, which was consistent with the results of qRT-PCR. We cloned and analyzed the differentially expressed gene BoGAPC and found that it was in the down-regulated mode 1 h after self-pollination, and the expression was the highest in the stigma, which was consistent with the result of GUS staining. The promoter region of the gene not only has stress response elements and plant hormone response elements, but also has a variety of specific elements for regulating floral organ development. Subcellular localization indicates that the BoGAPC protein is located in the cytoplasm and belongs to the active protein in the cytoplasm. The results of prokaryotic expression showed that the size of the BoGAPC protein was about 37 kDa, which was consistent with the expected results, indicating that the protein was induced in prokaryotic cells. The results of yeast two-hybrid and GST pull-down showed that the SRK kinase domain interacted with the BoGAPC protein. The above results suggest that the BoGAPDH family of B. oleracea plays an important role in the process of plant stress resistance, and the BoGAPC gene may be involved in the process of self-incompatibility in B. oleracea, which may respond to SI by encoding proteins directly interacting with SRK.


Debriefing and Learning Strategies: A Comparison between Two Reflective Analysis Styles with/without a Graphical Record of Strengths/Weaknesses.
Background: Clinical simulation efficiently complements the training of Nursing Degree students. The debriefing phase is the most important feature of simulation-based learning, where the students are able to acquire the necessary competences. It is at this stage where learning strategies and motivation play a crucial role. The objective of the study was to analyze the relationship between the style of debriefing utilized in the simulation sessions, and the learning strategies of Nursing Degree students who participated in a high-fidelity clinical simulation. Method: This was a quasi-experimental study conducted with a sample of 200 students in their third and fourth years at university. To obtain the data, an evaluation Questionnaire for the Evaluation of Learning Strategies of University Students (CEVEAPEU) was utilized, as well as two different types of structured debriefing styles, namely, with or without a graphical representation of the strengths/weaknesses during the analytical phase. The data analysis was performed with the SPSS® v25 program. Results: Statistically significant differences were found, with higher scores obtained when utilizing debriefing with a graphical representation, on both scales of the questionnaire (affective and cognitive), on the motivational, metacognitive and processing, and use of information subscales, and twelve learning strategies mostly belonging to the subscales of motivation; searching, collecting, and selecting information; and processing and using information. Conclusion: Debriefing with a graphical representation is deemed, a priori, as the most adequate approach for our context, based on the greater number of learning strategies utilized by our students. The use of a written graphical record of the strengths and weaknesses in the analytical phase is recommended.


Mimicking continuous capture chromatography for virus clearance using a single chromatography column model.
Continuous chromatography is increasingly being used across the biotechnology industry due to its economic advantages. For adoption in commercial manufacturing, also models for virus clearance studies must be available. It is demonstrated how for a virus clearance study for a multispecific antibody, the continuous protein A capture chromatography process, being run on multiple interconnected columns, can be mimicked with only a single column. With this mimicking small-scale model, resources and complexity can be minimized, when conducting virus clearance studies at a contract research organization (CRO) lab. Obtained log reduction values (LRV) for murine leukemia virus (xMuLV) and minute virus of mice (MVM) virus, used as model viruses, are comparable to batch protein A chromatography and results described by other groups. The feasibility of this mimicking small-scale model helps to further reduce barriers to adoption when implementing continuous chromatography.


Early- versus late-onset infectious keratitis after radial and astigmatic keratotomy: clinical spectrum in a referral practice.
To compare the clinical characteristics of early- versus late-onset keratitis after radial keratotomy (RK) and astigmatic keratotomy (AK). Referral subspecialty practice. This retrospective review comprised 19 patients with infectious keratitis after RK and AK. Early- versus late-onset groups were analyzed for predisposing conditions; infiltrate location, size, and depth; microbiologic data; and final visual outcome. Ten patients in the early-onset group developed keratitis within a mean of 7.4 days after surgery (range 3 to 14 days). Nine patients in the late-onset group developed keratitis a mean of 5.4 years after surgery (range 1.5 to 15.0 years). Staphylococcus aureus was the predominant organism in the early-onset group and Pseudomonas aeruginosa in the late-onset group. In the early-onset group, most infiltrates occurred in the paracentral aspect of the RK incision and extended to the middle or posterior stroma. In the late-onset group, most infiltrates occurred in the peripheral portion of the RK incision and were localized to the superficial stroma. A hypopyon was present in 7 of 10 ulcers in the early group and in 1 of 9 in the late group. Two patients in the early group developed endophthalmitis. Most patients in the late-onset group had incisional pseudocysts; 2 had other risk factors for keratitis. Final visual acuity was 20/40 or better in 7 of 10 patients in the early group and in 8 of 9 patients in the late group. Early-onset corneal ulcers after incisional refractive keratotomy were usually paracentral and deep, whereas late-onset ulcers were usually peripheral and superficial. Despite the predominance of Staphylococcus and Pseudomonas in the early- and late-onset groups, respectively, a variety of organisms may be responsible for infections in keratotomy incisions.


Exact analytical solution of the peristaltic nanofluids flow in an asymmetric channel with flexible walls and slip condition: application to the cancer treatment.
In the cancer treatment, magnetic nanoparticles are injected into the blood vessel nearest to the cancer's tissues. The dynamic of these nanoparticles occurs under the action of the peristaltic waves generated on the flexible walls of the blood vessel. Studying such nanofluid flow under this action is therefore useful in treating tissues of the cancer. In this paper, the mathematical model describing the slip peristaltic flow of nanofluid was analytically investigated. Exact expressions were deduced for the temperature distribution and nano-particle concentration. In addition, the effects of the slip, thermophoresis, and Brownian motion parameters on the temperature and nano-particle concentration profiles were discussed and further compared with other approximate results in the literatures. In particular, these results have been obtained at the same values of the physical examined parameters that was considered in Akbar et al., "Peristaltic flow of a nanofluid with slip effects," 2012. The results reveal that remarkable differences are detected between the exact current results and those approximately obtained in the literatures for behaviour of the temperature profile and nano-particles concentration. Accordingly, the current analysis and results are considered as optimal and therefore may be taken as a base for any future comparisons.


Pan-derived isotopic composition of atmospheric vapour in a Mediterranean wetland (Rhône River Delta, France).
A continuous record of atmospheric vapour isotopic composition (delta(A)) can be derived from the isotope mass balance of a water body submitted to natural evaporation. In this paper, we present preliminary results of the application of this method to a drying evaporation pan, located in a Mediterranean wetland, during a two-month summer period. Results seem consistent with few atmospheric vapour data based on the assumption of isotopic equilibrium with precipitation, but we observed a shift between pan-derived delta(A) and the composition of vapour samples collected by cold trapping. These results suggest that further investigations are necessary to evaluate the effect of diurnal variations of atmospheric conditions on the applicability of the pan-evaporation method, and on the representative of grab atmospheric samples. We also propose a sensitivity analysis for evaluating the impact of the different measured components on delta(A) calculation, and show an improvement in the method efficiency as the pan is drying.


Beef allergy in children with cow's milk allergy; cow's milk allergy in children with beef allergy.
To review the literature on the prevalence of beef allergy in children allergic to cow's milk and to report a series of patients with beef allergy evaluated for cow's milk allergy. A MEDLINE search for cow's milk allergy and beef allergy was conducted. Also included in this report is a clinical evaluation of both these entities in a population of children with atopic dermatitis. Data from the literature were summarized. Recruited patients with beef allergy were evaluated on the basis of history, serology, skin prick tests, and double-blind, placebo-controlled food challenge (entry criterion), and presented between 1992 and 2000. In the literature, between 13 and 20% of children with cow's milk allergy also have beef allergy. In our personal series of patients, 28 children (18 boys and 10 girls) diagnosed with beef allergy underwent skin prick tests and double-blind, placebo-controlled food challenge, which showed that 26 (92.9%) were allergic to cow's milk. Two children nonallergic to cow's milk were the only ones who were not sensitized to bovine serum albumin. Most children with beef allergy are also allergic to cow's milk and should avoid the consumption of dairy products. Sensitization to bovine serum albumin is a marker of cow's milk allergy in children with beef allergy. Elimination of beef from the diet of children with cow's milk allergy should be evaluated on an individual basis after diagnostic workup.


Alkyl caffeates as anti-Helicobacter pylori and scavenger of oxidants produced by neutrophils.
Helicobacter pylori pathogenic action involves the colonization of the gastrointestinal tract and a large production of reactive oxygen species (ROS) by the neutrophils attracted to the site of infection. The aim of this study was to evaluate caffeic acid and its alkyl esters as inhibitors of the release of ROS by Helicobacter pylori activated neutrophils and their bactericidal effect. The increased hydrophobicity caused by esterification had direct consequence in their efficiency as bactericidal agents against H. pylori and inhibitors of the production of ROS by neutrophils. The minimum inhibitory concentration (MIC) decreased from higher than 1000 μg/mL (caffeic acid) to 250 μg/mL to butyl and heptyl caffeate. The release of total ROS, superoxide anion and hypochlorous acid by activated neutrophils was also significantly decreased and the esters were more efficient than the acid precursor. In conclusion, the alkyl esters of caffeic acid have two properties that are complementary for the treatment of H. pylori infections: bactericidal activity and inhibitory effect upon generation of ROS by neutrophils. Hence, we propose that these easily synthesized and non-expensive substances should be applied to in vivo experimental models of H. pylori induced gastric infections.


Practical strategies and perceptions from community pharmacists following their experiences with conducting pharmacy practice research: a qualitative content analysis.
While prior research identified barriers to conducting research in community pharmacies, there remains a need to better understand facilitators to ensure successful collaborations between academic researchers and pharmacists. Our objective was to determine the experiences and perspectives of community pharmacists who have recently conducted a pharmacy practice-based research study to gain in-depth understanding of challenges as well as facilitators and identify strategies and solutions. We conducted a qualitative study involving one-on-one semi-structured telephone interviews with community pharmacists following the completion of a practice-based research study in their pharmacies. Interview transcripts were analysed using inductive content analysis involving open coding, creating categories and abstraction into final themes. Eleven pharmacists participated in the qualitative interviews. We identified six major themes including: (1) barriers (e.g. time constraints); (2) facilitators (e.g. ideal pharmacy layout); (3) support and resources from academic researchers (e.g. helpfulness of training, easy-to-use study materials); (4) pharmacist-initiated strategies for conducting research (beyond prior suggestions from researchers); (5) suggestions for future pharmacy practice research; and (6) motivation for conducting pharmacy practice research. These findings informed practical strategies targeted at academic researchers and pharmacists, respectively, to facilitate the conduct of research in community pharmacists across various stages of the research process. Our study adds to better understanding of community pharmacists' perspectives on conducting research and identifies practical solutions that can be readily implemented by academic researchers and pharmacists participating in research.


Canine choroidal melanoma with metastases.
A 3-year-old-female, spayed Golden Retriever was examined for a unilateral retinal detachment with exophthalmos. Ultrasonographically, a mass was detected with intra- and extraocular extension. The orbit was exenterated and the dog recovered uneventfully. Histopathologic diagnosis was a primary choroidal melanoma with orbital extension, however, the behavioral and cytologic features were benign. Routine examinations postsurgically were nonremarkable. Twenty-one months after surgery the dog was euthanized for respiratory collapse with radiographic signs of metastasis. Necropsy revealed black lesions in the lung and liver. Histopathologic diagnosis was metastatic melanoma with morphology and behavior identical to the primary choroidal melanoma. This is the first definitive case of a canine choroidal melanoma with metastasis.


Release of halide ions from the buried active site of the haloalkane dehalogenase LinB revealed by stopped-flow fluorescence analysis and free energy calculations.
Release of halide ions is an essential step of the catalytic cycle of haloalkane dehalogenases. Here we describe experimentally and computationally the process of release of a halide anion from the buried active site of the haloalkane dehalogenase LinB. Using stopped-flow fluorescence analysis and umbrella sampling free energy calculations, we show that the anion binding is ion-specific and follows the ordering I(-) > Br(-) > Cl(-). We also address the issue of the protonation state of the catalytic His272 residue and its effect on the process of halide release. While deprotonation of His272 increases binding of anions in the access tunnel, we show that the anionic ordering does not change with the switch of the protonation state. We also demonstrate that a sodium cation could relatively easily enter the active site, provided the His272 residue is singly protonated, and replace thus the missing proton. In contrast, Na(+) is strongly repelled from the active site containing the doubly protonated His272 residue. Our study contributes toward understanding of the reaction mechanism of haloalkane dehalogenase enzyme family. Determination of the protonation state of the catalytic histidine throughout the catalytic cycle remains a challenge for future studies.


[The role of endogenous opioid peptides in paraventricular nucleus of hypothalamus in the antagonism to myocardial ischemia by electroacupuncture at acupoint "Neiguan" (PC 6)].
To explore the mechanism of electroacupuncture at "Neiguan" (PC 6) antagonizing myocardial ischemia injury. Forty rabbits were randomly divided into 4 groups, model control group, naloxone control group, electroacupuncture plus cerebral spinal fluid group, and electroacupuncture plus naloxone group, 10 rabbits in each group. The effects of electroacupuncture at "Neiguan" (PC 6) after injection of naloxone into the paraventricular nucleus (PVN) of the hypothalamus on myocardial ultrastructure, II lead ECG and transmembrane potentials of the ischemic myocardial cell in the rabbit of myocardial ischemia were investigated. The injection of naloxone into PVN has no effect on myocardial functions in the normal rabbit and a little effect on ischemic myocardial functions, but at 60 min after myocardial ischemia, this has a certain protective action on myocardial functions (P < 0.05); electroacupuncture at "Neiguan" has obvious protective action on ischemic myocardium, which can be reduced by injection of naloxone into PVN (P < 0.05), but can not be blocked. (1) PVN plays an important role in the process of antagonizing myocardial ischemia by electroacupuncture at "Neiguan"; (2) endogenous opioid pepetides in PVN are involved in the acupuncture effect of antagonizing myocardial ischemia; (3) other transmitters in PVN and other nucleus groups in the center also can produce obvious effects in the antagonism to myocardial ischemia by electroacupuncture at "Neiguan".


Nandrolone decanoate increases satellite cell numbers in the chicken pectoralis muscle.
The anabolic androgenic steroid nandrolone decanoate has minimal androgenic effects and, thus, is widely used to induce muscle hypertrophy in both patients and athletes. Although increases in satellite cell numbers and satellite cells giving rise to new myonuclei are associated with hypertrophy in many experimental models, the relationship between nandrolone and satellite cells is poorly understood. Here we test the hypothesis that nandrolone administration is associated with an increase in satellite cell numbers in muscle. Nandrolone was injected at weekly intervals for four weeks into the right pectoralis muscle of female white leghorn chickens aged 63 days post hatch. Age/size/sex matched control birds received saline injections. The contralateral pectoralis was excised for study from each control and nandrolone treated bird. An antibody against Pax7 and immunocytochemical techniques were used to identify satellite cells. Nandrolone significantly increased mean pectoralis mass by approximately 22%, and mean fiber diameter by about 24%. All satellite cell indices that were quantified increased significantly in chicken pectoralis with administration of nandrolone. Nandrolone injected birds had on average higher satellite cell frequencies (#SC nuclei/all nuclei within basal lamina), number of satellite cells per millimeter of fiber, and satellite cell concentrations (closer together). Myonuclei were further apart (less concentrated) in nandrolone injected muscle. However, an overall increase in myonuclear numbers was revealed by a significantly greater mean number of myonuclei per millimeter of fiber in nandrolone injected muscle. Our results suggest that satellite cells may be key cellular vectors for nandrolone induced muscle fiber hypertrophy.


Thyroid Nodules: Advances in Evaluation and Management.
Thyroid nodules can be detected by ultrasonography in up to 68% of the general population. They are typically benign and are often discovered incidentally. The primary goal of thyroid nodule evaluation is to determine whether it is malignant. After thyroid ultrasonography has been performed, the next step is measurement of serum thyroid-stimulating hormone. If levels are low, a radionuclide thyroid uptake scan is indicated. Hyperfunctioning nodules are rarely malignant and do not require tissue sampling. Nonfunctioning nodules and nodules in a patient with a normal or high thyroid-stimulating hormone level may require fine-needle aspiration based on ultrasound characteristics and size. Nodules with suspicious features and solid hypoechoic nodules 1 cm or larger require aspiration. The Bethesda System (categories 1 through 6) is used to classify samples. Molecular testing can be used to guide treatment when aspiration yields an indeterminate result. Molecular testing detects mutations associated with thyroid cancer and can help inform decisions about surgical excision vs. continued ultrasound monitoring. Treatment of pregnant women with nonfunctioning thyroid nodules and of children with thyroid nodules is similar to that for nonpregnant adults, with the exception of molecular testing, which has not been validated in these populations.


Hybridization of mismatched or partially matched DNA at surfaces.
We investigate how probe density influences hybridization for unlabeled target oligonucleotides that contain mismatched sequences or targets that access different binding locations on the immobilized probe. We find strong probe density effects influencing not only the efficiency of hybridization but also the kinetics of capture. Probe surfaces are used repeatedly, and the potentially large contributions of sample-to-sample variations in surface heterogeneity and nonspecific adsorption are addressed. Results of kinetic, equilibrium, and temperature-dependent studies, obtained using in-situ surface plasmon resonance (SPR) spectroscopy, show that hybridization for surface immobilized DNA is quite different from the well-studied solution-phase reaction. Surface hybridization depends strongly on the target sequence and probe density. Much of the data can be explained by the presence of steric crowding at high probe density; however, the behavior of mismatched sequences cannot be understood using standard models of hybridization even at the lowest density studied. In addition to unusual capture kinetics observed for the mismatched targets, we find that the binding isotherms can be fit only if a heterogeneous model is used. For mismatched targets, the Sips model adequately describes probe-target binding isotherms; for perfectly matched targets, the Langmuir model can be used.


Biodegradable nanoparticles induce cGAS/STING-dependent reprogramming of myeloid cells to promote tumor immunotherapy.
Cancer treatment utilizing infusion therapies to enhance the patient's own immune response against the tumor have shown significant functionality in a small subpopulation of patients. Additionally, advances have been made in the utilization of nanotechnology for the treatment of disease. We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IMPs; named ONP-302) for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates.


[Differential expression of Bmp2, Bmp4 and Bmp3 in embryonic development of mouse anterior and posterior palate].
The palate is differently regulated and developed along the anterior-posterior axis. The Bmp signal pathway plays a crucial role in palatogenesis. Conditioned-inactivation of Bmp type I receptor Alk2 or Alk3 in the neural crest or craniofacial region leads to palatal cleft in mice. However, how different Bmp members are involved in palatogenesis remains to be elucidated. In the present study, mRNA expression patterns of Bmp2, Bmp3 and Bmp4 in the developing anterior and posterior palates were examined and compared, focusing on the fusion stage. To detect the expression of Bmp mRNA, antisense riboprobes were synthesized by in vitro transcription. Radioactive in situ hybridization was performed on sagital and coronal sections of mice head from E13 to E18. The expression of these Bmps were developmentally regulated in the anterior and posterior palates prior to, during and after palatal fusion. During palatal fusion, Bmp4 expression shifted from the anterior to the posterior palate, Bmp2 was highly expressed in both the anterior and posterior palates in this process, whereas Bmp3 was only localized in the posterior palate. They showed generally non-overlapping pattern in their expression domains. Thereafter, their expression was detected in both the anterior and posterior palates regulating osteogenesis and myogenesis respectively. Bmp signalling is involved in palatogenesis in multiple stages and has multiple roles in regulating anterior and posterior palatal development. Disturbances of Bmp signalling during palatogenesis might be a possible mechanism of cleft palate.


Epidemiology of prostate cancer chemoprevention.
In absolute terms, prostate cancer is a public health problem of major and increasing importance particularly as the population ages. Prostate cancer control comprises a series of actions ranging from primary prevention, through screening to improvements in therapy for prostate cancer. An exciting approach lies in the possibility of chemoprevention to reverse the process of carcinogenicity and prevent prostate cancer by this route. Indeed, there are several very interesting ideas being tested at this moment. One major difficulty is the long length of time which can elapse between exposure and the time at which clinical cancer can be found and diagnosed. In cases where delays are long, then preventative treatment should be initiated at an early age. This, and many other issues, current in prostate cancer, are rendered problematic by the age distribution of prostate cancer in the population. Although it is decreasing now, around the early 1990s, the median age of diagnosis of prostate cancer was around 75 in some European countries although considerably lower in population groups in the United States. The median age at death is between 77 and 80 in most countries. These special circumstances must be taken into account when discussing clinical trials of chemoprevention of prostate cancer. The importance of developing reliable intermediate endpoints which can be used in such studies in highlighted.


Assessing effects of PEEP and global expiratory lung volume on regional electrical impedance tomography.
This study was performed to assess the value of electrical impedance tomography (EIT) as an indicator of tidal (V(T)) and end expiratory lung volume (EELV). EIT measurements were performed in seven healthy piglets during constant tidal volume ventilation at incremental and decremental positive end-expiratory pressure (PEEP) levels. Tidal impedance changes were calibrated to volume using V(T) calculated from flow at the airway opening. Simultaneously, calibrated respiratory inductive plethysmography was used to measure EELV changes, and used as a reference standard. EIT systematically underestimated both V(T) and EELV changes when EELV deviated from the level at which it was calibrated. Calculated over the entire pressure-volume curve, EIT systematically underestimated V(T) by 28 ml, with a precision from -16 to 72 ml. EELV was systemically underestimated by 406 ml, with a precision of -38 to 849 ml. Nonlinear recruitment in the ventral regions of the lungs was the main cause of this underestimation. Tidal and end-expiratory changes in pulmonary impedance reflect corresponding changes in lung volume, but the increasing underestimation with increasing lung volume should be taken into account in the analysis of EIT data.


Remembered preoperative Quick disabilities of the arm, shoulder and hand (QuickDASH) scores.
The Quick disabilities of the arm, shoulder and hand (QuickDASH) patient-reported outcome measure is frequently used to assess disabilities and symptoms of the upper extremity. This study compares real preoperative QuickDASH scores and remembered preoperative QuickDASH scores. Remembered preoperative QuickDASH scores were obtained 45 months (39-67) after surgery. Patient material consisted of 160 patients operated for Dupuytren's contracture, carpal tunnel syndrome, thumb basal joint arthrosis, and shoulder pain. All patients had completed QuickDASH questionnaires before surgery. Paired T-tests, linear mixed models, and limits of agreement were used for analyses. There was a significant difference between remembered and real preoperative scores (mean 7.6, SD 15.6; SEM 1.2). Neither diagnosis, age, gender, nor time between surgery and review influenced the difference significantly. A linear mixed model was constructed to investigate the ability to retrospectively predict preoperative QuickDASH scores. Remembered preoperative QuickDASH cannot be used in individual patients because of the high inaccuracy. III.