Evidence for presynaptic cholinergic receptors on dopaminergic terminals: degeneration studies with 6-hydroxydopamine.
Intraventricular injections of 6-hydroxydopamine (6-OHDA) caused a significant decrease in the tyrosine hydroxylase of striatal synaptosomes of rats, without influencing GABA levels. Significant decreases in the muscarinic and nicotinic receptors also occurred in this preparation after 3 days. The receptors were measured by specific binding studies with N-methylatropine and alpha-bungarotoxin respectively. These results indicate that muscarinic and nicotinic receptors are located on the dopaminergic nerve terminals of corpus striatum.


Association Study of CHRNA7 Promoter Variants with Sensory and Sensorimotor Gating in Schizophrenia Patients and Healthy Controls: A Danish Case-Control Study.
Schizophrenia is a severe psychiatric disorder with a core component of impaired cognitive function still remaining as one of the greatest challenges in the pharmacological treatment of the disorder. The CHRNA7 gene, encoding the subunit of the human α7 nicotinic acetylcholine receptor (α7nAChR), is suggested as a susceptibility factor for schizophrenia. CHRNA7 has also been genetically linked to the P50 auditory evoked potential deficit, a candidate endophenotype of schizophrenia, but not to prepulse inhibition of the startle reflex (PPI). In this study, 95 antipsychotic-naïve schizophrenic patients and 450 unaffected controls were screened for CHRNA7 promoter variants to investigate the association with schizophrenia, P50 suppression and PPI. We found that the promoter variant -194C (rs28531779) was significantly associated with schizophrenia, but did not find any association of this variant with P50 suppression or PPI. In addition, individuals with CHRNA7 promoter variants had elevated startle magnitude in pulse-alone trials compared to individuals without a variant. The present findings provide further support for a role of the α7nAChR in schizophrenia and show a genetic link between CHRNA7 and startle magnitude, indicating that cholinergic neurotransmission involving the α7nAChR could be involved in sensory registration processes.


Heat-labile enterotoxin of Escherichia coli promotes intestinal colonization of Salmonella enterica.
Enterotoxigenic Escherichia coli (ETEC) is an important cause of infantile and travellers' diarrhoea, which poses a serious health burden, especially in developing countries. In addition, ETEC bacteria are a major cause of illness and death in neonatal and recently weaned pigs. The production of a heat-labile enterotoxin (LT) promotes the colonization and pathogenicity of ETEC and may exacerbate co-infections with other enteric pathogens such as Salmonella enterica. We showed that the intraintestinal presence of LT dramatically increased the intestinal Salmonella Typhimurium load in experimentally inoculated pigs. This could not be explained by direct alteration of the invasion or survival capacity of Salmonella in enterocytes, in vitro. However, we demonstrated that LT affects the enteric mucus layer composition in a mucus-secreting goblet cell line by significantly decreasing the expression of mucin 4. The current results show that LT alters the intestinal mucus composition and aggravates a Salmonella Typhimurium infection, which may result in the exacerbation of the diarrhoeal illness.


A mathematical model for predicting cardiovascular responses at rest and during exercise in demanding environmental conditions.
The present research describes the development and validation of a cardiovascular model (CVR Model) for use in conjunction with advanced thermophysiological models, where usually only a total cardiac output is estimated. The CVR Model detailed herein estimates cardio-dynamic parameters (changes in cardiac output, stroke volume, and heart rate), regional blood flow, and muscle oxygen extraction, in response to rest and physical workloads, across a range of ages and aerobic fitness levels, as well as during exposure to heat, dehydration, and altitude. The model development strategy was to first establish basic resting and exercise predictions for cardio-dynamic parameters in an "ideal" environment (cool, sea level, and hydrated person). This basic model was then advanced for increasing levels of altitude, heat strain, and dehydration, using meta-analysis and reaggregation of published data. Using the estimated altitude- and heat-induced changes in maximum oxygen extraction and maximum cardiac output, the decline in maximum oxygen consumption at high altitude and in the heat was also modeled. A validation of predicted cardiovascular strain using heart rate was conducted using a dataset of 101 heterogeneous individuals (1,371 data points) during rest and exercise in the heat and at altitude, demonstrating that the CVR Model performs well (R2 = 0.82-0.84) in predicting cardiovascular strain, particularly at a group mean level (R2 = 0.97). The development of the CVR Model is aimed at providing the Fiala thermal Physiology & Comfort (FPC) Model and other complex thermophysiological models with improved estimations of cardiac strain and exercise tolerance, across a range of individuals during acute exposure to environmental stressors.NEW & NOTEWORTHY The present research promotes the adaption of thermophysiological modeling to the estimation of cardiovascular strain in individuals exercising under acute environmental stress. Integration with advanced models of human thermoregulation opens doors for detailed numerical analysis of athletes' performance and physiology during exercise, occupational safety, and individual work tolerability. The research provides a simple-to-validate metric of cardiovascular function (heart rate), as well as a method to evaluate key principles influencing exercise- and thermoregulation in humans.


MicroRNA-146b acts as a potential tumor suppressor in human prostate cancer.
MicroRNAs (miRs) act as either tumor suppressors or oncogenes and are frequently deregulated in cancers. Although downregulation of miR-146b has been reported in various cancers, its role in prostate cancer is totally unknown. The miR-146b expression in 18 human prostate cancer lines with case-matched adjacent normal tissues was measured by quantitative RT-PCR. Furthermore, the expression levels of miR-146b in normal prostate and prostate cancer cell lines were assessed. Cell proliferation, apoptosis, migration and invasion assays were performed in overexpressing or knockdown miR-146b cells. miR-146b expression was significantly reduced in all prostate tumor tissues. Furthermore, miR-146b was significantly decreased in prostate cancer cells as compared to normal prostate cells. Loss-of-function and gain-of-function showed that miR-146b induced apoptosis and suppressed cell proliferation, migration and invasion of the prostate cancer cell lines. Our results demonstrated that miR-146b expression is downregulated in prostate tumor tissues and is a potential tumor suppressor miR, suggesting that miR-146b might be a potential clinical marker and therapeutic target for prevention and treatment of prostate cancer.


CB(1) receptor mediation of cannabinoid behavioral effects in male and female rats.
Cannabinoids have been shown to produce greater behavioral effects in female than male rats. Although central nervous system CB(1) receptors are known to mediate cannabinoid-induced behavioral effects in male rats, it is not known whether the same is true for females. To determine if cannabinoid-induced antinociception and catalepsy are similarly mediated by central CB(1) receptors in male and female rats. The ability of SR141716A, a CB(1) receptor selective antagonist, administered ICV (1-1000 microg) or IT (1-600 microg) to block 10 mg/kg IP delta(9)-THC-induced antinociception (paw pressure) and catalepsy (bar test), was compared in male and female rats. Delta(9)-THC alone produced slightly greater antinociception, and significantly greater catalepsy in females than males. When administered ICV, SR141716A partially antagonized delta(9)-THC-induced antinociception in both females and males. IT SR141716A also antagonized delta(9)-THC-induced antinociception in both sexes; it was slightly more potent in males but equally effective in males and females. SR141716A antagonized delta(9)-THC-induced catalepsy in a similar manner in males and females when given ICV or IT. These results confirm that delta(9)-THC-induced behavioral effects are mediated by central CB(1) receptors in male and female rats.


Prognostic value of continuous ST-segment monitoring in patients with non-ST-segment elevation acute coronary syndromes.
Patients with non-ST-segment elevation acute coronary syndromes constitute a heterogeneous group concerning prognosis. The 12-lead ECG at rest is recommended for early risk stratification but is unable to reflect the dynamic nature of myocardial ischemia and coronary thrombosis. This study investigated whether continuous ST-segment monitoring provides early prognostic information in such patients. We prospectively studied 183 patients admitted due to chest pain at rest suggestive of an acute coronary syndrome. ST-segment monitoring was performed continuously for 24 hours from admission. Cardiac-specific troponin I levels were determined on admission and every 6 hours for the first 24 hours. The endpoint was defined as death or nonfatal myocardial infarction, whichever occurred first by 30 days follow-up. ST episodes, defined as transient ST deviations of at least 0.1 mV, were detected in 50 patients (27.3%) and associated with worse 30-day outcome: 22.0% endpoint rate compared to 6.8% for patients without ST episodes (P = 0.003). In a multivariate analysis, the presence of ST episodes (hazard ratio, 3.07; 95% CI, 1.26 to 7.46; P = 0.014) and peak troponin I levels > 0.2 microg/L (hazard ratio, 2.65; 95% CI, 1.01 to 6.95; P = 0.048) were independent predictors of prognosis. The combination of ST-segment monitoring and peak troponin I identified patients at low (2.5%, n = 79), intermediate (14.5%, n = 76), and high (25.0%, n = 28) risk for the 30-day endpoint. In patients with non-ST-segment elevation acute coronary syndromes, continuous ST-segment monitoring provides on-line early prognostic information, in addition to troponin I levels.


Postoperative Healthcare Utilization of Elderly Adults After Cochlear Implantation.
To determine the association between geriatric age and postoperative healthcare utilization after cochlear implantation. Retrospective chart review. Tertiary referral center. Older adults (>59 yr) who underwent unilateral cochlear implantation from 2009 until 2016. Standard electrode length cochlear implantation. Postoperative surgical and audiological visit rate after cochlear implantation for those aged 60 to 69, 70 to 79, and 80+ years. Fifty-nine older adult patients were included in the study with a mean age of 71.5 ± 6.9 years (range, 60-88 yr), mean duration of hearing loss of 25.4 ± 19.6 years (range, 0.25-67 yr), and mean length of follow up of 37 ± 24.6 months (range, 6-107 mo). There was no significant difference in the mean number of surgical and audiological visits over both the first and second postoperative years between those aged 60 to 69, 70 to 79, and 80+ years. Additionally, on one-way multivariate analysis of covariance (MANCOVA), there was no significant difference in cumulative postoperative healthcare utilization measures between each age group, when controlling for postoperative AzBio scores, estimated household income, and driving distance to the hospital. Older geriatric adults do not have higher rates of postoperative healthcare utilization after cochlear implantation than their younger, geriatric hearing impaired counterparts, despite presumed higher rates of frailty and comorbidity.


Exploration of the adsorption capability by doping Pb@ZnFe2O4 nanocomposites (NCs) for decontamination of dye from textile wastewater.
In the present research article we explore the synthesis method and adsorption capability of ZnFe oxides nanocomposites by using Pb as dopant. A conventional and simple batch adsorption method is selected and optimized. Pb@ZnFe2O4 NCs were fabricated by facile method i.e. co-precipitation method and characterized by FESEM, XRD, IR, EDX. The removal of dye has monitored by UV method. An outstanding result is obtained as adsorption efficiency of 1042 mg g-1 shows more significant performance than currently available bench-mark adsorbents. The optimized parameters pH 7.1, Adsorbent Mass: 50 mg, Initial Dye Concentration: 150 mg/l and Agitation Time: 90 min results in 96.49 % removal of CR (Congo red) dye. A CCD (central composite design) is applied to evaluate the role of adsorption variables. Based on its excellent performance, cost effectiveness, facile fabrication and large surface area, the Pb@ZnFe2O4 has considerable potential for the manufacture of cost effective and efficient adsorbents for environmental applications.


Molecular basis of morphological changes in mitochondrial membrane accompanying induction of permeability transition, as revealed by immuno-electron microscopy.
The mitochondrial inner membrane typically shows a condensed structure when examined by electron microscopy. However, this typical structure is known to disappear upon induction of the mitochondrial permeability transition (PT). This change in the appearance of the mitochondrial membrane structure that accompanies the induction of PT is thought to reflect changes in the permeability of inner mitochondrial membrane; however, its molecular basis has remained uncertain. In the present study, changes in membrane status were examined by immuno-electron microscopy using antibodies against the voltage-dependent anion channel (VDAC), beta-subunit of F1-ATPase (F1beta), and cytochrome c (cyt. c). In control mitochondria, antibody against VDAC was observed at the rim of the mitochondria, whereas antibodies against F1beta and cytochrome c bound these molecules inside of the mitochondria. However, in PT-induced mitochondria, all three antibodies were observed at the mitochondrial rim. These results strongly suggest that the inner mitochondrial membrane is shoved to the rim region of mitochondria upon induction of mitochondrial PT.


Development and Validation of a Lifetime Risk Model for Kidney Failure and Treatment Benefit in Type 2 Diabetes: 10-Year and Lifetime Risk Prediction Models.
Individuals with type 2 diabetes are at a higher risk of developing kidney failure. The objective of this study was to develop and validate a decision support tool for estimating 10-year and lifetime risks of kidney failure in individuals with type 2 diabetes as well as estimating individual treatment effects of preventive medication. The prediction algorithm was developed in 707,077 individuals with prevalent and incident type 2 diabetes from the Swedish National Diabetes Register for 2002-2019. Two Cox proportional regression functions for kidney failure (first occurrence of kidney transplantation, long-term dialysis, or persistent eGFR <15 ml/min per 1.73 m2) and all-cause mortality as respective end points were developed using routinely available predictors. These functions were combined into life tables to calculate the predicted survival without kidney failure while using all-cause mortality as the competing outcome. The model was externally validated in 256,265 individuals with incident type 2 diabetes from the Scottish Care Information Diabetes database between 2004 and 2019. During a median follow-up of 6.8 years (interquartile range, 3.2-10.6), 8004 (1%) individuals with type 2 diabetes in the Swedish National Diabetes Register cohort developed kidney failure, and 202,078 (29%) died. The model performed well, with c statistics for kidney failure of 0.89 (95% confidence interval, 0.88 to 0.90) for internal validation and 0.74 (95% confidence interval, 0.73 to 0.76) for external validation. Calibration plots showed good agreement in observed versus predicted 10-year risk of kidney failure for both internal and external validation. This study derived and externally validated a prediction tool for estimating 10-year and lifetime risks of kidney failure as well as life years free of kidney failure gained with preventive treatment in individuals with type 2 diabetes using easily available clinical predictors. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2022_11_04_CJN05020422.mp3.


Small-scale gene duplications played a major role in the recent evolution of wheat chromosome 3B.
Bread wheat is not only an important crop, but its large (17 Gb), highly repetitive, and hexaploid genome makes it a good model to study the organization and evolution of complex genomes. Recently, we produced a high quality reference sequence of wheat chromosome 3B (774 Mb), which provides an excellent opportunity to study the evolutionary dynamics of a large and polyploid genome, specifically the impact of single gene duplications. We find that 27 % of the 3B predicted genes are non-syntenic with the orthologous chromosomes of Brachypodium distachyon, Oryza sativa, and Sorghum bicolor, whereas, by applying the same criteria, non-syntenic genes represent on average only 10 % of the predicted genes in these three model grasses. These non-syntenic genes on 3B have high sequence similarity to at least one other gene in the wheat genome, indicating that hexaploid wheat has undergone massive small-scale interchromosomal gene duplications compared to other grasses. Insertions of non-syntenic genes occurred at a similar rate along the chromosome, but these genes tend to be retained at a higher frequency in the distal, recombinogenic regions. The ratio of non-synonymous to synonymous substitution rates showed a more relaxed selection pressure for non-syntenic genes compared to syntenic genes, and gene ontology analysis indicated that non-syntenic genes may be enriched in functions involved in disease resistance. Our results highlight the major impact of single gene duplications on the wheat gene complement and confirm the accelerated evolution of the Triticeae lineage among grasses.


Continuous versus six months a year maximal androgen blockade in the management of prostate cancer: a randomised study.
To evaluate systematically interrupted androgen suppression (SIAS) 6 mo a year compared with continuous androgen suppression (CAS) in prostate cancer treatment. All patients underwent maximal androgen blockade for 6 mo. Then, depending on the randomisation arm, they continued (CAS) or stopped their treatment for 6 mo before they resumed it a year later and so on (SIAS). Primary end points were patient's health-related quality of life (HQOL) and time to progression. Secondary end points were cancer-specific and overall survival. Progression was defined by a clinical event or PSA value exceeding double the value obtained at the end of the first 6 mo of therapy. Sixty-two patients were randomised to CAS and 67 to SIAS. There were no significant differences between groups at baseline. Androgen suppression was associated with HQOL deterioration except for an improvement in urinary symptoms. The 6-mo off-therapy period was not long enough to regain normal testosterone values. There was no difference in HQOL scores between CAS and SIAS except that men in the latter group reported a greater need for painkillers but a better ability to have an erection. Progression occurred in 62 patients (48.1%) with no significant difference between CAS and SIAS with a mean follow-up of 44.8 mo. Death occurred in 41 patients and specific death in 19 patients (10% and 19% of the CAS and SIAS groups, respectively). Although patients in the SIAS group were maintained off-therapy 50% of the time, insufficient testosterone recovery in this group likely explains why differences between the two groups were moderate or absent with regards to HQOL and survival, respectively.


Impurity profiling of acetylspiramycin by liquid chromatography-ion trap mass spectrometry.
Investigation of acetylspiramycin (ASPM) and its related substances was carried out using a reversed-phase liquid chromatography/tandem mass spectrometry method. The identification of impurities in the ASPM complex was performed with a quadrupole ion trap mass spectrometer, with an electrospray ionization (ESI) source in the positive ion mode which provides MS(n) capability. A total of 83 compounds were characterized in commercial samples, among which 31 impurities that had never been reported and 31 partially characterized impurities were deduced using the collision-induced dissociation (CID) spectra of major ASPM components as templates. Most of the major impurities arise from the starting materials and the synthesis process. This work provides very useful information for quality control of ASPM and evaluation of its synthesis process.


The coracoid impingement of the subscapularis tendon: a cadaver study.
To study the anatomic relationships and varieties of anterior impingement of the rotator cuff, an examination of 124 shoulder joints from 62 embalmed cadavers was performed. The distance between the lesser tuberosity and the coracoid was measured at different degrees of humeral rotation in the shoulder joint. Neither lateral differences nor differences with respect to donor gender were found in the distance measurements between the coracoid process and the lesser tuberosity for any rotational angle. In addition, no significant differences were found between shoulders with and without rupture of the subscapularis tendon. No lateral dominance was found for the subscapularis tunnel area.


Potential plants for inflammatory dysfunction in the SARS-CoV-2 infection.
The inflammatory process is a biological response of the organism to remove injurious stimuli and initiate homeostasis. It has been recognized as a key player in the most severe forms of SARS-CoV-2, characterized by significantly increased pro-inflammatory cytokine levels, the so-called "cytokine storm" that appears to play a pivotal role in this disease. Therefore, the aim of this systematic review was to select clinical trials with anti-inflammatory plants and relate the activity of these plants to inflammatory markers of SARS-CoV-2 infection. PRISMA guidelines are followed, and studies of interest are indexed in PubMed and ClinicalTrials.gov databases. As a result, 32 clinical trials encompassing 22 plants were selected. The main anti-inflammatory mechanisms described in the studies are the inhibition of inflammatory cytokines, such as IL-6, TNF-a, IFN-γ, and IL-1; decreased CRP and oxidative marker levels; increased endogenous antioxidant levels; modulation of cardiovascular risk markers. The data found are not directly related to SARS-CoV-2 infection. However, they provide possibilities for new studies as plants have a wide array of phytochemicals, and detecting which ones are responsible for anti-inflammatory effects can provide invaluable contribution to studies aiming to evaluate efficacy in scenarios of SARS-CoV-2 infection.


Results of the treatment of children with recurrent gliomas with lomustine and vincristine.
Gliomas comprise over 50% of all childhood brain tumors. Treatment of recurrent childhood gliomas has been disappointing and the effectiveness of therapy has been difficult to judge because of the variable natural history of the disease. Information gathered recently has suggested that treatment with [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)] (CCNU) and vincristine (VCR) after radiotherapy is effective in prolonging survival in children with newly diagnosed anaplastic gliomas. The authors have used these same drugs--CCNU (100 mg/m2) and VCR (1.5 mg/m2 up to a maximum dose of 2 mg)--in 6-week cycles for a maximum of eight cycles in children with recurrent gliomas. To date, 15 patients have been treated; five patients had malignant gliomas and ten low-grade gliomas. Three children showed improvement, five had stable disease, and seven had progressive disease. Of the five patients with malignant gliomas, four progressed within two cycles of treatment and one had stable disease for 7 months on treatment and then relapsed. Seven of ten children with low-grade gliomas benefitted from treatment and six remain in continuous remission a median of 16 months after initiation of therapy. Three of these children are off all therapy 21, 30, and 30 months after treatment, respectively. Therapy was well tolerated and toxicity consisted primarily of reversible bone marrow suppression. The authors conclude that CCNU and VCR chemotherapy is effective in children with recurrent low-grade gliomas and can result in relatively long-term disease stabilization. In limited experience of the authors, it is not of benefit in children with recurrent anaplastic lesions.


Transforming Health Care from Volume to Value: Moving the Needle Through Population Health.
United States health systems face unique challenges in transitioning from volume-based to value-based care, particularly for academic institutions. Providing complex specialty and tertiary care dependent on servicing large geographic areas, and concomitantly meeting education and research academic missions may limit the time and resources available for focusing on the care coordination needs of complex local populations. Despite these challenges, academic medicine is well situated to capitalize on the promise of value-based care and to lead broad improvements in both teaching and nonteaching hospitals. If properly executed, value-based care and complex specialty care can be complementary and synergistic. We postulate that the transition from volume to value in population health requires all health care organizations to advance and formalize infrastructure in 3 core areas: organizational capabilities; provider engagement; and engagement of the patient, family, and community. Although these apply to all organizations, for academic health systems, this transition must also be interwoven with the other domains of the tripartite mission.


Nickel cobaltite nanowire arrays grown on nitrogen-doped carbon nanotube fiber fabric for high-performance flexible supercapacitors.
Flexible supercapacitors have received considerable attention for their potential application in flexible electronics, but usually suffer from relatively low energy density. Developing flexible electrodes with high capacitance and constructing asymmetric supercapacitors with large potential window has been considered as the most effective approach to achieve high energy density. Here, a flexible electrode with nickel cobaltite (NiCo2O4) nanowire arrays on nitrogen (N)-doped carbon nanotube fiber fabric (denoted as CNTFF and NCNTFF, respectively) was designed and fabricated through a facile hydrothermal growth and heat treatment process. The obtained NCNTFF-NiCo2O4 delivered a high capacitance of 2430.5 mF cm-2 at 2 mA cm-2, a good rate capability of 62.1 % capacitance retention even at 100 mA cm-2 and a stable cycling performance of 85.2 % capacitance retention after 10,000 cycles. Moreover, the asymmetric supercapacitor constructed with NCNTFF-NiCo2O4 as positive electrode and activated CNTFF as negative electrode exhibited a combination of high capacitance (883.6 mF cm-2 at 2 mA cm-2), high energy density (241 μW h cm-2) and high power density (80175.1 μW cm-2). This device also had a long cycle life after 10,000 cycles and good mechanical flexibility under bending conditions. Our work provides a new perspective on constructing high-performance flexible supercapacitors for flexible electronics.


Myelin oligodendrocyte glycoprotein peptide-induced experimental allergic encephalomyelitis and T cell responses are unaffected by immunoproteasome deficiency.
The inoculation of MOG peptides into C57BL/6 mice induces CD4(+) and CD8(+) T cells, and recent work has shown that adoptive transfer of the latter population, after extensive in vitro stimulation, can cause EAE in naïve recipient mice. Herein, we have evaluated the incidence and severity of EAE, and the induction of CD4(+) and CD8(+) T cells, following MOG peptide inoculation of wt mice and of LMP-2KO mice that lack an intact immunoproteasome, a cytoplasmic organelle that is induced by chronic inflammation and that may be important for the presentation of MHC class I epitopes to CD8(+) T cells. We report that EAE, evaluated by both clinical and histological criteria, is similar in LMP-2KO mice and wildtype C57B/6 mice (wt) in response to immunization with MOG peptides MOG(35-55) and MOG(40-54), suggesting that the immunoproteasome does not play a key role in the development of demyelinating disease. Furthermore, and consistent with previous reports, peptide-specific CD8(+) T cells were barely detectable in the CNS of peptide-immunized mice, although peptide-specific CD4(+) T cells were abundant. Therefore, we used a new technique to look for autoreactive CD8(+) T cells in MOG peptide-immunized mice, and we report the identification of CD4(+) and CD8(+) T cells that, as late as 19 days after peptide injection, are actively producing IFNgamma in vivo, in response to in vivo antigen contact.


[Epidermoid carcinoma of paranasal sinuses. 61 cases treated at the Claudius-Reguad Center from 1961 to 1976 (author's transl)].
Authors present a critical review of 61 cases of squamous carcinoma of paranasal sinuses. Most of these cases were diagnosed at an advanced stage, allowing only external radiotherapy to be proposed. The mean delivred dose was 6,000 to 6,500 rads, mainly to telecobaltherapy. Survival rates are poor (SVI = 50%, SV3 = 14%, SV5 = 8%) in the same range than values previously published by others. However, it seems possible to point out some practical trends in order to improve the management of the disease:--in all cases, irradiated volumes must be large;--prophylactic irradiation of cervical nodes in also a key point, especially when tumor reaches the oral cavity, the skin or the pterygomaxillary fossa.


In vitro activity of conventional antifungal drugs and natural essences against the yeast-like alga Prototheca.
Two outbreaks of mastitis due to the yeast-like alga Prototheca zopfii recently occurred in dairy herds in Lombardia (Italy) involving 180 and 150 lactating cows, respectively. To determine the in vitro susceptibility of Prototheca isolates to conventional antifungal agents and to essential oils. Twenty P. zopfii isolated from milk during these outbreaks, six P. zopfii isolated from fresh water and two Prototheca sp. reference strains were submitted to antifungal susceptibility testing by broth microdilution assay following the CLSI guidelines for yeasts. The tested isolates were shown to be resistant to fluconazole and caspofungin. A wide range of voriconazole MICs was observed. In contrast, amphotericin B, itraconazole and posaconazole appeared active with MICs < or = 1 mg/L. Bergamot and tea tree oils seemed to exert an interesting activity against this yeast-like alga. Difficulties in treating animals with conventional drugs and the potent in vitro activity of essential oils demonstrated here raise the interest in further investigations on the therapeutic use of these non-conventional natural products.


Treatment of Fatigue in Parkinson Disease.
Which pharmacological and nonpharmacological interventions are associated with improvement in general, physical, or mental fatigue and minimal adverse effects in patients with Parkinson disease (PD)? Rasagiline, modafinil, and doxepin are associated with improvement in fatigue and are not associated with increased risk of adverse effects in patients with PD. However, the quality of evidence is limited and does not provide a clear basis for treatment decisions.


In vivo MR spectroscopic imaging of polyunsaturated fatty acids (PUFA) in healthy and cancerous breast tissues by selective multiple-quantum coherence transfer (Sel-MQC): a preliminary study.
The spatial distribution of polyunsaturated fatty acids (PUFA) in healthy and cancerous human breast tissues was measured in vivo with a selective multiple-quantum coherence transfer (Sel-MQC) technique. This method selectively detected the olefinic methylene protons (-CH = CH-) of PUFA at 5.3 ppm that were coupled with allylic methylene protons (-CH(2)-CH(2)-CH=) of unsaturated acyl chain at 2.8 ppm. Unwanted lipid coherences and tissue water signal were dephased in a single scan. Breast PUFA were mapped at 1 cm(3) voxel resolution in sagittal slices of nine breasts in six healthy female volunteers that were compared to invasive ductal carcinoma (IDC) in one breast cancer patient. The healthy breast tissue displayed continuous PUFA distribution. In some individuals, PUFA appeared throughout the breast tissue; in others they were only located in the central breast area. Decreased PUFA levels were detected in the IDC of the breast cancer patient. The magnetic resonance spectroscopic imaging (MRSI) measurement was consistent with the histological findings, ultrasound, and mammography images. PUFA patterns are sensitive to abnormal breast tissue changes including malignant transformations, and thus may serve as a biomarker for early diagnosis and therapeutic monitoring of breast disease.


Deciphering the role of protein kinase CK2 in the maturation/stability of F508del-CFTR.
F508del-CFTR, the most common mutation in cystic fibrosis (CF) patients, impairs CFTR trafficking to plasma membrane leading to its premature proteasomal degradation. Several post-translational modifications have been identified on CFTR with multiple roles in stability, localization and channel function, and the possibility to control the enzymes responsible of these modifications has been long considered a potential therapeutic strategy. Protein kinase CK2 has been previously suggested as an important player in regulating CFTR functions and it has been proposed as a pharmacological target in a combinatory therapy to treat CF patients. However, the real implication of CK2 in F508del-CFTR proteostasis, and in particular the hypothesis that its inhibition could be important in CF therapies, is still elusive. Here, by using immortalized cell lines, primary human cells, and knockout cell lines deprived of CK2 subunits, we do not disclose any direct correlation between F508del-CFTR proteostasis and CK2 expression/activity. Rather, our data indicate that the CK2α' catalytic subunit should be preserved rather than inhibited for F508del rescue by the correctors of class-1, such as VX-809, disclosing new important features in CF therapeutic approaches.


PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming.
Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy regulation. Previous studies suggested that PDK4 is increased in the calcified vessels of patients with atherosclerosis and is closely associated with mitochondrial function, but the precise regulatory mechanisms remain largely unknown. This study aims to investigate the role of PDK4 in vascular calcification and the molecular mechanisms involved. Using a variety of complementary techniques, we found impaired autophagic activity in the process of vascular smooth muscle cells (VSMCs) calcification, whereas knocking down PDK4 had the opposite effect. PDK4 drives the metabolic reprogramming of VSMCs towards a Warburg effect, and the inhibition of PDK4 abrogates VSMCs calcification. Mechanistically, PDK4 disturbs the integrity of the mitochondria-associated endoplasmic reticulum membrane, concomitantly impairing mitochondrial respiratory capacity, which contributes to a decrease in lysosomal degradation by inhibiting the V-ATPase and lactate dehydrogenase B interaction. PDK4 also inhibits the nuclear translocation of the transcription factor EB, thus inhibiting lysosomal function. These changes result in the interruption of autophagic flux, which accelerates calcium deposition in VSMCs. In addition, glycolysis serves as a metabolic adaptation to improve VSMCs oxidative stress resistance, whereas inhibition of glycolysis by 2-deoxy-D-glucose induces the apoptosis of VSMCs and increases the calcium deposition in VSMCs. Our results suggest that PDK4 plays a key role in vascular calcification through autophagy inhibition and metabolic reprogramming.


The role of allergen components for the diagnosis of latex-induced occupational asthma.
Recombinant Hevea brasiliensis (rHev b) natural rubber latex (NRL) allergen components have been developed to assess the patients' allergen sensitization profile and to improve the diagnosis of NRL allergy. To examine whether the determination of specific IgE (sIgE) reactivity to a panel of recombinant allergen components would be helpful for diagnosing NRL-induced occupational asthma (OA) in predicting the outcome of a specific inhalation test. sIgE levels to NRL extract and 12 recombinant NRL allergen components were assessed in 82 subjects with OA ascertained by a positive specific inhalation challenge (SIC) with NRL gloves and in 25 symptomatic subjects with a negative challenge. The sensitivity, specificity, positive predictive value, and negative predictive value of a NRL-sIgE level ≥0.35 kUA /l as compared to the result of SICs were 94%, 48%, 86%, and 71%, respectively. The positive predictive value increased above 95% when increasing the cutoff value to 5.41 kUA /l. Subjects with a positive SIC showed a significantly higher rate of sIgE reactivity to rHev b 5, 6.01, 6.02, and 11 than those with a negative SIC. A sIgE sum score against rHev b 5 plus 6.01/6.02 ≥ 1.46 kUA /l provided a positive predictive value >95% with a higher sensitivity (79%) and diagnostic efficiency (Youden index: 0.67) as compared with a NRL-sIgE ≥5.41 kUA /l (49% and 0.41, respectively). In suspected OA, high levels of sIgE against rHev b 5 combined with rHev b 6.01 or 6.02 are the most efficient predictors of a bronchial response to NRL.


Exercise testing of the child with obesity.
As the prevalence of childhood obesity increases, exercise testing of obese children is likely to increase as well. This article discusses the implications of pediatric obesity for exercise testing and provides some recommendations for conducting tests and evaluating results. Studies comparing obese and nonobese children during exercise testing indicate that obese children are capable of meeting the challenges of exercise testing to nearly the same extent as their nonobese peers. Their physiologic responses, at least for the levels of obesity reported in the literature, are not sufficiently different from their nonobese counterparts to necessitate major changes in test protocols. Laboratory staff should pay special attention to fostering confidence in the obese child during the pretest routine.


[Hughes' operation and combined procedures].
The Hughes procedure is a standard and widely used technique for lower eyelid reconstruction. This paper presents the results of 55 patients who underwent reconstruction of the anterior and posterior lamella with the Hughes procedure at the University eye clinic in Salzburg between 2002 and 2012. This study included 55 patients who underwent lower eyelid reconstruction performed with the Hughes procedure including a full skin graft. In 95 % of patients (52/55) this method was performed after tumor resection. The defect size of the lower lid was at least 10 mm horizontally and ranged between 10 and 15 mm. Of the patients three were treated with a combined Hughes and Tenzel procedure whereas in five cases the Hughes procedure was combined with an autologous tarsoconjunctival flap of the contralateral upper lid and a local full skin rotational flap. In 42 out of 55 patients both the eyelid function as well as the restoration of good cosmesis could be achieved. In 6 out of the remaining 13 patients suffering from minor complications, the function and cosmesis were restored after secondary minor surgery or additional conservative treatment. For six patients, further reconstructive surgery was necessary and one experienced a major complication in the form of a recurrence of basal cell carcinoma necessitating exenteration. The Hughes procedure is a well-suited technique for eyelid reconstruction of shallow defects extending beyond 10 mm horizontally and involving up to 100 % of the eyelid. The latter require a combined procedure such as the Hughes procedure and an autologous tarsoconjunctival flap and skin graft.


Left coronary pressure-flow relations of the beating and arrested rabbit heart at different ventricular volumes.
To study the effect of cardiac contraction on left coronary artery pressure-flow relations at different vascular volumes and to compare these relations in the beating heart with those in the heart arrested in systole and diastole. Maximally vasodilated, Tyrode perfused, rabbit hearts (n = 6) with an intra-ventricular balloon were used. The left coronary artery was separately perfused via a cannula in the left main coronary artery. The slopes and the intercepts of left coronary pressure-flow relations were determined in the beating and arrested heart at different chamber volumes. A 3-factor design with repeated measures was used to compare the effect of three factors: phase of contraction (systole and diastole), chamber volume (V0 and V1, left ventricular end-diastolic pressure 1.4 and 20 mm Hg, respectively) and the type of contraction (beating and arrested; a measure of capacitive effects). The phase of contraction has a significant effect on the intercepts (> 40 mmHg, p = 0.00032) but not on the slopes of the pressure-flow relations. Chamber volume had a small effect on the intercepts (< 5 mm Hg, p = 0.037), but not on the slopes of the pressure-flow relations. The type of contraction has a significant effect on the slopes (approximately 10%, p = 0.00021) but not on the intercepts of the pressure-flow relations. In the isolated Tyrode perfused rabbit heart left coronary pressure-flow relations are mainly determined by contraction, while left ventricular chamber volume and capacitive effects contribute little.


Pulsed radiofrequency applied to the suprascapular nerve in painful cuff tear arthropathy.
The purpose of this study was to assess the efficacy of pulsed radiofrequency (PRF) applied to the suprascapular nerve for pain relief in medically unfit patients with painful cuff tear arthropathy. Twelve patients with chronic shoulder pain due to cuff tear arthropathy were recruited. The mean age was 68 years (range, 60-83 years). The suprascapular nerve was targeted at the suprascapular notch with PRF. The patients were assessed with the Oxford score, Constant score, and visual analog scale (VAS) pain score before ablation and 3 and 6 months after ablation. Statistical analysis was undertaken by use of the Friedman test. Ten patients showed improvement in the VAS score (P = .24) and Constant score (P = .005) and eleven in the Oxford score (P = .001). There was a deterioration in the VAS scores between 3 and 6 months, suggesting that the benefits were starting to wear off with time (P > .05). We conclude that PRF may be a useful therapeutic adjunct in patients with painful, end-stage rotator cuff tear arthropathy who are medically unfit for surgery.


The "hot potato" topic: challenges and facilitators to promoting respectful maternal care within a broader health intervention in Tanzania.
In recent years, mistreatment during childbirth has captured the public health and maternal health consciousness as not only an affront to women's rights but also a formidable deterrent to the uptake of facility-based childbirth - and thus to reductions in maternal mortality. The challenge ahead is to determine what can be done to address this public health problem. A modest but growing body of research has demonstrated that interventions to foster Respectful Maternity Care (RMC) can enact change, albeit in the relatively controlled context of a trial or study. Herein we describe our experiences in weaving elements of RMC across tiers of an existing maternal and newborn health program. As a commentary, this document does not outline program results, but instead highlights challenges and facilitators to promoting RMC within a large-scale, multi-district health platform. We conclude with lessons learned during the process and urge that others share their program learning experiences in an effort to strengthen the knowledge base on what works and what does not work in terms of addressing this complex, context-sensitive issue.


Trends in the approval of cancer therapies by the FDA in the twenty-first century.
The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies.


Brachial artery flow-mediated dilation and asymmetrical dimethylarginine in the cardiovascular risk in young Finns study.
Elevated asymmetrical dimethylarginine (ADMA) is a novel risk factor for atherosclerosis that may impair endothelial function by interfering with endothelial nitric oxide synthesis. To gain insight into the effects of ADMA on systemic endothelial function, we examined the association between ADMA and brachial artery flow-mediated dilation (FMD) in a large population of young adults. Plasma ADMA and brachial FMD, as well as conventional cardiovascular risk factors, were measured in 2096 white adults aged 24 to 39 years. In univariate analysis, ADMA was inversely correlated with FMD (r=-0.07, P=0.003). The inverse association between ADMA and FMD remained significant in a multivariable regression model adjusted for age, sex, conventional cardiovascular risk factors, estimated glomerular filtration rate, and brachial artery baseline diameter (beta+/-SE -1.56+/-0.62%, P=0.01). We conclude that elevated plasma ADMA concentrations are associated with decreased brachial FMD responses in healthy adults. These data provide evidence at the population level that ADMA levels are associated with endothelial function.


Divergence of endocardial QT interval components during programmed electrical stimulation including observations during induction of sustained ventricular tachyarrhythmias.
Measurements were made in 12 normal subjects and during induction of sustained ventricular tachyarrhythmias in 31 patients with remote myocardial infarction. QT interval measurements were made semiautomatically with computer assistance and the total QT interval was divided into early (QT1) and late (QT2) components. QT intervals and QT interval dispersion between two right ventricular endocardial sites were plotted against the degree of prematurity of the last extrastimulus (S2, S3, or S4). In the control group, total QT and QT1 intervals shortened with increasing prematurity of the last extrastimulus (p < 0.001). Slopes (positive) were steeper with faster pacing rates (600, 500, or 400 ms) and more extrastimuli (1 to 3). The relationship between QT2 intervals and prematurity of the last extrastimulus was flat, but the slope was slightly negative (p = 0.05 to < 0.001) and did not vary with changes in pacing cycle length or number of extrastimuli. QT interval dispersion in the control group was minor (95% CI 0-40 ms). During induction of sustained ventricular tachyarrhythmias, total QT and QT1 intervals were longer (y intercepts) than in the control group (p < 0.05 at 400-ms pacing cycle length) and their dispersion was increased (p < 0.05). Generally, QT2 intervals were shorter (p < 0.05 at 600-ms pacing cycle length) during induction of ventricular arrhythmias in comparison with the control group but dispersion was increased (p < 0.05 at 400-ms pacing cycle length). QT intervals and QT interval dispersion show an orderly and predictable relationship with prematurity of the last extrastimulus in normal subjects. These patterns differ during induction of sustained ventricular tachyarrhythmias. Such differences may be exploited to derive clinically predictive and useful measurements.


The Mamu B 17-restricted SIV Nef IW9 to TW9 mutation abrogates correct epitope processing and presentation without loss of replicative fitness.
CD8(+) cytotoxic T lymphocytes (CTL) play an important role in controlling virus replication in HIV- and SIV-infected humans and monkeys, respectively. Three well-studied SIV CTL determinants are the two Mamu A()01-restricted epitopes Gag CM9 and Tat SL8, and the Mamu B()17-restricted epitope Nef IW9. Point mutations leading to amino acid replacements in these epitopes have been reported to mediate SIV escape from CTL control. We found that synthetic peptides containing mutations in SIV Gag CM9 and Tat SL8 were no longer recognized by the respective CTL. On the other hand, the described I-to-T replacement at the N-terminal amino acid residue of the SIV Nef IW9 epitope only moderately affected CTL recognition of the variant peptide, TW9. In an attempt to dissect the mechanism of escape of the Nef TW9 mutation, we investigated the effect of this mutation on CTL recognition of CD4(+)T cells infected with an engineered SIV(mac)239 that contained the TW9 mutation in Nef. Although, the wild type and mutant virus both infected and efficiently replicated in rhesus macaque CD4(+)T cells, the TW9 mutant virus failed to induce IFN-gamma expression in an SIV Nef IW9-specific CTL clone. Thus, unlike escape from Gag CM9- or Tat SL8-specfic CTL control presumably by loss of epitope binding, these results point to a defect at the level of processing and/or presentation of the variant TW9 epitope with resultant loss of triggering of the cognate TCR on CTL generated against the wild type peptide. Our data highlight the value of functional assays using virus-infected target cells as opposed to peptide-pulsed APC when assessing relevant escape mutations in CTL epitopes.


MicroRNA-1179 suppresses the proliferation and enhances vincristine sensitivity of oral cancer cells via induction of apoptosis and modulation of MEK/ERK and PI3K/AKT signalling pathways.
The role of miR-1179 in the development of cancer has been proved by different studies. However, the expression profile and role of miR-1179 is yet to be explored in human oral cancer. Consistently, this study was undertaken to explore the molecular role of miR-1179 in regulation of the human oral cancer development and progression. The results showed miR-1179 to be significantly (p < 0.05) overexpressed in all the oral cancer cell lines relative to normal cells. The repression of miR-1179 transcript levels not only suppressed the proliferation of oral cancer cells but also increased their sensitivity to vincristine. The decline in proliferative rates was attributed to induction of autophagy in oral cancer cells as confirmed by transmission electron microscopic analysis. Western blot analysis showed that the expression of LC3B-II increased and that of beclin 1 decreased while LC3B-I expression remained constant upon miR-1179 inhibition. Inhibition of miR-1179 caused significant decrease in the migration and invasion of the oral cancer cells. The migration and invasion found to be 47% and 32% for SCC-9 and 24% and 28% for SCC-25 cells upon miR-1179 inhibition. At molecular level, the miR-1179 was shown to exert its anticancer effects via deactivation of MEK/ERK and PI3K/AKT signalling cascades. In conclusion, the findings point towards the potential of miR-1179 in the treatment of oral cancer.


Cystic duct patch closure of remnant bile duct in living donor hepatectomy when primary closure is difficult: An easy solution.
In living donor hepatectomy, hepatic duct division is a crucial step and often a technical challenge, with the aim of obtaining a good hepatic duct for anastomosis in the recipient and an adequate stump in the donor for closure. Very rarely, after duct division, the remaining stump may not be adequate for primary closure. In such a difficult situation, the options would be either to close stump transversely or a Roux-en-Y Hepaticojejunostomy. We describe a novel surgical technique of "Cystic duct patch repair", utilizing the available local tissues for closure of bile duct wall. Two year follow up of this technique showed satisfactory results with no evidence of stricture and normal liver functions. In living donor hepatectomy, "Cystic duct patch closure" may be used if the post closure cholangiogram is not satisfactory. Although the best method is prevention by ensuring a stump for closure, very rarely this error can occur and can be sorted by cystic duct patch repair.


Clinical differences in spinal opioid efficacy.
The case report describes a patient who presented with two simultaneously-occurring but distinct pain syndromes. Epidural morphine controlled the pain from the abdominoperineal resection, while the pain from a deep venous thrombosis was not masked. Such differential effects of epidural morphine on pain of varying origin supports physiological observations on the specificity of the site of action of spinal opioids.


Effects of delta-9-tetrahydrocannabinol on drug distribution and metabolism. Antipyrine, pentobarbital, and ethanol.
Delta-9-tetrahydrocannabinol (THC) has been reported to inhibit drug metabolism in animals. Twenty-two hospitalized healthy volunteer subjects received THC, 60 to 180 mg/day in divided doses for 14 days. Body weight increased and plasma proteins decreased in all subjects, which is consistent with previously reported plasma volume expansion. Total bilirubin was significantly lower, while other liver function tests remained normal. A within-subject comparison of the pharmacokinetics of antipyrine, pentobarbital, or ethanol given before, during, and after THC was performed. Antipyrine plasma half-life increased during THC in 5 of 6 subjects--mean, 7.9 hr +/- 3.3 (SD) to 9.6 +/- 3.8. Pentobarbital half-life increased in 7 of 8 subjects--mean, 16.9 hr +/- 2.0 to 20.8 +/- 4.2. Blood ethanol disappearance rate decreased in 7 of 8 subjects from a mean of 0.26 mg/100 ml/min +/- 0.05 to 0.23 +/- 0.07. The effect of THC on disappearance rate of these drugs appeared to be due to a combination of: (1) increased distribution volume, due in part to expansion of extracellular fluid volume noted during THC ingestion, and (2) diminished metabolic clearance. THC also delayed absorption of pentobarbital and ethanol in several subjects. This is consistent with THC effects of slowing intestinal motility in animals. The effects of THC on absorption and drug elimination must be considered in evaluating interactions with other drugs.


Deciphering the role of polystyrene microplastics in waste activated sludge anaerobic digestion: Changes of organics transformation, microbial community and metabolic pathway.
Microplastics are ubiquitous in the natural environment, which inevitably affect the relevant biochemical process. Nevertheless, the knowledge about the impacts of microplastics on organics transformation and corresponding microbial metabolism response in anaerobic environment is limited. Here, polystyrene (PS) microplastics were selected as model microplastics to explore their potential impacts on organics transformation, microbial community and metabolic pathway during sludge anaerobic digestion system operation. The results indicated that the PS microplastics exhibited the dose-dependent effects on methane production, i.e., the additive of 20-40 particles/g TS of PS microplastics improved the maximum methane yield by 3.38 %-8.22 %, whereas 80-160 particles/g TS additive led to a 4.78 %-11.04 % declining. Overall, PS microplastics facilitated the solubilization and hydrolysis of sludge, but inhibited the acidogenesis process. Key functional enzyme activities were stimulated under low PS microplastics exposure, whereas were almost severely inhibited due to the increased oxidative stress induced from excess PS microplastics. Microbial community and further metabolic analysis indicated that low PS microplastics improved the acetotrophic and hydrogenotrophic methanogenesis, while a high level of PS microplastics shifted methanogenesis from acetotrophic to hydrogenotrophic pathway. Further analysis showed that the reacted PS microplastics exhibited greater toxicity and ecological than the raw PS microplastics due to that they are more likely to adsorb contaminants. These findings revealed the dosage-dependent relationships between microplastics and organics transformation process in anaerobic environments, providing new insights for assessing the impact of PS microplastics on sludge anaerobic digestion.


Circadian and seasonal variations of glucocorticoid receptors in normal human lymphocytes.
Circulating human lymphocytes are known to contain specific glucocorticoid receptors. Using a competitive binding whole cell assay, we have examined the binding of [3H] dexamethasone to peripheral lymphocytes of normal male subjects. Lymphocytes were found to contain 2000-10000 glucocorticoid receptor sites/cell and the Kd value was in the range of 0.5-9 X 10(-9) M. The number and affinity of glucocorticoid receptors did not change throughout a 1-year observation time. In contrast, there was a significant diurnal variation in receptor content (38% higher at 11 p.m. than at 8 a.m.), while receptor affinity did not change.


Hybrid incompatibility "snowballs" between Solanum species.
Among the reproductive barriers that can isolate species, hybrid sterility is frequently due to dysfunctional interactions between loci that accumulate between differentiating lineages. Theory describing the evolution of these incompatibilities has generated the prediction, still empirically untested, that loci underlying hybrid incompatibility should accumulate faster than linearly with time--the "snowball effect." We evaluated the accumulation of quantitative trait loci (QTL) between species in the plant group Solanum and found evidence for a faster-than-linear accumulation of hybrid seed sterility QTL, thus empirically evaluating and confirming this theoretical prediction. In comparison, loci underlying traits unrelated to hybrid sterility show no evidence for an accelerating rate of accumulation between species.


Clinical protocols and trainee knowledge about mechanical ventilation.
Clinical protocols are associated with improved patient outcomes; however, they may negatively affect medical education by removing trainees from clinical decision making. To study the relationship between critical care training with mechanical ventilation protocols and subsequent knowledge about ventilator management. A retrospective cohort equivalence study, linking a national survey of mechanical ventilation protocol availability in accredited US pulmonary and critical care fellowship programs with knowledge about mechanical ventilation among first-time examinees of the American Board of Internal Medicine (ABIM) Critical Care Medicine Certification Examination in 2008 and 2009. Exposure to protocols was defined as high intensity if an examinee's training intensive care unit had 2 or more protocols for at least 3 years and as low intensity if 0 or 1 protocol. Knowledge, measured by performance on examination questions specific to mechanical ventilation management, calculated as a mechanical ventilation score using item response theory. The score is standardized to a mean (SD) of 500 (100), and a clinically important difference is defined as 25. Variables included in adjusted analyses were birth country, residency training country, and overall first-attempt score on the ABIM Internal Medicine Certification Examination. Ninety of 129 programs (70%) responded to the survey. Seventy-seven programs (86%) had protocols for ventilation liberation, 66 (73%) for sedation management, and 54 (60%) for lung-protective ventilation at the time of the survey. Eighty-eight (98%) of these programs had trainees who completed the ABIM Critical Care Medicine Certification Examination, totaling 553 examinees. Of these 88 programs, 27 (31%) had 0 protocols, 19 (22%) had 1 protocol, 24 (27%) had 2 protocols, and 18 (20%) had 3 protocols for at least 3 years. Forty-two programs (48%) were classified as high intensity and 46 (52%) as low intensity, with 304 trainees (55%) and 249 trainees (45%), respectively. In bivariable analysis, no difference in mean scores was observed in high-intensity (497; 95% CI, 486-507) vs low-intensity programs (497; 95% CI, 485-509). Mean difference was 0 (95% CI, -16 to 16), with a positive value indicating a higher score in the high-intensity group. In multivariable analyses, no association of training was observed in a high-intensity program with mechanical ventilation score (adjusted mean difference, -5.36; 95% CI, -20.7 to 10.0). Among first-time ABIM Critical Care Medicine Certification Examination examinees, training in a high-intensity ventilator protocol environment compared with a low-intensity environment was not associated with worse performance on examination questions about mechanical ventilation management.


Robust photocatalytic water reduction with cyclometalated Ir(III) 4-vinyl-2,2'-bipyridine complexes.
Novel [Ir(C^N)(2)(N^N)](+) complexes with N^N ligands containing vinyl groups were synthesized resulting in quintupled turn-over numbers for the photocatalytic hydrogen production compared to the analogous non-vinyl compounds.


Impact of postoperative endoscopy upon clinical outcomes after endoscopic sinus surgery.
After endoscopic sinus surgery (ESS), endoscopy is used to gauge surgical success and clinical outcomes. Prior studies have not examined this topic prospectively using validated outcome metrics across multiple institutions. A multi-institutional, prospective study of patients with chronic rhinosinusitis (CRS) who underwent ESS completed the 22-item Sino-Nasal Outcome Test (SNOT-22), missed productivity, and medication usage questionnaires 6 months postoperatively. Lund-Kennedy endoscopy scoring (LKES) was performed with reviewers blinded to patient-reported data. A control cohort of non-CRS patients was recruited for comparison. Complete data was available on 183 CRS patients and 48 non-CRS control patients. Approximately 50% of patients achieve perfect or near perfect endoscopy (LKES 0 to 2) after ESS. Postoperative endoscopy correlated with total SNOT-22 scores (r = 0.278, p < 0.001), with the strongest correlations to rhinologic and extranasal subdomains in the nasal polyp cohort. Improved postoperative endoscopy was associated with decreased antibiotic and oral steroid usage, but had little association with missed productivity. Among patients who achieved near perfect postoperative endoscopy, those with nasal polyps had SNOT-22 scores that were similar to non-CRS control patients (mean SNOT-22 scores 17.7 and 16.3, respectively). However, CRS patients without nasal polyps remained more symptomatic than non-CRS controls and CRS with nasal polyps patients despite nearly perfect endoscopy (mean SNOT-22 score 21.6). Postoperative endoscopy correlates with SNOT-22 and medication usage in CRS patients. Polyp patients who achieve near perfect endoscopy have similar symptoms to healthy controls; however, nonpolyp patients with near perfect endoscopy still have rhinologic and extranasal symptoms that are worse than healthy controls.


Synthesis of some 1,4,5,6,7,8-hexahydroquinoline derivatives and their calcium antagonistic activity.
Twenty-seven new 2-methyl-3-acetyl-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives have been prepared. Their structures were confirmed by UV, IR, 1H-NMR and elementary analysis. The calcium antagonistic activity of these compounds was tested in K(+)-depolarized taenia coli precontracted with 1 mmol/l Ca+2.


Structure elaboration of isoniazid: synthesis, in silico molecular docking and antimycobacterial activity of isoniazid-pyrimidine conjugates.
Designing small molecule-based new drug candidates through structure modulation of the existing drugs has drawn considerable attention in view of inevitable emergence of resistance. A new series of isoniazid-pyrimidine conjugates were synthesized in good yields and evaluated for antitubercular activity against the H37Rv strain of Mycobacterium tuberculosis using the microplate Alamar Blue assay. Structure-anti-TB relationship profile revealed that conjugates 8a and 8c bearing a phenyl group at C-6 of pyrimidine scaffold were most active (MIC99 10 µM) and least cytotoxic members of the series. In silico docking of 8a in the active site of bovine lactoperoxidase as well as a cytochrome C peroxidase mutant N184R Y36A revealed favorable interactions similar to the heme enzyme catalase peroxidase (KatG) that activates isoniazid. This investigation suggests a rationale for further work on this promising series of antitubercular agents.


Quantification of dopamine transporters in the mouse brain using ultra-high resolution single-photon emission tomography.
Functional imaging of small animals, such as mice and rats, using ultra-high resolution positron emission tomography (PET) and single-photon emission tomography (SPET), is becoming a valuable tool for studying animal models of human disease. While several studies have shown the utility of PET imaging in small animals, few have used SPET in real research applications. In this study we aimed to demonstrate the feasibility of using ultra-high resolution SPET in quantitative studies of dopamine transporters (DAT) in the mouse brain. Four healthy ICR male mice were injected with (mean+/-SD) 704+/-154 MBq [(99m)Tc]TRODAT-1, and scanned using an ultra-high resolution SPET system equipped with pinhole collimators (spatial resolution 0.83 mm at 3 cm radius of rotation). Each mouse had two studies, to provide an indication of test-retest reliability. Reference tissue kinetic modeling analysis of the time-activity data in the striatum and cerebellum was used to quantitate the availability of DAT. A simple equilibrium ratio of striatum to cerebellum provided another measure of DAT binding. The SPET imaging results were compared against ex vivo biodistribution data from the striatum and cerebellum. The mean distribution volume ratio (DVR) from the reference tissue kinetic model was 2.17+/-0.34, with a test-retest reliability of 2.63%+/-1.67%. The ratio technique gave similar results (DVR=2.03+/-0.38, test-retest reliability=6.64%+/-3.86%), and the ex vivo analysis gave DVR=2.32+/-0.20. Correlations between the kinetic model and the ratio technique ( R(2)=0.86, P<0.001) and the ex vivo data ( R(2)=0.92, P=0.04) were both excellent. This study demonstrated clearly that ultra-high resolution SPET of small animals is capable of accurate, repeatable, and quantitative measures of DAT binding, and should open up the possibility of further studies of cerebral binding sites in mice using pinhole SPET.


Functions for diverse metabolic activities in heterochromatin.
Growing evidence demonstrates that metabolism and chromatin dynamics are not separate processes but that they functionally intersect in many ways. For example, the lysine biosynthetic enzyme homocitrate synthase was recently shown to have unexpected functions in DNA damage repair, raising the question of whether other amino acid metabolic enzymes participate in chromatin regulation. Using an in silico screen combined with reporter assays, we discovered that a diverse range of metabolic enzymes function in heterochromatin regulation. Extended analysis of the glutamate dehydrogenase 1 (Gdh1) revealed that it regulates silent information regulator complex recruitment to telomeres and ribosomal DNA. Enhanced N-terminal histone H3 proteolysis is observed in GDH1 mutants, consistent with telomeric silencing defects. A conserved catalytic Asp residue is required for Gdh1's functions in telomeric silencing and H3 clipping. Genetic modulation of α-ketoglutarate levels demonstrates a key regulatory role for this metabolite in telomeric silencing. The metabolic activity of glutamate dehydrogenase thus has important and previously unsuspected roles in regulating chromatin-related processes.


Removal of the more-experienced eye decreases visual field deficits in cats reared with unequal alternating monocular exposure.
Unequal alternating monocular exposure produces a nasal field deficit for the less-experienced eye, which persists despite prolonged unrestricted binocular exposure. We now report that this deficit decreases after the more experienced eye is removed. Prior to enucleation, the visual field of the less-experienced eye was restricted to the temporal hemifield; 5 months after enucleation of the more-experienced eye, this field extended into the nasal field. Our results are consistent with those in monocularly-deprived cats, and with the occasional recovery of human amblyopes after loss of the fixating eye.


Shrub cover homogenizes small mammals' activity and perceived predation risk.
Altered disturbance regimes, increasing atmospheric CO2, and other processes have increased woody cover and homogenized vegetation in savannas across the planet. African savannas with extensive versus minimal woody cover often have vastly different animal communities. However, we lack a clear mechanistic understanding of why animal communities are changing with vegetation structure. Our goal for this study was to understand how vegetation structure in an African savanna shaped the perceived predation risk of small mammals, hence affecting their activity. Using a reciprocal measure of standard giving-up-densities, amount of food eaten, we found sharp declines in rodents' perceived predation risk and increased rodent activity underneath shrub cover. This response was consistent across species; however, species showed subtle differences in their responses to grassy vegetation. Our findings suggest that areas of minimal or extensive shrub cover (shrub encroachment) may be homogenizing rodents' perceptions of predation risk and thus shaping their use of space.


Probocis lateralis: case report and embryologic analysis.
A child with a lateral trunk replacing one side of the external nose is presented with a detailed X-ray study of the deformed head. In the explanation of the etiology and teratogenesis of this facial anomaly, the modern embryologic development of the head is reviewed and correlated with the findings of this anomaly. It is felt that the lesion responsible for a proboscis lateralis involves the organizer tissue for the naso-face. As a secondary phenomenon, the development of the maxillary process is retarded and a spectrum of defects, common to many mid-face derangements, is identified and explained.


Circularly polarized luminescence spectroscopy reveals low-energy excited states and dynamic localization of vibronic transitions in CP43.
Circularly polarized luminescence (CPL) spectroscopy is an established but relatively little-used technique that monitors the chirality of an emission. When applied to photosynthetic pigment assemblies, we find that CPL provides sensitive and detailed information on low-energy exciton states, reflecting the interactions, site energies and geometries of interacting pigments. CPL is the emission analog of circular dichroism (CD) and thus spectra explore the optical activity only of fluorescent states of the pigment-protein complex and consequently the nature of the lowest-energy excited states (trap states), whose study is a critical area of photosynthesis research. In this work, we develop the new approach of temperature-dependent CPL spectroscopy, over the 2-120 K temperature range, and apply it to the CP43 proximal antenna protein of photosystem II. Our results confirm strong excitonic interactions for at least one of the two well-established emitting states of CP43 named "A" and "B". Previous structure-based models of CP43 spectra are evaluated in the light of the new CPL data. Our analysis supports the assignments of Shibata et al. [Shibata et al. J. Am. Chem. Soc. 135 (2013) 6903-6914], particularly for the highly-delocalized B-state. This state dominates CPL spectra and is attributed predominantly to chlorophyll a's labeled Chl 634 and Chl 636 (alternatively labeled Chl 43 and 45 by Shibata et al.). The absence of any CPL intensity in intramolecular vibrational sidebands associated with the delocalized "B" excited state is attributed to the dynamic localization of intramolecular vibronic transitions.


Biotransformation of Cobicistat: Metabolic Pathways and Enzymes.
Cobicistat (COBI) is a pharmacoenhancer for antiretroviral therapy. The current study was designed to profile the metabolic pathways of COBI and to determine the enzymes that contribute to COBI metabolism. We screened COBI metabolites in mice and human liver microsomes. We also used cDNAexpressed human cytochromes P450 (CYPs) to explore the role of human enzymes in COBI metabolism. Twenty new and three known metabolites of COBI were identified in mouse urine and feces. These new metabolic pathways of COBI include glycine conjugation, N-acetyl cysteine conjugation, morpholine ring-opening, and thiazole ring-opening. Twelve of COBI metabolites were further confirmed in mouse and human liver microsomes, including nine new metabolites. Consistent with the previous report, CYP3A4 and CYP2D6 were determined as the major enzymes that contribute to COBI metabolism. This study provided a full map of COBI metabolism. These results can be used to manage CYP-mediated drug-drug interactions and adverse drug reactions that are associated with COBI-containing regimens in human.


Pore-Scale Experimental Investigation of the Effect of Supercritical CO2 Injection Rate and Surface Wettability on Salt Precipitation.
Injectivity is one of the most important factors to evaluate the feasibility of CO2 geological storage. Salt precipitation due to the mass of dry CO2 injected into a saline reservoir may cause a significant decrease in injectivity. However, the coupling effect of injection parameters and reservoir conditions on salt precipitation is not clear. Here, we conducted pore-scale visualization experiments to study the morphology and distribution of salt precipitation in porous structures and their effects on permeability reduction. The experimental results are achieved by controlling the supercritical CO2 injection rate and the surface wettability at the reservoir temperature and pressure. It is found that for hydrophilic and neutral porous surfaces, ex situ precipitation occurs and blocks the entirety of pore throats and bodies, which results in a significant reduction in permeability. Increasing the CO2 injection rate can suppress the capillary reflow and prevent the permeability reduction. For a hydrophobic porous surface, in situ precipitation occurs and occupies much smaller pore volume, which has a slight effect on permeability reduction compared to the hydrophilic samples at the same injection rate. Increasing the CO2 injection rate and dewetting the injection well and formation nearby reduce the possibility of salt accumulation, which has less effect on CO2 injectivity.


Reconstructing the blood metabolome and genotype using long-range chromatin interactions.
-Maintenance of tight controls on circulating blood metabolites is crucial to normal, healthy tissue and organismal function. A number of single nucleotide polymorphisms (SNPs) have been associated with changes in the levels of blood metabolites. However, the impacts of the metabolite-associated SNPs are largely unknown because they fall within non-coding regions of the genome. -We aimed to identify genes and tissues that are linked to changes in circulating blood metabolites by characterizing genome-wide spatial regulatory interactions involving blood metabolite-associated SNPs. -We systematically integrated chromatin interaction (Hi-C), expression quantitative trait loci (eQTL), gene ontology, drug interaction, and literature-supported connections to deconvolute the genetic regulatory influences of 145 blood metabolite-associated SNPs. -We identified 577 genes that are regulated by 130 distal and proximal metabolite-associated SNPs across 48 different human tissues. The affected genes are enriched in categories that include metabolism, enzymes, plasma proteins, disease development, and potential drug targets. Our results suggest that regulatory interactions in other tissues contribute to the modulation of blood metabolites. -The spatial SNP-gene-metabolite associations identified in this study expand on the list of genes and tissues that are influenced by metabolic-associated SNPs and improves our understanding of the molecular mechanisms underlying pathologic blood metabolite levels.


Baseline characteristics as 3-year predictors of tooth fracture and crack progression: Findings from The National Dental Practice-Based Research Network.
The authors of this practice-based study estimated the risk of experiencing tooth fractures and crack progression over 3 years and correlated baseline patient-, tooth-, and crack-level characteristics with these outcomes. Two-hundred-and-nine National Dental Practice-Based Research Network dentists enrolled a convenience sample of 2,601 participants with a cracked vital posterior tooth that had been examined for at least 1 recall visit over 3 years. Data were collected at the patient, tooth, and crack levels at baseline, annual follow-up visits, and any interim visits. Associations between these characteristics and the subsequent same-tooth fractures and crack progression were quantified. Of the 2,601 teeth with a crack or cracks at baseline, 78 (3.0%; 95% confidence interval, 2.4% to 3.7%) subsequently developed a fracture. Of the 1,889 patients untreated before year 1, 232 (12.3%; 95% confidence interval, 10.9% to 13.8%) had some type of crack progression. Baseline tooth-level characteristics associated with tooth fracture were the tooth was maxillary and had a wear facet through enamel and a crack was detectable with an explorer, on the facial surface, and in a horizontal direction. Crack progression was associated with males and teeth with multiple cracks at baseline; teeth with a baseline facial crack were less likely to show crack progression. There was no commonality between characteristics associated with tooth fracture and those associated with crack progression. Development of tooth fractures and crack progression over 3 years were rare occurrences. Specific characteristics were associated with the development of tooth fracture and crack progression, although none were common to both. This information can aid dentists in assessing factors that place posterior cracked teeth at risk of experiencing adverse outcomes.


The purification of Q-containing tRNAs by periodate modification. Purification and nucleoside composition of two related Drosophila tyrosine tRNAs.
A simple procedure for the purification of Drosophila tRNAs which contain the hypermodified nucleoside Q was developed. The cis-diol group of Q renders it susceptible to attack by sodium periodate, with the resultant formation of a hydrophobic pyrrol ring structure. The increase in hydrophobicity after periodate modification, of those tRNA species which contain the Q nucleoside, causes them to be selectively retarded on benzoylated DEAE-cellulose or RPC-5 columns, and allows their isolation in essentially pure form. Utilizing this property, the Q-containing tyrosine tRNA from Drosophila, tRNATyr1delta, was purified. The non-Q-containing tyrosine tRNA, tRNA, tRNATyr1gamma, was also purified, and the nucleoside compositions of the two were determined and compared. In addition to the Q nucleoside, these tRNAs appear to differ by the presence (tRNATyr1delta) or absence (tRNATyr1gamma) of 5-methylcytidine. In all other respects, these tRNAs appear to be identical, and are probably products of the same gene which differ in their levels of post-transcriptional modification.


Denver Developmental Test Findings and their Relationship with Sociodemographic Variables in a Large Community Sample of 0-4-Year-Old Children.
The aim of this study was to investigate the prevalence of developmental problems and relationship with sociodemographic variables in a community sample of young children. Participants included 1000 children (558 males, 442 females, age range 1-48 months, mean 18.4 months, SD 7.8 months). Children were referred generally by their parents for developmental evaluation and consultation in response to a public announcement in a district area in Istanbul, Turkey. An interview form and the Denver Developmental Screening Test II (DDST) were used for sociodemographic data and developmental evaluation. The χ2 test and Pearson's correlation test were used for data analysis. Seven hundred forty-one out of 1000 children (74.1%) had normal, 140 (14%) had risky, and 119 (11.9%) had abnormal findings on the DDST results. The probability of abnormal findings on the DDST results was significantly higher in males (p=0.003), the 2-4-year-old group (p<0.05), families with more than one child (p=0.001), consanguineous marriages (p<0.01), low parental educational levels and low household income (p<0.01), and in children without a history of breastfeeding (p=0.000). Immigration status and delivery mode did not have a significant effect on the probability of abnormal findings on the DDST results (p>0.05). Sociodemographic factors have a noteworthy impact on development. Determining these factors is important especially during the first years of life.


Heligmosomoides polygyrus: retarded development and stunting of larvae by antibodies specific for excretory/secretory antigens.
The migration of young adult-stage Heligmosomoides polygyrus from beneath the muscularis mucosa to the lumen of the intestine was monitored to compare the rate of development and maturation of larvae in normal and previously infected mice. The development of surviving larvae was significantly retarded in mice that had experienced one or more previous infections and the adult worms arising from a challenge infection were stunted and appeared anaemic. Identical effects were observed with worms recovered from mice that had been injected with immune mouse serum at the time of challenge, and the magnitude of these effects was related to the amount of serum given. Larval maturation was also retarded in mice immunized with larval excretory/secretory (ES) antigens, even though the antibody response was poor due to the very small (submicrogram) amounts of antigen available for injection. In contrast, larvae developed at a normal rate in mice that had been hyperimmunized with killed exsheathed larvae. These mice had serum antibody titres against both "internal" and cuticular antigens similar to those of highly immune (4x-infected) mice, but they had no detectable antibody against ES antigens. The results indicate that the growth and development in vivo of H. polygyrus larvae are retarded by antibodies specific for larval ES antigens. Stunting is permanent, with female worms being affected more severely than males and egg output per worm correspondingly reduced.


Long noncoding RNA H19 act as a competing endogenous RNA of Let-7g to facilitate IEC-6 cell migration and proliferation via regulating EGF.
Intestinal mucosal injury is one of the most significant complications of burns. In our previous study, it was found that autophagy could alleviate burn-induced intestinal injury, but the underlying mechanisms are still unclear. Irregular expression of long noncoding RNAs (lncRNAs) is present in many diseases, including burns. However, the relationship between lncRNAs and intestinal mucosal injury requires further elucidation. In this study, we established a burn mice model and detected the expression level of autophagy-related proteins. Then, H19 content after autophagy intervention was tested in vitro and in vivo. The interaction of H19 with Let-7g and that of Let-7g with epidermal growth factor (EGF) were verified by dual-luciferase reporter assays. We found that the expression of the autophagy-associated proteins LC3-II and Beclin-1 was raised in the intestinal tract of the burn mice model. Similarly, the transfection of H19 raised autophagy levels. H19 was elevated after autophagy intervention in vitro and in vivo. H19 overexpression was able to promote IEC-6 cell migration and proliferation. Let-7g was suppressed by the overexpression of H19 and the combination of Let-7g mimic was able to abolish the physiological effect of H19. Moreover, the suppression of Let-7g increased the expression of EGF protein, which heightened IEC-6 cell migration and proliferation. Besides this, dual-luciferase assays revealed that Let-7g was a direct target of H19 as well as the EGF gene. Taken together, autophagy-mediated H19 increases in mouse intestinal tract after severe burn and functions as a sponge to Let-7g to regulate EGF, which suggests that H19 serves as a potential therapeutic target and biomarker for intestinal mucosal injury after burns.


Naturalistic distraction and driving safety in older drivers.
In this study, we aimed to quantify and compare performance of middle-aged and older drivers during a naturalistic distraction paradigm (visual search for roadside targets) and to predict older drivers performance given functioning in visual, motor, and cognitive domains. Distracted driving can imperil healthy adults and may disproportionally affect the safety of older drivers with visual, motor, and cognitive decline. A total of 203 drivers, 120 healthy older (61 men and 59 women, ages 65 years and older) and 83 middle-aged drivers (38 men and 45 women, ages 40 to 64 years), participated in an on-road test in an instrumented vehicle. Outcome measures included performance in roadside target identification (traffic signs and restaurants) and concurrent driver safety. Differences in visual, motor, and cognitive functioning served as predictors. Older drivers identified fewer landmarks and drove slower but committed more safety errors than did middle-aged drivers. Greater familiarity with local roads benefited performance of middle-aged but not older drivers.Visual cognition predicted both traffic sign identification and safety errors, and executive function predicted traffic sign identification over and above vision. Older adults are susceptible to driving safety errors while distracted by common secondary visual search tasks that are inherent to driving. The findings underscore that age-related cognitive decline affects older drivers' management of driving tasks at multiple levels and can help inform the design of on-road tests and interventions for older drivers.


Hyalinizing trabecular tumor of the thyroid gland: characteristic features on ultrasonography.
We report a case of hyalinizing trabecular tumor of the thyroid gland and describe the characteristic ultrasonographic features of this tumor. This was a rare tumor of follicular cell origin with a trabecular pattern of growth and marked intratrabecular hyalinization. The tumor had an irregular shape, a delicately jagged border, and hypoechoic and heterogeneous internal echoes on B-mode ultrasonography. Very rich intratumoral blood flow, the so-called "tumor inferno" was evident on power Doppler ultrasonography. In the clinical management of thyroid nodules, clinicians should be aware of this peculiar type of thyroid tumor and its characteristic ultrasonographic findings.


Prediction of sinus node dysfunction in patients with long-standing persistent atrial fibrillation using the atrial fibrillatory cycle length.
Sinus node dysfunction (SND) occasionally coexists with long-standing atrial fibrillation (AF) but is unidentifiable during AF. We aimed to identify the predictors of underlying SND when deciding the indications for long-standing persistent AF ablation. We included 105 patients undergoing ablation of long-standing persistent AF to assess the frequency of a permanent pacemaker implantation (PMI) for SND that manifested after sinus conversion and to determine the relationship between the corrected sinus node recovery time (CSNRT) and other clinical parameters obtained before the ablation including the atrial fibrillatory cycle length (AFCL). We identified 7 patients (7%) requiring a PMI for SND after AF termination. The patients with a PMI were nearly all females (6/7) and had a significantly longer CSNRT (1197 ± 647 vs 612 ± 349 milliseconds; P = .0046) and more prolonged AFCL (179 ± 19 vs 153 ± 22 milliseconds; P = .0028) than those without. The age (r = 0.26; P = .011), female sex (r = 0.25; P = .012), hypertension (r = 0.22; P = .038), and AFCL (r = 0.4; P < .0001) were significantly correlated with the CSNRT. A stepwise multivariate linear regression analysis including these parameters revealed that the AFCL was the only independent determinant of the CSNRT (β = 0.38; P = .0012). A receiver operating characteristic curve identified an AFCL of more than 162 milliseconds as the optimal cutoff value for predicting SND requiring a PMI (area under the curve, 0.84; sensitivity, 86%; specificity, 74%; P = .0066). A prolonged AFCL was significantly associated with SND. Thus, assessing the AFCL in the patients with long-standing persistent AF may be helpful for the risk stratification of underlying SND.


Synthesis and anti-inflammatory testing of some new compounds incorporating 5-aminosalicylic acid (5-ASA) as potential prodrugs.
This work includes the synthesis of 15 final compounds (6a-h and 7b-h) as prodrugs of 5-ASA in the form of the acid itself, esters and amides linked by an amide linkage through a spacer to the endocyclic ring N of nicotinamide. Also, 15 new intermediate compounds were prepared. The target compounds (6b, 6f, 7b, and 7e-h) revealed potent analgesic and anti-inflammatory activities in comparison to sulfasalazine and 5-ASA. In addition, ulcerogenicity, LD50, in vivo and in vitro metabolism of compound 7f were determined.


Testicular AQP1 expression in a rat model of testicular Ischemia-Reperfusion injury.
Aquaporin 1 (AQP1) is the archetype of all aquaporins and involved in rapid cellular water fluxes and cell volume regulation. This study was conducted for the investigation of AQP1 expression in normal testicular tissues and those with I/R injury in a rat model. A TT rat model was established using male Wister rats (4 weeks old, 180-220 g), and AQP1 distribution in the testicular tissues was detected by immunohistochemistry. The wet/dry (W/D) weight ratios of the testes were determined at 12 h, 24 h, 36 h, 48 h, or 5 days after the establishment of the TT model. At each time point, pathological sections were prepared and the mRNA and protein expression levels of AQP1 were determined by RT-qPCR and Western blotting, respectively. Immunohistochemical staining indicated that AQP1 distributes in testicular vascular endothelial cells and interstitial connective tissues. The testicular edema was observed 12 and 24 h after TT, as indicated by the increase in wet/dry weight ratio and pathological changes, such as enlarged testicular interstitium, atrophy of spermatogenic tubules, and epineurium tubule exfoliation. Increase in the expression levels of Aqp1 mRNA and AQP1 protein levels peaked at 24 h. Edema was alleviated at 36 and 48 h, as manifested by the gradual thinning of the spermatogenic tubules epithelium with narrowed interstitium and weakened inflammatory cell infiltration. Meanwhile, the mRNA and protein levels of AQP1 dramatically decreased. At 5 days after TT, edema was nearly absent, and the mRNA and protein levels of AQP1 were restored to basal levels. Testicular torsion increases AQP1 expression and W/D ratios in testis tissues. The upregulation of AQP1 expression and decline in AQP1 level are consistent to the development and alleviation of edema in testis tissues that underwent testicular torsion. Changes in AQP1 expression were consistent with edema severity in the testes, indicating a close relationship between the expression of AQP1 and the extent of edema in testicular I/R.


Metabolic syndrome and risk of death in older adults with major psychiatric disorders: Results from a 5-year prospective multicenter study.
No study has explored the association of individual components of metabolic syndrome with mortality in older patients with psychiatric disorders. In this report, we examined whether metabolic syndrome or any of its components predicted mortality in a cohort of older adults with psychiatric disorders. We used data from a multicenter 5-year prospective cohort, including 634 in- and out-patients with schizophrenia, bipolar or major depressive disorder. Metabolic syndrome was assessed at baseline following NCEP-ATPIII criteria. Cause of death was categorized as cardiovascular disorder (CVD) mortality, non-CVD disease-related mortality (e.g., infections), suicide and accident. 122 participants (44.0%) were diagnosed with metabolic syndrome at baseline. In the full sample, there was no significant association between metabolic syndrome or any of its components with all-cause, CVD and non-CVD mortality. However, for the subpopulation of older adults with major depressive disorder, metabolic syndrome was significantly associated with increased all-cause and disease-related mortality after adjustment for age, sex and smoking status (p = 0.032 and p = 0.036, respectively). There was a significant interaction between metabolic syndrome and psychiatric diagnoses indicating that in participants with major depressive disorder, metabolic syndrome had a significantly greater effect on all-cause mortality (p = 0.025) and on disease-related mortality (p = 0.008) than in participants with either bipolar disorder or schizophrenia. Our findings do not support an association between metabolic syndrome and increased mortality in older patients with major psychiatric disorders. Several explanations are discussed, including a survival bias, a lack of sensitivity of the used cut-offs and a ceiling effect of metabolic syndrome on mortality in this very high-risk population. The latter hypothesis could also explain the significant association between metabolic syndrome and mortality in the depressive subgroup, where a ceiling effect is yet to be reached, given the less marked premature mortality in depressive patients compared to those with bipolar disorder or schizophrenia.


Analyzing bioterror response logistics: the case of smallpox.
To evaluate existing and alternative proposals for emergency response to a deliberate smallpox attack, we embed the key operational features of such interventions into a smallpox disease transmission model. We use probabilistic reasoning within an otherwise deterministic epidemic framework to model the 'race to trace', i.e., attempting to trace (via the infector) and vaccinate an infected person while (s)he is still vaccine-sensitive. Our model explicitly incorporates a tracing/vaccination queue, and hence can be used as a capacity planning tool. An approximate analysis of this large (16 ODE) system yields closed-form estimates for the total number of deaths and the maximum queue length. The former estimate delineates the efficacy (i.e., accuracy) and efficiency (i.e., speed) of contact tracing, while the latter estimate reveals how congestion makes the race to trace more difficult to win, thereby causing more deaths. A probabilistic analysis is also used to find an approximate closed-form expression for the total number of deaths under mass vaccination, in terms of both the basic reproductive ratio and the vaccination capacity. We also derive approximate thresholds for initially controlling the epidemic for more general interventions that include imperfect vaccination and quarantine.


The effect of soil amendment derived from P-enhanced sludge pyrochar on ryegrass growth and soil microbial diversity.
The application of pyrolyzed sewage sludge for land remediation is increasingly being considered as a technical solution to reuse nutrients in the sludge and mitigate the burden of sludge treatment. In this study, the enhancement effect of Ca-based additives, via phosphorus pyrolysis transformation promotion, was systematically investigated for the growth of ryegrass and soil microbial diversity. In the pot experiment, pyrochar-modified methods mainly changed the content of available phosphorus and organic matter in the soil and then affected ryegrass growth. Soils treated with pyrochar prepared with CaO and Ca(OH)2 addition were dominated by phosphorus precipitation-capable Ramlibacter, while metal uptake-accelerating Massilia showed a high prevalence in the group treated with pristine sludge pyrochar. The results showed that the species composition of CaO and Ca(OH)2 treated groups were similar, while the groups treated with Ca3(PO4)2 and pristine sludge pyrochar exhibited similar compositional structures of microbial species. Furthermore, less than 3% of Pb accumulated in the shoots of the Ca-based additive-treated groups, but more than 35% of Pb was distributed in shoots treated with pristine sludge pyrochar. Therefore, the application of P-enhanced pyrochar adjusted by Ca-based additives to soil was beneficial to the growth of ryegrass and preventing metal transfer from soil to ryegrass. Based on both macroscopic and microscopic information, we summarized the promotion effect of P-enhanced pyrochar on ryegrass growth and soil physicochemical properties with the aim of designing a smart pyrochar for waste-to-resource applications.