ATP binding site mutagenesis reveals different subunit stoichiometry of functional P2X2/3 and P2X2/6 receptors.
The aim of the present experiments was to clarify the subunit stoichiometry of P2X2/3 and P2X2/6 receptors, where the same subunit (P2X2) forms a receptor with two different partners (P2X3 or P2X6). For this purpose, four non-functional Ala mutants of the P2X2, P2X3, and P2X6 subunits were generated by replacing single, homologous amino acids particularly important for agonist binding. Co-expression of these mutants in HEK293 cells to yield the P2X2 WT/P2X3 mutant or P2X2 mutant/P2X3 WT receptors resulted in a selective blockade of agonist responses in the former combination only. In contrast, of the P2X2 WT/P2X6 mutant and P2X2 mutant/P2X6 WT receptors, only the latter combination failed to respond to agonists. The effects of α,β-methylene-ATP and 2-methylthio-ATP were determined by measuring transmembrane currents by the patch clamp technique and intracellular Ca(2+) transients by the Ca(2+)-imaging method. Protein labeling, purification, and PAGE confirmed the assembly and surface trafficking of the investigated WT and WT/mutant combinations in Xenopus laevis oocytes. In conclusion, both electrophysiological and biochemical investigations uniformly indicate that one subunit of P2X2 and two subunits of P2X3 form P2X2/3 heteromeric receptors, whereas two subunits of P2X2 and one subunit of P2X6 constitute P2X2/6 receptors. Further, it was shown that already two binding sites of the three possible ones are sufficient to allow these receptors to react with their agonists.


Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication.
Because uncontrolled echocardiographic surveys suggested that up to 30% to 38% of users of fenfluramine and dexfenfluramine had valvular disease, these drugs were withdrawn from the market. To determine the risk for new or worsening valvular abnormalities among users of fenfluramine or dexfenfluramine who underwent echocardiography before they began to take these medications. Cohort study. Academic primary care practices. 46 patients who used fenfluramine or dexfenfluramine for 14 days or more and had echocardiograms obtained before therapy. Follow-up echocardiography. The primary outcome was new or worsening valvulopathy, defined as progression of either aortic or mitral regurgitation by at least one degree of severity and disease that met U.S. Food and Drug Administration criteria (at least mild aortic regurgitation or moderate mitral regurgitation). Two patients (4.3% [95% CI, 0.6% to 14.8%]) receiving fenfluramine-phentermine developed valvular heart disease. One had baseline bicuspid aortic valve and mild aortic regurgitation that progressed to moderate regurgitation. The second patient developed new moderate aortic insufficiency. Users of diet medications are at risk for valvular heart disease. However, the incidence may be lower than that reported previously.


Egg morphology, laying behavior and record of the host plants of Ricania speculum (Walker, 1851), a new alien species for Europe (Hemiptera: Ricaniidae).
The exotic planthopper, Ricania speculum (Ricaniidae) was recently detected in Liguria, in northern Italy, and recorded as a first alert for Europe. The first morphological description of eggs and laying behavior are given. Eggs are inserted into the woody tissue of a wide range of different host plants in such a unique manner among native and alien planthoppers of Italy that it can be used to describe the prevalence and diffusion of the species in new environments, though in the absence of juveniles and/or adults. In addition, the paper lists the host plants utilized for egg laying and describes the eggs.


In the rat, tumor necrosis factor alpha administration results in an increase in both UCP2 and UCP3 mRNAs in skeletal muscle: a possible mechanism for cytokine-induced thermogenesis?
Since the discovery of the new members of the UCP (uncoupling protein) family, UCP2 and UCP3, very few studies have dealt with the regulation of their expression. Bearing this in mind, administration of a single intravenous injection of TNF-alpha (100 microg/kg body weight) to rats resulted in a significant increase in UCP2 (242%) and UCP3 (113%) gene expression in skeletal muscle. The results suggest a possible role for UCP2 and UCP3 in the increase of energy expenditure associated with cytokine treatment.


Reduction in temporal lobe size in siblings with schizophrenia: a magnetic resonance imaging study.
Twenty-eight individuals with familial schizophrenia, from 16 unrelated families (12 sibling pairs and 4 individuals whose siblings refused scanning), and 21 normal control subjects were examined by cerebral magnetic resonance imaging (MRI). Measurements of the cerebrum, temporal lobes, and cerebral lateral ventricles were obtained using consecutive coronal sections containing these structures. Temporal lobe volume was significantly decreased by approximately 10% in these early onset schizophrenic siblings compared with normal controls. These findings add to recent post-mortem and neuroradiological evidence for morphological alteration in the temporal lobes in schizophrenia.


The effects of prostacyclin on gastric intramucosal pH in patients with septic shock.
To investigate whether infusing prostacyclin (PGI2) in patients with septic shock improves splanchnic oxygenation as assessed by gastric intramucosal pH (pHi). Interventional clinical study. Surgical ICU in a university hospital. 16 consecutive patients with septic shock according to the criteria of the ACCP/SCCM consensus conference all requiring norepinephrine to maintain arterial blood pressure. All patients received PGI2 (10 ng/kg x min) after no further increase in oxygen delivery could be obtained by volume expansion, red cell transfusion and dobutamine infusion. The results were compared with those before and after conventional resuscitation. The patients received continuous PGI2 infusion for 33-32 days. O2 uptake was measured directly in the respiratory gases, pHi was determined by tonometry. Baseline O2 delivery, O2 uptake and pHi were 466 +/- 122 ml/min.m2, 158 +/- 38 ml/min.m2, and 7.29 +/- 0.09, respectively. While O2 uptake remained unchanged, infusing PGI2 increased O2 delivery (from 610 +/- 140 to 682 +/- 155 ml/min.m2, p < 0.01) and pHi (from 7.32 +/- 0.09 to 7.38 +/- 0.08, p < 0.001) beyond the values obtained by conventional resuscitation. While 9 of 11 patients with final pHi > 7.35 survived, all patients with final pHi < 7.35 died (p < 0.01). Infusing PGI2 in patients with septic shock increases pHi probably by enhancing blood flow to the splanchnic bed and thereby improves splanchnic oxygenation even when conventional resuscitation goals have been achieved.


Brunner's missing 'Aha experience' delayed progress in diabetes research by 200 years.
In 1889, the pancreatectomy performed on a dog by Joseph von Mehring and Oskar Minkowski led to the discovery of the pancreatic origin of diabetes disease. Already 200 years before, Johann Conrad Brunner had successfully performed eight pancreatectomies on dogs and had precisely described the symptoms of polyphagia, polyuria, and polydipsia. He did not, however, recognize the association with the diabetes disease and thus missed an opportunity to accelerate the course of diabetes research by 200 years.


[Perinatal complications in patients with chronic renal insufficiency on hemodialysis].
Pregnant patients with chronic renal insufficiency treated with hemodialysis experience adverse perinatal results. To compare perinatal complications of patients with chronic renal insufficiency undergoing hemodialysis who become pregnant vs. the complications of women with chronic renal insufficiency not undergoing dialysis but who then require dialysis during gestation. Transversal and retrospective study that included three patients with chronic renal insufficiency on chronic hemodialysis who became pregnant (group A) and three patients with chronic renal insufficiency without hemodialysis at the time of conception but who required dialysis during gestation (group B). Perinatal results were compared. Statistical analysis was performed with measures of central tendency and dispersion and Student t-test. Group A had 25 sessions vs. group B with 29 hemodialysis sessions (p = 0.88). Maternal complications were anemia 100% (six cases), Cesarean delivery 83.3% (group A 2 cases vs. group B 2 cases), preeclampsia 50% (group A 2 cases vs. group B 1 case), uncontrolled hypertension 50% (group A 2 cases vs. group B 1 case), preterm delivery 50% (group A 2 cases vs. group B 1 case), transfusion 33.3% (group A 2 cases), polyhydramnios 33.3% (group A 1 case vs. group B 1 case) and abortion 16.6% (group A 1 case). Fetal complications included fetal loss 16.6% (group A 1 case), neonatal mortality 33.3% (group A 1 cases vs. group B 1 case), prematurity 50% (group A2 cases vs. group B 1 case), fetal distress 50% (group A 1 case vs. group B 2 cases), respiratory failure 33.3% (group A 2 cases) and fetal growth restriction 16.6% (group A 1 case). Frequency of perinatal complications is elevated in both groups.


Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema.
Neurodegeneration and brain edema are hallmarks of human malignant brain tumors. Here we show that genetic or pharmacological inhibition of the glutamate transporter xCT (X(c-) system, encoded by SLC7a11) in vivo leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. These results show a crucial role for xCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.


Kinetic Estimation of GFR Improves Prediction of Dialysis and Recovery after Kidney Transplantation.
The early prediction of delayed graft function (DGF) would facilitate patient management after kidney transplantation. In a single-centre retrospective analysis, we investigated kinetic estimated GFR under non-steady-state conditions, KeGFR, in prediction of DGF. KeGFR(sCr) was calculated at 4h, 8h and 12h in 56 recipients of deceased donor kidneys from initial serum creatinine (sCr) concentrations, estimated creatinine production rate, volume of distribution, and the difference between consecutive sCr values. The utility of KeGFR(sCr) for DGF prediction was compared with, sCr, plasma cystatin C (pCysC), and KeGFR(pCysC) similarly derived from pCysC concentrations. At 4h, the KeGFR(sCr) area under the receiver operator characteristic curve (AUC) for DGF prediction was 0.69 (95% CI: 0.56-0.83), while sCr was not useful (AUC 0.56, (CI: 0.41-0.72). Integrated discrimination improvement analysis showed that the KeGFR(sCr) improved a validated clinical prediction model at 4h, 8h, and 12h, increasing the AUC from 0.68 (0.52-0.83) to 0.88 (0.78-0.99) at 12h (p = 0.01). KeGFR(pCysC) also improved DGF prediction. In contrast, sCr provided no improvement at any time point. Calculation of KeGFR from sCr facilitates early prediction of DGF within 4 hours of renal transplantation.


Role of mitochondrial fission in neuronal injury in pilocarpine-induced epileptic rats.
Mitochondrial fission has been reported to be involved in oxidative stress, apoptosis and many neurological diseases. However, the role of mitochondrial fission in seizures, which could induce oxidative stress and neuronal loss, remains unknown. In this study, we used pilocarpine to elicit seizures in rats. Meanwhile, we used mitochondrial division inhibitor 1 (mdivi-1), a selective inhibitor of mitochondrial fission protein dynamin-related protein1 (Drp1), to suppress mitochondrial fission in epileptic model of rats in vivo. We found that mitochondrial fission was increased after seizures and the inhibition of mitochondrial fission by mdivi-1 significantly attenuated oxidative stress and reduced neuronal loss after seizures, shown by the decreased 8-hydroxy deoxyguanosine (8-oHdG) content, the increased superoxide dismutase (SOD) activity, the reduced expression of cytochrome c and caspase3 and the increased surviving neurons in the hippocampus. These results indicated that mitochondrial fission is up-regulated after seizures and the inhibition of mitochondrial fission is protective against neuronal injury in seizures, the underlying mechanism may be through the mitochondria/reactive oxygen species (ROS)/cytochrome c pathway.


Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials.
Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction has been identified as an important but manageable adverse effect of targeted therapy. Several studies have suggested that patients who develop hypothyroidism respond better to TKIs, but this relationship is not well elucidated. We evaluated the relationship between new-onset hypothyroidism and clinical response in patients with advanced cancers treated with TKIs at our institution. We retrospectively reviewed records for patients from four clinical trials that included at least one TKI therapy between January 2006 and December 2011. Patients with preexisting thyroid disease, including thyroid cancer, hypothyroidism, or hyperthyroidism, were excluded. Analysis of 197 patients was performed. Response was determined using RECIST 1.0. Clinical benefit was described as complete response, partial response, or stable disease greater than 4 months. Multivariable logistic regression analysis was performed to correlate patient characteristics with clinical response. The median age for the 197 patients was 58 years (range, 13-85 years), and 56 % were female. Of the 197 patients, 52 (26 %) developed hypothyroidism after therapy. Clinical benefit rates were 50 % in patients with new-onset hypothyroidism versus 34 % in patients without hypothyroidism. In the univariate model, the odds ratio (OR) for new-onset hypothyroidism was 1.9 [95 % confidence interval (CI) (1.0, 3.6) and p = 0.05]. We grouped tumor types into six categories (breast, colorectal carcinoma, melanoma, non-small cell lung cancer, pancreas, and other). When adjusted for tumor type, age (>50 years) and sex, the OR was 2.9 [95 % CI (1.3, 6.5) and p = 0.012] for new-onset hypothyroidism. New-onset hypothyroidism was associated with favorable clinical response in patients who received TKI treatment.


Power output during women's World Cup road cycle racing.
Little information exists on the power output demands of competitive women's road cycle racing. The purpose of our investigation was to document the power output generated by elite female road cyclists who achieved success in FLAT and HILLY World Cup races. Power output data were collected from 27 top-20 World Cup finishes (19 FLAT and 8 HILLY) achieved by 15 nationally ranked cyclists (mean +/- SD; age: 24.1+/-4.0 years; body mass: 57.9+/-3.6 kg; height: 168.7+/-5.6 cm; VO2max 63.6+/-2.4 mL kg(-1) min(-1); peak power during graded exercise test (GXT(peak power)): 310+/-25 W). The GXT determined GXT(peak power), VO2peak lactate threshold (LT) and anaerobic threshold (AT). Bicycles were fitted with SRM powermeters, which recorded power (W), cadence (rpm), distance (km) and speed (km h(-1)). Racing data were analysed to establish time in power output and metabolic threshold bands and maximal mean power (MMP) over different durations. When compared to HILLY, FLAT were raced at a similar cadence (75+/-8 vs. 75+/-4 rpm, P=0.93) but higher speed (37.6+/-2.6 vs. 33.9+/-2.7 km h(-1), P=0.008) and power output (192+/-21 vs. 169+/-17 W, P=0.04; 3.3+/-0.3 vs. 3.0+/-0.4 W kg(-1), P=0.04). During FLAT races, riders spent significantly more time above 500 W, while greater race time was spent between 100 and 300 W (LT-AT) for HILLY races, with higher MMPs for 180-300 s. Racing terrain influenced the power output profiles of our internationally competitive female road cyclists. These data are the first to define the unique power output requirements associated with placing well in both flat and hilly women's World Cup cycling events.


Sampling error in the diagnosis of colorectal cancer is associated with delay to surgery: a retrospective cohort study.
Accurate histopathologic diagnosis of colorectal cancer is important for treatment decision-making and timely care. The aim of this study was to measure rates and predictors of sampling errors for biopsy specimens attained at flexible lower gastrointestinal endoscopy, and to determine whether these events lead to a delay in surgical care. This is a retrospective observational study of patients who underwent elective resection for colorectal adenocarcinoma between January 2007 and June 2020. Primary outcomes were proportion of incorrectly diagnosed colorectal adenocarcinomas at index endoscopy by histopathology, and time between endoscopy and surgery. Secondary outcomes were predictors of sampling error, and diagnostic yield of repeat endoscopy. Sampling errors occurred in 217/962 (22.6%) flexible endoscopies for colorectal adenocarcinomas. Negative biopsies were associated with a longer median time to surgery (87.6 days, IQR 48.8-180.0) compared to true positive biopsies (64.0 days, IQR 38.0-119.0), p < 0.001. Controlling for lesion location, neoadjuvant therapy, endoscopist specialty, year, and repeat endoscopies, time to surgery remained 1.40-fold longer (p < 0.001) following sampling error. Repeat endoscopy occurred following 62/217 (28.6%) cases of sampling errors, yielding a correct diagnosis of cancer in 38/62 (61.3%) cases. On multivariable analysis, sampling errors were less likely to occur for lesions endoscopists described as suspicious for malignancy (OR 0.12, 95% CI 0.07-0.21) or simple polyps (OR 0.24, 95% CI 0.08-0.70) compared to endoscopically unresectable polyps. Colorectal cancers are frequently improperly sampled, which may lead to treatment delays for these patients. When cancer is suspected, surgeons should take care to ensure timely management.


Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?
Large-scale genomic studies of schizophrenia have identified hundreds of genetic loci conferring risk to the disorder. This progress offers an important route toward defining the biological basis of the condition and potentially developing new treatments. In this review, we discuss insights from recent genome-wide association study, copy number variant, and exome sequencing analyses of schizophrenia, together with functional genomics data from the pre- and postnatal brain, in relation to synaptic development and function. These data provide strong support for the view that synaptic dysfunction within glutamatergic and GABAergic (gamma-aminobutyric acidergic) neurons of the cerebral cortex, hippocampus, and other limbic structures is a central component of schizophrenia pathophysiology. Implicated genes and functional genomic data suggest that disturbances in synaptic connectivity associated with susceptibility to schizophrenia begin in utero but continue throughout development, with some alleles conferring risk to the disorder through direct effects on synaptic function in adulthood. This model implies that novel interventions for schizophrenia could include broad preventive approaches aimed at enhancing synaptic health during development as well as more targeted treatments aimed at correcting synaptic function in affected adults.


Increased Risk of Type 2 Diabetes in Patients With Thyroid Cancer After Thyroidectomy: A Nationwide Cohort Study.
Abnormal thyroid function after thyroidectomy and subsequent thyroid-stimulating hormone suppression can have detrimental effects on glucose homeostasis in patients with thyroid cancer. To investigate whether thyroidectomy increases the risk of type 2 diabetes in patients with thyroid cancer and to explore the association between levothyroxine dosage and type 2 diabetes risk. A retrospective population-based cohort study using the Korean National Health Insurance database. We included 36 377 thyroid cancer patients without known diabetes who underwent thyroidectomy between 2004 and 2013. Matched subjects with nonthyroid cancer were selected using 1:1 propensity score matching. The main outcome measure was newly developed type 2 diabetes mellitus. Patients with thyroid cancer who underwent thyroidectomy had a higher risk of developing type 2 diabetes mellitus than the matched controls (hazard ratio [HR] 1.43, 95% CI 1.39-1.47). Among patients with thyroid cancer, when the second quartile group (in terms of the mean levothyroxine dosage; 101-127 μg/day) was considered the reference group, the risk of type 2 diabetes mellitus increased in the first quartile (<101 μg/day; HR 1.45, 95% CI 1.36-1.54) and fourth quartile groups (≥150 μg/day; HR 1.37, 95% CI 1.29-1.45); meanwhile, the risk decreased in the third quartile group (128-149 μg/day; HR 0.91, 95% CI 0.85-0.97). Patients with thyroid cancer who underwent thyroidectomy were more likely to develop type 2 diabetes mellitus than the matched controls. There was a U-shaped dose-dependent relationship between the levothyroxine dosage and type 2 diabetes mellitus risk.


Auditory environmental context affects visual distance perception.
In this article, we show that visual distance perception (VDP) is influenced by the auditory environmental context through reverberation-related cues. We performed two VDP experiments in two dark rooms with extremely different reverberation times: an anechoic chamber and a reverberant room. Subjects assigned to the reverberant room perceived the targets farther than subjects assigned to the anechoic chamber. Also, we found a positive correlation between the maximum perceived distance and the auditorily perceived room size. We next performed a second experiment in which the same subjects of Experiment 1 were interchanged between rooms. We found that subjects preserved the responses from the previous experiment provided they were compatible with the present perception of the environment; if not, perceived distance was biased towards the auditorily perceived boundaries of the room. Results of both experiments show that the auditory environment can influence VDP, presumably through reverberation cues related to the perception of room size.


Trace element deficiency is highly prevalent and associated with infection and mortality in patients with alcoholic hepatitis.
Malnutrition is common in patients with alcohol-related liver disease and is associated with outcome in patients with alcoholic hepatitis. Trace elements (cobalt, copper, iron, selenium and zinc) are micronutrients essential for many cellular processes including antioxidant pathways. The prevalence and relevance of trace element deficiency is unknown in alcoholic hepatitis. To determine the prevalence of trace element deficiency and its association with clinical outcomes in patients with alcoholic hepatitis. Serum was obtained from patients with alcoholic hepatitis, alcohol-related cirrhosis and healthy volunteers as part of clinical trials, cohort studies and a biobank. Trace element concentration was measured by inductively coupled plasma mass spectrometry. Association of trace element levels with development of infection within 90 days and mortality within 28 and 90 days was evaluated by multivariate logistic regression. Sera from 302 patients with alcoholic hepatitis, 46 with alcohol-related cirrhosis and 15 healthy controls were analysed for trace element concentration. The prevalence of zinc deficiency (85%) and selenium deficiency (67%) in alcoholic hepatitis was higher than in alcohol-related cirrhosis (72% [p=0.04] and 37% [p<0.001], respectively). Zinc, selenium, copper and chromium were significantly different between groups. Iron deficiency was a predictor of development of infection within 90 days. Zinc deficiency was a predictor of mortality within 28 and 90 days. Trace element deficiency in patients with alcoholic hepatitis is highly prevalent and associated with infection and mortality. Supplementation with selected trace elements may improve clinical outcomes in this patient group but further insight is required of their biological and clinical effects.


Development of Obesity: Mechanisms and Physiology.
Normal adult animals living in nonstressful environments that receive nutritionally sound diets balance their energy expenditure with their energy intake over the long-term. Most knowledge of mechanisms underlying the precise balance of energy is derived from research on rodent models and human correlates. This knowledge is believed applicable and pertinent for understanding causes of obesity in dogs and cats. The roles of satiation and adiposity feedback, cognitive input, energy expenditure, and physical activity are reviewed. Dietary and environmental factors especially relevant to promotion of overweight body condition are reviewed. These include dietary fat and palatability, inactive and stressful lifestyle, and obesogenic effects of neutering.


Health Economic Evaluation of a High and Low Molecular Weight Hyaluronic Acid Formulation for the Treatment of Knee Osteoarthritis. Post Hoc Analyses from a Randomized Clinical Trial.
In a recent randomized placebo-controlled trial, a single intra-articular injection of a high and low molecular weight hyaluronic acid formulation (HA-HL) was shown to be effective in providing a clinically meaningful reduction in pain and functional limitation up to 24 weeks in subjects with painful knee osteoarthritis (OA). The objective of this post hoc analyses is to assess the cost-effectiveness of HA-HL compared with placebo using individual patient data from this clinical trial in a Swiss health care perspective. A total of 692 patients fulfilling the inclusion criteria were randomly allocated to HA-HL or placebo groups. Each patient received one intra-articular injection of HA-HL or placebo at baseline and was then followed-up for a total duration of 24 weeks with five follow-up visits (i.e., after weeks 1, 6, 12, 18, and 24). The EQ-5D-5L five-point verbal Likert scale was used to calculate the health utility and the related quality-adjusted life-years (QALYs) using the area-under-the-curve (AUC) method. For the costs, the price of HA-HL in Switzerland was used. The primary threshold for the incremental cost/effectiveness ratio (ICER) below which HA-HL was considered as cost-effective was 91,540 Swiss francs (CHF) per QALY (i.e., US $100,000). No significant difference between the baseline characteristics of the HA-HL group and the placebo group was observed. With a mean ICER of 27,212 CHF per QALY (95% CI 20,135-34,289), HA-HL was considered as cost-effective compared to placebo. Sensitivity analyses (e.g., using lower or upper limit prices or using other threshold values) gave similar results, i.e., ICERs far below the threshold values of cost-effectiveness. These results confirm the role of HA-HL as a cost-effective therapeutic option in the management of OA. However, more studies taking into account the utilization of other health care resources are needed.


Interaction of metal ions withe nucleic acids. Interaction of copper(II) with xanthosine and its derivatives.
It was found that in the interaction of xanthosine with copper(II) nitrogen N-7, and not oxygen atoms of carbonyl groups, is involved. In aqueous solution of XMP, copper(II) interacts not only with N-7 and the phosphate group but also with ribose. In a crystalline copper(II)-XMP complex [Cu(C10H11O9N4P).H2O], only the phosphate group and N-7 are involved.


Serum 25-hydroxyvitamin D concentrations and colorectal cancer incidence in adults with type 2 diabetes.
To examine the association of serum 25-hydroxyvitamin D (25[OH]D) with colorectal cancer (CRC) risk in adults with type 2 diabetes (T2D). Using UK Biobank data, this study included 18,453 adults with T2D. Serum 25(OH)D concentrations were determined by the chemiluminescent immunoassay method. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC outcomes. During a median follow-up of 8.8 years, there were 284 incident CRC cases. Compared with adults with serum 25(OH)D concentrations <25.0 nmol/L, the adjusted HRs (95% CIs) for lower to higher serum 25(OH)D concentrations (25.0 to <50.0, 50.0 to <75.0, and ≥75.0 nmol/L) were 0.61 (0.46-0.82), 0.50 (0.34-0.74), and 0.53 (0.30-0.94), respectively (Ptrend = 0.001). The risk of CRC decreased by 19.0% for per 1-SD increment in serum 25(OH)D concentrations. A nonlinear association of serum 25(OH)D concentrations with CRC risk was observed using a restricted cubic spline analysis (P nonlinearity = 0.002). Higher serum 25(OH)D concentrations were significantly and nonlinearly associated with a lower risk of CRC. These findings highlight the potential benefits of maintaining adequate vitamin D levels in CRC prevention among adults with T2D.


Intra- and postoperative adverse events in awake craniotomy for intrinsic supratentorial brain tumors.
To determine the frequency and consequences of intra- and postoperative adverse events in awake craniotomy for intrinsic supratentorial brain tumors. Despite the growing prevalence of awake craniotomy intra- and postoperative, adverse events related to this surgery are poorly discussed. We studied 25 patients undergoing awake craniotomy with maximum safe resection of intrinsic supratentorial brain tumors in the awake-asleep-awake protocol. Surgery-related inconveniences occurred in 23 patients (92%), while postoperative adverse events were observed in 17 cases (68%). Seven patients suffered from more than one postoperative complication. The most common surgery-related inconvenience was intraoperative hypertension (8 cases, 32%), followed by discomfort (7 cases, 28%), pain during surgery (5 cases, 20%), and tachycardia (3 cases, 12%). The most common postoperative adverse event was a new language deficit that occurred in 10 cases (40%) and remained permanent in one case (4%). Motor deficits occurred in 36% of cases and were permanent in one case (1%). Seizures were observed in 4 cases (16%) intra- and in 2 cases (8%) postoperatively. Seizures appeared more frequently in patients with multilobar insular-involving gliomas and in patients without prophylactic antiepileptic drug therapy. Surgery-related inconveniences and postoperative adverse events occur in most awake craniotomies. The most common intraoperative adverse event is hypertension, pain, and tachycardia. The most frequent postoperative adverse events are new language deficits and new motor deficits.


A review of the aetiology and management of fractured dental implants and a case report.
Osseo-integrated dental implants offer a predictable treatment for the replacement of missing teeth. Despite the high success, complications can occur such as loss of integration, peri-implantitis and mucositis as well as mechanical problems. The latter includes screw loosening and more significantly fracture of the implant itself. As implant use is increasing, practitioners are more likely to face, and have to deal with, such complications. This report describes the management of a patient with a fractured Brånemark fixture in the maxilla. The likely causes are discussed and the treatment options highlighted together with the decision making process which lead to the final management.


Characteristics of Long-Term Care Residents That Predict Adverse Events after Hospitalization.
Adverse events (AEs) occur frequently in long-term care (LTC) residents transitioning from the hospital back to an LTC facility. Measuring the association between resident characteristics and AEs can inform AE risk reduction strategies. Prospective cohort analysis. A total of 32 nursing homes from six New England states. A total of 555 LTC residents contributing 762 transitions from the hospital back to LTC. We measured the association between all AEs and preventable AEs developing in the 45 days following discharge back to LTC and demographic variables, hospital length of stay (LOS), Charlson Comorbidity Index (CCI) (0-1, 2-3, 4-5 and ≥6), dependency in activities of daily living (ADLs) using the Minimum Data Set Long Form Scale (in quintiles 0-12, 13-15, 16, 17-18, and ≥19), and number of regularly scheduled medications (0-9, 10-13, 14-17, and ≥18). To understand the independent association of each resident characteristic with AEs and preventable AEs, we constructed multiple Cox proportional hazards models. There were 283 discharges with one or more AEs and 212 with preventable AEs. Characteristics independently associated with higher risk of an AE included hospital LOS 9 or more days (hazard ratio [HR] = 1.49; 95% confidence interval [CI] = 1.02-2.17); CCI of 4 to 5 (HR = 1.74; 95% CI = 1.13-2.67) or 6 or higher (HR = 1.58; 95% CI = 1.01-2.46); 18 or more regularly scheduled medications (HR = 1.53; 95% CI = 1.07-2.18); and 19 and above on ADL dependency (HR = 1.78; 95% CI = 1.21-2.62). Results from models with preventable AEs were similar to those with all AEs. Increased LOS, higher comorbidity burden, greater dependency in ADLs, and polypharmacy were the resident characteristics most strongly associated with risk of AEs and preventable AEs. We recommend heightened vigilance in the care of LTC residents with these characteristics transitioning back to LTC. We also recommend research to assess strategies to reduce the risk of AEs.


Effect of salivary urea, pH and ureolytic microflora on dental calculus formation and its correlation with periodontal status.
Dental calculus, formed by mineralization of plaque predisposes to the development of periodontal disease. To evaluate the influence of salivary urea and the presence of ureolytic bacteria on dental calculus formation and periodontal status in patients with good, fair and poor oral hygiene. An observational cross-sectional study was carried out on 135 patients, 18-60 years of age. Based on the simplified calculus index, patients were divided into three groups, good oral hygiene, fair oral hygiene and poor oral hygiene. Clinical parameters such as plaque index, gingival index, pocket probing depth and clinical attachment level and salivary pH were recorded for each subject. Saliva samples were collected to evaluate the urea levels using autoanalyzer method. Supragingival calculus samples were collected and presence and quantification of ureolytic bacteria were done by gram staining and bacterial culture and confirmed by biochemical reaction. For statistical analysis, test like Shapiro-Wilk test, Kruskal Wallis and Spearman's rho were used. Increase in salivary pH was associated with increased odds of higher calculus index score (odds ratio = 2.785). There was a non-significant weak correlation between salivary urea and ureolytic bacteria in dental calculus in all the three groups (p > 0.05). Higher calculus index score was associated with increased odds of presence of ureolytic bacteria (odds ratio>1). Higher level of ureolytic bacteria with increasing calculus index score may breakdown the salivary urea to ammonia resulting in a ureolytic pH rise that facilitate calcium phosphate saturation leading to more calculus formation.


Bunions in dancers.
Although dancers put a great deal of stress through the first metatarsophalangeal joint (MTPJ), it is unlikely that dancing causes bunions; however, such forces may produce an environment in which bunions may develop. It is best to employ conservative measures rather than surgical intervention in dancers who have a painful bunion. Any surgery on the first MTPJ will adversely affect dorsiflexion of this joint, which is a critical motion for dancers. Two types of bunions (slowly progressive and rapidly progressive) are commonly seen; arthritic bunions occur in dancers who have mild arthrosis and loss of cartilage on the head of the first MTPJ. Secondary problems arising from bunions include metatarsalgia, stress fractures, sesamoiditis, and flexor hallucis longus tendonitis.


The relation of PTSD symptoms to migraine and headache-related disability among substance dependent inpatients.
Despite emerging evidence for the comorbidity of posttraumatic stress disorder (PTSD) and migraine, few studies have examined the relation of PTSD and migraine, particularly among clinical populations at-risk for both conditions (e.g., substance-dependent patients). This study examined the role of PTSD symptoms in migraine and headache-related disability within a sample of 153 substance-dependent inpatients (37.25% female, Mean age 36.46). PTSD symptoms predicted both migraine and headache-related disability above and beyond gender, depression and anxiety symptoms, the experience of a Criterion A traumatic event, and current alcohol use disorder. Findings highlight the strong association between migraine and PTSD symptoms in a unique population at risk for both conditions.


One-pot synthesis of nano Zr-based metal-organic frameworks for fluorescence determination of quercetin and Hg2.
In this study, a nanoscale Zr-based metal-organic framework (nano-Zr-MOF) was prepared by one-pot method using meso-tetra(4-carboxyphenyl)porphyrin as organic ligand and Zr4+ as metal unit. The nanoscale structure endows it with excellent dispersion in water. The nano-Zr-MOF exhibited intense red fluorescence, which could be significantly quenched by the addition of quercetin, probably due to its electron-rich framework. The high selectivity for quercetin detection was verified with analogues and common ions as interfering agents. Moreover, the nano-Zr-MOF could be used as a highly selective and sensitive sensor for the detection of Hg2+. The detection limits for quercetin and Hg2+ were 0.026 μM and 0.039 μM, respectively. This fluorometric method was successfully applied to detect quercetin in red wine and food samples with satisfactory recoveries ranging from 83.7-112.3% and 81.8-115.9%, respectively. The recovery in detection of Hg2+ in lake water were ranging from 97.1-109.2%.


Self-Protection versus Fear of Stricter Firearm Regulations: Examining the Drivers of Firearm Acquisitions in the Aftermath of a Mass Shooting.
Discovering causal mechanisms underlying firearm acquisition can provide critical insight into firearm-related violence in the United States. Here, we established an information-theoretic framework to address the long-disputed dichotomy between self-protection and fear of firearm regulations as potential drivers of firearm acquisition in the aftermath of a mass shooting. We collected data on mass shootings, federal background checks, media output on firearm control and shootings, and firearm safety laws from 1999 to 2017. First, we conducted a cluster analysis to partition States according to the restrictiveness of their firearm-related legal environment. Then, we performed a transfer entropy analysis to unveil causal relationships at the State-level in the Wiener-Granger sense. The analysis suggests that fear of stricter firearm regulations is a stronger driver than the desire of self-protection for firearm acquisitions. This fear is likely to cross State borders, thereby shaping a collective pattern of firearm acquisition throughout the Nation.


Analysis of spin-echo rephasing with pulsatile flow in 2D FT magnetic resonance imaging.
The effects of pulsatile flow on spin phases in spin-echo magnetic resonance imaging are considered. General expressions for the spin phases of the first four echoes are derived in terms of the Fourier coefficients of flow. These expressions are valid for any time-dependent acceleration and, hence, are not restricted to constant acceleration. The derived expressions are then theoretically evaluated for aortic flow and examined at different points in the cardiac cycle. Our results show that rephasing may occur at certain points in the cardiac cycle for either even or odd echoes depending upon the particular Fourier coefficients of the velocity function and the spin-echo delay time. However, even-echo rephasing is not always necessarily valid. Furthermore, the possibility of determining the flow velocities in the body with an appropriate series of imaging studies is also discussed.


[Malignant stomach ulcer: diagnostic value of extemperaneous cytology and cyto-guided biopsy].
A prospective trial of extemporaneous cytology has been conducted in 113 patients with gastric ulcer. The diagnostic effectiveness was 97% but the yield of traditional biopsy in 13 patients with malignant ulcer was 52%. Cyto-guided biopsy, performed in 46 patients (8 with malignant ulcer), increased the yield to 97%.


Hypercapnic acidosis attenuates lung injury induced by established bacterial pneumonia.
Hypercapnic acidosis protects against lung injury after ischemia-reperfusion, endotoxin-induced and ventilation-induced lung injury. The effects of hypercapnic acidosis in the setting of established pulmonary sepsis are not known. The authors investigated whether hypercapnic acidosis -- induced by adding carbon dioxide to inspired gas -- would be beneficial or deleterious in established Escherichia coli pneumonia in an in vivo model, in the presence and absence of antibiotic therapy. Adult male Sprague-Dawley rats were anesthetized and ventilated. In the first set of experiments, rats were anesthetized, E. coli (5-6.4 x 10(9)/ml colony-forming units) was instilled intratracheally, and the animals were allowed to recover. After 6 h, during which time a severe pneumonia developed, they were reanesthetized and randomly assigned to normocapnia (fraction of inspired carbon dioxide [Fico(2)] = 0.00, n = 10) or hypercapnic acidosis (Fico(2) = 0.05, n = 10). The second set of experiments was performed in a manner identical to that of series 1, but all rats (n = 10 per group) were given intravenous ceftriaxone (30 mg/kg) at randomization. All animals received normocapnia or hypercapnic acidosis for 6 h, and the severity of lung injury was assessed. In the absence of antibiotic therapy, hypercapnic acidosis reduced the pneumonia-induced increase in peak airway pressure and the decrease in static lung compliance compared with control conditions. In the presence of antibiotic therapy, which substantially reduced lung bacterial counts, hypercapnic acidosis significantly attenuated the extent of pneumonia-induced histologic injury. Hypercapnic acidosis reduced the magnitude of the lung injury induced by established E. coli pneumonia.


Living in environmental justice areas worsens asthma severity and control: Differential interactions with disease duration, age at onset, and pollution.
Impoverished and historically marginalized communities often reside in areas with increased air pollution. We evaluated the association between environmental justice (EJ) track and asthma severity and control as modified by traffic-related air pollution (TRAP). We performed a retrospective study of 1526 adult asthma patients in Allegheny County, Pa, enrolled in an asthma registry during 2007-20. Asthma severity and control were determined using global guidelines. EJ tract designation was based on residency in census tracts with ≥30% non-White and/or ≥20% impoverished populations. TRAP exposures (NO2 and black carbon) for each census tract were normalized into pollution quartiles. Generalized linear model analyses determined the effect of EJ tract and TRAP on asthma. TRAP exposure in the highest quartile range was more frequent among patients living in an EJ tract (66.4% vs 20.8%, P < .05). Living in an EJ tract increased the odds of severe asthma in later onset asthma. The odds of uncontrolled asthma increased with disease duration in all patients living in EJ tracts (P < .05). Living in the highest quartile of NO2 also increased the odds of uncontrolled asthma in patients with severe disease (P < .05), while there was no effect of TRAP on uncontrolled asthma in patients with less severe disease (P > .05). Living in an EJ tract increased the odds of severe and uncontrolled asthma and was influenced by age at onset, disease duration, and potentially by TRAP exposure. This study underscores the need to better understand the complex environmental interactions that affect lung health in groups that have been economically and/or socially marginalized.


Epidemiology and practice of emergency medicine in a developing country.
To analyze the emergency medicine system in a developing country and identify areas of need and potential collaboration. Convenience sample surveys of all emergency visits over a 2-week period, hospital admission and health department statistics, and interviews with government officials, health providers, and EMS managers. Port of Spain General Hospital, Trinidad and Tobago. The ED has more than 100,000 visits per year. No records are kept. No physician in this study had emergency medicine training; only one had completed any residency. The survey included 3,710 patients: 40.5% were admitted, and .3% died. Injuries accounted for 41.6% of all visits, asthma 7.8%. The mean time elapsed before a patient was seen was .5 hour; mean time to discharge, 1.9 hours. In only 9% of patients were laboratory tests performed. Prehospital providers had limited equipment and training. The ED and prehospital systems provide high-volume and often high-acuteness care. Barriers to improved care include limited specialized training and lack of medical records.


Protein-energy malnutrition: the nature and extent of the problem.
The paper begins by describing how the names 'protein malnutrition' and 'protein-energy malnutrition' (PEM) developed from the local name 'Kwashiorkor'. The central feature of severe PEM is oedema; the classical theory suggests that the cause is a deficiency of protein, but other factors are also involved. In the community mild-moderate PEM is defined by deficits in growth. A distinction has to be made between low weight for height (wasting) and low height for age (stunting), Stunting in particular affects some 50% of children worldwide. Its causes and consequences are briefly discussed. In adults, severe PEM has essentially the same features as in children and includes the condition'famine oedema' or 'hunger oedema'; there are again controversies about its cause. In the community, chronic malnutrition is assessed by the body mass index (BMI) (Wt/Ht(2)). Grades of deficiency have been defined and examples are given of functional consequences of a low BMI. Secondary malnutrition differs from primary PEM because of the role played by cytokines and other concomitants of illness or injury. The importance is emphasized of chronicity or duration in determining the clinical picture.


Association of CD33 and MS4A cluster variants with Alzheimer's disease in East Asian populations.
CD33 and MS4A cluster variants have been identified to modulate the risk of Alzheimer's disease (AD) in several recent genome-wide association studies (GWAS) in Caucasians. In the present study, we first conducted a case-control study to investigate the CD33 single nucleotide polymorphisms (SNPs) rs3865444 and rs3826656 and the MS4A cluster SNPs rs610932 and rs670139 in a cohort from eastern China that comprised 126 late-onset Alzheimer's disease (LOAD) patients and 129 healthy controls. The results revealed that the frequency of rs3826656 major (G) allele carriers was higher among the LOAD patients than among the controls [P=0.005; odds ratio (OR), 1.760; 95% confidence interval (CI), 1.185-2.615]. In apolipoprotein E (APOE) ε4 allele carriers, the G allele of the SNP rs3865444 was found to be associated with an increased risk of LOAD (P=0.002; OR, 3.391; 95% CI, 1.512-7.605). Next, we re-evaluated the association between these variants and LOAD by conducting a meta-analysis using data from studies of East Asian populations, including the present case-control study, and confirmed that rs3826656 increased the risk of LOAD. In addition, we identified a significant association between rs610932 and LOAD (P=0.035; OR, 0.79; 95% CI, 0.63-0.98). Note that heterogeneity should be considered during the interpretation of these results; significant heterogeneity was identified among studies on rs3865444, even in a subgroup analysis based on stratification of studies by the country of origin. In summary, our results suggest that CD33 and MS4A cluster variants are associated with LOAD susceptibility in East Asian populations.


Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids.
An intramolecular non-stabilized azomethine ylide dipolar cycloaddition was applied toward the first non-racemic synthesis of the fully-oxygenated bridged pyrrolizidine core (45) of (+)-stemofoline (1) in eleven steps from a commercially available starting material.


Ruptured hydatid cyst in the right thorax: differential diagnosis to pleural empyema.
We present a case of a hydatid cyst (Echinococcus granulosus) rupturing into the right pleural cavity. Clinical and radiological findings were consistent with a pleural effusion caused by pneumonia and led primarily to a wrong diagnosis. Pleural fluid analysis was suspicious for parapneumonic pleural empyema. After thoracoscopy led to the correct diagnosis a combined surgical and chemotherapy approach achieved complete remission.


Becoming pregnant: exploring the perspectives of women living with diabetes.
The risk of adverse pregnancy outcome for women with type 1 diabetes is reduced through tight diabetes control. Most women enter pregnancy with inadequate blood glucose control. Interview studies with women suggest the concept of 'planned' and 'unplanned' pregnancies is unhelpful. To explore women's accounts of their journeys to becoming pregnant while living with type 1 diabetes. Semi-structured interviews with 15 women living with pre-gestational type 1 diabetes, between 20 and 30 weeks gestation and with a normal pregnancy ultrasound scan. Four UK specialist diabetes antenatal clinics. Interviews explored women's journeys to becoming pregnant and the impact of health care. Analysis involved comparison of women's accounts of each pregnancy and a thematic analysis. Women's experiences of becoming pregnant were diverse. Of the 40 pregnancies described, at least one positive step towards becoming pregnant was taken by 11 women in 23 pregnancies but not in the remaining 17 pregnancies, with variation between pregnancies. Prior to and in early pregnancy, some women described themselves as experts in their diabetes but most described seeking and/or receiving advice from their usual health professionals. Three women described pre-conception counselling and the anxiety this provoked. For women living with type 1 diabetes each pregnancy is different. The concept of planned and unplanned pregnancy is unhelpful for designing health care. Formal preconception counselling can have unintended consequences. Those providing usual care to women are well positioned to provide advice and support to women about becoming pregnant, tailoring it to the changing needs and situation of each woman.


Robust Photoelectrochemical Oxygen Evolution with N, Fe-CoS2 Nanorod Arrays.
Photoelectrochemical water splitting is a promising approach to enhance the efficiency of water splitting. However, it is still challenging to develop an efficient oxygen evolution reaction (OER) electrocatalyst that can be coupled with light due to inefficient light utilization. Here, we demonstrate that N, Fe-co-doped CoS2 (N, Fe-CoS2) nanorod arrays can act as a highly efficient photo-coupled electrochemical OER catalyst. In dark conditions, the N, Fe-doped CoS2 on self-supported stainless steel (SS) mesh shows a small OER overpotential (215 mV) at a current density of 10 mA cm-2, a reduced Tafel slope (43.2 mV dec-1), and negligible activity decay after 10 000 cycles. Upon visible-NIR light illumination, the N, Fe-doped anode exhibits superior photoelectrochemical performance because of the enhanced photoresponse, excellent light harvesting ability and promoted interfacial kinetics of charge separation. Our well-designed photoelectrochemical OER electrode can not only serve as a light absorption semiconductor but also the active catalytic sites for the OER reaction; the electrode composed of the single phase can efficiently avoid photocarrier recombination at the grain boundary. This study provides an insight into photoanode synthesis for photoelectrochemical OER and offers guidance on the future electrocatalyst design.


Intimate partner violence and substance use risk among young men who have sex with men: The P18 cohort study.
Substance use is prevalent among young men who have sex with men (YMSM) and may be associated with intimate partner violence (IPV). Experiences of IPV are associated with several adverse health conditions among adult MSM, but there is a gap in knowledge about this relationship among YMSM, which warrants further investigation. This study employs baseline data from a prospective cohort study to examine lifetime experiences of IPV in relation to substance use in the previous 30 days among n=528 YMSM in New York City from 2009 to 2011. To examine the extent to which IPV (any experiences, victimization, and perpetration) are related to substance use (alcohol, marijuana, stimulant, and other drugs) in the last 30 days, distinct 2-step multinomial logistic regression models, controlling for sociodemographic differences, were constructed. 44.3% reported lifetime IPV experience, with 39.2% of reporting victimization and 30.5% reporting perpetration. IPV is associated with a 1.6 increased odds of 2 or more instances of alcohol use, a 1.6-1.8 increased odds of 2 or more instances of marijuana use, a 1.8-2.5 increased odds of 2 or more instances of stimulant use, and a 4.1-6.1 increased odds of 2 or more instances of other substance use. Findings highlight the strong association between IPV and increased frequency of substance use among YMSM and provide support that violence may exist as part of a syndemic facing YMSM. Prevention and intervention strategies may be improved by addressing substance use in the context of IPV and other related health challenges.


Assessing experienced tranquillity through natural language processing and landscape ecology measures.
Identifying tranquil areas is important for landscape planning and policy-making. Research demonstrated discrepancies between modelled potential tranquil areas and where people experience tranquillity based on field surveys. Because surveys are resource-intensive, user-generated text data offers potential for extracting where people experience tranquillity. We explore and model the relationship between landscape ecological measures and experienced tranquillity extracted from user-generated text descriptions. Georeferenced, user-generated landscape descriptions from Geograph.UK were filtered using keywords related to tranquillity. We stratify resulting tranquil locations according to dominant land cover and quantify the influence of landscape characteristics including diversity and naturalness on explaining the presence of tranquillity. Finally, we apply natural language processing to identify terms linked to tranquillity keywords and compare the similarity of these terms across land cover classes. Evaluation of potential keywords yielded six keywords associated with experienced tranquillity, resulting in 15,350 extracted tranquillity descriptions. The two most common land cover classes associated with tranquillity were arable and horticulture, and improved grassland, followed by urban and suburban. In the logistic regression model across all land cover classes, freshwater, elevation and naturalness were positive predictors of tranquillity. Built-up area was a negative predictor. Descriptions of tranquillity were most similar between improved grassland and arable and horticulture, and most dissimilar between arable and horticulture and urban. This study highlights the potential of applying natural language processing to extract experienced tranquillity from text, and demonstrates links between landscape ecological measures and tranquillity as a perceived landscape quality. The online version of this article (10.1007/s10980-020-01181-8) contains supplementary material, which is available to authorized users.


Novel insights into gene therapy in the cornea.
Corneal disease remains a leading cause of impaired vision world-wide, and advancements in gene therapy continue to develop with promising success to prevent, treat and cure blindness. Ideally, gene therapy requires a vector and gene delivery method that targets treatment of specific cells or tissues and results in a safe and non-immunogenic response. The cornea is a model tissue for gene therapy due to its ease of clinician access and immune-privileged state. Improvements in the past 5-10 years have begun to revolutionize the approach to gene therapy in the cornea with a focus on adeno-associated virus and nanoparticle delivery of single and combination gene therapies. In addition, the potential applications of gene editing (zinc finger nucleases [ZNFs], transcription activator-like effector nucleases [TALENs], Clustered Regularly Interspaced Short Palindromic Repeats/Associated Systems [CRISPR/Cas9]) are rapidly expanding. This review focuses on recent developments in gene therapy for corneal diseases, including promising multiple gene therapy, while outlining a practical approach to the development of such therapies and potential impediments to successful delivery of genes to the cornea.


Immunohistochemical expression of filaggrin is decreased in proton pump inhibitor non-responders compared with proton pump inhibitor responders of eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is an allergic gastrointestinal disease that features eosinophilic infiltration of esophageal mucosa, but the role of barrier dysfunction of the epithelium in its pathogenesis remains to be elucidated. Clinically, EoE is divided into proton pump inhibitor-non-responders (PPI-NR) and PPI-responders (PPI-R). Our main aims were to investigate the differences of expression of epidermal differential complex (EDC) proteins and desmoglein that are considered to play important roles in formation of the epidermal skin barrier between these two conditions and to seek the usefulness of the differences in pathological diagnosis. Conventional histopathological findings and allergic background were also compared. Twenty-nine PPI-NR and 44 PPI-R were recruited, and 35 reflux esophagitis patients were also enrolled. After clinical information and histopathological findings were reviewed, immunohistochemical expression of EDC proteins (filaggrin, loricrin, and involucrin) and desmoglein in all three groups were examined and semi-quantitatively scored. Regarding allergic conditions, the prevalence of asthma was significantly higher in PPI-NR than in PPI-R. Other allergic conditions showed no differences. Histopathological findings did not exhibit the statistical difference between PPI-NR and PPI-R. However, immunostaining score of filaggrin in PPI-NR was significantly lower than in PPI-R, although the expressions of involucrin, loricrin and desmoglein demonstrated no differences. The results suggest a role of reduced filaggrin expression in the difference of effectiveness of PPI treatment between PPI-NR and PPI-R. Moreover, immunohistochemical determination of filaggrin expression in EoE patients could be informative in the clinical decision of how to treat the patients.


A study of the reaction catalysed by alginate lyase VI from the sea mollusc, Littorina sp.
The molecular weight of polymeric alginic acid digested by alginate lyase (poly(1,4-beta-D-mannuronide) lyase, EC 220.127.116.11) was determined at various stages of the lysis. Low molecular weigh fragments were detected only after 60-100% lysis. Some high molecular weight fragments remained intact even after addition of a fresh aliquot of enzyme to the digest. The enzyme showed maximal activity at pH 5.6 in 0.05 M salt. Enzyme activity was stimulated by addition of 7.5 mM CaCl2 and 0.2 M NaCl, when the pH optimum was between 8 and 8.5. Only mannuronic acid was detected at the reducing end of fragments after exhausive enzymolysis, reduction and hydrolysis. On studying the reaction products by NMR, a double-bound signal (sigma = 5.98 ppm) was observed. A considerable decrease in intensity of the D-mannuronic acid residue signal was detected after hydrolysis of alginate lyase VI on poly-(ManUA-GulUA), but not poly(GulUA). The results suggest that alginate lyase VI may be an endoalginate lyase that splits glycoside bonds only between two mannuronic acid residues.


Synthesis of indole-tethered [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids as anti-pancreatic cancer agents.
New indole-tethered [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (8a-j) and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) were synthesized using [4+2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes with indole-ketenes. All molecular hybrids were structurally characterized by spectroscopic techniques (IR, NMR, and HRMS) and screened for their anti-pancreatic cancer activity in vitro. The [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) showed stronger anti-pancreatic cancer activity than the [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one hybrids (8a-j) against the PANC-1 cell line. Compound 9d bearing an ortho-chlorophenyl moiety emerged as the most potent anti-pancreatic cancer agent with an IC50 value of 7.7 ± 0.4 µM, much superior to the standard drug Gemcitabine (IC50 > 500 µM). The discovery of these [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids elicits their potentials as pursuable candidates for pancreatic cancer chemotherapy.


A gradient of diffusible substance in a monolayer of cultured cells.
Monolayers of hypoxanthine phosphoribosyl transferase-deficient and their corresponding wildtype cells have been placed adjacent to each other with a newly described method. Autoradiographs from such preparation after incubation with 3H-hypoxanthine allow the direct visualization of gradients of incorporated radioactivity at the border between the two cell types. The gradients can be described by an exponential function, and the amount of radioactivity incorporated decreases to less than 1% at a distance of 1 mm from the wild-type cells. A possible mechanism to convert exponential gradients to linear ones over a certain concentration range is discussed.


Effect of hibernation length on termination of diapause in European Tettigoniidae (Insecta: Orthoptera).
The effect of the length of cold treatment on development time of embryos of eight Central European tettigoniid species was investigated in laboratory experiments, using chilling periods of 3, 4, 5, 6, 9, and 12 months. Two different types of response were observed: (1) The hatching date was not influenced by hibernation length (Conocephalus) or only after the 3-month cold treatment (Phaneroptera, Platycleis), or (2) The time required for post-diapause development was significantly reduced by each 1-month increase in the length of cold treatment up to 6 months (Meconema, Metrioptera, Tettigonia).Thus, the correct timing of hatching is achieved by one of two different strategies. In lat-hatching species, the influence of hibernation length is small. Premature appearance is prevented by a high thermal threshold. In early-hatching species, the embryos are obviously able to measure the length of the chilling period. Thus, they gradually change their physiological state so that the potential speed of postdiapause development increases as the 'winter' is prolonged. This strategy can be understood as an adaptation to the necessity of hatching at low or moderate temperatures. Field experiments with two Tettigonia species confirm the laboratory data.


Long-term efficacy of anchored barbed sutures in the face and neck.
The thread lift is a minimally invasive procedure that uses barbed sutures, inserted subcutaneously, to produce lifting of ptotic tissue of the face and neck. There are currently very limited data on longevity and patient satisfaction following barbed suture lifting procedures. The purpose of this study was to assess long-term efficacy following the use of barbed sutures. A satisfaction survey was mailed to 20 patients who were a minimum of 6 months (range, 6 to 16 months) postprocedure. Physician assessment of pre- and postprocedure photographs was also performed. At an average of 11.5 months postprocedure, patients felt that the barbed suture lift met their expectations, rating their satisfaction a 6.9 on a scale of 1 to 10. Independent physicians rated the overall improvement an average of 4.6 of 10. Higher scores were noted in Zone 1 (tear trough/malar fat pad and nasolabial folds) compared to Zone 2 (marionette lines, jowls, and jawline definition) and Zone 3 (platysmal bands and neck contour). The barbed suture lift procedure provides moderate long-term and sustained improvement for facial laxity, with most improvement seen in the tear trough/malar fat pads and nasolabial folds. In this study, clinical efficacy was seen up to 16 months postprocedure.


Electrochemical devices made from conducting nanowire networks self-assembled from amyloid fibrils and alkoxysulfonate PEDOT.
Proteins offer an almost infinite number of functions and geometries for building nanostructures. Here we have focused on amyloid fibrillar proteins as a nanowire template and shown that these fibrils can be coated with the highly conducting polymer alkoxysulfonate PEDOT through molecular self-assembly in water. Transmission electron microscopy and atomic force microscopy show that the coated fibers have a diameter around 15 nm and a length/thickness aspect ratio >1:1000 . We have further shown that networks of the conducting nanowires are electrically and electrochemically active by constructing fully functional electrochemical transistors with nanowire networks, operating at low voltages between 0 and 0.5 V.


The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys.
Extrasynaptic glutamate has been shown to regulate dopamine function in the mesocorticolimbic pathway, which plays an important role in the behavioral pharmacology of psychostimulants. Basal levels of glutamate are primarily regulated by the cystine-glutamate transporter and provide glutamatergic tone on extrasynaptic glutamate receptors. The present study examined the effects of a cystine-glutamate transporter enhancer on the neurochemical and behavioral effects of cocaine and amphetamine in nonhuman primates. It was hypothesized that augmenting extrasynaptic glutamate release with N-acetyl-L-cysteine (NAC), a cystine prodrug, would attenuate cocaine- or amphetamine-induced increases in extracellular dopamine and their corresponding behavioral-stimulant and reinforcing effects. In vivo microdialysis was used to evaluate cocaine-induced changes in extracellular dopamine (DA) in the caudate nucleus (n=3). NAC significantly attenuated cocaine-induced increases in dopamine but had inconsistent effects on amphetamine-induced increases in dopamine (n=4). Separate groups of subjects were either trained on a fixed-interval schedule of stimulus termination (n=6) or on a second-order schedule of self-administration (n=5) to characterize the behavioral-stimulant and reinforcing effects of psychostimulants, respectively. Systemic administration of NAC did not alter the behavioral-stimulant effects of either cocaine or amphetamine. Furthermore, cocaine self-administration and reinstatement of previously extinguished cocaine self-administration were not altered by pretreatment with NAC. Hence, drug interactions on caudate neurochemistry in vivo were not reflected in behavioral measures in squirrel monkeys. The present results in nonhuman primates do not support the use of NAC as a pharmacotherapy for cocaine abuse, although rodent and clinical studies suggest otherwise.


Phosphodiesterase 4 inhibitors and db-cAMP inhibit TNF-alpha release from human mononuclear cells. Effects of cAMP and cGMP-dependent protein kinase inhibitors.
We investigated the effects of specific inhibitors of cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) on the inhibitory activity of phosphodiesterase (PDE) type 4 inhibitors and of the cell permeable analogue of cAMP, db-cAMP on LPS-induced TNF-alpha release from human mononuclear cells. Incubation from 30 min of mononuclear cells with dbcAMP (10(-5) to 10(-3) M), rolipram (10(-9) M to 10(-5) M) or Ro 20-1724 (10(-9) M to 10(-5) M) significantly inhibited LPS-induced TNF-alpha release. When mononuclear cells were preincubated for 30 min with the selective PKA inhibitor, H89 (10(-4) M), but not with the selective PKG inhibitor, Rp-8-pCPT-cGMPs (10(-4) M), a significant reduction of the inhibitory effect of db-cAMP was noted. Thirty min incubation of mononuclear cells with Rp-8-pCPT-cGMPs induced a significant reduction of the inhibitory activities of both rolipram and Ro 20-1724 (10(-9) to 10(-5) M) on LPS-induced TNF-alpha release, whereas H89 elicited a moderate, but significant inhibition. The present data indicate that db-cAMP inhibits TNF-alpha release from human mononuclear cells through a PKA-dependent mechanism. In contrast, PDE 4 inhibitors elicit their in vitro anti-inflammatory activities via a PKG-dependent rather than PKA-dependent activation.


The cytotoxicity of a Grb2-SH3 inhibitor in Bcr-Abl positive K562 cells.
Chronic myelogenous leukemia (CML) is characterized by the presence of Bcr-Abl oncoprotein. Gleevec has been designed to treat many CML patients by specifically targeting Bcr-Abl, but resistance to it is already apparent in many cases. In CML cells, Bcr-Abl activates several signaling pathways, including the Ras-dependent pathway, in which growth factor receptor binding 2 (Grb2) acts as an adaptor protein. A specific Grb2-SH3 inhibitor (denoted as peptidimer-c) that disrupts Grb2-Sos complex was designed and synthesized in our laboratory. In this study, we investigated the effect and the molecular mechanism of this inhibitor. Peptidimer-c was shown to bind to Grb2 in K562 cells, a cell line over-expressing Bcr-Abl oncoprotein. It caused cytotoxicity in the cells, and inhibited their ability of colony formation in the semi-solid medium. It was shown to induce apoptosis of K562 cells in a dose-dependent mode, the apoptotic effect of peptidimer-c being associated with caspase-3 activation. The effect of peptidimer-c on growth inhibition was also shown to be accompanied by S-phase arrest of cell cycle mediated by down-regulation of cyclin A and Cdk2, as well as phospho-Cdk2. The above results indicated that peptidimer-c may be another potential therapeutic agent for CML, which can induce S-phase arrest in the Bcr-Abl positive K562.


A practical method of Ludox density gradient centrifugation combined with protargol staining for extracting and estimating ciliates in marine sediments.
Methodological impediments have long been the main problem in estimating the ecological role of marine benthic ciliates. Percoll density centrifugation is currently the most efficient technique for extracting ciliates from fine-grained sediments, while the high cost and low density of Percoll limit its wide application. We developed a protocol of density gradient centrifugation using the cheap sol Ludox HS 40 in combination with the quantitative protargol stain (QPS) to enumerate and identify marine benthic ciliates. The combined Ludox-QPS method involves sample collection and salt reduction, extraction with Ludox centrifugation, and preparation with the QPS technique. The recovery efficiency of Ludox was first tested with azoic sandy and muddy sediments. A 94-100% recovery rate of ciliates was reached. The method was further tested with natural sandy, muddy-sand and muddy sediments. Excellent extraction efficiencies were consistently obtained: an average of 97.6% for ciliates in sand, and 96.9-97.8% for nematodes in the three types of sediments. The high efficiencies indicate that the method allows for simultaneous enumeration of micro- and meiobenthos. Advantages of the new method include: (i) reliable and cost-efficient operation; (ii) appropriate centrifugation for both micro- and meiobenthos; and (iii) applicability to large samples and routine ecological surveys.


Reflective practice in nurse education: a step towards equity in education and health care.
In the past, the Australian health care system, whose mainstream services are essentially monocultural, has not always successfully met the needs of clients from a variety of cultural groups. Entry of more young immigrant people into the essential health services is one strategy which may assist in bringing positive benefits to health care consumers from non-English speaking backgrounds (NESB). For NESB students, however, the tertiary education experience frequently produces inequities similar to those encountered by NESB consumers of health care, and failure rates of these students are often disproportionately high. This paper describes the process of reflective practice used to investigate the needs of NESB students enrolled in the first year of an undergraduate nursing degree, and the strategies subsequently initiated to improve educational outcomes for these students. In terms of academic success, outcomes for NESB students involved in the investigation were markedly improved in comparison to the previous year. More importantly, the project fostered reflection on teaching practices, and led to modifications which, although small, represented a positive step towards equity.


Tailoring the biologic responses of 3D printed PEEK medical implants by plasma functionalization.
The objective of this study was to determine the effect of two plasma surface treatments on the biologic responses of PEEK medical implants manufactured by fused filament fabrication (FFF) 3D printing technology. This study created standard PEEK samples using an FFF 3D printer. After fabrication, half of the samples were polished to simulate a smooth PEEK surface. Then, argon (Ar) or oxygen (O2) plasma was used to modify the bioactivity of FFF 3D printed and polished PEEK samples. Scanning electron microscopy (SEM) and a profilometer were used to determine the microstructure and roughness of the sample surfaces. The wettability of the sample surface was assessed using a drop shape analyzer (DSA) after plasma treatment and at various time points following storage in a closed environment. Cell adhesion, metabolic activity, proliferation, and osteogenic differentiation of SAOS-2 osteoblasts were evaluated to determine the in vitro osteogenic activity. SEM analysis revealed that several spherical nanoscale particles and humps appeared on sample surfaces following plasma treatment. The wettability measurement demonstrated that plasma surface treatment significantly increased the surface hydrophilicity of PEEK samples, with only a slight aging effect found after 21 days. Cell adhesion, spreading, proliferation, and differentiation of SAOS-2 osteoblasts were also up-regulated after plasma treatment. Additionally, PEEK samples treated with O2 plasma demonstrated a higher degree of bioactivation than those treated with Ar. Plasma-modified PEEK based on FFF 3D printing technology was a feasible and prospective bone grafting material for bone/dental implants.


The use of dexmedetomidine to facilitate acute discontinuation of opioids after cardiac transplantation in children.
To report the use of dexmedetomidine to facilitate rapid opioid and benzodiazepine withdrawal in children with transplanted hearts and to review the receptor physiology and pharmacodynamic impact of dexmedetomidine on the denervated heart. Case series. Intensive care unit at a tertiary pediatric medical center. The series included a 6-month-old infant with pulmonary atresia who had a 3-month exposure to high-dose opioids and benzodiazepines and had undergone cardiac transplantation 4 wks before the use of dexmedetomidine and a 7-yr-old boy who had been sedated while undergoing extracorporeal membrane oxygenation for 3 wks before transplantation and started to receive dexmedetomidine 3 days after transplantation. Administration of dexmedetomidine to facilitate the discontinuation of opioids and benzodiazepine. Successful rapid withdrawal from opioids and benzodiazepines while maintaining hemodynamic stability. To our knowledge, this report describes the first use of dexmedetomidine to facilitate opioid withdrawal in children with a cardiac transplant. Dexmedetomidine allowed for the preservation of satisfactory hemodynamic parameters during acute withdrawal from opioids in children with denervated hearts.


Inflammation promotes progression of thrombi in intracranial thrombotic aneurysms.
Advances in the understanding of the pathogenesis of arteriosclerosis, abdominal aorta aneurysms and dissections, and carotid artery plaques have focused on chronic inflammation. In this study, we report that inflammatory changes of thrombi contribute to the enlargement and growth of giant intracranial thrombotic aneurysms. Surgical and postmortem samples were collected from 12 cases of large or giant intracranial thrombotic aneurysms diagnosed via pathological investigations. Degeneration of the aneurysmal wall and the infiltration of inflammatory cells in the thrombi were assessed. The number of blood cells and immunohistochemical stain-positive cells was enumerated, and the inflammation and neovascularization in the thrombi were assessed. In all cases, the appearance of inflammatory cells (CD68+ cells, CD206+ cells, lymphocytes, and neutrophils) was apparent in the thrombi. The number of CD34+ cells was moderately correlated with the number of CD68+ cells, and CD34+ cells significantly and strongly correlated with the number of CD206+ cells. Based on the number of neutrophils per CD68+ cells, we classified the cases into 2 groups: a macrophage inflammation-dominant group and a neutrophilic inflammation-dominant group. The neutrophilic inflammation-dominant group had significantly more cases with previous treatments and neurological symptoms due to mass effect than the macrophage inflammation-dominant group. Chronic inflammation due to macrophages in thrombi is a fundamental mechanism in the enlargement of an intracranial thrombotic aneurysm, and neutrophilic inflammation can accelerate this process. Microvascularization in thrombi is linked to inflammation and might promote thickening of the intima and repeated intimal microbleeds.


Neonatal small left colon syndrome.
Neonatal small left colon syndrome is a functional disease of the lower colon which produces typical signs and symptoms of intestinal obstruction. It is manifest in the first 24-48 hours of life, particularly in infants of diabetic mothers and, if detected early, it can be fully cured by radiographic contrast enemas, not unlike meconium plug syndrome. Intestinal perforation and death may occur, however. The etiology of the disease is unknown but it may relate to neurohumoral imbalances between the autonomic nervous system and glucagon.


Medicinal herb use in a population-based survey of adults: prevalence and frequency of use, reasons for use, and use among their children.
There is sparse population-based data on health factors related to medicinal herb use and use of medicinal herbs in children. For a sample of American adults, we estimated the prevalence and frequency of medicinal herb use, factors related to use, reasons for use, patient-physician discussion, and the proportion of respondents who gave herbs to their children. The data used in this study was from the 2001 North Carolina Behavioral Risk Factor Surveillance System, a population-based telephone survey of English-speaking adults (n = 2982). Approximately 20% of respondents reported using medicinal herbs in the past year. Of these, 34% reported discussion of herb use with a physician; 69% reported taking herbs to maintain health, 20% to prevent illness, and 11% to treat illness. Of the total sample, 7% reported using herbs everyday and 5% of the respondents reported giving their children herbal medicines in the past year. Medicinal herb use is common in this population sample. The lack of discussion between users and their physicians highlights the importance of patient-physician communication to avoid possible herb-drug interactions and surgical complications. Herb use appears to be a popular strategy for maintaining health. Children may be vulnerable to herbal toxicity and therefore clinicians need to know about their medicinal herb use and counsel appropriately.


Rough wave-like heaped overburden promotes establishment of woody vegetation while leveling promotes grasses during unassisted post mining site development.
Geodiversity plays an important role in species establishment during spontaneous succession. At post-mining sites in the Czech Republic in 2003, we established plots in which the surface of the heaped overburden was either kept wave-like or leveled. Based on surveys conducted from 2006 to 2015, leveled plots were increasingly dominated by grasses and herbs (and especially by the grass Calamagrostis epigejos) while the wave-like plots were increasingly dominated by the trees Salix caprea and Betula pendula. In 2015, a detailed survey was conducted of the dominant species. Both S. caprea and B. pendula occurred more often in wave-like plots than in leveled plots; this was particularly true for trees taller than 1 m, which were absent in leveled plots. In wave-like plots, leaf and root biomasses of both woody species were higher on the wave slopes than on the wave depressions. Nitrogen content was higher but content stress indicating proline in leaves of S. caprea was lower in wave-like plots than in leveled plots. In wave-like plots, both woody species occurred mainly on wave slopes but C. epigejos occurred mainly in the depressions. We speculate that trees were more abundant in wave-like plots than in leveled plots because the waves trapped tree seeds and snow and because the soil porosity was greater in wave-like than in leveled plots. Grasses may have preferred the leveled plots because soil porosity was lower and clay content was higher in leveled than in wave-like plots.


Predictability of the community-function landscape in wine yeast ecosystems.
Predictively linking taxonomic composition and quantitative ecosystem functions is a major aspiration in microbial ecology, which must be resolved if we wish to engineer microbial consortia. Here, we have addressed this open question for an ecological function of major biotechnological relevance: alcoholic fermentation in wine yeast communities. By exhaustively phenotyping an extensive collection of naturally occurring wine yeast strains, we find that most ecologically and industrially relevant traits exhibit phylogenetic signal, allowing functional traits in wine yeast communities to be predicted from taxonomy. Furthermore, we demonstrate that the quantitative contributions of individual wine yeast strains to the function of complex communities followed simple quantitative rules. These regularities can be integrated to quantitatively predict the function of newly assembled consortia. Besides addressing theoretical questions in functional ecology, our results and methodologies can provide a blueprint for rationally managing microbial processes of biotechnological relevance.


Thirty-year experience with repair of pectus deformities in adults.
A plethora of studies have described repair of pectus deformities in children, but only few reports have described this repair in adults. The purpose of this study was to review our 30-year experience with surgical repair of pectus deformities in adults. A retrospective review of all adult patients (> 16 years old) who underwent repair of congenital pectus deformities from 1971 through 2001. There were 77 patients, 64 men and 13 women. Sixty-eight patients underwent surgery for pectus excavatum and 9 for pectus carinatum; median age was 22 years old (range, 16 to 68 years old). Indication for repair was medical concerns in all patients. Preoperative symptoms were dyspnea on exertion in 43 patients, shortness of breath at rest in 22 patients, chest pain in 8 patients, and palpitations in 8 patients. Preoperative electrocardiogram findings included right bundle branch block in 9 patients, sinus bradycardia in 8 patients, left atrial enlargement in 6 patients, and right atrial dilatation in 5 patients. Patterns of the pectus defect were symmetric and localized in 29 patients, symmetric and diffuse in 21, asymmetric and localized in 18, and asymmetric and diffuse in 9 patients. Intraoperative classifications were severe in 38 patients, moderate in 33 patients, and mild in 6 patients. There were no operative deaths. Complications occurred in 11 patients (14.3%). Mean hospital stay was 4 days (range, 2 to 8 days). Mean follow-up was 12 +/- 7 years (range, 4 months old to 24 years old); 1 patient (1.3%) required reoperation for recurrent pectus excavatum. Patient satisfaction and relief of medical symptoms was excellent in 70 patients (90.9%), good in 6 patients, and fair in 1 patient. Repair of congenital defects of the sternum in adults can be performed safely with low morbidity and no mortality. Long-term results are excellent with requirement for reoperation rare.


Problematic video game use scale: initial psychometric properties with psychiatrically hospitalized adolescents.
Excessive video game use among youth has been a growing concern in the United States and elsewhere. The aims of this study are to establish validity of a video game measure in a large adolescent inpatient sample, identify clinical factors underlying problem video game use, and identify associations with measures of psychopathology. Three hundred eighty participants admitted to an adolescent inpatient psychiatric unit between November 2007 and March 2009 were administered a battery of self-report measures, including a questionnaire developed for this study that assessed reinforcers and consequences of past-year video game use (ie, Problematic Video Game Use Scale). Factor analysis was used to identify the underlying structure of behaviors associated with problem video game use. A factor analysis of the Problematic Video Game Use Scale indicated 2 primary factors. One was associated with engaging in problem behaviors that impaired the adolescent's functioning as a result of playing video games and one reflected the reinforcing effects of playing video games. Both factors were associated with measures of psychopathology, although associations were generally stronger for impairment in functioning than for reinforcing effects. Both factors were significantly correlated with self-reported daily video game use (P < .001). Two underlying factors emerged to account for problem video game playing: impairment in functioning and reinforcing effects. Initial evidence of the content validity of the video game measure was established. Findings highlight the importance of assessing video game use among an adolescent population, the factors associated with video game use, and associations with symptoms of psychopathology. Limitations include a common reporter for multiple measures and cross-sectional data that do not allow for causal links to be made.


Clinical and economic consequences of dyspepsia in the community.
Dyspepsia is a common problem where many sufferers do not seek healthcare. The clinical impact of the condition in the community and the economic costs were assessed using data from a large cross sectional survey. Dyspepsia may be costing society 1 billion pounds each year in the UK. Thus dyspepsia is a huge clinical and economic burden and cost effective management strategies and treatments are urgently required.


Reliable registration of preoperative MRI with histopathology after temporal lobe resections.
Conventional and novel magnetic resonance imaging (MRI) techniques can detect cerebral abnormalities in patients with refractory focal epilepsies. Correlation of preoperative MRI and histopathology is important to validate MRI findings, but in practice is far from straightforward. Peroperative neuronavigation and placement of markers on tissue is of limited use in temporal lobe resections. MRI scanning of the resected specimen for registration with in vivo MRI is complicated by anisotropic tissue deformation. We have developed a method to facilitate registration of preoperative MRI with the resected specimen and to enable correlation of MRI findings with histopathology. Sixteen en bloc temporal lobe resections undertaken for refractory temporal lobe epilepsy were studied. The specimens were fixed in formalin and then cut coronally by using a cradle with parallel blades at 5-mm intervals to ensure evenly thick tissue slices in the same orientation. Volumetric T1-weighted preoperative MRIs were reformatted, and consecutive slices (0.94 mm) cut in the same orientation as the resected lobe were visually compared with photographs of tissue slices by two independent observers. In 15 (94%) of 16 cases, a <2-mm difference was found between the two observers' matches of MRI slices with tissue slices. In the last case, a 4-mm difference was noted. In all cases, a consensus was reached by the two observers. The suggested MRI-histology matches were within the resections seen on postoperative scans. Careful labelling and postoperative handling and slicing ensured histopathologic tissue slices of uniform thickness and slicing angle. This technique can be applied to a range of MRI datasets, enabling exploration of the pathologic basis of abnormalities on conventional and novel MRI acquisitions.


The impact of socioeconomic deprivation on congenital hand differences: A retrospective cohort study.
Socioeconomic deprivation is an established risk factor for a range of adverse perinatal and infant outcomes. The primary aim of this study was to investigate any association between socioeconomic deprivation and the prevalence of Congenital Hand Differences (CHDs). This retrospective cross-sectional study was undertaken at a single tertiary referral center over a five year period (March 2015 to February 2020). The inclusion criterion was all patients referred for a review at a CHD clinic. As a measure of socioeconomic status, patients were assigned to a deprivation quintile using the Scottish Index of Multiple Deprivation (SIMD): quintile 1 indicates the most deprived area and quintile 5 indicates the least deprived area. CHDs were classified according to the Oberg-Manske-Tonkin (OMT) Classification. During the study period 259 patients were identified. The overall prevalence of CHD was 15 per 100,000 per year, mean referral age was 2.6 years (Standard Deviation: 4 years) and 135 patients (52%) were female. Areas of greater social deprivation had a significantly higher prevalence of CHD (22 per 100,000 per year in quintile 1 vs. 13 per 100,000 per year in quintile 5; p < 0.001), surgery (75% of patients in quintile 1 vs 43% of patients in quintile 5; p = 0.003), and younger referral age (1.5 years in quintile 1 vs 4.4 years in quintile 5; p = 0.003). This study has shown a greater CHD prevalence rate amongst patients from more socially deprived areas. In the most deprived group, the patient referral age was also significantly younger and surgical intervention rate was higher.


Immune Networks and Therapeutic Targeting of iNKT Cells in Cancer.
One of the primary goals in tumor immunotherapy is to reset the immune system from tolerogenic to immunogenic - a process in which invariant natural killer T (iNKT) cells are implicated. iNKT cells develop in the thymus and perform immunosurveillance against tumor cells peripherally. When optimally stimulated, iNKT cells differentiate and display more efficient immune functions. Some cells survive and act as effector memory cells. We discuss the putative roles of iNKT cells in antitumor immunity, and posit that it may be possible to develop novel therapeutic strategies to treat cancers using iNKT cells. In particular, we highlight the challenge of uniquely energizing iNKT cell-licensed dendritic cells to serve as effective immunoadjuvants for both arms of the immune system, thus coupling immunological networks.


[Prolonged posttetanic changes in the sensorimotor cortex of the waking rabbit in response to stimulation of the fibers of the substantia alba in the neocortex and corpus callosum].
Study of posttetanic changes in the sensorimotor cortex of the alert rabbit in response to stimulation of callosal fibres of the white matter have shown that in comparison to the control level either a prolonged increase (potentiation) of the tested evoked potentials to the stimulation of the same structures takes place, or the amplitude of the tested evoked potentials decreases (depression). Both processes can take place simultaneously in different layers of the cortex.


Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.
The chemotherapeutic agent paclitaxel causes peripheral neuropathy, a dose-limiting side effect, in up to 68% of cancer patients. In this study, we investigated the impact of paclitaxel therapy on the skin of breast cancer patients with chemotherapy-induced peripheral neuropathy (CIPN), building upon previous findings in zebrafish and rodents. Comprehensive assessments, including neurological examinations and quality of life questionnaires, were conducted, followed by intraepidermal nerve fiber (IENF) density evaluations using skin punch biopsies. Additionally, RNA sequencing, immunostaining for Matrix-Metalloproteinase 13 (MMP-13), and transmission electron microscopy provided insights into molecular and ultrastructural changes in this skin. The results showed no significant difference in IENF density between the control and CIPN patients despite the presence of patient-reported CIPN symptoms. Nevertheless, the RNA sequencing and immunostaining on the skin revealed significantly upregulated MMP-13, which is known to play a key role in CIPN caused by paclitaxel therapy. Additionally, various genes involved in the regulation of the extracellular matrix, microtubules, cell cycle, and nervous system were significantly and differentially expressed. An ultrastructural examination of the skin showed changes in collagen and basement membrane structures. These findings highlight the presence of CIPN in the absence of IENF density changes and support the role of skin remodeling as a major contributor to CIPN.


Response of tissue-cultured cynomolgus monkey kidney cells to botulinum C2 toxin.
C2 toxin (C2T) elaborated by Clostridium botulinum types C and D is composed of two nonlinked protein components, designated components I and II. The toxin, a mixture of untrypsinized component I and trypsinized component II, induced marked morphological changes of tissue-cultured cynomolgus monkey kidney cells; the characteristic response of the cells to the toxin was rounding, which increased proportionally to log dose of the toxin. The components alone and a combination of untrypsinized components I and II showed little activity. The rounding of the cultured cells was not accompanied by inhibition of protein and nucleic acid syntheses of the cells, although the rounded cells ultimately lost viability. Immunofluorescence studies showed that component II, either trypsinized or untrypsinized, bound to the cell surface, whereas component I bound to the cells only in the presence of trypsinized component II. The present results support the previously proposed idea concerning the mode of action of C2T, that components I and II of C2T act together as a molecule with dual functions; component II as the recognizer of the receptor site on the cell surface membranes and component I as the effector in the cytoplasm by preferential inactivation of cytoskeletal actin, which results in alteration of cell morphology, and subsequently in cellular damage.


Idiopathic Bone Cavity: Clinicopathologic Features from a Case Series with Emphasis on Differential Diagnosis of Chronic Apical Periodontitis.
Idiopathic bone cavity (IBC) is an uncommon bone lesion that usually affects youngsters as an unilocular radiolucency with predilection for the posterior mandible. Because the lesion is frequently located in proximity to the adjacent teeth, chronic apical periodontitis is commonly included as a differential diagnosis. The aim of the present study was to analyze the clinical and radiologic features of a series of IBCs diagnosed in a single service. All cases diagnosed as IBC were retrieved from the files of an oral pathology laboratory, and the clinical and radiologic characteristics were described with a focus on the differential diagnosis with chronic apical periodontitis. Thirty cases composed the final sample. The mean age of the affected patients was 22 years old; there was no sex predilection, and most lesions were located on the posterior (47%) and anterior (43%) mandible. Most lesions presented as unilocular radiolucencies (87%), and 90% were located in close association with the adjacent teeth. The associated teeth presented no endodontic involvement, and all proved to be vital. IBC usually affects young patients as an unilocular radiolucency in close association with the adjacent teeth. Careful radiologic analysis and vitality tests of the adjacent teeth are essential to rule out chronic apical periodontitis, thus avoiding any unnecessary endodontic treatment.


Come a little bit closer! Lipid droplet-ER contact sites are getting crowded.
Not so long ago, contact sites between the endoplasmic reticulum (ER) and lipid droplets (LDs) were largely unexplored on a molecular level. In recent years however, numerous proteins have been identified that are enriched or exclusively located at the interfaces between LDs and the ER. These comprise members of protein classes typically found in diverse types of contacts, such as organelle tethers and lipid transfer proteins, but also proteins that have no similarities to known contact site machineries. This structurally heterogeneous group of contact site residents might be required to fulfill unique aspects of LD-ER contact biology, such as de novo LD biogenesis, and maintenance of lipidic connections between LDs and ER. Here, we summarize the current knowledge on the molecular components of this special organelle contact site, and discuss their features and functions.