The cytokeratin profile of medullary carcinoma of the breast.
The cytokeratin (CK) phenotype and vimentin expression of 31 medullary carcinomas was studied using commercially available antibodies on archived material. Comparing the phenotype of typical and atypical tumours and the phenotype of metastases, the biological significance of cytokeratin and vimentin expression in medullary carcinomas of the breast was determined. Antibodies to CK4, CK5 and 6, CK7, CK14, CK8 and 18, CK19, CK20 and to vimentin were used. All the typical and atypical medullary carcinomas and the metastases (10 cases) stained negatively for CK4 and positively for CK8-18 (CAM5.2). Almost all the tumours were CK7 and CK19 positive and CK20 negative. Twelve per cent of the tumours contained CK14. Twenty-five per cent of the typical, 43% of the atypical and 20% of the metastatic medullary carcinomas showed CK5-6 positivity. No association between the cytokeratin-vimentin profile of the tumours and axillary node metastases, tumour size or oestrogen receptor status was found but instability of CK expression was demonstrated by comparing the primary tumours with their metastases. : Medullary carcinomas of the breast express all the glandular type CKs including CK19 and additionally a proportion of the tumours expresses some of the CKs typical for myoepithelial cells. There was no correlation with prognostic factors.


The histoautoradiographic localization of taurocholate in rat liver after bile duct ligation. Evidence for ongoing secretion and reabsorption processes.
To determine whether in complete obstructive cholestasis taurocholate is taken up by hepatocytes and if so whether it is secreted into bile, tritium-labelled taurocholate was localized by histoautoradiography on cryoslices from normal rat livers and from those after bile duct ligation. In non-cholestatic livers the hepatocytes of acinar zones 1 as well as the lumina and the epithelia of bile ductules and ducts became intensely labelled directly after injection of [3H]taurocholate into a mesenterial vein. Four hours and 4 days after bile duct ligation, hepatocytes of all three acinar zones became labelled, but in contrast to the normal state, pericanalicular concentration of silver grains was not observed, not even within 5 min. Fifteen days after bile duct obstruction, cryoslices taken 2 min after injection of [3H]taurocholate exhibited an intense silver grain labelling of all acinar zones, with the highest density at bile canalicular areas of the liver cell plates as well as the proliferated bile ductules and bile ducts. The biliary epithelium of small bile ductules and ducts of non-cholestatic and of bile duct-obstructed livers were also covered with silver grains; the epithelium of larger ducts exhibited significant labelling predominantly at the lateral sites of the cells. The biliary epithelium of the common bile duct was not significantly labelled. The results indicate that in complete obstructive cholestasis (a) taurocholate continues to be taken up from blood by hepatocytes and secreted into bile, but in terms of varying duration of obstruction, (b) all acinar zones are involved in bile salt transport, (c) in the initial phase (4 h and 4 days respectively after bile duct obstruction) hepatocytes fail to concentrate taurocholate at the canalicular site, (d) in a consecutive phase, in which bile ductules and ducts proliferate (demonstrated for a 15-day cholestasis), the taurocholate concentration at the canalicular site of hepatocytes is re-established and biliary secretion seems to be enhanced, (e) the biliary epithelium of bile ductules and ducts may play a significant role in the reabsorption and/or regurgitation of bile salts from bile to blood. Reabsorption/regurgitation of biliary constituents may also be operative in the non-cholestatic state but may become significantly enhanced with bile ductular proliferation.


Cation channels in the Arabidopsis plasma membrane.
In vivo analyses have identified different functional types of ion channels in various plant tissues and cells. The Arabidopsis genome contains approximately 70 genes for ion channels, of which 57 might be cation-selective channels (K(+), Ca(2+) or poorly discriminating channels). Here, we describe the different families of (putative) cation channels: the Shakers, the two-P-domain and Kir K(+) channels (encoded by the KCO genes), the cyclic-nucleotide-gated channels, the glutamate receptors, and the Ca(2+) channel TPC1. We also compare molecular data with the data obtained in planta, which should lead to a better understanding of the identity of these channels and provide clues about their roles in plant nutrition and cell signalling.


ZBP-89 enhances Bak expression and causes apoptosis in hepatocellular carcinoma cells.
ZBP-89 can enhance tumor cells to death stimuli. However, the molecular mechanism leading to the inhibitory effect of ZBP-89 is unknown. In this study, 4 liver cell lines were used to screen for the target of ZBP-89 on cell death pathway. The identified Bak was further analyzed for its role in ZBP-89-mediated apoptosis. The result showed that ZBP-89 significantly and time-dependently induced apoptosis. It significantly upregulated the level of pro-apoptotic Bak. ZBP-89 targeted a region between -457 and -407 of human Bak promoter to stimulate Bak expression based on the findings of Bak promoter luciferase report gene assay and electrophoretic mobility shift assay. ZBP-89-induced Bak increase and ZBP-89-mediated apoptosis were markedly suppressed by Bak siRNA, confirming that Bak was specifically targeted by ZBP-89 to facilitate apoptosis. In conclusion, this study demonstrated that ZBP-89 significantly induced apoptosis of HCC cells via promoting Bak level.


ERP comparison study of face gender and expression processing in unattended condition.
This paper explores the differences within the underlying brain mechanism for facial expression and gender information processing. The study recorded Event-Related Potentials (ERPs) of participants while they were performing a cross-change detection task, in which the cross was peripherally surrounded by four facial stimuli. For investigating facial expression processing, either four faces with positive expressions from two females and two males were presented infrequently among four faces with negative expressions, or four faces with negative expressions from two females and two males were presented infrequently among four faces with positive expressions. For gender information processing, four female faces were presented infrequently among four male faces, or vice versa. The findings showed that the latency of facial emotion-related visual mismatch negativity (vMMN) was shorter than that of facial gender-related vMMN, and that their related brain regions presented some differences. The results can be viewed as evidence of the difference by which the human brain processes facial emotion and gender information.


[Differences of Sex Development (DSD): Controversies and Challenges].
DSD for "Differences of Sex Development" or "Sexual Differences Development" refers to situations where chromosomal, gonadal or anatomical sex is atypical. DSD 46,XX are mainly represented by congenital adrenal hyperplasia (HCS) and are not a diagnostic issue. DSD 46,XY involve genes for the determination and differenciation of the bipotential gonad, making sometimes difficult the choice of sex at birth. They remain without diagnosis in about half of the cases, despite the new genetic techniques (exome, NGS). The management of DSD is complex as well as are the long-term consequences, particularly in terms of options for medical or surgical treatments, fertility and quality of life of patients that should be discussed. This review describes the main causes of DSD and the recent issues of their clinical management. It addresses the difficult question of identity of these patients, in a society that leaves no place for difference.


The Effect of Centers for Medicare and Medicaid's Inpatient Psychiatric Facility Quality Reporting Program on the Use of Restraint and Seclusion.
Patients in inpatient psychiatry settings are uniquely vulnerable to harm. As sources of harm, research and policy efforts have specifically focused on minimizing and eliminating restraint and seclusion. The Centers for Medicare and Medicaid's Inpatient Psychiatric Facility Quality Reporting (IPFQR) program attempts to systematically measure and reduce restraint and seclusion. We evaluated facilities' response to the IPFQR program and differences by ownership, hypothesizing that facilities reporting these measures for the first time will show a greater reduction and that ownership will moderate this effect. Using a difference-in-differences design and exploiting variation among facilities that previously reported on these measures to The Joint Commission, we examined the effect of the IPFQR public reporting program on the use and duration of restraint and seclusion from the end of 2012 through 2017. There were a total of 9705 observations of facilities among 1841 unique facilities. Results suggest the IPFQR program reduced duration of restraint by 48.96% [95% confidence interval (95% CI), 16.69%-68.73%] and seclusion by 53.54% (95% CI, 19.71%-73.12%). There was no change in odds of zero restraint and, among for-profits only, a decrease of 36.89% (95% CI, 9.32%-56.07%) in the odds of zero seclusion. This is the first examination of the effect of the IPFQR program on restraint and seclusion, suggesting the program was successful in reducing their use. We did not find support for ownership moderating this effect. Additional research is needed to understand mechanisms of response and the impact of the program on nontargeted aspects of quality.


Concurrent measurement of heart rate and instrumental avoidance behavior in the Rhesus monkey.
A graphical method has been developed for the concurrent recording of heart beats and lever responses during behavioral experiments. The EKG signal fed into any DC amplifier goes to a fixed level trigger circuit and relay driver with its own power supply. The signal from this drives any standard cumulative recorder. Lever response rates are recorded concurrently on an additional cumulative recorder using the same paper speed.


Differential transcriptomic analysis of crayfish (Procambarus clarkii) from a rice coculture system challenged by Vibrio parahaemolyticus.
Rice-crayfish (Procambarus clarkii) coculture is an effective farming mode and has been promoted in various regions of China. However, infection in crayfish can be a significant economic drain. We found crayfish infected with Vibrio parahemolyticus (VP), and to understand the molecular mechanisms of the immune responses of crayfish to VP infection, Illumina sequencing was employed to identify changes in the mRNA of hepatopancreatic tissue. A total of 47.30 and 43.01million high-quality transcriptome reads were generated from the hepatopancreatic samples of the experimental group (EG) and control group (CG), respectively. We found 5559 genes were significantly differentially expressed, including 2521 up-regulated genes (45.35%) and 3038 down-regulated genes (54.65%). These genes were enriched in 126 GO terms and 76 KEGG pathways (P ≤ 0.05), including the MAPK and PI3K-Akt signaling pathways and cell adhesion molecules, with 23 up-regulated genes and 3 down-regulated genes related to immune responses in the EG relative to the CG. Histopathological analysis revealed that the epithelial cells of the hepatopancreatic tubules in the EG were severely atrophic, necrotic, and exfoliated, resulting in thin and collapsing hepatopancreatic tubules. The expression patterns of 8 differentially expressed genes involved in immune responses were validated by quantitative real-time RT-PCR. These results provide a valuable basis for the immune responses of crayfish to acute hepatopancreatic necrosis disease at transcriptome level.


Unmasking Heterogeneity of Sleep Apnea.
Sleep apnea is heterogeneous in multiple dimensions. There are different physiological risk factors that may have clinical relevance. However, assessing them is challenging. An approach to ascertain them using a simple model of ventilatory control has been proposed. It is based, however, on untenable assumptions. There are limited validation data and reproducibility is not stellar. There are also different symptom subtypes. They have been found in multiple population-based and clinical cohorts worldwide. Symptomatic benefit from therapy is most marked in the excessively sleepy subtype. This group may also be the group at increased CV risk from obstructive sleep apnea.


Inhibition of ovarian luteinizing hormone (LH) and follicle-stimulating hormone receptor levels with an LH-releasing hormone agonist during the estrous cycle in the rat.
A single injection of the luteinizing hormone (LH)-releasing hormone (LHRH) agonist [D-Ala6,des-Gly-NH2(10)]LHRH ethylamide to female rats on diestrus I produced a marked reduction in ovarian LH/human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH) receptor levels, uterine weight, and plasma progesterone levels measured 2 days later on expected proestrus. A maximal inhibitory effect was seen after a dose of only 40 ng of the peptide. No consistent effect of the LHRH analog was seen on ovarian prolactin receptors. When the analog was injected on day 7 of pregnancy, the inhibition of ovarian LH/hCG receptors was of shorter duration and was much less sensitive than that in nonpregnant animals. These data indicate that ovarian LH and FSH receptors levels are highly sensitive to changes in endogenous gonadotropin secretion and suggest that the gonadotropin surge occurring spontaneously on proestrus may play an important role in the regulation of ovarian gonadotropin receptors during the estrous cycle.


The effects of cranberry juice consumption on antioxidant status and biomarkers relating to heart disease and cancer in healthy human volunteers.
Consumption of fruit and vegetables is associated with a decreased risk of heart disease and cancer. This has been ascribed in part to antioxidants in these foods inactivating reactive oxygen species involved in initiation or progression of these diseases. Non-nutritive anthocyanins are present in significant amounts in the human diet. However, it is unclear whether they have health benefits in humans. To determine whether daily consumption of anthocyanin-rich cranberry juice could alter plasma antioxidant activity and biomarkers of oxidative stress. 20 healthy female volunteers aged 18-40 y were recruited. Subjects consumed 750 ml/day of either cranberry juice or a placebo drink for 2 weeks. Fasted blood and urine samples were obtained over 4 weeks. The total phenol, anthocyanin and catechin content of the supplements and plasma were measured. Anthocyanin glycosides were identified by tandem mass spectrometry (MS-MS). Vitamin C, homocysteine (tHcy) and reduced glutathione (GSH) were measured by HPLC. Total antioxidant ability was determined using electron spin resonance (ESR) spectrometry and by the FRAP assay. Plasma total cholesterol, high density lipoprotein (HDL), and low density lipoprotein (LDL) cholesterol and triglycerides (TG) were measured. Glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) activities were measured in erythrocytes. Urine was collected for analysis of malondialdehyde (MDA) by HPLC and 8-oxo-deoxyguanosine (8-oxo-dG) by ELISA. Endogenous and induced DNA damage were measured by single cell gel electrophoresis (SCGE) in lymphocytes. Vitamin C, total phenol, anthocyanin and catechin concentrations and FRAP and ESR values were significantly higher in the cranberry juice compared with the placebo. Cyanidin and peonidin glycosides comprised the major anthocyanin metabolites [peonidin galactoside (29.2%) > cyanidin arabinoside (26.1%) > cyanidin galactoside (21.7%) > peonidin arabinoside (17.5%) > peonidin glucoside (4.1%) > cyanidin glucoside (1.4 %)]. Plasma vitamin C increased significantly (P<0.01) in volunteers consuming cranberry juice. No anthocyanins (plasma) or catechins (plasma or urine) were detectable and plasma total phenols, tHcy,TC,TG,HDL and LDL were unchanged. The antioxidant potential of the plasma, GSH-Px, CAT and SOD activities, and MDA were similar for both groups. Supplementation with cranberry juice did not affect 8-oxo-deoxyguanosine in urine or endogenous or H(2)O(2)-induced DNA damage in lymphocytes. Cranberry juice consumption did not alter blood or cellular antioxidant status or several biomarkers of lipid status pertinent to heart disease. Similarly, cranberry juice had no effect on basal or induced oxidative DNA damage. These results show the importance of distinguishing between the in vitro and in vivo antioxidant activities of dietary anthocyanins in relation to human health.


Experimenting with ASL-based arterialized cerebral blood volume as a novel imaging biomarker in grading glial neoplasms.
Perfusion imaging is one of the methods used to grade glial neoplasms, and in this study we evaluated the role of ASL perfusion in grading brain glioma. The aim is to evaluate the role of arterialized cerebral blood volume (aCBV) of multi-delay ASL perfusion for grading glial neoplasm. This study is a prospective observational study of 56 patients with glial neoplasms of the brain who underwent surgery, and only cases with positive diagnosis of glioma are included to evaluate the novel diagnostic parameter. In the study, ASL-derived normalized aCBV (naCBV) and T2*DSC-derived normalized CBV (nCBV) are showing very high correlation (Pearson's correlation coefficient value of 0.94) in grading glial neoplasms. naCBV and nCBF are also showing very high correlation (Pearson's correlation coefficient value of 0.876). The study also provides cutoff values for differentiating LGG from HGG for normalized aCBV(naCBV) of ASL, normalized CBV (nCBV), and normalized nCBF derived from T2* DCS as 1.12, 1.254, and 1.31, respectively. ASL-derived aCBV also shows better diagnostic accuracy than ASL-derived CBF. This study is one of its kind to the best of our knowledge where multi-delay ASL perfusion-derived aCBV is used as a novel imaging biomarker for grading glial neoplasms, and it has shown high statistical correlation with T2* DSC-derived perfusion parameters.


Adipose-derived stem cell transplantation improves learning and memory via releasing neurotrophins in rat model of temporal lobe epilepsy.
Epilepsy is a common neurological disease and its most common type is temporal lobe epilepsy (TLE). Novel therapeutics is needed as many TLE patients are resistant to treatments like anticonvulsants or temporal lobectomy. Stem cell therapy has great promise in regeneration medicine. In the current study, we tried to investigate the potential protective effects of adipose-derived stem cell (ADSC) transplantation in epileptic rats. Epilepsy model was established by intra-hippocampal injection of kainic acid (KA) in rats. ADSCs were isolated, differentiated and transplanted into hippocampus of KA rats. There were three groups of rats: normal control group receiving saline injection and no transplantation, KA + sham group receiving KA injection and sham transplantation surgery and KA + transplantation group receiving KA injection and ADSC transplantation. We found that ADSCs were highly positive for CD44, CD90, CD29 and CD105, and neural differentiation induced the expression of neuronal markers like Tuj1, MAP2, NeuN and PSD-95. EEG recording showed that KA induced seizure activity while ADSC transplantation inhibited seizure activity. In training session of Morris water maze task, KA injection impaired the learning capacity of rats while ADSC transplantation restored the learning capacity at 2-week or 2-month post transplantation. In probe session of Morris water maze task, KA injection impaired the memory of rats while ADSC transplantation restored the memory at 2-week or 2-month post transplantation. Transplanted ADSCs released BDNF, NT3 and NT4. Pro-apoptotic BAX was reduced while anti-apoptotic BCL-2 and BCL-xL were increased in hippocampus post ADSC transplantation. Our study suggests that ADSC transplantation inhibits KA-induced seizures and improves the learning and memory function of epileptic rats.


Preclinical diabetic cardiomyopathy: relation of left ventricular diastolic dysfunction to cardiac autonomic neuropathy in men with uncomplicated well-controlled type 2 diabetes.
Diabetic cardiomyopathy is an ill-defined entity. This study was designed to explore the possible association between left ventricular diastolic dysfunction (LVDD) and cardiac autonomic neuropathy (CAN) independently from metabolic control. Three groups of 10 age-matched men each with well-controlled type 2 diabetes were studied: (1) subjects with normal diastolic function, (2) subjects with LVDD characterized by impaired LV relaxation, and (3) subjects with a more severe form of LVDD characterized by a pseudonormalized pattern of LV filling. No subject had evidence of clinical diabetic complications, coronary artery disease (CAD), hypertension, congestive heart failure, or thyroid or overt renal disease, and all had a negative maximal exercise test. LVDD was evaluated by Doppler echocardiographic and CAN was evaluated using spectral analysis of heart rate variability (HRV; time and frequency domains) from 24-hour Holter recordings. Findings showed that the high frequency power (HF: 0.15 to 0.4 Hz) tends to decrease with worsening diastolic function; 5.0 +/- 0.2 ms(2) (mean +/- SE) in group 1, 4.2 +/- 0.3 ms(2) in group 2, and 3.9 +/- 0.4 ms(2) (P =.03) in group 3, respectively, whereas the low frequency power (LF: 0.04 to 0.15 Hz) was similar between groups. In the time domain, the mean squared differences of the successive RR intervals (rMSDD) also showed the same pattern, ie, 31.0 +/- 2.8 ms, 23.8 +/- 1.6 ms, and 21.5 +/- 2.9 ms in groups 1, 2, and 3, respectively (P =.03). The E/A ratio correlated significantly with indices of parasympathetic modulation (HF; r = 0.448, P =.013; rMSDD: r = 0.457, P =.011; pNN50: r = 0.425, P =.019). LVDD and CAN are associated in patients with otherwise uncomplicated well-controlled type 2 diabetes. The parameters defining these 2 abnormalities may serve to better define diabetic cardiomyopathy as a distinct entity and could eventually become useful prognostic indicators as it has been shown in nondiabetic populations.


Genetic risk score associations for myocardial infarction are comparable in persons with and without rheumatoid arthritis: the population-based HUNT study.
Persons with rheumatoid arthritis (RA) have increased risk of myocardial infarction (MI). Overlapping associations with MI of weighted genetic risk scores (wGRS) for coronary artery disease (CAD) and RA is unknown in a population-based setting. Data from the prospective Nord-Trøndelag Health Study (HUNT2: 1995-1997 and HUNT3: 2006-2008) were used. wGRS added each participant's carriage of all risk variants weighted by the coefficient from published association studies. Published wGRS for CAD and RA were analysed in Cox regression with MI as outcome, age as analysis time, and censoring at the first MI, death, or 31.12.2017. 2609 of 61,465 participants developed MI during follow-up (mean 17.7 years). The best-fitting wGRS for CAD and RA included 157 and 27 single-nucleotide polymorphisms, respectively. In multivariable analysis including traditional CAD risk factors, the CAD wGRS was associated with MI [hazard ratio = 1.23 (95% CI 1.18-1.27) for each SD increase, p < 0.0001] in RA patients (n = 433) and controls. The RA wGRS was not significant (p = 0.06). Independently from traditional risk factors, a CAD wGRS was significantly associated with the risk for MI in RA patients and controls, whereas an RA wGRS was not. The captured genetic risk for RA contributed little to the risk of MI.


The association between subjective-objective discrepancies in sleep duration and mortality in older men.
A discrepancy in subjective and objective estimations of sleep duration, which often diverge, could have long-term adverse effects on health outcomes in older adults. Using data from 2674 older adult men (≥ 65 years of age) of the Osteoporotic Fractures in Men Sleep Study, we assessed the longitudinal association between misperception index (MI), calculated as MI = (objective sleep duration - subjective sleep duration)/objective sleep duration, and all-cause mortality. During the follow-up with a mean (standard deviation) of 10.8 (4.2) years, 1596 deaths were observed. As a continuous variable, MI showed a linear relationship with all-cause mortality after adjusting for multiple covariates, including polysomnography-measured objective sleep duration [fully adjusted hazard ratio (HR), 0.69; 95% confidence interval [CI], 0.56-0.84]. As a categorical variable, the lowest MI quartile (vs. the interquartile MI range) was associated with increased mortality (fully adjusted HR, 1.28; 95% CI, 1.12-1.46), whereas the highest MI quartile was not associated with mortality (fully adjusted HR, 0.97; 95% CI, 0.85-1.11). The subjective overestimation of sleep duration may be a risk factor for all-cause mortality in older men. Future studies should examine why subjective overestimation of sleep duration is associated with all-cause mortality from a physiological perspective.


Infantile chronic tubulo-interstitial nephritis with cortical microcysts: variant of nephronophthisis or new disease entity?
Over a 15-year period we observed seven children (four girls, three boys) who presented within the first months of life with severe renal failure and acidosis, associated with hypertension in five patients and polyuria in four. In addition, one patient had a severe cholestatic liver disease. In two families, a similarly affected sibling had died previously. Four patients were referred with the clinical diagnosis of polycystic kidney disease because of moderate enlargement of kidneys, but renal imaging (intravenous pyelography and ultrasonography) did not confirm this diagnosis. A renal biopsy, performed in all patients, showed similar features characterized by a diffuse chronic tubulo-interstitial nephritis (TIN) and particularly by the presence of microcystic dilatation of proximal tubules and Bowman's space. Liver pathology was normal in two patients, including one with hepatomegaly. However, in the patient with cholestasis there was inflammatory portal fibrosis with mild duct proliferation. Progression of the renal disease was extremely rapid and all patients reached end-stage renal failure (ESRF) before the age of 2 years (11-22 months). Two children had successful renal transplants. Although this chronic TIN shares some features with nephronophthisis, we suggest that it represents a distinct entity both on clinical and morphological grounds. The specific clinical features of this disease are its early onset and rapid progression to ESRF. Pathologically, it differs from nephronophthisis by the absence of medullary cysts and thickened tubular basement membranes and by the presence of cortical microcysts.


Varieties of rhodopsin in frog rod outer segment membranes: analysis by isoelectric focusing.
Purified ROS membranes from cattle, R. pipiens and R. catesbeiana adults and tadpoles were investigated by analytical and preparative isoelectric focusing and SDS-polyacrylamide gel electrophoresis. The rhodopsin from single specimens of R. pipiens displayed two closely-spaced bands with Mr at 34.7 and 37.0 k on SDS polyacrylamide gels. Both were found to be phosphorylated when prepared from retinas incubated with 32Pi and then exposed to light. When purified ROS membranes were solubilized in octyl glucoside and examined by isoelectric focusing followed by SDS-polyacrylamide gel electrophoresis, the low-Mr component focused in two bands (I, IIa) at pH 8.8 and 8.1. Band I and a trace amount of band IIa were observed if band I was eluted and refocused. The high-Mr component focused in one band (IIb) at pH 8.0. Identical isoelectric focusing patterns were observed with ROS membranes from R. catesbeiana tadpoles and the dorsal and ventral retina areas from R. catesbeiana adults. Bovine rhodopsin, on the other hand, had a single Mr component and focused in a major band at pH 6.2.


Transcription factor expression and hormone production in pancreatic AR42J cells.
AR42J is an exocrine pancreatic cell line that has been reported to differentiate towards an endocrine phenotype when stimulated with various growth factors, such as activin A, hepatocyte growth factor (HGF), betacellulin or glucagon-like peptide 1. In our experiments, AR42J-B13 cells differentiated morphologically in response to the growth factor treatment as reported previously. However, they failed to express the insulin gene. We found that the cells did not express several transcription factors known to be found in the beta-cell, including Nkx6.1, isl-1, Pax4 and Pax6. In addition, the mRNA level for pdx-1 and Nkx2.2 were very low in comparison to the insulinoma cell lines INS-1 and RINm5F. However, some transcription factors typically found in beta-cells and neuroendocrine cells were expressed also in the AR42J-B13 cells. These included BETA2/NeuroD, HNF1alpha, C/EBPbeta and IA-1. Unlike the insulinoma cells, AR42J cells expressed the exocrine transcription factor p48. In order to induce endocrine differentiation, we transfected the AR42J-B13 cells with the full length cDNAs of isl-1, Nkx6.1, Nkx2.2 and pdx-1 under the control of the CMV promoter, both separately and in combinations. The expression of Nkx2.2 led consistently to the appearance of pancreatic polypeptide but not insulin, glucagon or somatostatin mRNA. The PP mRNA expression in Nkx2.2 cDNA transfected cells was independent of the growth factor treatment used for differentiating AR42J cells. In conclusion, the AR42J-B13 line possesses some features of a pancreatic neuroendocrine cell. However, we were unable to confirm the capacity of these cells to differentiate into insulin-producing cells. Our results indicate that Nkx2.2 plays a role in the transcriptional regulation of PP expression.


Assessment of clinical and radiographic peri‑implant parameters in the obese and non-obese, along with destructive pro-inflammatory cytokines IL-1β - and IL-6 in patients treated with Photodynamic therapy.
The present study aims to compare and evaluate radiographic and clinical parameters along with salivary proinflammatory cytokine profiles (IL-1β - and IL-6) in the obese with peri‑implantitis. Obese and non-obese participants in the present study were 80. The nonobese and obese participants were scrutinized based on inclusion and exclusion criteria. All participants both obese and non-obese were subjected to full mouth mechanical debridement (MD). A single session of Photodynamic therapy (PDT) was provided to all obese participants. Clinical peri‑implant parameters peri‑implant plaque index (PIPI), Peri-implant bleeding on probing (PIBoP), peri‑implant probing depth (PIPD) were assessed at baseline, three months, and six months. Marginal bone loss (MBL) was also assessed. Enzyme-linked immunosorbent assay (ELISA) was used to check the levels of IL-1β - and IL-6 in unstimulated whole saliva samples. All the parameters were assessed using the Kruskal Wallis test and analysis of variance (ANOVA). Overall characteristics were assessed using descriptive statistics. SPSS software was used for statistical analysis. Clinical baseline periodontal parameters PIPI, PIBoP, PIPD, and MBL in non-obese participants were significantly lower compared to group I obese participants at baseline (p < 0.05). At 3 months follow-up PDT adjunct to MD in group 1 obese participants PIPI and PIPD were significantly lower compared to MD alone in non-obese participants PIP1 and PIPD. At 6 months follow up, non-obese participants with peri‑implantitis treated with MD demonstrated PIPI and PIPD significantly lower compared to obese participants treated with PDT adjunct to MD CONCLUSION: PDT adjunctive to MD enhanced periodontal parameters i.e., peri‑implant probing depth, peri‑implant plaque index, and peri‑implant bleeding on probing in obese with peri‑implantitis. Moreover, obese individuals with peri‑implantitis demonstrated high levels of proinflammatory cytokines IL-1β and IL-6 than control.


Antianginal drugs and relationship between epicardial ST segment depression and moderate regional myocardial blood flow reduction in experimental partial coronary artery occlusion.
The aim of the study was to determine whether moderate reduction in regional myocardial blood flow is related to epicardial ST segment depression and to the changes in grade and extent induced in this variable by antianginal drugs. Blood flow through the anterior descending coronary artery was reduced to 25-30% of control in open chest dogs, using a cuff flow meter as a monitor, and glyceryl trinitrate, propranolol and nifedipine were infused 60 min later. Regional left ventricular blood flow was measured with 15 mu radioactive microspheres and electrocardiograms were recorded from the epicardial surface of the anterior left ventricular wall before and after administration of the drugs. 20 adult male greyhounds were used, weighing 19-24 kg. Under control conditions there was a poor correlation between ST segment depression and regional flow. Neither glyceryl trinitrate nor nifedipine had any significant effect on ST segment depression in sites overlying zones with a flow range of 80-105% of normal flow. On the other hand, glyceryl trinitrate, but not nifedipine, decreased ST segment depression in sites overlying the central ischaemic zone (35-80% of control posterior wall flow). With propranolol, mean ST depression was decreased significantly in sites overlying the central ischaemic zone (35-80% of control flow), but not in sites overlying zones with flows ranging from 80-105% of normal. Propranolol reduced blood flow to all zones. Epicardial ST segment depression is unreliable for the quantitative exploration of the grade and extent of myocardial ischaemia.


Modeling Sexual Selection in Túngara Frog and Rationality of Mate Choice.
The males of the species of frogs Engystomops pustulosus produce simple and complex calls to lure females, as a way of intersexual selection. Complex calls lead males to a greater reproductive success than what simple calls do. However, the complex calls are also more attractive to their main predator, the bat Trachops cirrhosus. Therefore, as M. Ryan suggests in (The túngara frog: a study in sexual selection and communication. University of Chicago Press, Chicago, 1985), the complexity of the calls lets the frogs keep a trade-off between reproductive success and predation. In this paper, we verify this trade-off from the perspective of game theory. We first model the proportion of simple calls as a symmetric game of two strategies. We also model the effect of adding a third strategy, males that keep quiet and intercept females, which would play a role of intrasexual selection. Under the assumption that the decision of the males takes into account this trade-off between reproductive success and predation, our model reproduces the observed behavior reported in the literature with minimal assumption on the parameters. From the model with three strategies, we verify that the quiet strategy could only coexists with the simple and complex strategies if the rate at which quiet males intercept females is high, which explains the rarity of the quiet strategy. We conclude that the reproductive strategy of the male frog E. pustulosus is rational.


Correlates of protective immune response in tuberculous pleuritis.
Tuberculous pleuritis (TB) provides a good model to study the correlates of protective immune response at the site of infection. To study the in vivo correlates of immunity, cell subset profile and cytokine assay in plasma (BL) and pleural fluid (PF) of 82 patients were done. Lymphocyte proliferation and cytokine response to mycobacterial antigens were measured in 32 subjects to understand the in vitro correlates. Increase in CD4(+) cells and CD4(+)/CD8(+) ratio with selective concentration of interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12 in PF suggests that the CD4(+) population may be of TH1 type. We observed an accelerated lymphoproliferative response to purified protein derivative (PPD) and heat killed Mycobacterium tuberculosis (MTB) in PF cells of both TB and non-TB (NTB) subjects. Interestingly, in in vitro studies, IL-4 levels together with IFN-gamma were significantly increased in the supernatants of PF mononuclear cells (PFMC) of TB patients and showed a shift in immune response towards TH0/TH2 type. PPD and MTB antigens induced an enhanced proliferation of PFMC and also increased in vitro IL-4 response together with apoptosis, thus eliciting a dual response.


The effects of dietary iron concentration on gastrointestinal and branchial assimilation of both iron and cadmium in zebrafish (Danio rerio).
Zebrafish (Danio rerio) were fed either a diet containing 33mgFekg(-1) (low) or 95mgFekg(-1) (normal) for 10 weeks, after which short-term Cd and Fe uptake by the gastrointestinal tract and gill was assessed. Carcass metal content and transcript levels of the iron importer, Divalent Metal Transporter 1 (DMT1) and an iron exporter, ferroportin1, in both the gastrointestinal tract and gill were also measured. Fish fed the low Fe diet accumulated 13 times more Cd into their livers via the gastrointestinal tract than those fed the normal Fe diet. However, no significant increase in liver Fe accumulation was measured. Concomitantly, when exposed to 48nmolCdL(-1) fish fed the low Fe diet exhibited a approximately 4-fold increase in Cd accumulation on the gill and in the liver, compared to those fed a normal diet. In addition, fish fed the low Fe diet also significantly accumulated more Fe on the gill (nine-fold increase) and into the carcass (four-fold increase) when exposed to 96nmolFeL(-1), compared to fish fed a normal diet. Surprisingly, carcass Fe, Ca and Mg concentrations were increased in fish fed the low Fe diet, which suggests that Fe body levels may not be a good indicator of whether a fish is more or less susceptible to increased non-essential metal accumulation via an Fe uptake pathway. However, significantly elevated transcript levels of DMT1 and ferroportin1 (2.7- and 3.8-fold induction, respectively) were seen in the gastrointestinal tract, and DMT1 in the gills (1.8-fold induction) of zebrafish fed a low Fe diet. The correlation between Cd uptake and DMT1 expression suggests that one route of uptake of Cd, either from the diet or from the water, could be via DMT1.


Development of an Inexpensive RGB Color Sensor for the Detection of Hydrogen Cyanide Gas.
An inexpensive red, green, blue (RGB) color sensor was developed for detecting low ppm concentrations of hydrogen cyanide gas. A piece of glass fiber filter paper containing monocyanocobinamide [CN(H2O)Cbi] was placed directly above the RGB color sensor and an on chip LED. Light reflected from the paper was monitored for RGB color change upon exposure to hydrogen cyanide at concentrations of 1.0-10.0 ppm as a function of 25%, 50%, and 85% relative humidity. A rapid color change occurred within 10 s of exposure to 5.0 ppm hydrogen cyanide gas (near the NIOSH recommended exposure limit). A more rapid color change occurred at higher humidity, suggesting a more effective reaction between hydrogen cyanide and CN(H2O)Cbi. The sensor could provide the first real time respirator end-of-service-life alert for hydrogen cyanide gas.


Intra-cerebral haemorrhage but not neurodegenerative disease appears over-represented in deaths of Australian cadaveric pituitary hormone recipients.
Recent scientific reports and epidemiological studies have engendered mounting concerns regarding the potential human-to-human transmissibility of non-prion neurodegenerative and related diseases. This study investigated whether recipients of cadaveric pituitary hormone treatments are at increased risk of death from non-prion neurodegenerative and related diseases. A retrospective national cohort study based on death certificates of recipients of the cadaveric pituitary hormone treatments (n = 184) as part of the Australian Human Pituitary Hormone Program (AHPHP; n = 2940) 1967-1985. Standardised mortality ratios (SMR) from non-prion neurodegenerative and other diseases were estimated based on the Australian population. Allowing for potential diagnostic mis-attributions, there was no significant increase in the SMR from non-prion central nervous system (CNS) neurodegenerative disease, especially dementia and/or Alzheimer's disease (0.47; [95% CI: 0.19, 1.12] P = 0.081). The SMR for intra-cerebral haemorrhage, potentially related to cerebral amyloid angiopathy (CAA), was increased (2.77; [95% CI: 1.12-5.75] P = 0.009), although accommodation of possible mis-diagnosis through conflation of this category with other stroke causes of death emphasising likely intra-cranial haemorrhage showed no persisting significant increase in mortality in cadaveric pituitary hormone recipients, including all deaths recorded as due to intra-cranial haemorrhage (1.72; [95% CI: 0.80, 3.26] P = 0.123). In the setting of recent evidence strongly supporting the likelihood of brain-to-brain horizontal transmission and subsequent propagation and deposition of abnormally folded proteins associated with non-prion neurodegenerative and related disorders, this study offers further tentative support for deaths directly stemming from transmission of non-prion disease related to cadaveric pituitary hormone treatment. Acknowledging the limitations of the present study, however, ongoing detailed assessments of this potential risk are necessary.


Blue diode laser versus traditional infrared diode laser and quantic molecular resonance scalpel: clinical and histological findings after excisional biopsy of benign oral lesions (Erratum).
This erratum corrects the spelling of an author's name.


Influence of inflammation and aging on macrophage inhibitory cytokine-1 gene expression in rat ventral prostate.
We have previously reported that the macrophage inhibitory cytokine-1 (MIC-1) gene is downregulated in human symptomatic benign prostatic hyperplasia. The aim of this study was to investigate the histologic changes and MIC-1 gene expression in the prostate of young nonbacterial prostatitis model (Y-NBP) and aging rats. A total of 35 Wistar male rats, 13 weeks old, were castrated and subjected to (a) castration alone for 14 days, (b) Y-NBP-14d (0.25 mg/2 mL/kg beta-estradiol injection for 14 days), or (c) Y-NBP-30d (beta-estradiol injection for 30 days). A total of 5 male rats, 10 months old, were also analyzed. We used 21 male rats, 13 weeks old, who had undergone sham surgery as the controls. The ventral lobes of the prostate were histologically examined with Masson's trichrome staining or immunostaining using an anti-macrophage antibody. The MIC-1 mRNA levels were quantitatively assessed using real-time reverse transcriptase-polymerase chain reaction. The MIC-1 gene mRNA levels in the castration alone, Y-NBP-14d, and Y-NBP-30d rat prostates were greater than those in the control rats (P < .005). In contrast, those of the 10-month-old rats were lower than those of the controls (P = .0093). The mean stroma-to-epithelium ratio in the Y-NBP-30d rats, 10-month-old rats, and 13-week-old controls was 1.28, 0.26, and 0.10, respectively (Y-NBP-30d vs 10-month-old rats, P = .0008; 10-month-old vs 13-week-old rats, P = .001). The number of infiltrating macrophages in the Y-NBP-14d, Y-NBP-30d, and 10-month-old rats was greater than that of the 13-week-old controls (P < .001). Castration causes induction of MIC-1 gene expression. Estradiol treatment has little effect on MIC-1 gene expression but causes a significant increase in the stroma-to-epithelium ratio. The aging rat prostate is more similar to human benign prostatic hyperplasia than is the Y-NBP model in light of MIC-1 gene expression and histologic changes.


Obesity in Cystic fibrosis: prevalence, trends and associated factors data from the US cystic fibrosis foundation patient registry.
Strong emphasis has been placed historically on increasing weight and improving nutritional status in cystic fibrosis patients. Due to correlation between nutritional indices (e.g. BMI) and lung function, CF Nutrition Guidelines have recommended BMI percentile goals at the 50th percentile or higher. Trends in increasing BMI across CF programs suggest significantly increasing proportions of overweight and obese status in recent years. We identify that between 2000 and 2019 there has been a relative decrease in underweight status by ∼40%, simultaneously with a > 300% increase in overweight status, and >400% increase in obesity. Patient specific factors associated with higher prevalence of obesity included age ≥46, living in a zip code where the median income was < $20,000, having at least one allele with a class IV or V mutation, a ppFEV1 >90 prescribed ivacaftor, and not prescribed pancreatic enzymes. Program specific factors were not identified.


Contralateral limb and patient survival after leg amputation.
Fifty-three patients who required amputation for ischemic disease of the legs were evaluated actuarially. The incidence of subsequent contralateral amputation and the length of patient survival were found to be nearly identical to incidence rates reported during the 1960s. The diffuse end-stage nature of the atherosclerotic process which led to the initial amputation in both time periods accounted for the similarity. Operative mortality decreased from more than 10 percent to 1.5 percent, presumably because of improved cardiovascular support and early rehabilitation.


Exploring differential patterns of situational risk for binge eating and heavy drinking.
This study was designed to compare risk situations for binge eating vs. heavy drinking among women who struggle with both problems. Participants were 41 women in treatment for an alcohol problem who also self-reported binge eating. Participants completed the Inventory of Binge Eating Situations (IBES; [Baker, J. M. (1998). Binge eating and binge drinking among university women. Unpublished master's thesis, Department of Psychology, Queen's University, Kingston, Ontario, Canada]) and the Inventory of Drinking Situations (IDS-42; [Annis, H. M., Graham, J. M., & Davis, C. S. (1987). Inventory of Drinking Situations (IDS) user's guide. Toronto, Canada: Addiction Research Foundation]) to measure frequency of binge eating and heavy drinking, respectively, in eight categories of situations. A 2 (substance) x8 (situation) repeated measures ANOVA revealed a significant substancexsituation interaction. Further exploration of this interaction indicated that heavy drinking is more likely than binge eating to occur in reward and interpersonal situations involving pleasant emotions, pleasant times with others, social pressure, and conflict with others. In contrast, binge eating and heavy drinking are equally likely to occur in relief situations involving unpleasant emotions, and physical discomfort, as well as in situations involving urges and temptations, and testing control. Implications of findings for the treatment of co-occurring binge eating and heavy drinking in women are discussed.


Randomised clinical trial of cryoballoon versus irrigated radio frequency catheter ablation for atrial fibrillation-the effect of double short versus standard exposure cryoablation duration during pulmonary vein isolation (CIRCA-DOSE): methods and rationale.
Pulmonary vein isolation (PVI) is an effective therapy for paroxysmal atrial fibrillation (AF), but it has limitations. The two most significant recent advances have centred on the integration of real-time quantitative assessment of catheter contact force into focal radio frequency (RF) ablation catheters and the development of dedicated ablation tools capable of achieving PVI with a single ablation lesion (Arctic Front cryoballoon, Medtronic, Minneapolis, MN, USA). Although each of these holds promise for improving the clinical success of catheter ablation of AF, there has not been a rigorous comparison of these advanced ablation technologies. Moreover, the optimal duration of cryoablation (freezing time) has not been determined. Patients undergoing an initial PVI procedure for paroxysmal AF will be recruited. Patients will be randomised 1:1:1 between contact-force irrigated RF ablation, short duration cryoballoon ablation (2 min applications) and standard duration cryoballoon ablation (4 min applications). The primary outcome is time to first documented AF recurrence on implantable loop recorder. With a sample size of 111 per group and a two-sided 0.025 significance level (to account for the two main comparisons), the study will have 80% power (using a log-rank test) to detect a difference of 20% between contact force RF catheter ablation and either of the two cryoballoon ablation groups. Factoring in a 4% loss to follow-up, 116 patients per group should be randomised and followed for a year (total study population of 348). The study was approved by the University of British Columbia Office of Research (Services) Ethics Clinical Research Ethics Board. Results of the study will be submitted for publication in a peer-reviewed journal. NCT01913522; Pre-results.


Hepatotoxicity and inhalation anesthetics: views in the era of isoflurane.
The halogenated inhalation anesthetics continue to be an important group of drugs in current anesthesia practice. The purpose of this article is to discuss current concepts of the mechanisms of halothane-induced hepatotoxicity and to attempt to answer the question: Do all halogenated inhalation anesthetics share halothane's propensity to hepatotoxicity?


Finding optimal surface sites on heterogeneous catalysts by counting nearest neighbors.
A good heterogeneous catalyst for a given chemical reaction very often has only one specific type of surface site that is catalytically active. Widespread methodologies such as Sabatier-type activity plots determine optimal adsorption energies to maximize catalytic activity, but these are difficult to use as guidelines to devise new catalysts. We introduce "coordination-activity plots" that predict the geometric structure of optimal active sites. The method is illustrated on the oxygen reduction reaction catalyzed by platinum. Sites with the same number of first-nearest neighbors as (111) terraces but with an increased number of second-nearest neighbors are predicted to have superior catalytic activity. We used this rationale to create highly active sites on platinum (111), without alloying and using three different affordable experimental methods.


Investigation into the elastic properties of ex vivo porcine corneas subjected to inflation test after cross-linking treatment.
The aim of this work was to evaluate the effect of cross-linking (CXL) on ex vivo porcine corneal elastic properties, using an inflation procedure. Twelve corneas were subjected to standard CXL (370 nm, 3 mW/cm2, 30 minutes), while 12 were used as controls. Corneal thickness was measured by Visante optical coherence tomography, before and immediately after treatment, and before inflation test. Both intraocular pressure and radial apical cornea displacement were measured during inflation. Stress-strain curves were obtained by applying the linear shell theory. The elastic modulus was evaluated by calculating the slope of the stress-strain curves. Results showed a statistically significant increase in elastic modulus (p<0.0001), with a mean of 3,868 ± 502 kPa for cross-linked corneas and 2,727 ± 238 kPa for untreated corneas, when subjected to high pressure (40-60 kPa). CXL significantly increased porcine cornea stiffness by about 42%. Findings did not show any significant difference within the physiological range of pressure (2-4 kPa). The inflation test has been proven to be a valuable tool for the investigation of corneal biomechanics, maintaining both integrity and geometry of corneal tissue.


Health inequalities across socio-economic groups: comparing geographic-area-based and individual-based indicators.
To compare health inequality estimates obtained with different types of indicators of socio-economic status (SES), and study whether some of these are better predictors of health status, as indicated by observed disability data, than others. Australian data were used to compare the use of the geographically based Socio-economic Index for Areas (SEIFA) in health inequality studies with two individual-based SES indicators able to account for family income and size. Inequalities in disability prevalences by SES were measured using age-standardized rate ratios. Logistic regression was used to determine which type of SES measure is a better predictor of the observed disability prevalences. Estimates of health inequalities obtained with the SEIFA were considerably lower than those obtained with the individual-based SES indicators. With the SEIFA, the proportion of disabled people amongst the most disadvantaged 20% of Australians was estimated to be 82% higher than amongst the most advantaged 20%, compared with over 150% with the individual-based SES measures. Also, the individual-based indicators were considerably better predictors of observed disability status than the SEIFA. An individual-level SES indicator, such as one based on family income, is a better predictor of people with a disability than a geographic-area-based index. Also, the main reason for the considerably lower inequality estimates obtained with the SEIFA is that, unlike the individual-based indicators, such location-based indices cannot account for the significant, often age-related variations in SES that exist amongst people living in a particular area.


Incidence of Endophthalmitis after Intravitreal Bevacizumab using Aliquots Prepared On-site in 2 Operating Rooms in Kuwait.
To report the incidence of endophthalmitis after intravitreal injection of bevacizumab and the outcomes of treatment of endophthalmitis at two centers in Kuwait. The aliquots of bevacizumab were prepared under aseptic precautions and administered in the operating theater on the same day at both centers. All patients received antibiotic drops after injection of bevacizumab. Data were collected on the number of cases that received intravitreal bevacizumab (IVB) and those that developed endophthalmitis were identified at the two centers. All cases of endophthalmitis received an intravitreal antibiotic injection and additional treatments as warranted. Data were collected on the outcomes of endophthalmitis treatment. There were 5 cases of endophthalmitis among a total of 5429 injections (0.09%: Confidence interval: 0.084-0.1). The incidence was 3 cases among 4690 (0.06%) and 2 cases among 739 injections (0.027%) at each center, respectively (P = 0.08). Four cases of endophthalmitis were culture-positive and organisms isolated were, coagulase negative Staphylococcus in 2 cases, Staphylococcus lugdunensis and Streptococcus pneumoniae in 1 case each. The final visual acuity was better than pre-IVB in 3 cases, same as pre-IVB in 1 case and worse in 1 case with streptococcal infection. No eyes developed phthisis bulbi or required enucleation. The incidence of endophthalmitis after intravitreal injection of bevacizumab using aliquots prepared in the operating room is comparable to other studies. There were no clusters of endophthalmitis cases.


Neurobehavioral relationships and puberty: another transformation?
In a follow-up study of the Groningen Perinatal Project (GPP) on minor neurological dysfunction (MND) at 12 and 14 years the onset of puberty appeared to play a role. The children were selected on the presence (n = 185) and absence (n = 185) of MND at 9 years. Puberty was defined by the presence of three or more physical puberty signs. With the onset of puberty the incidence of MND decreased. The neurobehavioral relationships became more explicit after the onset of puberty. All types of MND were related to behavioural and cognitive problems at this developmental stage. In normal children, boys showed an increase of strength during puberty whereas the movements of girls became more fluent. The apparent changes in neurological function during puberty were interpreted as a transformation of the central nervous system. The possible causes are discussed. The conclusion is that gonadal hormones and especially oestrogens, play a role. The fact that two-thirds of the children with MND and behavioural problems outgrow the problems during puberty, can be of great help. Finally, any longitudinal study of brain function, which includes the age of puberty, should pay attention to the pubescent stage.


Impact of zone geometry on the introduction of myopic defocus in young adult eyes wearing multi-zone lenses.
Multizone contact lenses control myopia progression by proposed introduction of myopic defocus. This project investigated how much of the pupil area and how many dioptres of myopic defocus are introduced by different lens zone geometries with near- and off-axis viewing. Ten young myopic adults (18-25 years) binocularly wore four soft contact lenses including a single vision (SV), concentric-ring dual-focus (DF), centre-distance multifocal (MF) and a RingBoost™ (RB) multi-zone design containing a combination of coaxial and non-coaxial zones. A modified aberrometer captured aberrations and pupil sizes at four target vergences between -0.25 and -4.00 D (on-axis) and across the central ±30° of the horizontal retina (off-axis). Defocus was quantified as the difference between the measured refractive state and the target vergence within each zone of a multi-zone design within the pupil and compared with that of equivalent zone areas of the SV lens. The percentage of the pupil containing myopic defocused light for each lens was calculated. Defocus within the distance correction zones of multi-zone lenses was similar to that of the SV lens. When viewing on-axis at -0.25 D target vergence, on average 11% of the pupil was myopic with SV, whereas 62%, 84% and 50% of the pupil was myopic for the DF, MF and RB designs, respectively. At -4.00 D target vergence, all lenses exhibited a systematic decrease in the percentage of pupil area having myopic defocus (SV: 3%; DF: 18%; MF: 5% and RB: 26%). The off-axis proportions were similar across multi-zone lenses; however, multi-zone lenses retained approximately 1.25-3.0× more myopic defocus than the SV lens. Subjects accommodated using the distance-correction zones of multi-zone lenses. Multi-zone contact lenses introduced significant myopic defocus on-axis and across the central ±30° retina. However, the magnitude and proportion of defocus were influenced by zone geometry, add power and pupil size.


Povidone-iodine bladder injury in rats and protection with heparin.
Povidone-iodine (Betadine) has been proposed for clinical use in controlling bacterial infections by intravesical instillation in concentrations ranging from 0.1 to 1 per cent. The effects, however, of povidone-iodine on the urothelium of the bladder have not been well studied. We performed experiments to see if injury to the urothelium occurred from intravesical instillation in female rats. Injury was indeed found with concentrations of 0.3 per cent and 1 per cent povidone-iodine, as judged by the observations of increased bladder weight due to edema, histological examination, in vivo bladder staining, crystal adhesion and bacterial adhesion upon the bladder mucosa after povidone-iodine injury. Further study showed that the urothelium recovered in 6 to 7 days after povidone-iodine injury, while a 3rd experiment demonstrated at least partial protection from bacterial and crystal adhesion to povidone-iodine injured urothelium by immediate treatment with heparin instillation in the bladder.


Diagnostic work up: Laboratory and biomarkers.
This chapter will focus on the diagnostic work around sexual dysfunction in Parkinson's disease, especially laboratory tests and biomarkers. A number of methods to analyze if sexual dysfunction is caused by neural pathology, vascular dysfunction or other mechanisms are now available. Other methods can be used to differentiate between psychogenic/functional reasons behind sexual dysfunction and organic ones. The role of biomarkers for diagnosis, but also for understanding the reason behind and for counteracting sexual dysfunction is becoming more evident. There is also a rich and increasing number of scales and other instruments available for detecting and quantifying sexual hypo- and hyperactivity. When investigating the reason behind sexual dysfunction in patients with Parkinson's disease comorbidities should also be considered. Finally, early and pronounced sexual dysfunction might in some cases be an indication that differential diagnosis, like Multisystem Atrophy, should be thought about. All these aspects of the diagnostic procedures around sexual dysfunction in Parkinson's disease will be covered in this chapter.


Using natural sequences and modularity to design common and novel protein topologies.
Protein design is still a challenging undertaking, often requiring multiple attempts or iterations for success. Typically, the source of failure is unclear, and scoring metrics appear similar between successful and failed cases. Nevertheless, the use of sequence statistics, modularity and symmetry from natural proteins, combined with computational design both at the coarse-grained and atomistic levels is propelling a new wave of design efforts to success. Here we highlight recent examples of design, showing how the wealth of natural protein sequence and topology data may be leveraged to reduce the search space and increase the likelihood of achieving desired outcomes.


Caspase inhibition reduces apoptosis and increases survival of nigral transplants.
Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. The main practical constraints of neural grafting are the shortage of human donor tissue and the poor survival of dopaminergic neurons grafted into patients, which is estimated at 5-10% (refs. 3,4). The required amount of human tissue could be considerably reduced if the neuronal survival was augmented. Studies in rats indicate that most implanted embryonic neurons die within 1 week of transplantation, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. Here we examined the effects of caspase inhibition by Ac-YVAD-cmk on cell death immediately after donor tissue preparation and on long-term graft survival. Treatment of the embryonic nigral cell suspension with Ac-YVAD-cmk mitigated DNA fragmentation and reduced apoptosis in transplants. It also increased survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby substantially improved functional recovery.


Assessing the anti-collagenase activity and phytochemical evaluation of eight plants cultivated in Egypt; developing a validation method for the ellagic acid content in Chrysophyllum oliviforme using HPLC-DAD.
Preventing aging signs is a vast cosmetic quest hence; the authors felt the necessity to focus on emerging new plant extracts by the evaluation of anti-aging potential of eight plants cultivated in Egypt. Total phenolics (TPC), total flavonoids content (TFC) and collagenase assay were performed; only four plants were subjected to (ORAC) assay, ferrozine iron metal chelation assay and (HPLC) analysis against polyphenolic standard; validation method according to ICH guidelines for ellagic acid content in C. oliviforme by HPLC-DAD was performed, molecular docking simulation was implemented by (MOE) module. C. oliviforme exhibited the highest anti-collagenase with the lowest (IC50), (TPC = 299.70 ± 16.97 mg/GAE), method of validation of C. oliviforme extract following the ICH guidelines of ellagic acid content (147.446 ± 0.00041 mg/g); C. oliviforme was the most potent extract and was standardized to be reproducible for the industrial scale.


When Critical View of Safety Fails: A Practical Perspective on Difficult Laparoscopic Cholecystectomy.
The incidence of common bile duct injuries following laparoscopic cholecystectomy (LC) remains three times higher than that following open surgery despite numerous attempts to decrease intraoperative incidents by employing better training, superior surgical instruments, imaging techniques, or strategic concepts. This paper is a narrative review which discusses from a contextual point of view the need to standardise the surgical approach in difficult laparoscopic cholecystectomies, the main strategic operative concepts and techniques, complementary visualisation aids for the delineation of anatomical landmarks, and the importance of cognitive maps and algorithms in performing safer LC. Extensive research was carried out in the PubMed, Web of Science, and Elsevier databases using the terms "difficult cholecystectomy", "bile duct injuries", "safe cholecystectomy", and "laparoscopy in acute cholecystitis". The key content and findings of this research suggest there is high intersocietal variation in approaching and performing LC, in the use of visualisation aids, and in the application of safety concepts. Limited papers offer guidelines based on robust data and a timid recognition of the human factors and ergonomic concepts in improving the outcomes associated with difficult cholecystectomies. This paper highlights the most relevant recommendations for dealing with difficult laparoscopic cholecystectomies.


Cognitive conjunction and cognitive functions.
We argue that conjunction analysis does not solve the problems with subtraction analyses that it sets out to solve and that it has additional problems of its own. We argue that detailed analyses of the tasks set to identify cognitive functions are required for both conjunction and subtraction analyses to achieve their goals of localizing cognitive operations using functional neuroimaging techniques.


Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.
To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Prospective observational study. 23 hospital based clinics in England, Scotland, and Northern Ireland. 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Primary predefined aggregate clinical outcomes: any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders. The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point. In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.


Loss-aversion or loss-attention: the impact of losses on cognitive performance.
Losses were found to improve cognitive performance, and this has been commonly explained by increased weighting of losses compared to gains (i.e., loss aversion). We examine whether effects of losses on performance could be modulated by two alternative processes: an attentional effect leading to increased sensitivity to task incentives; and a contrast-related effect. Empirical data from five studies show that losses improve performance even when the enhanced performance runs counter to the predictions of loss aversion. In Study 1-3 we show that in various settings, when an advantageous option produces large gains and small losses, participants select this alternative at a higher rate than when it does not produce losses. Consistent with the joint influence of attention and contrast-related processes, this effect is smaller when a disadvantageous alternative produces the losses. In Studies 4 and 5 we find a positive effect on performance even with no contrast effects (when a similar loss is added to all alternatives). These findings indicate that both attention and contrast-based processes are implicated in the effect of losses on performance, and that a positive effect of losses on performance is not tantamount to loss aversion.


Role of Checkpoint Inhibitors in the Management of Gastroesophageal Cancers.
This article reviews the essential clinical trials that have led to these immunotherapy approvals and explores the use of predictive biomarkers, such as PD-L1 expression and MSI status, to identify patients who are most likely to benefit from immunotherapies. This case review series describe findings from different clinical trials and contribute to the evolving understanding of the role of CPIs in managing advanced gastroesophageal cancers and may lead to improved treatment options and patient outcomes. Ongoing clinical trials also hold promise for expanding treatment options and improving patient outcomes in the future. The systematic review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The protocol has not been registered. A systematic literature review was conducted to identify relevant clinical trials and studies that describe the role of immune checkpoint inhibitors in managing advanced gastroesophageal cancers. Electronic database (PubMed, Clinicaltrials.gov, Society of Immunotherapy of Cancer, Aliment Pharmacology & Therapeutics, BMC cancer, Molecular Cancer Research, Nature Reviews Molecular Cell Biology, American Association for Cancer Research, Science, Nature, Cancer Discovery, Journal of the National Cancer Institute, Advanced Immunology, Oncotarget, Nature Medicine, Nature Genetics, Gut, Pathology and Oncology Research, Journal of Clinical Oncology, The New England Journal of Medicine, Gastrointestinal oncology, JAMA Oncology, Journal of Gastrointestinal Oncology, Current Oncology, Annals of Oncology, The Lancet, JCO Oncology Practice, Future Oncology, Gastric Cancer, CA: A Cancer Journal for Clinicians, American Journal of Gastroenterology, Gastroenterology, Journal of the National Cancer Institute, International Journal of Epidemiology, Helicobacter, Gastroenterology Review) were searched using a combination of relevant keywords and MESH terms. The search encompassed articles published up to 5/2023. Additionally, manual searches of reference lists of selected articles and pertinent review papers were conducted to ensure comprehensive coverage of relevant studies. Studies were included if they provided insights into clinical trials evaluating the efficacy and safety of CPIs in treating advanced gastroesophageal cancers. Relevant case reviews and trials exploring combination therapies involving CPIs were also considered. Articles discussed in the utilization of predictive biomarkers were included to assess their impact on treatment outcomes. Data from selected studies were extracted to inform the narrative review. Key findings were summarized, including clinical trial designs, patient populations, treatment regimens, response rates, progression-free survival (PFS), overall survival (OS), and adverse events. The role of predictive biomarkers, particularly PD-L1 expression and MSI status, in identifying patients likely to benefit from CPIs was critically evaluated based on study results. Ongoing clinical trials investigating novel combination strategies and exploring the broader scope of CPIs in gastroesophageal cancers were also highlighted. The collected data were synthesized to provide a comprehensive overview of the crucial clinical trials that have contributed to the approval of CPIs for advanced gastroesophageal cancers. The role of CPIs in different lines of therapy, including first-line regimens, was discussed. Furthermore, the evolving landscape of predictive biomarkers was examined, emphasizing their potential significance in optimizing patient selection for CPI therapy. Ongoing clinical trials were reviewed to underscore the continuous efforts in expanding treatment options and improving patient outcomes in the future.


Which nanny--the state or industry? Wowsers, teetotallers and the fun police in public health advocacy.
There is no option for avoiding the 'Nanny'. The only option for communities is to make sensible choices about which 'Nanny' will dominate their lives and at what time, which 'Nanny' will make us healthy and which 'Nanny' will undermine our health and our freedoms. Those political ideologues who use 'nanny statism' largely do so to further their own agenda and are invariably inconsistent in how they apply their concept of non-interference. Who's afraid of the 'Nanny State' is not the question should be asking. Rather the question ought to be--which Nanny should cause the greatest concern? The prime reason that the 'Nanny State' conjures fear is that it is a threat to the freedoms that are a key element of democratic societies. The tenet understood by the concept of the 'Nanny State' is that the more regulation that is made by the State, the more freedoms are whittled away and it is the intention of the wowsers, the teetotallers and the fun police to do so. It is time to rethink the 'nanny' concept, from the narrow sense of loss of individual freedoms (and one which favours 'free enterprise' and money making interests of big industry) to that which enables individuals and populations freedom from domination. Such a change particularly pertains to our understandings of the role of government. Pettit's work in framing the notion of freedom in terms of 'dominance' rather than 'interference' is pertinent. It provides a more realistic way in which to understand why industry uses the 'Nanny State' argument. It is to maintain its own dominance (i.e. in matters of public health) rather than allowing governments to interfere with that dominance. Public health advocacy work is regularly undermined by the 'Nanny State' phrase. This paper explores a series of examples which illustrate how public health is being undermined by the 'Nanny Industry' and how industry uses fear of government regulation to maintain its own dominance, to maintain its profits and to do so at a significant financial and social cost to the community and to public health.


Protective effects of paeonol against lipopolysaccharide-induced liver oxidative stress and inflammation in gibel carp (Carassius auratus gibelio).
Paeonol (2'-hydroxy-4'-methoxyacetophenone) is a phenol that exhibits antioxidant and anti-inflammatory capabilities. In this study, the underlying mechanism of paeonol against LPS-induced oxidative stress and inflammatory responses in gibel carp was investigated. Three hundred healthy gibel carp were divided into five groups (n = 9), intraperitoneally injected with LPS and thereafter treated with paeonol (16 mg/kg and 64 mg/kg). Fish were anesthetized with MS-222 (100 mg/L), and samples were collected at 72 h to investigate plasma biochemical indexes, liver histopathology, antioxidant enzymatic activity, and TLR receptor-related gene expression. Fish injected with LPS (20 mg/kg) exhibited significantly increased plasma aminotransferase (ALT), aminotransferase (AST), lactate dehydrogenase (LDH), glucose (GLU), diamine oxidase (DAO), and alkaline phosphatase (ALP) levels (P < 0.05). In addition, LPS challenge significantly enhanced myeloperoxidase (MPO) and malondialdehyde (MDA) contents, whereas those of catalase (CAT) and glutathione peroxidase (GSH-Px) decreased (P < 0.05). However, treatment with paeonol attenuated these LPS-induced changes (P < 0.05). The mRNA expression of TLR4, TIRAP, MyD88, TRAF6, NF-κB, TNF-α, IL-1β, and IL-8, which were activated by LPS challenge (P < 0.05), were downregulated by paeonol. Additionally, histopathological examination demonstrated that paeonol alleviates LPS-induced hepatic tissue lesions in fish. Taken together, the results suggest that paeonol mitigates LPS-induced liver oxidative stress and inflammation in gibel carp.


Variabilities in alkaloid concentration of Sceletium tortuosum (L.) N.E. Br in response to different soilless growing media and fertigation regimes in hydroponics.
This study was designed to investigate the variations in alkaloid concentrations of Sceletium tortuosum when grown in soilless mediums under different fertigation regimes and to examine the suitability of the plant for hydroponic cultivation. A mother plant obtained from Verve Dynamics (Pty) Ltd (a manufacturer and supplier of purified botanical extracts) was cultivated into three hundred plants used for this research study. Twenty treatments were evaluated with 15 sample replicates. Treatments were made up of 4 different soilless growing media, namely: pure silica sand, 50% silica sand with 50% coco-peat, 50% silica sand with 50% vermiculite, and 50% silica sand with 50% perlite. These growing media were tested in conjunction with 5 different fertigation regimes (FR). Plants grown in FR1 received aqueous nutrient solution once every week, FR2 received aqueous nutrient solution once every second week, FR3 received aqueous nutrient solution once every third week, FR4 received aqueous nutrient solution once every fourth week and FR5 received aqueous nutrient solution once every fifth week respectively. Results from this experiment showed that different soilless growing media and fertigation had varying effects on alkaloid concentrations in S. tortuosum. It was also observed that roots contained higher amounts of delta 7 mesembrenone and mesembrenone, while shoots contained higher amounts of the alkaloid mesembrine.


The bone marrow biopsy, osteoscan, and peripheral blood in non-hematopoietic cancer.
Bone marrow biopsies were obtained from the iliac crests of 101 male patients with unresectable cancers of non-hematopoietic origin. Tumor cells were identified in 31% of the biopsies. Bone scintophotography studies were performed on 67 patients with positive or suspicious scans reported in 67%. Abnormal peripheral blood smears were encountered in 51% of 100 patients. Histologically established marrow metastases associated with a positive osteoscan and an abnormal peripheral smear occurred in 8% of the patients. The association of either one of the latter two with a positive histologic specimen was observed in about one-half of the patients. The significance of these associations is discussed.


Use of intracellular pH and annexin-V flow cytometric assays to monitor apoptosis and its suppression by bcl-2 over-expression in hybridoma cell culture.
Accurate identification and quantitation of apoptosis is essential for developing efficient strategies for optimisation of culture viability and productivity in cell lines of industrial significance. We have examined the possibility of using carboxy-seminaphthorhodafluor-1-acetoxymethylester (carboxy SNARF-1-AM), a pH sensitive fluoroprobe and FITC-labelled annexin V (AV), a probe specific to phosphatidylserine exposed on the surface of apoptotic cells, to monitor apoptosis and to determine the relationship between intracellular pH (pHi), apoptosis and cell cycle in hybridoma cells. Temporal changes in the distribution of proliferative capacity (S phase), metabolic activity (pHi), and cell death population dynamics were effectively and reliably determined using flow cytometry. Intracellular acidification was shown to precede the occurrence of apoptosis during batch culture and after treatment with campothecin, staurosporine and under adverse bioreactor conditions such as glutamine deprivation and oxygen deficiency. These results showed that the decrease in pHi can be used as an indicator of cellular deterioration and cell death. AV in combination with propidium iodide permitted the identification of viable, transient apoptotic and necrotic cells in heterogeneous cultures of control (PEF) cells. Hybridoma cells over-expressing bcl-2 were protected from intracellular acidification and phosphatidylserine exposure, which was associated with the suppression of apoptosis in these cells. A decrease in pHi was apparent even before the accumulation of the normally acidic G1 phase and the development of a sub-G1 region, characteristic of apoptotic cell behaviour. The pHi assay can therefore be used as a tool to predict future cell culture performance. reserved.


Global Women's Health Education in Canadian Obstetrics and Gynaecology Residency Programs: A Survey of Program Directors and Senior Residents.
To become culturally competent practitioners with the ability to care and advocate for vulnerable populations, residents must be educated in global health priorities. In the field of obstetrics and gynaecology, there is minimal information about global women's health (GWH) education and interest within residency programs. We wished to determine within obstetrics and gynaecology residency programs across Canada: (1) current GWH teaching and support, (2) the importance of GWH to residents and program directors, and (3) the level of interest in a national postgraduate GWH curriculum. We conducted an online survey across Canada of obstetrics and gynaecology residency program directors and senior obstetrics and gynaecology residents. Of 297 residents, 101 (34.0%) responded to the survey and 76 (26%) completed the full survey. Eleven of 16 program directors (68.8%) responded and 10/16 (62.5%) provided complete responses. Four of 11 programs (36.4%) had a GWH curriculum, 2/11 (18.2%) had a GWH budget, and 4/11 (36.4%) had a GWH chairperson. Nine of 10 program directors (90%) and 68/79 residents (86.1%) felt that an understanding of GWH issues is important for all Canadian obstetrics and gynaecology trainees. Only 1/10 program directors (10%) and 11/79 residents (13.9%) felt that their program offered sufficient education in these issues. Of residents in programs with a GWH curriculum, 12/19 (63.2%) felt that residents in their program who did not undertake an international elective would still learn about GWH, versus only 9/50 residents (18.0%) in programs without a curriculum (P < 0.001). Obstetrics and gynaecology residents and program directors feel that GWH education is important for all trainees and is currently insufficient. There is a high level of interest in a national postgraduate GWH educational module.


Inhibition of NF-κB by deoxycholic acid induces miR-21/PDCD4-dependent hepatocellular apoptosis.
MicroRNAs (miRNAs/miRs) are key regulators of liver metabolism, while toxic bile acids participate in the development of several liver diseases. We previously demonstrated that deoxycholic acid (DCA), a cytotoxic bile acid implicated in the pathogenesis of non-alcoholic fatty liver disease, inhibits miR-21 expression in hepatocytes. Here, we investigated the mechanisms by which DCA modulates miR-21 and whether miR-21 contributes for DCA-induced cytotoxicity. DCA inhibited miR-21 expression in primary rat hepatocytes in a dose-dependent manner, and increased miR-21 pro-apoptotic target programmed cell death 4 (PDCD4) and apoptosis. Both miR-21 overexpression and PDCD4 silencing hampered DCA-induced cell death. Further, DCA decreased NF-κB activity, shown to represent an upstream mechanism leading to modulation of the miR-21/PDCD4 pathway. In fact, NF-κB overexpression or constitutive activation halted miR-21-dependent apoptosis by DCA while opposite results were observed upon NF-κB inhibition. In turn, DCA-induced oxidative stress resulted in caspase-2 activation and NF-κB/miR-21 inhibition, in a PIDD-dependent manner. Finally, modulation of the NF-κB/miR-21/PDCD4 pro-apoptotic pathway by DCA was also shown to occur in the rat liver in vivo. These signalling circuits may constitute appealing targets for bile acid-associated liver pathologies.


Tumour-stroma ratio to predict pathological response to neo-adjuvant treatment in rectal cancer.
Management of rectal cancer has advanced, with an increasing use of neoadjuvant chemoradiotherapy (nCRT). This opens options for organ preserving treatment for those with a major response to nCRT. However, the degree of clinical response, based on MRI and post-treatment biopsies, only poorly matches the degree of actual pathological response. In order to select patients with major pathological response without surgical resection, it is of importance to define tumour markers predicting the degree of pathological response to nCRT. The intra-tumoural tumour-stroma ratio (TSR) might be this marker. TSR in pre-treatment biopsies was estimated according to the method described by van Pelt et al. The degree of pathological response was assessed on the tumour resection according to tumour regression grading (TRG) by Mandard. The primary endpoint of this study was the difference in pathological response to nCRT between TSR-high and TSR-low groups. We found that 26.2% of patients with major response was classified as TSR-high, while 73.8% of patients were classified as TSR-low. A high TSR in pre-treatment biopsies was associated with a lower chance of major-response to nCRT (OR = 0.37, 95%CI; 0.19-0.73), p = 0.004), independent of tumour stage and time between nCRT and surgery. In rectal cancer, TSR in pre-treatment biopsies predicts pathologic response to nCRT, with a high TSR bringing twice the risk of poor to no response compared to low TSR. In future, assessment of TSR may fulfil a role in a therapeutic algorithm identifying patients who will or will not respond to nCRT prior to treatment initiation.


Syncope is a frequently under-diagnosed condition in infants and toddlers and has similar features to those seen in adolescents and adults.
Vagal syncope may not be readily recognised by the caregivers of younger children, often leading to extensive diagnostic evaluation. Our aim was to determine the characteristics of syncope in younger children and to assess whether this age group was more prone to undergoing extensive diagnostic work-ups and receiving wrong aetiological diagnoses. We collected clinical data on children up to six years of age, referred to our paediatric neurology clinic between 2007 and 2014 following one or more episodes of sudden loss of consciousness. A family history of syncope was present in 59.5% of the 37 children, and a trigger for syncope was identified in 30 children. Most of the episodes were short, with witnesses reporting an immediate or quick recovery. Most of the children underwent diagnostic procedures, particularly an electroencephalogram, and all the results were normal. Epilepsy did not develop in any of these cases. Syncope recurred in 22 patients during a two-year follow-up. Vagal syncope had similar features in toddlers and young children to those seen in adolescents and adults. Its diagnosis should be considered following loss of consciousness due to an identifiable trigger and rapidly regaining consciousness to avoid unnecessary diagnostic procedures and hospitalisation.


Chemical and sensory characterization of Brazilian virgin olive oils.
Brazil is an emerging virgin olive oil producer country whose oils have been scarcely studied till now and, in particular, no data are present in literature about their volatile profiles and organoleptic characteristics as well as the Pearson's correlations between chemical and sensory parameters. Hence, giving insights about these aspects was the aim of the current investigation. The volatile profiles showed the presence of the aldehydes responsible for the positive attribute of VOOs (i.e. trans-2-Hexenal and hexanal) although, in some cases, volatiles from anaerobic and aerobic fermentation were also detected. The panel test showed low values of fruity and pungent notes (mean values of 1.1 and 0.6, respectively) whereas the bitter taste was detected only in one sample, probably due to the low amount of total phenolic compounds (ranging from 40 to 280 mg kg-1). Accordingly to the volatiles analysis, slight defects of the oils were evidenced by the panelists. Tocopherols ranged from 123 to 222 mg kg-1; carotenoids from 10.69 to 26.18 mg kg-1, chlorophylls from 14.06 to 54.90 mg kg-1, antioxidant activity from 976 to 1790 μmol TE g-1, and fatty acid ethyl esters from 2.56 to 19.22 mg kg-1. Positive Pearson's correlations were highlighted between hydroxytyrosol derivatives and antioxidant activity (r = 0.9601, p < .0001), trans-2-hexenal and fruity median (r = 0.6526, p < .05), acetic acid and vinegary defect (r = 0.7854, p < .0001), and fatty acid ethyl esters and vinegary defect (r = 0.8418, p < .0001). Our findings give first insights about sensory characteristics of Brazilian virgin olive oils and their association with chemical quality parameters. Finally, based on the obtained data, an improvement of preliminary operations (harvesting, storage) of the extraction process is recommended.


Biomonitoring of perfluorinated compounds in children and adults exposed to perfluorooctanoate-contaminated drinking water.
40,000 residents in Arnsberg, Germany, had been exposed to drinking water contaminated with perfluorinated compounds (PFCs). Internal exposure of the residents of Arnsberg to six PFCs was assessed in comparison with reference areas. One hundred seventy children (5-6 years of age), 317 mothers (23-49 years), and 204 men (18-69 years) took part in the cross-sectional study. Individual consumption of drinking water and personal characteristics were assessed by questionnaire and interview. Perfluorooctanoate (PFOA), perfluorooctanesulfonate (PFOS), perfluorohexanoate, perfluorohexanesulfonate (PFHxS), perfluoropentanoate, and perfluorobutanesulfonate (PFBS) in blood plasma and PFOA/PFOS in drinking water samples were measured by solid-phase extraction, high-performance liquid chromatrography, and tandem mass spectrometry detection. Of the various PFCs, PFOA was the main compound found in drinking water (500-640 ng/L). PFOA levels in blood plasma of residents living in Arnsberg were 4.5-8.3 times higher than those for the reference population (arithmetic means Arnsberg/controls: children 24.6/5.2 microg/L, mothers 26.7/3.2 microg/L, men 28.5/6.4 microg/L). Consumption of tap water at home was a significant predictor of PFOA blood concentrations in Arnsberg. PFHxS concentrations were significantly increased in Arnsberg compared with controls (p < 0.05). PFBS was detected in 33% of the children, 4% of the women, and 13% of the men in Arnsberg compared with 5%, 0.7%, and 3%, respectively, in the reference areas (p < 0.05). Regression analysis showed that age and male sex were significant predictors of PFOS, PFOA, and PFHxS; associations of other regressors (diet, body mass index) varied among PFCs. PFC concentrations in blood plasma of children and adults exposed to PFC-contaminated drinking water were increased 4- to 8-fold compared with controls.


PRSS2 regulates EMT and metastasis via MMP-9 in gastric cancer.
Serine protease 2 (PRSS2) is upregulated in gastric cancer tissues, correlates with poor prognosis and promotes migration and invasion of gastric cancer cells. However, the exact mechanism by which PRSS2 promotes metastasis in gastric cancer is unclear. We examined serum PRSS2 levels in healthy controls and gastric cancer patients by enzyme linked immunosorbent assay (ELISA) and analyzed the correlation between PRSS2 serum level with the clinicopathological characteristics of gastric cancer patients and matrix metalloproteinase-9 (MMP-9) expression. A lentiviral MMP-9 overexpression vector was constructed and used to transfect gastric cancer cells with stable silencing of PRSS2, and migration, invasion and epithelial-mesenchymal transition (EMT) of gastric cancer cells were examined. High serum PRSS2 levels were detected in gastric cancer patients and associated with lymphatic metastasis and TNM stage. Serum PRSS2 was positively correlated with serum MMP-9 level. PRSS2 silencing inhibited EMT, and knock-down of PRSS2 partially abrogated cell metastasis and EMT caused by overexpression of MMP-9. These results suggest that PRSS2 promotes the migration and invasion of gastric cancer cells through EMT induction by MMP-9. Our findings suggest that PRSS2 may be a potential early diagnostic marker and therapeutic target of gastric cancer.


Donor age affects liver regeneration during early period in the graft liver and late period in the remnant liver after living donor liver transplantation.
The aim of the present study was to evaluate the influence of donor age on liver regeneration and surgical outcomes in recipients and donors. Among 101 cases of adult-to-adult living donor liver transplantation (LDLT) between March 2002 and March 2011, according to donor age: younger (Y) <50 years of age or older (O) ≥ 50 years of age, the donors and recipients using right (R) or left (L) graft were divided into groups Y/R (n = 51) and O/R (n = 17), and groups Y/L (n = 26) and O/L (n = 7), respectively. Remnant liver volume (RemLV) and graft liver volume (GLV) were estimated by computed tomography (CT) volumetry. A disintegrin and metalloprotease with thrombospondin type I domain 13 (ADAMTS13) activities and von Willebrand factor (vWF) antigen levels were measured as factors reflecting thrombotic microangiopathy. Among the donors, RemLV/total liver volume (TLV) was lower in group O/R than in group Y/R, although there were no significant differences by t-test with the Bonferroni correction (rough p value = 0.02 at 6 months and rough p value > 0.05 at 1, 3, and 12 months). Donor age (≥ 50 years) was independently correlated with impaired remnant liver regeneration at 6 months in right lobe LDLT (p = 0.04). Among the recipients, GLV/standard liver volume (SLV) was lower during the first month, although there were no significant differences between the two groups by t-test with the Bonferroni correction (rough p value = 0.03 at 1 week and rough p value >0.05 at 2 weeks and 1 and 3 months). Donor age (≥ 50 years) was independently correlated with impaired graft liver regeneration at 1 week in both right and left lobe LDLT (p < 0.05). ADAMTS13 activities were lower in group O/R than in group Y/R, although there were no significant differences by t-test with the Bonferroni correction (rough p value = 0.049 on postoperative days (POD) 1 and 28 and rough p value >0.05 on POD 7 and 14). vWF/ADAMTW13 ratios were higher on POD 14, although there were no significant differences between the two groups by t-test with the Bonferroni correction (rough p value = 0.044 on POD 14 and rough p value >0.05 on POD 1, 7, 14, and 28). The surgical outcomes using older donor livers for LDLT were comparable to those using younger donor livers. When using older donor livers, however, we should pay attention to the liver volume for recipients as well as donors, because older donor livers might have impaired regenerative ability.


Effects of six-cycle completion and earlier use of radium-223 therapy on prognosis for metastatic castration-resistant prostate cancer: A real-world multicenter retrospective study.
To evaluate the effect of 6-cycle completion and earlier use of radium-233 dichloride (Ra223) on the prognosis of patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively evaluated 75 patients with bone metastases-predominant mCRPC who were treated with Ra223 between August 2016 and August 2021. The primary purpose of the study was to assess the effect of Ra223 completion (6 cycles) on patient prognosis, and the secondary purpose was to investigate factors associated with Ra223 incompletion (fewer than 6 cycles) and overall survival. The median age of the patients was 72 years. The median number of Ra223 administrations was 6 (interquartile range, 5-6), and the median Ra223 completion rate was 75%. The median time from mCRPC diagnosis to Ra223 administration was 17 months, and the median number of prior treatments was 2. Multivariable analysis indicated that unfavorable performance status (>0), prostate-specific antigen (PSA) level >10 ng/ml, extension of bone metastasis score 3 to 4, and Ra223 incompletion were significantly associated with poor overall survival. In addition, EOD 3 to 4 and 3 or more prior CRPC treatments were significantly associated with Ra223 incompletion. Six-cycle completion and earlier administration of Ra233 are potentially associated with favorable survival. Unfavorable factors (EOD 3-4 and ≥3 prior treatments) were significantly associated with Ra223 incompletion.


Whipple's disease.
This article reviews the microbiology, pathophysiology, epidemiology, clinical manifestations, diagnostic testing, and treatment of Whipple's disease, an illness caused by Tropheryma whipplei and characterized by multivariate clinical manifestations including an inflammatory arthropathy. Diagnosis is confirmed by tissue sampling with periodic acid-Schiff staining and/or polymerase chain reaction. Clinical manifestations most frequently manifest in the gastrointestinal tract, musculoskeletal system, neurologic system, heart, and eyes, but can affect any site. Successful therapy with appropriate antibiotics is potentially curable, but recurrences may occur.