Pulmonary versus systemic hemodynamics in determining exercise capacity of patients with chronic left ventricular failure.
Right, but not left ventricular ejection fraction correlates with exercise capacity in patients with left ventricular failure, suggesting an important role of the pulmonary circulation. Hemodynamics were measured at rest and during bicycle exercise to symptomatic maximum in 41 patients with chronic left ventricular failure. Maximal oxygen consumption averaged only 12.8 +/- 5.2 ml/min/kg. Pulmonary wedge pressure rose from 21.9 +/- 8.2 to 35.9 +/- 9.3 mm Hg during exercise, while pulmonary arterial mean pressure rose from 31.8 +/- 10.9 to 50.4 +/- 12.9 mm Hg (both p less than 0.0001). Resting cardiac index and resting systemic arterial mean pressure did not correlate with maximal oxygen consumption (r = 0.23 and 0.20, respectively), which, however, did correlate with pulmonary wedge pressure (r = -0.54, p less than 0.001), pulmonary arterial mean pressure (r = -0.49, p less than 0.01), and total pulmonary resistance (r = -0.43, p less than 0.01). Maximal oxygen consumption did not correlate with resting systemic vascular resistance (r = -0.20) or resting pulmonary vascular resistance (r = -0.26). During exercise, total pulmonary resistance remained unchanged at 6.5 +/- 3.8 U while systemic vascular resistance fell significantly. The relation between total pulmonary resistance and exercise capacity and the failure of total pulmonary resistance to fall during exercise suggest that afterload on the right ventricle may be an important determinant of exercise capacity in patients with chronic left ventricular failure.


Screening for Hypertension and Lowering Blood Pressure for Prevention of Cardiovascular Disease Events.
Hypertension affects 1 in 3 American adults. Blood pressure (BP)-lowering therapy reduces the risk of cardiovascular disease. The United States Preventive Services Task Force recommends all adults be screened for hypertension. Most patients whose office BP is elevated should have out-of-office monitoring to confirm the diagnosis. Ambulatory BP monitoring is preferred for out-of-office measurement, but home BP monitoring is a reasonable alternative. Guidelines for treatment are stratified by age (<60 vs >60 years) and include cutoffs for recommended treatment BPs and target BP goals. Quality of hypertension care is improved by incorporating population health management using registries and medication titration.


Dosage adjustments of cefazolin according to the pharmacokinetics of this new cephalosporin.
Serum and urine levels of cefazolin were studied: 1. following a single 500mg intra-muscular dose of the drug in normal subjects (n = 10), in patients with renal impairment (n = 12) and in patients undergoing maintenance hemodialysis (n = 10); 2. following a single 500 mg intra-venous dose of the drug in normal subjects (n = 10). In normal subjects, serum half-lives averaged 1.75 hour after intravenous injection (Ke = 0.395) and 2.22 hours after intra-muscular injection (Ke = 0.312); urinary recovery of cefazolin over a six hours period amounted to 61% after intra-venous injection and to 47.5% after intra-muscular injection. The renal clearance of the drug approximated 40 ml/mn. A linear correlation (Ke = 0.022 + 0.0028 CrCl) was established between the overall elimination rate-constants and the creatinine clearances in the subjects under investigation. The various pharmacokinetic constants thus obtained can be used to calculate the maintenance doses, loading doses and dosage intervals adjusted according to creatinine clearances. These data actually yield dosage regimes adapted to each individual case according to the degree of renal function.


The bioartificial renal tubule assist device to enhance CRRT in acute renal failure.
Current therapy for acute tubular necrosis (ATN) continues to have an exceedingly high mortality rate, exceeding 50% even with dialytic or hemofiltrative support. Current renal replacement therapy in ATN only substitutes for filtration function of the kidney but not its cellular metabolic functions. Replacing these metabolic functions may optimize current therapy for this devastating disease process. In this regard, a renal tubule assist device (RAD) has been developed to be placed in an extracorporeal continuous hemoperfusion circuit in series with a hemofilter. The RAD consists of porcine renal proximal tubule cells grown as confluent monolayers of a multifiber bioreactor with a membrane surface area from 0.4 to 1.6 m2. The cells along the inner surface of the hollow fibers are immunoprotected from the patient's blood by the hollow fiber membrane. In preliminary experiments in uremic dogs, this device has been shown to tolerate a uremic environment while providing reabsorptive, metabolic, and endocrinologic activity. Pilot human trials of the RAD are anticipated within the next year to improve current renal replacement therapy in ATN.


Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome.
Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose, 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were assessed for neurobehavioral deficits followed by sacrifice and evaluation of brain infarct volume, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. As adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metalloproteinase 9 (MMP-9) upregulation, and tight junction protein deregulation, which resulted in lesser hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation and reduced infarct volume. This concurred with a remarkable decrease in high-mobility group box protein 1 (HMGB-1) and nuclear factor kappa B (NF-κB) stimulation, leading to less priming of NLRP3 inflammasome. This preclinical study supports verapamil as a safe adjuvant that may complement thrombolytic therapy by inhibiting TXNIP's detrimental role in hyperglycemic stroke.


Immunopathogenesis of Sjögren's syndrome.
Sjögren's syndrome (SS) is an autoimmune disease characterized by the sicca symptoms of dry eyes and dry mouth. Glandular dysfunction is thought to arise from destruction associated with lymphocytic infiltration. The degree of glandular destruction, however, does not correlate with the severity of sicca symptoms, suggesting that other mechanisms are involved, including abnormalities in parasympathetic neurotransmission. Autoantibodies against the muscarinic acetylcholine receptor have been implicated in this process, but multiple other autoantibodies have been found. Cytokines elaborated in the inflammatory lesions also appear to be involved and dysregulation of apoptosis are also involved in the pathogenesis of SS. A new two-stage model of SS has been proposed. First, there is a lymphocyte-independent phase during which inappropriate apoptosis results in the generation of apoptotic autoantigens which then attract lymphocytes. Subsequently, in the second lymphocyte-dependent phase, an immune attack causes further cell death and salivary dysfunction. Although the disease generally takes a rather stable and benign course, patients with SS have a significant risk of developing B cell lymphoma.


Trends in asthma readmissions among children and adolescents over time by age, gender and season.
Little is known about asthma readmissions within 28 days over time by age or gender. We explored trends in childhood asthma hospital readmission rates over time by age, gender and season. Using a large database of 53,156 childhood admissions with a primary diagnosis of asthma from the Department of Health Victoria Australia for 1997-2009, we explored asthma hospital readmissions rates by seasonality, gender and age (2-18 years) using chi square tests, logistic regression models and graphical techniques. Approximately 9459 (28%) of the children had two or more admissions over the whole study period, contributing to 55% (29,056/53,156) of all admissions. Approximately 5% of admissions were repeat admission within 28 days. Over time, despite a decline in asthma incidence, the rate of readmission within 28 days increased, particularly in the 2-12 year age groups. Girls were at greater risk of readmission within 28 days (odds ratio [OR] = 1.15; 95% CI: 1.004-1.32; p = 0.04) and 12 months (OR = 1.11; 95% CI: 1.05-1.19; p = 0.001). Grass pollen season was associated with readmissions within 28 days, but only in boys (p = 0.01). Over time, despite a fall in asthma incidence, readmission rates for childhood asthma significantly increased in younger age groups with girls at a higher risk of being readmitted than boys. Increased risk of repeat admission for boys was observed during the grass pollen season. These findings highlight high-risk groups, which has implications for both clinical services and patient care. More detailed monitoring of readmission rates amongst various risk groups over time is required.


Impact of initial dialysis modality on the survival of patients with ESRD in eastern China: a propensity-matched study.
There are conflicting research results about the survival differences between hemodialysis(HD) and peritoneal dialysis (PD). The present study estimated the survival and the relative mortality hazard for incident HD and PD patients with end stage renal disease (ESRD) in eastern China. This study examined a cohort of patients with ESRD who initiated dialysis therapy in Zhejiang province between Jan of 2010 and Dec of 2014, followed up until the end of 2015. PD patients were matched in a 1:1 fashion with HD patients, and Kaplan-Meier analysis was used to explore the survival of them. The Cox proportional hazard regression model was applied to identify the factors that predict survival by treatment modality. Subgroup analyses were conducted by stratifying patients according to gender, age, causes of ESRD and comorbidities. Among a total of 22,379 enrolled patients (17,029 HD patients and 5350 PD patients), 5350 matched pairs were identified, and followed for a median of 29 months (3 ~ 72 months). Kaplan-Meier survival curve revealed that overall mortality rate was significantly higher in HD patients than in PD patients (log-rank test, P < 0.001), after adjusting by gender, age, primary causes of ESRD and comorbidities. HD was consistently associated with an increased risk for morality compared with PD in the matched cohort (adjusted hazard ratio (AHR): 1.140, 95%CI: 1.023 ~ 1.271). In subgroup analyses, male, younger patients, or nondiabetic patients aged less than 65 years after adjustment of covariates, initiating with PD was associated with a significantly lower mortality compared with HD. In the multivariate Cox proportional risks model, age, diabetic nephropathy (DN), other/unknown causes of ESRD, and patients with a history of cardiovascular disease or cancer showed statistical significance in explaining survival of incident ESRD patients. ESRD patients who initiated dialysis with PD yielded superior survival rates compared to HD. Increased use of PD as initial dialysis modality in ESRD patients could be encouraged in Chinese population.


Pulmonary hypertension and polymorphonuclear leukocyte elastase after esophageal cancer operations.
To evaluate the role of polymorphonuclear leukocyte (PMN) elastase in pulmonary impairment occurring after operation for esophageal cancer, 10 patients were randomized preoperatively into two equal groups. One group received a placebo infusion and the other, an infusion of the PMN elastase inhibitor ulinastatin. In the placebo group, the mean plasma PMN elastase level increased from 154 +/- 23 micrograms/L preoperatively to 449 +/- 56 micrograms/L at 6 hours postoperatively (p less than 0.01), whereas the mean plasma fibronectin concentration decreased from 490 +/- 70 micrograms/mL preoperatively to 265 +/- 81 micrograms/L on postoperative day 2 (p less than 0.01). The mean pulmonary vascular resistance increased markedly from 151 +/- 24 dynes.s.cm-5.m-2 preoperatively to 284 +/- 76 dynes.s.cm-5.m-2 at 6 hours postoperatively (p less than 0.01). In the group given ulinastatin, 150,000 units every 12 hours from the start of the operation, the mean PMN elastase value at 6 hours postoperatively was lower (275 +/- 66 micrograms/L; p less than 0.01) and the fibronectin level on postoperative days 1 and 2, higher (p less than 0.05). A lower pulmonary vascular resistance was noted into day 2 (p less than 0.05). Our results suggest that PMN elastase may participate in the development of postoperative pulmonary impairment.


Phase I and pharmacological study of oral 9-aminocamptothecin colloidal dispersion (NSC 603071) in patients with advanced solid tumors.
9-Aminocamptothecin colloidal dispersion (9-ACCD; NSC 603071) is a specific inhibitor of topoisomerase I that can be given p.o. This Phase I trial was conducted to determine the toxicity profile, maximal tolerated dose, and pharmacokinetics profile, including bioavailability, of p.o. 9-ACCD in patients with advanced solid tumors. After receiving one i.v. dose of 9-ACCD, patients were treated with 9-ACCD p.o., starting with a 2-week schedule, to establish the safety. Once safety was established, patients were treated continuously for 4 weeks followed by a rest period of 2 weeks at dosages of 0.2, 0.3, 0.45, 0.56, 0.7, and 0.63 mg/m(2)/day. Serial blood samples were collected for the pharmacokinetics study on day 1 after the i.v. dose and day 2 after p.o. administration. Lactone and total 9-aminocamptothecin were analyzed by high-pressure liquid chromatographic assay. Thirty-two patients were treated on the study. The dose-limiting toxicity was myelosuppression at the dosage of 0.7 mg/m(2)/day. Other toxic effects included nausea, vomiting, fatigue, and transient elevation of the total bilirubin level. The maximal tolerated dose was 0.63 mg/m(2)/day. There was no objective response. The mean terminal half-life of p.o. total 9-ACCD was 1.2 +/- 1.2 h, and the volume of distribution was 17.7 +/- 20.6 l/m(2). The mean bioavailability of total 9-ACCD was 68.1 +/- 36.4%. Despite good tolerance of p.o. administration, the lack of clinical activity and variable absorption of 9-ACCD suggested that further development might not be warranted.


Cytological evidence for preferences of identical over homologous but not-identical meiotic pairing.
A spontaneous tetraploid/diploid chimera involving meiotic cells of a male individual of Euchorthippus pulvinatus gallicus was heterozygous for the C-banding pattern in chromosome pair 8. This allowed the study of the possible existence of competition in meiotic pairing between identical and homologous but not-identical chromosomes. The results suggest the existence of such a competition. An excess of bivalents formed by identical chromosomes was observed. It is suggested that during the pairing process slight specificity or activity differences between chromosomes with a high degree of resemblance would be responsible for the pairing preferences found.


Functionalizing porous zirconium terephthalate UiO-66(Zr) for natural gas upgrading: a computational exploration.
The ligand functionalization effect on the CO(2)/CH(4) separation performance of the MOF type UiO-66(Zr) was explored computationally. The -SO(3)H and -CO(2)H functionalized forms show the highest selectivity, good working capacity and medium ranged CO(2) adsorption enthalpy that make these materials very promising for physisorption-based processes.


Treatment of infantile E. coli gastroenteritis with specific bovine anti-E. coli milk immunoglobulins.
A milk immunoglobulin concentrate (MIC) containing antibodies to enteropathogenic E. coli strains was prepared by hyperimmunisation of pregnant cows and using the milk obtained during the first 6 to 8 days of lactation. The sterile concentrate contained 70 to 80% protein and 35 to 40% immunoglobulin. The antibacterial activity was measured by bacterial passive agglutination, bacteriostatic activity in vitro, phagocytic clearance in vivo, and a protection test in mice. Though differences in titers were observed, adequate immunologic activity was demonstrated by these tests. Clinical studies were performed with 60 patients (aged 10 days to 18 months) suffering from diarrhoea with isolation of enteropathogenic E. coli. They were treated for 10 days with MIC and stool cultures were done prior to, during, and 2, 3 and 4 days after termination of treatment. Among 51 patients infected with E. coli strains incorporated in the vaccine, stool cultures became negative in 43 (84.3%) after treatment with MIC and 8 remained positive. Nine patients infected with strains O 78:K80(B-) and O 114:K--(B-)--which were not included in the vaccine used for immunisation--served as controls. Only one patient in this group became negative. If all patients receiving antibiotics for non intestinal infections during the treatment period are omitted the results remained unaltered: MIC was effective in 32 out of 38 patients (84.2%). These differences were highly significant. These results provide evidence that treatment with specific MIC is effective in eliminating enteropathogenic E. coli from the intestine.


Community education to improve utilization of emergency obstetric services in Ghana. The Kumasi PMM Team.
Focus group studies in the Ashanti region showed that people avoided utilizing health facilities because of lack of confidence in the services and concern about the availability of drugs and supplies, among other reasons. After services at the health center were upgraded, community education activities began in early 1994. These activities were carried out through existing mechanisms--e.g. Ministry of Health (MOH) outreach workers and village health workers, public health nurses and midwives, and village health committees. They addressed a variety of audiences, including women's and church groups, emphasizing early recognition and treatment of obstetric complications, and the improved availability of services. The number of women with obstetric complications admitted to the health center rose from 26 in 1993 to 73 in 1995. It was the impression of the health center staff that women were also coming for treatment more promptly. The cost of this intervention was US$1950. This was mostly project funds, with the government and community together contributing approximately one-fifth. Once services are available, community education and information activities can enhance utilization. The cost of such activities can be reduced, and sustainability promoted, by involving MOH personnel and community groups.


Serum autoantibodies in the early detection of esophageal cancer: a systematic review.
Antibodies against tumor-associated antigens (TAAs) have been found in serum of patients with various types of cancers and may serve as biomarkers for early detection of esophageal cancer as well. This systematic review aims to give an overview about known autoantibodies and their diagnostic value in esophageal cancer. We conducted a systematic literature search in two databases to identify studies which performed serological testing for autoantibodies in esophageal cancer patients and controls. Data on study characteristics and results were extracted independently by two reviewers. Overall, 45 articles reporting the detection of 35 different autoantibodies met the inclusion criteria of this review. The most common antibody detection method was enzyme-linked immunosorbent assay (ELISA), and the most frequently assessed autoantibody was anti-p53, which was tested in 17 studies and for 15 studies of which a meta-analysis was conducted to comprehensively evaluate the diagnostic value. Most antibodies were assessed in only one study, and only few authors have evaluated the diagnostic value of combinations of multiple autoantibodies. For single autoantibodies, specificity was generally very high (median 98.3 %), but sensitivity was mostly rather low (median 26.7 %). For some autoantibody combinations, substantially higher sensitivity at reasonably high levels of specificity could be achieved. Development of extended and optimized multimarker panels of autoantibodies might be a promising approach for esophageal cancer early detection.


Functional principal component model for high-dimensional brain imaging.
We explore a connection between the singular value decomposition (SVD) and functional principal component analysis (FPCA) models in high-dimensional brain imaging applications. We formally link right singular vectors to principal scores of FPCA. This, combined with the fact that left singular vectors estimate principal components, allows us to deploy the numerical efficiency of SVD to fully estimate the components of FPCA, even for extremely high-dimensional functional objects, such as brain images. As an example, a FPCA model is fit to high-resolution morphometric (RAVENS) images. The main directions of morphometric variation in brain volumes are identified and discussed.


The current state of animal models in research: A review.
Animal models have provided invaluable information in the pursuit of medical knowledge and alleviation of human suffering. The foundations of our basic understanding of disease pathophysiology and human anatomy can largely be attributed to preclinical investigations using various animal models. Recently, however, the scientific community, citing concerns about animal welfare as well as the validity and applicability of outcomes, has called the use of animals in research into question. In this review, we seek to summarize the current state of the use of animal models in research.


Development and validation of a clinical prediction model for return to work after arthroscopic anterior crucial ligament reconstruction.
Occupational reintegration after anterior cruciate ligament (ACL) rupture is an important clinical issue including economic and health-related perspectives. This study aims to develop and validate a clinical prediction model of return to work in patients with ACL reconstruction surgery considering evidence-based clinical, anthropometric and occupational factors. Data of 562 patients with an ACL rupture receiving an arthroscopic ACL reconstruction were used for analysis. A model for the binary outcome of experiencing an inability to work period of less or more than 14 days (model 1), and a model for finding predictor variables that are linearly associated with a continuous longer inability to work period of over 14 days (model 2) was calculated. Pre-operative determinants including patient characteristics and peri-operative factors were used as predictors for both models. For model 1, the highest increase in odds was observed for the occupational type of work, followed by injury of the medial collateral ligament together with partial weight bearing. Small protective effects were observed for female sex, meniscal suture and work with light occupational strain. The type of occupational work, together with revision surgery, a longer duration of limited range of motion and the presence of cartilage therapy were risk factors for longer inability to work. Discrimination and calibration statistics were satisfactory in internal validation. Within the framework of clinical consideration, these prediction models will serve as an estimator for patients, their treating physicians and the socioeconomic partners to forecast the individual cost and benefit of ACL injury.


Gene expression and morphological responses of Lolium perenne L. exposed to cadmium (Cd2+) and mercury (Hg2+).
Soil contamination with heavy metals is a major problem worldwide, due to the increasing impact mainly caused by anthropogenic activities. This research evaluated the phytoremediation capacity of, Lolium perenne for heavy metals such as cadmium (Cd2+) and mercury (Hg2+), and the effects of these metals on morphology, biomass production, and the changes on gene expression. Seeds of L. perenne were exposed to six concentrations of Cd2+ and Hg2+ in the range of 0 to 25 mg L-1, and two mixtures of Cd2+-Hg2. The Non-Observed Effect Level (NOEL) was established with dose response curves and the expression of specific genes was evaluated applying a commercially available quantitative reverse transcription (RT-qPCR) assay. There was no significant effect when exposing the seeds to Hg2+, for Cd2+ the maximum concentration was established in 0.1 mg L-1, and for the two concentrations of mixtures, there was a negative effect. An increase of expression of genes that regulate antioxidant activity and stress was found when the plant was exposed to heavy metals. Given the high tolerance to metals analyzed that was reflected both, the development of the plant and in its molecular response, these results highlight that L. perenne is a plant with phytoremediator potential.


Case report: Crossed testicular ectopia.
Crossed testicular ectopia is a rare congenital anomaly in which both testes descend through a single inguinal canal. The typical presentation is that of ipsilateral inguinal hernia and contralateral cryptorchidism. This is a case report of crossed testicular ectopia in a 6-month-old male infant with depiction of herniorrhaphy and laparoscopic intraabdominal findings.


Mortality among twins and singletons in sub-Saharan Africa between 1995 and 2014: a pooled analysis of data from 90 Demographic and Health Surveys in 30 countries.
Sub-Saharan Africa has the world's highest under-5 and neonatal mortality rates as well as the highest naturally occurring twin rates. Twin pregnancies carry high risk for children and mothers. Under-5 mortality has declined in sub-Saharan Africa over the last decades. It is unknown whether twins have shared in this reduction. We pooled data from 90 Demographic and Health Surveys for 30 sub-Saharan Africa countries on births reported between 1995 and 2014. We used information on 1 685 110 singleton and 56 597 twin livebirths to compute trends in mortality rates for singletons and twins. We examined whether the twin-singleton rate ratio can be attributed to biological, socioeconomic, care-related factors, or birth size, and estimated the mortality burden among sub-Saharan African twins. Under-5 mortality among twins has declined from 327·7 (95% CI 312·0-343·5) per 1000 livebirths in 1995-2001 to 213·0 (196·7-229·2) in 2009-14. This decline of 35·0% was much less steep than the 50·6% reduction among singletons (from 128·6 [95% CI 126·4-130·8] per 1000 livebirths in 1995-2001 to 63·5 [61·6-65·3] in 2009-14). Twins account for an increasing share of under-5 deaths in sub-Saharan Africa: currently 10·7% of under-5 mortality and 15·1% of neonatal mortality. We estimated that about 315 000 twins (uncertainty interval 289 000-343 000) die in sub-Saharan African each year. Excess twin mortality cannot be explained by common risk factors for under-5 mortality, including birthweight. The difference with singletons was especially stark for neonatal mortality (rate ratio 5·0, 95% CI 4·5-5·6). 51·7% of women pregnant with twins reported receiving medical assistance at birth. The fate of twins in sub-Saharan Africa is lagging behind that of singletons. An alarming one-fifth of twins in the region dies before age 5 years, three times the mortality rate among singletons. Twins account for a substantial and growing share of under-5 and neonatal mortality, but they are largely neglected in the literature. Coordinated action is required to improve the situation of this extremely vulnerable group. None.


Change in triglyceride-glucose index predicts the risk of cardiovascular disease in the general population: a prospective cohort study.
Previous studies has shown a significant relationship between baseline triglyceride-glucose (TyG) index and subsequent cardiovascular disease (CVD). However, the effect of longitudinal changes in TyG index on the risk of CVD remains uncertain. This study aimed to investigate the association between change in TyG index and the risk of CVD in the general population. The current study included 62,443 Chinese population who were free of CVD. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2], and change in TyG index was defined as the difference between the TyG index in 2010 and that in 2006. Multivariable-adjusted Cox proportional hazard models and restricted cubic spline analysis were used to examine the association between change in TyG index and the risk of CVD. During a median follow-up of 7.01 years, 2530 (4.05%) incident CVD occurred, including 2018 (3.23%) incident stroke and 545 (0.87%) incident myocardial infarction (MI). The risk of developing CVD increased with the quartile of change in TyG index, after adjustment for multiple potential confounders, the hazard ratios for the Q4 group versus the Q1 group were 1.37 (95% confidence interval [CI], 1.21-1.54) for the overall CVD, 1.38 (95% CI, 1.19-1.60) for stroke, and 1.36 (95% CI, 1.05-1.76) for MI. Restricted cubic spline analysis also showed a cumulative increase in the risk of CVD with increases in the magnitude of change in TyG index. The addition of change in TyG index to a baseline risk model for CVD improved the C-statistics (P = 0.0097), integrated discrimination improvement value (P < 0.0001), and category-free net reclassification improvement value (P < 0.0001). Similar results were observed for stroke and MI. Substantial changes in TyG index independently predict the risk of CVD in the general population. Monitoring long-term changes in TyG may assist with in the early identification of individuals at high risk of CVD.


The human caveolin 1 gene upstream purine complex and neurodegeneration--a common signature.
The caveolin 1 gene (CAV1) is over-expressed in experimental animal models of multiple sclerosis (MS). Increased expression of this gene has also been reported in the Alzheimer's disease (AD) brain. Loss of this gene, on the other hand, has recently been reported to be associated with neruodegeneration. We have recently reported skew in the homozygote haplotypes of the human CAV1 gene -1.5 kb upstream purine complex in patients afflicted with MS and late-onset AD vs. controls. In order to examine reproducibility of those findings, we sequenced the region in independent groups of MS patients (n=120) and controls (n=150). We report two novel extreme homozygote haplotypes at 86-bp and 142-bp in the patients vs. controls. The above haplotypes were also detected in the previously reported cases of late-onset AD. The range of homozygote haplotypes in the controls was detected at between 106-bp to 122-bp. Following pooling of the neurodegenerative (n=486) and non-neurodegenerative (n=610) subjects studied for the human CAV1 purine complex to date, twenty haplotypes were found to be homozygous in the neurodegenerative, and not in the control pool (p<0.000001). Six overlapping haplotypes were detected in the MS and AD patients (p<0.007), strengthening the role of this region as a common etiological factor in the pathophysiology of neurodegenerative disorders, possibly through inflammatory mechanisms. Those overlapping haplotypes contained motif lengths that were non-existent in the control homozygote pool. The CAV1 purine complex GGAA and GAAA motifs are binding sites for numerous inflammatory transcription factors including the Ets, STAT, and IRF family members. Further work on the functionality of this region will shed light on the downstream events to the disease-linked haplotypes.


On-line solid-phase extraction and high-performance liquid chromatographic determination of chlorthalidone in urine.
A simple and rapid on-line method for the determination of chlorthalidone in urine is proposed. The sample containing the internal standard is injected in a CN precolumn. After a 2-ml water rinsing, the precolumn is coupled for 30 s to the HPLC column via a switching, valve, allowing the on-line elution of the compounds of interest. Analysis is carried out by reversed-phase chromatography with an acetonitrile-0.01 M phosphate buffer pH 7 (20:80, v/v) eluent, using UV detection at 214 nm. While the LC separation is performed, the precolumn is regenerated and conditioned, and is ready to receive the next sample at the end of the run. Accurate (> 95%) and precise (< 10%) analyses, in the range of 0.1-20 micrograms/ml of chlorthalidone in urine, have been achieved using this method.


Impact of extreme rainfall on non-point source nitrogen loss in coastal basins of Laizhou Bay, China.
Extreme rainfalls often lead to large amounts of nitrogen (N) loss from river basins. However, the composition and spatial variation of N loss caused by extreme events and the effects of control measures are not well understood. To shed light into this question, the Soil and Water Assessment Tool (SWAT) was used to evaluate the spatiotemporal characteristics of organic and inorganic nitrogen (ON and IN) losses in the coastal basins of Laizhou Bay during typhoons Rumbia and Lekima. The effects of best management practices on controlling N loss were also explored during such extreme rainfall events. Results showed that extreme rainfall promoted transport of ON more than IN. The mass of ON and IN transported by the two typhoons exceeded 57 % and 39 % of the average annual N flux, respectively, and the loads were positively correlated with streamflow. During the two typhoons, the loss of ON was mainly concentrated in areas with steep slopes (θ > 15°) and natural vegetation (forests, grasslands, and shrublands). The IN loss was higher in areas with a 5-10° slope. Furthermore, subsurface flow was the main IN transport mechanism in areas with steep slope (θ > 5°). Simulations showed that implementation of filter strips in areas with slopes exceeding 10° can reduce N loss, with much greater reductions in ON (>36 %) than IN (>0.3 %). This study provides important insights into N loss during extreme events and the key role filter strips can play in trapping them before they reach downstream waterbodies.


Iliac vein stenting is a safe and effective treatment for iliac vein compression syndrome: A systematic review of Chinese data.
This study was a systematic review of available data from China, and our aim was to evaluate the safety and efficacy of stenting in iliac vein compression syndrome. We searched the PubMed, National Knowledge Infrastructure, Chongqing Weipu Information Company, and Cochrane Central Register for Controlled Trials databases, and key references. Twelve studies were included (nine retrospective analyses, two retrospective case series studies, and one prospective cohort study) involving 2292 patients and 1897 stented limbs. The overall primary patency rates ranged from 81.8% to 100%. Studies showed significant improvements in patients' symptoms, and ulcer healing rates ranged from 71.4% to 100% in stented limbs. The incidence of severe complications ranged from 0 to 16.8%. For Chinese patients with iliac vein compression syndrome, stenting provided significant efficacy regarding favorable patency rates, symptom relief, and complications. However, the quality of evidence to support the use of iliac vein stenting to treat iliac vein compression syndrome is currently weak, especially for Chinese patients.


Transcriptomic and Chromatin Accessibility Analysis of the Human Macular and Peripheral Retinal Pigment Epithelium at the Single-Cell Level.
Some human retinal diseases are characterized by pathology that is restricted to specific cell types and to specific regions of the eye. Several disease entities either selectively affect or spare the macula, the retina region at the center of the posterior pole. Photoreceptor cells in the macula are involved in high-acuity vision and require metabolic support from non-neuronal cell types. Some macular diseases involve the retinal pigment epithelium (RPE), an epithelial cell layer with several metabolic-support functions essential for the overlying photoreceptors. In the current study, the ways in which RPE confers region-specific disease susceptibility were determined by examining heterogeneity within RPE tissue from human donors. RPE nuclei from the macular and peripheral retina were profiled using joint single-nucleus RNA and ATAC sequencing. The expression of several genes differed between macular and peripheral RPE. Region-specific ATAC peaks were found, suggesting regulatory elements used exclusively by macular or peripheral RPE. Across anatomic regions, subpopulations of RPE were identified that appeared to have differential levels of expression of visual cycle genes. Finally, loci associated with age-related macular degeneration were examined for a better understanding of RPE-specific disease phenotypes. These findings showed variations in the regulation of gene expression in the human RPE by region and subpopulation, and provide a source for a better understanding of the molecular basis of macular disease.


Erythroid differentiation in mouse erythroleukemia cells depends on Tmod3-mediated regulation of actin filament assembly into the erythroblast membrane skeleton.
Erythroid differentiation (ED) is a complex cellular process entailing morphologically distinct maturation stages of erythroblasts during terminal differentiation. Studies of actin filament (F-actin) assembly and organization during terminal ED have revealed essential roles for the F-actin pointed-end capping proteins, tropomodulins (Tmod1 and Tmod3). Tmods bind tropomyosins (Tpms), which enhance Tmod capping and F-actin stabilization. Tmods can also nucleate F-actin assembly, independent of Tpms. Tmod1 is present in the red blood cell (RBC) membrane skeleton, and deletion of Tmod1 in mice leads to a mild compensated anemia due to mis-regulated F-actin lengths and membrane instability. Tmod3 is not present in RBCs, and global deletion of Tmod3 leads to embryonic lethality in mice with impaired ED. To further decipher Tmod3's function during ED, we generated a Tmod3 knockout in a mouse erythroleukemia cell line (Mel ds19). Tmod3 knockout cells appeared normal prior to ED, but showed defects during progression of ED, characterized by a marked failure to reduce cell and nuclear size, reduced viability, and increased apoptosis. Tmod3 does not assemble with Tmod1 and Tpms into the Triton X-100 insoluble membrane skeleton during ED, and loss of Tmod3 had no effect on α1,β1-spectrin and protein 4.1R assembly into the membrane skeleton. However, F-actin, Tmod1 and Tpms failed to assemble into the membrane skeleton during ED in absence of Tmod3. We propose that Tmod3 nucleation of F-actin assembly promotes incorporation of Tmod1 and Tpms into membrane skeleton F-actin, and that this is integral to morphological maturation and cell survival during erythroid terminal differentiation.


Epidemiological survey of an outbreak of multiresistant Serratia marcescens by PCR-fingerprinting.
During an outbreak of Serratia marcescens from May to November 1993 43 strains obtained from 27 ICU patients infected or colonized with multiresistant S. marcescens were genotypically characterized with random amplified polymerase chain reaction (RAPD-PCR)-fingerprinting. In addition, 43 epidemiologically unrelated control isolates were selected. PCR-fingerprinting identified ten different genotypes of S. marcescens among the outbreak related strains. One predominant genotype was demonstrated in 21/43 isolates of 11/27 patients. A cluster of this genotype was found in seven/eight patients on the cardiosurgical ICU. The epidemiologically unrelated strains all showed different genotypes as compared to the predominant type. This survey proved RAPD-PCR to be a highly discriminatory and reproducible method for epidemiological studies of S. marcescens strains in nosocomial outbreaks.


The Role of Robotic Visceral Surgery in Patients with Adhesions: A Systematic Review and Meta-Analysis.
Abdominal adhesions are a risk factor for conversion to open surgery. An advantage of robotic surgery is the lower rate of unplanned conversions. A systematic review was conducted using the terms "laparoscopic" and "robotic". Inclusion criteria were: comparative studies evaluating patients undergoing laparoscopic and robotic surgery; reporting data on conversion to open surgery for each group due to adhesions and studies including at least five patients in each group. The main outcomes were the conversion rates due to adhesions and surgeons' expertise (novice vs. expert). The meta-analysis included 70 studies from different surgical specialities with 14,329 procedures (6472 robotic and 7857 laparoscopic). The robotic approach was associated with a reduced risk of conversion (OR 1.53, 95% CI 1.12-2.10, p = 0.007). The analysis of the procedures performed by "expert surgeons" showed a statistically significant difference in favour of robotic surgery (OR 1.48, 95% CI 1.03-2.12, p = 0.03). A reduced conversion rate due to adhesions with the robotic approach was observed in patients undergoing colorectal cancer surgery (OR 2.62, 95% CI 1.20-5.72, p = 0.02). The robotic approach could be a valid option in patients with abdominal adhesions, especially in the subgroup of those undergoing colorectal cancer resection performed by expert surgeons.


Efficient and Stable 3D/2D Perovskite Solar Cells through Vertical Heterostructures with (BA)4 AgBiBr8 Nanosheets.
Perovskite solar cells (PVSCs) have drawn great attention due to their high processability and superior photovoltaic properties. However, their further development is often hindered by severe nonradiative recombination at interfaces that decreases power conversion efficiency (PCE). To this end, a facile strategy to construct a 3D/2D vertical heterostructure to reduce the energy loss in PVSCs is developed. The heterostructure is contrived through the van der Waals integration of 2D perovskite ((BA)4 AgBiBr8 ) nanosheets onto the surface of 3D-FAPbI3 -based perovskites. The large bandgap of (BA)4 AgBiBr8 enables the formation of type-I heterojunction with 3D-FAPbI3 -based perovskites, which serves as a barrier to suppress the trap-assisted recombination at the interface. As a result, a satisfying PCE of 24.48% is achieved with an improved open-circuit voltage (VOC ) from 1.13 to 1.17 V. Moreover, the 2D perovskite nanosheets can effectively mitigate the iodide ion diffusion from perovskite to the metal electrode, hence enhancing the device stability. 3D/2D architectured devices retain ≈90% of their initial PCE under continuous illumination or heating after 1000 h, which are superior to 3D-based devices. This work provides an effective and controllable strategy to construct 3D/2D vertical heterostructure to simultaneously boost the efficiency and stability of PVSCs.


Synthesis, characterization, molecular docking studies and biological evaluation of some novel hybrids based on quinazolinone, benzofuran and imidazolium moieties as potential cytotoxic and antimicrobial agents.
Hybridization of bioactive natural and synthetic compounds is one of the most promising novel approaches for the design of hit and lead compounds with new molecular structures. In this investigation, a series of novel hybrid structures bearing quinazolinone, benzofuran and imidazolium moieties were designed and synthesized. Novel hybrid compounds were prepared and their structures were characterized by spectral and analytical data. In order to evaluate the biological activities, the synthesized hybrid compounds were studied for in vitro antibacterial activity against three Gram positive bacteria (Staphylococcus aureu, Bacillus subtilis, Listeria monocitogenes) and three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella entritidis) and also, Candida albicans as one yeast-like fungi strain. Cytotoxic activities of the synthesized compounds were also evaluated by the MTT assay in the human breast cancer cell line (MCF-7) and finally docking studies of cytotoxic derivatives were performed on aromatase enzyme. The results of antimicrobial activity showed that compound 14e, with two halogen atoms on quinazolinone and benzofuran was the most active against all the tested strains of microorganisms with the MIC value 16-128 µg/ml. Some of the tested compounds showed good cytotoxicity on MCF-7, and compound 14c with IC50=0.59 micromolar (μM) was found to be the most cytotoxic compound among the studied hybrid derivatives. The docking analysis showed acceptable binding interactions for these compounds. Based on the obtained results, the hybrid derivatives of quinazolinone, benzofuran and imidazolium could be regarded as efficient candidates for further molecular developments of anticancer and antimicrobial agents.


Chronic urine ascites secondary to proximal migrating of double-J ureteral stent into peritoneal cavity: A case report.
Implanting of a prophylactic double J stent during ureteroneocystostomy has been adopted as routine procedure for preventing anastomotic complications. In extremely rare events, the coiled distal end of the stent migrates upward through ureterovesical anastomosis into the peritoneal cavity. We report below a case that presented with chronic urinary ascites secondary to ureteral stent displacement which was successfully treated by endoscopic intervention.


Clinical efficacy, safety and tolerability of BIO-C (micronized Silymarin) as a galactagogue.
The authors have previously reported the use of Silymarin (a Silybum marianum standardized extract) as a promoter of milk production in cows. Due to the important psychological impact of hypogalactia in women after delivery, we evaluated the role of Silymarin as a safe and effective galactogogue for human species. 50 healthy women during lactation were enrolled in order to verify the galactogogue role played by an oral treatment with micronized Silymarin (420 mg/day) in comparison with an undistinguishable placebo product. Women orally treated for 63 days with Silymarin showed a clear galactagogue role for the product with an increase of 85.94% of the daily milk production (placebo: +32.09%). No drop out, nor unwanted effects were reported in both groups. Compliance and tolerability were also very good. Silymarin may be considered as a safe and effective herbal product that can be orally administered in order to improve the daily milk production in healthy women after delivery, without affecting milk quality.


Observations on the intrinsic innervation of the islet of Langerhans of Rattus rattus rufescens (Indian black rat).
The innervation of Langerhans' islets appeared rather profuse. Generally the nerve fibres of the peri-insular plexus formed a basket enveloping the islet of Langerhans. The peri-insular ganglia were occasionally seen. No autonomic interstitial cells of Cajal nor nerve endings were observed in the islet of Langerhans, due to the thickness of the sections. The 'complexes sympathico-neuro-insulaires' were occasionally seen. The plexuses and neural terminal network were seen connected to each other; thus they are not separate entities.


Leucaena leucocephala extract has estrogenic and antiestrogenic actions on female rat reproduction.
Leucaena feed has been reported to cause disruptive effects on livestock reproduction, such as low calving percentages in cows, abortion in female goats and pigs, dead fetuses and fetal resorption in pregnant rats. In this study, the effects of Leucaena on different female reproductive variables were analyzed in two different reproductive conditions: gonadally intact and ovariectomized (OVX) female rats. Leucaena (LEU) was administered to females in both experimental conditions for 30 consecutive days. The effects of the legume extract were compared with those of Daidzein (DAI), a phytoestrogen, and of the female hormone estradiol (E2). In intact females, LEU disrupted the estrous cycle and female sexual behavior, decreased the number of follicles and corpora lutea, increased uterine and vaginal epithelium in proestrus and diestrus periods, increased uterine and vaginal relative weights during diestrus, and decreased serum progesterone during proestrus. All these effects were similar to those of DAI but lower than E2-induced effects. In OVX females, LEU decreased body weight, induced lordosis, stimulated vaginal epithelium cornification, increased vaginal weight, and augmented vaginal epithelium thickness. Again, these effects were similar to the effects of DAI and lower than the effects observed with E2. These results indicate that, in gonadally intact females, LEU can produce antiestrogenic effects in sexual behavior but estrogenic effects on uterine and vaginal weight and epithelia, without modifying serum levels of E2. In OVX females, in total absence of endogenous E2, LEU induced estrogenic effects on vaginal weight and epithelia, as well as on sexual behavior.


The contribution of tumor and host tissue factor expression to oncogene-driven gliomagenesis.
Glioblastoma multiforme (GBM) is an aggressive form of glial brain tumors, associated with angiogenesis, thrombosis, and upregulation of tissue factor (TF), the key cellular trigger of coagulation and signaling. Since TF is upregulated by oncogenic mutations occurring in different subsets of human brain tumors we investigated whether TF contributes to tumourigenesis driven by oncogenic activation of EGFR (EGFRvIII) and RAS pathways in the brain. Here we show that TF expression correlates with poor prognosis in glioma, but not in GBM. In situ, the TF protein expression is heterogeneously expressed in adult and pediatric gliomas. GBM cells harboring EGFRvIII (U373vIII) grow aggressively as xenografts in SCID mice and their progression is delayed by administration of monoclonal antibodies blocking coagulant (CNTO 859) and signaling (10H10) effects of TF in vivo. Mice in which TF gene is disrupted in the neuroectodermal lineage exhibit delayed progression of spontaneous brain tumors driven by oncogenic N-ras and SV40 large T antigen (SV40LT) expressed under the control of sleeping beauty transposase. Reduced host TF levels in low-TF/SCID hypomorphic mice mitigated growth of glioma subcutaneously but not in the brain. Thus, we suggest that tumor-associated TF may serve as therapeutic target in the context of oncogene-driven disease progression in a subset of glioma.


Overexpression of an alfalfa GDP-mannose 3, 5-epimerase gene enhances acid, drought and salt tolerance in transgenic Arabidopsis by increasing ascorbate accumulation.
GDP-mannose 3', 5'-epimerase (GME) catalyses the conversion of GDP-D-mannose to GDP-L-galactose, an important step in the ascorbic acid (ascorbic acid) biosynthetic pathway in higher plants. In this study, a novel cDNA fragment (MsGME) encoding a GME protein was isolated and characterised from alfalfa (Medicago sativa). An expression analysis confirmed that MsGME expression was induced by salinity, PEG and acidity stresses. MsGME overexpression in Arabidopsis enhanced tolerance of the transgenic plants to salt, drought and acid. Real-time PCR analysis revealed that the transcript levels of GDP-D-mannose pyrophosphorylase (GMP), L-galactose-phosphate 1-P phosphatase (GP) and GDP-L-galactose phosphorylase (GGP) were increased in transgenic Arabidopsis (T3 generation). Moreover, the ascorbate content was increased in transgenic Arabidopsis. Our results suggest that MsGME can effectively enhance tolerance of transgenic Arabidopsis to acid, drought and salt by increasing ascorbate accumulation.


Effect of Raillietina echinobothrida infection on blood values and intestinal tissues of domestic fowls of Bangladesh.
An examination of the blood profile of domestic fowls infected with Raillietina echinobothrida revealed anaemia with a significant increase of total leukocyte counts and decrease of total serum protein. The pathological changes in the intestines were characterised by villous atrophy, enteritis with cellular infiltration and formation of characteristic granulomas.


Open-loop Audio-Visual Stimulation for sleep promotion in older adults with comorbid insomnia and osteoarthritis pain: results of a pilot randomized controlled trial.
Osteoarthritis is commonly comorbid with insomnia in older adults. While cognitivebehavioral therapy for insomnia is the recommended first-line treatment for insomnia, alternative efficacious non-pharmacological options are needed. This study examined sleep and pain in 30 community-dwelling older adults with comorbid insomnia and osteoarthritis pain randomized to two weeks of 30 min of bedtime active (n = 15, mean age 66.7 ± 5.2) or placebo control (n = 15, mean age 68.9 ± 5.0) Audiovisual Stimulation (AVS). After AVS use, improvements in sleep, pain, and depression were reported for both groups but between-group comparisons were non-significant. A posthoc analysis examined the effects of AVS in the 11 subjects who reported sleep latency complaints (≥30 min). No significant group differences were found for this small sleep latency subsample; however, the pre-post effect sizes (ES) of active AVS versus placebo were greatly increased for the subsample relative to the total sample for sleep (ES = 0.41 versus 0.18 for the Insomnia Severity Index, and 0.60 versus 0.03 for the Pittsburgh Sleep Quality Index, respectively). A similar enhanced effect pattern was found for pain (ES = 0.41 versus 0.15 for the Brief Pain Inventory). Study findings suggest that the 30-min AVS program may have potential to improve sleep in older adults with sleep onset but not sleep maintenance difficulty. Despite study limitations of a small sample size and lack of follow-up, results offer valuable insights into the functionality of AVS treatment. Future research should focus on subjects with sleep onset complaints, who are most likely to receive benefit from this treatment modality.


The prevalence of depression in two districts of Uganda.
Little information is available on the prevalence of depression in Uganda. Given the recent political history of Uganda, depression may be common. The aim was to estimate the point prevalence of probable clinical depressive disorder among the general population in two contrasting districts of Uganda. Translated versions (in Madi and Lusoga) of the 13-item Beck Depression Inventory (BDI) were administered to a systematic sample of adult residents in the Adjumani and Bugiri districts of Uganda. The overall prevalence of probably clinically significant depression (BDI score of 20-39) was 17.4%. Significantly higher rates were found in women and in Adjumani District. Depression is common in Uganda and particularly in the more troubled and less socially cohesive district of Adjumani.


Primary structure of the gene for glycyl-tRNA synthetase from Bombyx mori.
The primary structure of the gene encoding Bombyx mori glycyl-tRNA synthetase was determined by sequence analysis of one cDNA and two genomic clones. The sequence of the protein deduced from the nucleotide sequence was verified by sequence analysis of eight peptides. The M(r) 77,667 protein is encoded in a single open reading frame of 2061 nucleotides. There are no introns in the gene. The deduced protein sequence has no obvious similarity to Escherichia coli glycyl-tRNA synthetase but contains a sequence in its amino terminus that is similar to a sequence found in the Drosophila melanogaster and human glutamyl-tRNA synthetases, the hamster and human histidyl-tRNA synthetases, bovine tryptophanyl-tRNA synthetase, and the mammalian peptide chain release factor. The B. mori glycyl-tRNA synthetase also has sequence similarity with the Saccharomyces cerevisiae (cytoplasmic and mitochondrial), E. coli, and human threonyl-tRNA synthetases. This sequence similarity occurs in a sequence motif that is characteristic of other class II aminoacyl-tRNA synthetases. Two transcription start sites approximately 100 nucleotides apart were identified by ribonuclease mapping. One of the transcription start sites is used preferentially in the posterior silk gland. The peak in mRNA accumulation occurs 80-100 h prior to the peak in glycyl-tRNA synthetase activity and enzyme protein.


Current topics on therapeutic apheresis.
Remarkable advances have been made in the area of pharmacotherapy such as immunosuppressants and biologics in recent years. However, there is always the possibility that adequate pharmacotherapy cannot be carried out due to resistance, organ damage, allergies, and adverse drug reactions. The idea of aiming for treatment that is safer and more effective by using concomitant therapeutic apheresis to mitigate drug therapies that cause severe tissue injury has surfaced. In the present report, I would like to discuss new findings related to disorders such as rheumatoid arthritis, ulcerative colitis, and chronic hepatitis C that are already covered by insurance and the indications, methods, and clinical efficacy of therapeutic apheresis for disorders such as dilatative cardiomyopathy, pyoderma gangrenosum, and pulmonary fibrosis that are currently being evaluated and investigated in the hope that they will be covered in the future.


Control of redox potential in hybridoma cultures: effects on MAb production, metabolism, and apoptosis.
Culture redox potential (CRP) has proven to be a valuable monitoring tool in several areas of biotechnology; however, it has been scarcely used in animal cell culture. In this work, a proportional feedback control was employed, for the first time, to maintain the CRP at different constant values in hybridoma batch cultures for production of a monoclonal antibody (MAb). Reducing and oxidant conditions, in the range of -130 and +70 mV, were maintained in 1-l bioreactors through automatic control of the inlet gas composition. Cultures at constant DOT, in the range of 3 and 300 %, were used for comparison. The effect of constant CRP on cell concentration, MAb production, metabolism of glucose, glutamine, thiols, oxygen consumption, and programmed cell death, was evaluated. Reducing conditions resulted in the highest viable cell and MAb concentrations and thiols production, whereas specific glucose and glutamine consumption rates remained at the lowest values. In such conditions, programmed cell death, particularly apoptosis, occurred only after nutrient exhaustion. The optimum specific MAb production rate occurred at intermediate CRP levels. Oxidant conditions resulted in a detrimental effect in all culture parameters, increasing the specific glucose, glutamine, and oxygen consumption rates and inducing the apoptotic process, which was detected as early as 24 h even when glutamine and glucose were present at non-limiting concentrations. In most cases, such results were similar to those obtained in control cultures at constant DOT.


Penicillium strains as dominant degraders in soil for coffee residue, a biological waste unsuitable for fertilization.
Coffee residue is an agricultural waste which inhibits the growth of several crops. Therefore coffee residue-degrading microbes in soil were screened, isolated and characterized. Forty isolates were obtained after enrichment culture of soil samples. Seven strains (fast degraders) showed strong degrading activity, while 18 strains (slow degraders) showed weak degrading activity. DNA analysis suggested that the fast degraders are Penicillium, and the slow degraders are Penicillium, Trichoderma/Hypocrea, Fusarium/Gibberella, Phaeoacremonium/Togninia or Acidocella. The all fast degraders are cellulolytic, mannolytic and pectinolytic. Although it is generally thought that fungi such as Trichoderma contribute largely to aerobic degradation of cellulosic biomass, our data suggested that Penicillium overwhelms them in coffee residue degradation. It was implied that polysaccharides in coffee residue are not degraded independently by different microbes, but degraded simultaneously by strains with cellulolytic, mannolytic and pectinolytic activity. Since there is no report of an ascomycete possessing all the three enzyme activities, the fast degraders are ecologically important and have the potential to be used as producers of the costly enzymes from agricultural wastes. The present results advance our understanding of microbial degradation of a phytotoxic agricultural waste, and offer a new tool for recycling it.


A technique to access difficult to find upper extremity veins for right heart catheterization: the levogram technique.
Upper extremity venous access provides a safer alternative for performance of right heart catheterization compared to femoral venous access. We describe a technique to access deep veins of the upper extremity, in patients undergoing transradial catheterization, using levophase contrast venography. This technique allows the operator to access deep veins of the upper extremity without the need for additional equipment, staff or training, using traditional basic catheterization laboratory skills and equipment.


A case report: Secondary cancers due to oncological treatment modalities.
Breast cancer (BC) is one of the most common cancers worldwide. In recent years, numerous non-chemotherapy agents have been developed for BC treatment, including targeted agents, new hormonal therapies, and immunotherapies. However, despite the widespread use of these agents, chemotherapies are still an important cornerstone in BC treatment. Similarly, serious de-escalation studies in radiotherapy use have been conducted in recent years. These two treatment modalities, which we frequently use in the treatment of BC due to their effectiveness, may also have serious side effects. In this article, I will present a case of multiple myeloma (MM) and myxofibrosarcoma (MFS) that occurred many years later in a patient who completed adjuvant chemotherapy and radiotherapy for BC. MM has developed due to previous chemotherapy and MFS has developed due to previous radiotherapy. We usually treat our cancer patients with chemotherapy or radiotherapy to prolong their lives. In addition to the benefits we provide, may negatively affect the lifetime and quality of life by causing the development of metachronous secondary cancers in some patients. In this case report, I will present the "ironic" side of oncology science and treatment.


Author Correction: Listeria monocytogenes impairs SUMOylation for efficient infection.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Provocation of Migraine after Maximal Exercise: A Test-Retest Study.
Exercise is often recommended in migraine treatment, but strenuous physical activity is also reported as a migraine trigger. The main aim of this study was to evaluate whether migraine can be triggered by a maximal exercise test, using a prospective test-retest method. A secondary aim was to compare the participants who responded to the maximal exercise test with a migraine attack with those who did not suffer a migraine attack after the test. A total of 19 patients reporting exercise as a potential trigger for their migraines were included in the study. After a baseline period of 1 month with measurements of migraine frequency, a cycle ergometer test until exhaustion was used twice on each patient. A total of 14 patients were test-retested, and of these, 3 reported migraine following both tests, 5 after one of the tests, and 6 did not report migraine after either test. We observed a higher risk of migraine after 1 or 2 tests in patients with a higher baseline migraine frequency (p = 0.036). In conclusion, the study showed that although maximal aerobic exercise can trigger migraine attacks, it does not always provoke an attack even in those who report exercise as a migraine trigger.


VARIABLE SELECTION ON EUROSTA'S GALL SIZE, I: THE EXTENT AND NATURE OF VARIATION IN PHENOTYPIC SELECTION.
Natural fluctuations in environmental conditions are likely to induce variation in the intensity or direction of natural selection. A long-term study of the insect, Eurosta solidaginins Fitch (Diptera; Tephritidae), which induces stem galls on the perennial herb Solidago altissima (Asteraceae) was performed to explore the patterns of variation in phenotypic selection. The intensity of selection imposed by parasitoids and predators on gallmaking larvae, for gall size, was measured across 16 populations over the course of 4 generations, for a total of 64 population-generations. Directional selection was quantified by i, the selection intensity, and variance selection by j', a measure of the intensity of selection on phenotypic variance. Size-dependent attack by parasitoids caused upward directional selection (mean ip = 0.42; SE = 0.023), while size-dependent bird attack favored larvae that induced smaller galls (mean ib = -0.07; SE = 0.013. The mean net directional selection intensity was 0.35 (SE = 0.030), which indicates that insects inducing larger galls are generally favored by selection. The opposing patterns of size-dependent attack resulted in stabilizing selection in half the population generations, with an overall average. j' of -0.11 (SE = 0.078). The magnitude of directional selection was strongly influenced by the population mean gall size and weakly by the optimal gall size. The intensity of variance selection was strongly influenced by the shape of the fitness function, with sigmoidal and Gaussian-like shapes causing greater depletion of phenotypic variance.


Impact of Medicaid Expansion on Medicaid-covered Utilization of Buprenorphine for Opioid Use Disorder Treatment.
Buprenorphine has been proven effective in treating opioid use disorder. However, the high cost of buprenorphine and the limited prescribing capacity may restrict access to this effective medication-assisted treatment for opioid use disorder. To examine whether Medicaid expansion and physician prescribing capacity may have impacted buprenorphine utilization covered by Medicaid. We used a quasi experimental difference-in-differences design to compare the pre-post changes in Medicaid-covered buprenorphine prescriptions and buprenorphine spending between the 26 states that implemented Medicaid expansions under the Affordable Care Act in 2014 and those that did not. All Medicaid enrollees in the expansion states and the nonexpansion and late-expansion states. Quarterly Medicaid prescriptions for buprenorphine and spending on buprenorphine from the Centers for Medicare and Medicaid Services Medicaid Drug Utilization files 2011 to 2014. State implementation of Medicaid expansions in 2014 was associated with a 70% increase (P<0.05) in Medicaid-covered buprenorphine prescriptions and a 50% increase (P<0.05) in buprenorphine spending. Physician prescribing capacity was also associated with increased buprenorphine utilization. Medicaid expansion has the potential to reduce the financial barriers to buprenorphine utilization and improve access to medication-assisted treatment of opioid use disorder. Active physician participation in the provision of buprenorphine is needed for ensuring that Medicaid expansion achieves its full potential in improving treatment access.


Pifithrin-alpha has a p53-independent cytoprotective effect on docosahexaenoic acid-induced cytotoxicity in human hepatocellular carcinoma HepG2 cells.
Pifithrin-alpha (PFT) is an inhibitor of p53 and is known to protect against a variety of p53-mediated genotoxic agents. In this report, we examined the inhibitory effects of PFT against docosahexaenoic acid (DHA)-induced cytotoxicity in the human hepatocellular carcinoma (HCC) cell line HepG2. PFT significantly abrogated DHA-induced cytotoxicity in wild-type HepG2 cells (normal expression of p53) and after p53-knockdown by siRNA, as well as in Hep3B (p53 null) and Huh7 (p53 mutant) cells. DHA-induced cytotoxicity is mediated by induction of oxidative stress, and PFT inhibited this event, but it does not exert antioxidant effects. PFT significantly suppressed the release of cytochrome c from mitochondria to cytosol, as well as changes in the mitochondrial membrane potential (ΔΨM) by DHA. Therefore, protection of mitochondria by PFT is crucial for its inhibition of DHA-induced cytotoxicity. Although it has been reported that PFT is able to block p53 function, our data suggest that PFT also has a p53-independent inhibition mechanism. This work provided insights into the mechanisms of PFT action on DHA-induced cytotoxicity in HCC.


Growth failure secondary to moyamoya syndrome.
We describe a boy who presented at the age of 7 years with short stature due to hypopituitarism. Six months after starting appropriate hormone replacement treatment at the age of 8 he suffered his first generalised convulsion. Further neuroradiological investigation led to the diagnosis of moyamoya syndrome.


Recent advances in cell membrane chromatography for traditional Chinese medicines analysis.
Traditional Chinese medicines (TCMs) have been used for preventative care for thousands of years. The active components are the basis for the pharmacodynamics of TCMs, and they can be an important source of lead compounds. As a bioaffinity chromatography technique, cell membrane chromatography (CMC) has been developed for almost 20 years since 1996. It has been proven to be a useful method for studying drug-receptor interactions and screening active components from medicinal herbs. In our review in 2007 (Drug Discov. Ther., 1 (2007) 104-107), the preparation, identification, evaluation, and preliminary applications of CMC stationary phases were presented. In this article, we briefly review some of the latest progress and applications about CMC including instrument development, research on drug-receptor interactions, screening active components from TCMs, and quality control of TCMs.


Combination treatment of ultrasound and ozone for improving solubilization and anaerobic biodegradability of waste activated sludge.
The hydrolysis is known to be the rate-limiting step of biological sludge anaerobic degradation. The disruptions of sludge flocs and microbial cell walls by ultrasound combined with ozone treatment (US/O(3)) were investigated in laboratory-scale experiments. The results showed that temperature, O(3) dose, US energy density and pH had a positive effect on the disintegration of sludge. The organic substrates were released into the liquor, which induced the increases of soluble chemical oxygen demand (COD(S)) and turbidity in the aqueous phase. Accordingly, the biodegradability of sludge was improved. The COD(S) increased from 1821 to 2513 mg/l after reaction for 30 min when NaHCO(3) was added, which indicated that the ozone molecule played a major role in the disintegration of waste activated sludge. The COD(S) was 2483 mg/l after 60 min O(3) treatment followed by 60 min US treatment, and it changed into 3040 mg/l after 60 min US/O(3) treatment, which proved that US/O(3) induced a synergetic effect. The pH-drop of sludge from 6.8 to 5.21 might be attributed to the increase of volatile fatty acid from 61.35 to 111.96 mg/l during the US/O(3) treatment process.


Uncommitted role of enterococcal surface protein, Esp, and origin of isolates on biofilm production by Enterococcus faecalis isolated from bovine mastitis.
This study was conducted in order to determine the occurrence of esp and biofilm formation among Enterococcus faecalis causing mastitis isolated from different bovine and environmental origins. A total of 41 E. faecalis isolates were obtained from clinical mastitis before antibiotic therapy, subclinical mastitis, dried manure bedding samples, and postpartum milk samples. Isolates were screened for biofilm formation using microtiter plate method using tryptic soy broth with 0.25% glucose as media. Isolates were tested for the presence of the esp gene, which has been reported to be essential for biofilm formation in enterococci, by means of the polymerase chain reaction. Analysis of the relationship between the presence of esp and the biofilm formation capacity in E. faecalis showed that the esp gene was not identified in any of the 18 biofilm-producing E. faecalis isolates. Moreover, two of the three non-biofilm-producing E. faecalis strains were esp positive. In addition, the biofilm assay mean values were not changed with different origins of isolation. These results suggest the following: (1) lack of strict association between the presence of esp and biofilm formation and (2) widespread biofilm formation capacity among different sources of E. faecalis isolates derived from bovine mastitis.


The efficacy of the COMFORT score and pain management protocol in ventilated pediatric patients following cardiac surgery.
An optimal scoring system for pain assessment in pediatric intensive care is necessary to determine the efficacy of analgesics. We assess the COMFORT scale in postoperative ventilated children and study the effect of pain and sedation protocols on their outcomes. We included postoperative ventilated patients. The unit-based pain management protocol was used. The assessment of the COMFORT and FLACC scales was performed by 2-nurses at 2-h intervals on the day of surgery and at 4-h intervals during the first 2-postoperative days or until the patient was ex-tubated. The patients' outcomes were compared with age-matched and RACHS score matched patients prior to the application of the pain protocol. One-hundred-ten prospective patients were included. The mean age and weight was 24 months and 9.8 ± 8.4 kg, respectively. There was a weak, statistically significant correlation between the COMFORT and FLACC scales, with a range of (r = 0.01-0.7). The COMFORT scale demonstrated good internal consistency, with a Cronbach's alpha of 0.75. The mean ventilation days were 1.3 ± 3, with a mean ICU and hospital stay of 5 ± 5 and 10 ± 9 days, respectively. The 110 patients were compared to 50 retrospective matching patients. The prospective group demonstrated statistically less ventilation days, ICU stay time and hospital stay time, with P-values of 0.0004, 0.001 and 0.0003, respectively. The COMFORT scale is a valuable and reliable pain assessment tool for use in postoperative ventilated pediatric patients. The implementation of a pain and sedation protocol decreased the incidence of withdrawal and the duration of mechanical ventilation as well as ICU and hospital stays.


Effect of estrus-associated glycoprotein and tissue inhibitor of metalloproteinase-1 secreted by oviduct cells on in vitro bovine embryo development.
The effect of two glycoproteins (estrus-associated glycoprotein [EGP] and tissue inhibitor of metalloproteinase [TIMP-1]) secreted by bovine oviduct cells on in vitro bovine embryo development was assessed. A first set of experiments was conducted to determine whether the embryotrophic activity of the bovine oviduct-conditioned medium (BOCM) was correlated with the presence of EGP or TIMP-1. EGP and TIMP-1 were detected in BOCM, supporting the development of 22% zygotes to the blastocyst stage, as well as in BOCM yielding a low blastocyst rate (3-4% blastocysts). These glycoproteins do not seem to be necessary for bovine embryo development up to the blastocyst stage in our BOCM. In a second experiment, zygotes were cultured in modified synthetic oviduct fluid (mSOF) supplemented with different concentrations (0.5, 5, 50, and 500 micrograms/ml) of purified bovine EGP. In the third experiment, since purified bovine TIMP-1 was not available, zygotes were cultured in BOCM depleted of TIMP-1 by immunoprecipitation treatment. Adding EGP to mSOF, or removing TIMP-1 from BOCM, did not affect bovine embryo development up to the blastocyst stage, or mean number of cells per blastocyst after 8 days of culture. The results indicate that, under our culture conditions, EGP and TIMP-1 do not play an important role in sustaining bovine embryo development, and do not influence blastocyst quality, assessed in terms of total number of cells per embryo.


Efficacy of a combination of dutasteride, tadalafil, and solifenacin in the treatment of previously unsuccessful patients.
To evaluate the efficacy and safety of simultaneous administration of dutasteride, tadalafil and solifenacin in the treatment of benign prostatic hyperplasia (BPH) with overactive bladder symptoms and lower urinary tract obstruction in previously unsuccessfully treated men. Patients in Group A (n=97) received dutasteride 0.5 mg/day, tadalafil 2.5 mg/day, and solifenacin 2.5 mg/day; Group B (n=95) received dutasteride 0.5 mg/day, tadalafil 5 mg/day, and solifenacin 5 mg/day; Group C (n=103) received dutasteride 0.5 mg/day, tadalafil 20 mg/day, and solifenacin 10 mg/day. The functional status of the lower urinary tract was assessed using the International Prostate Symptom Score (I-PSS), Overactive Bladder Questionnaire (OABq), International Index of Erectile Function (IIEF), and Male Sexual Health Questionnaire Ejaculatory Dysfunction (MSHQ-EjD) as well as uroflowmetry. The total score of the sexual function remained unchanged in Group B of patients 81.3 points vs. 80.2 points (p>0.05) according to MSHQ-EjD, 61.4 points vs. 51.2 points (p>0.05) according to IIEF data. The total assessment of symptoms of hyperactivity significantly decreased in Group C according to OABq data after the 4th week of the study (17.5 points vs. 26.1 points, p<0.05) and remained below the baseline until the end of the study (15.2 points). The simultaneous administration of standard doses of dutasteride, solifenacin, and tadalafil for 3 months is safe, effective, and can be recommended for patients with BPH to reduce symptoms of obstruction and hyperactivity of the bladder and maintain sexual function.


CT before and after ERCP: detection of pancreatic pseudotumor, asymptomatic retroperitoneal perforation, and duodenal diverticulum.
A prospective study was done to investigate the occurrence of morphologic changes after ERCP that present as pancreatic pseudotumor on CT scan. Fifty-eight patients underwent CT before and after ERCP. In addition, post-ERCP complications and the value of routinely obtained CT before ERCP were assessed. Thirty-nine patients could be fully analyzed; 12 underwent a papillotomy (group 1). Pseudotumor of the pancreatic head was demonstrated on CT after ERCP in them (17%). No changes were seen in the 27 patients who underwent diagnostic ERCP (group 2) (p = 0.048). Asymptomatic retroperitoneal perforation after papillotomy was diagnosed in 3 patients (13%). Routinely obtained CT scans before ERCP defined a specific etiology of the biliary obstruction in 12% of patients not suggested by ultrasound. Duodenal diverticulum was found in 4 patients, resulting in a sensitivity of 36% and a specificity of 100% for CT. Oral contrast (600 ml) administered a few hours before endoscopy never hampered the endoscopist. Pancreatic pseudotumor on CT after ERCP occurred only when papillotomy was performed. CT remains a valuable diagnostic tool after diagnostic ERCP. Asymptomatic perforation may occur following ERCP with papillotomy. Routinely obtained CT before ERCP was not profitable for the endoscopist in more than 80% of our patients.


Inter-subject P300 variability relates to the efficiency of brain networks reconfigured from resting- to task-state: Evidence from a simultaneous event-related EEG-fMRI study.
The P300 event-related potential (ERP) varies across individuals, and exploring this variability deepens our knowledge of the event, and scope for its potential applications. Previous studies exploring the P300 have relied on either electroencephalography (EEG) or functional magnetic resonance imaging (fMRI). We applied simultaneous event-related EEG-fMRI to investigate how the network structure is updated from rest to the P300 task so as to guarantee information processing in the oddball task. We first identified 14 widely distributed regions of interest (ROIs) that were task-associated, including the inferior frontal gyrus and the middle frontal gyrus, etc. The task-activated network was found to closely relate to the concurrent P300 amplitude, and moreover, the individuals with optimized resting-state brain architectures experienced the pruning of network architecture, i.e. decreasing connectivity, when the brain switched from rest to P300 task. Our present simultaneous EEG-fMRI study explored the brain reconfigurations governing the variability in P300 across individuals, which provided the possibility to uncover new biomarkers to predict the potential for personalized control of brain-computer interfaces.


Study of unusual phenomenon of contact firing on gelatine block using .38 Special revolver--forensic importance.
Gunshot wounds in suicide cases are self-inflicted wounds. Self-inflicted wounds in suicide cases are usually caused by contact firing and are of great forensic significance. Evaluation of contact wound may be associated with difficulties if the bore gets obstruction prior to firing. This paper investigates the phenomenon and interprets the results of test firing conducted on 20% gelatine block at 10 degrees C, using .38 Special revolver with obstruction of a bullet in the bore. Test firings were conducted in three different muzzle-target contact conditions keeping the muzzle pressed against the gel block in each case. The physical evidence and the wound ballistic parameter namely bullet track, remaining velocity of the bullets and volume of permanent cavity have been studied. When compared with the results of contact firing conducted with the same firearm without having any bore obstruction under similar conditions, it has been found that the physical evidence and the wound ballistic parameters would be helpful for interpretation of such unusual incidents for forensic inference.


Shrinkage and distortion of the rabbit corneal endothelial cell mosaic caused by a high osmolality glutaraldehyde-formaldehyde fixative compared to glutaraldehyde.
The purpose of this study was to quantitatively compare cell dimensions and cell layer organization of the corneal endothelium after chemical fixation. Rabbit corneas (9-10 weeks of age) were prepared immediately postmortem for transmission electron microscopy (TEM) and scanning electron microscopy (SEM) using either a widely used high osmolality fixative (glutaraldehyde-formaldehyde, after Karnovsky; 1% formaldehyde, 2.5% glutaraldehyde, 0.1 M cacodylate, pH 7.6, 850 mOsm/kg) or a glutaraldehyde fixative (2% glutaraldehyde in 80 mM cacodylate, pH 7.4, 330 mOsm/kg). With the glutaraldehyde-formaldehyde fixative, TEM revealed gross shrinkage (up to 40%) and distortion of the cytoplasm and organelles, while the regions of the cell-cell junctions were not attenuated but included dilated extracellular space. With the glutaraldehyde fixative, TEM also revealed shrinkage but the cytoplasm was less compact than with the high osmolality fixative. The overall cell shrinkage and relative accentuation of the cell-cell borders was confirmed by SEM, which also revealed that the 11 to 20% area shrinkage was also related to the number of cell sides.


Alternative markers for the long-term detection of oral testosterone misuse.
The screening of testosterone misuse in the doping control field is normally performed by the measurement of the ratio between the concentrations of testosterone and epitestosterone excreted as glucuronides (T/E). Despite the satisfactory results obtained with this approach, the measurement of T/E presents some limitations like the long-term detection of oral testosterone administration. Recently, several testosterone metabolites released after basic treatment of the urine have been reported (androsta-1,4-dien-3,17-dione, androsta-4,6-dien-3,17-dione, 17β-hydroxy-androsta-4,6-dien-3-one and 15-androsten-3,17-dione). In the present work, the usefulness of these metabolites for the detection of oral testosterone misuse has been evaluated and compared with the conventional T/E measurement. For this purpose, 173 urine samples collected from healthy volunteers were analysed in order to obtain reference concentrations for the four metabolites released after alkaline treatment. On the other hand, urine samples collected from five volunteers before and after testosterone undecanoate administration were also analysed. Concentrations of androsta-4,6-dien-3,17-dione and 17β-hydroxy-androsta-4,6-dien-3-one showed a similar behaviour as the T/E, allowing the detection of the misuse for several hours after administration. More promising results were obtained by quantifying androsta-1,4-dien-3,17-dione and 15-androsten-3,17-dione. The time in which the concentrations of these analytes could be differentiated from the basal level was between 3 and 6 times longer than the obtained with T/E, as a result, an improvement in the detection of testosterone abuse can be achieved. Moreover, several ratios between these compounds were evaluated. Some of them improved the detection of testosterone misuse when comparing with T/E. The best results were obtained with those ratios involving androsta-1,4-dien-3,17-dione.


Coil Embolization and Left Ventricular Assist Device After Arterial Switch Operation.
Aortopulmonary collateral arteries are frequently found in patients with transposition of the great arteries after catheterization. Although most of them are asymptomatic, it may cause heart failure or pulmonary hemorrhage after an arterial switch operation. Here we report a case of symptomatic aortopulmonary collateral arteries after arterial switch, which necessitated support with a centrifugal pump and left ventricular assistive device because of severe mitral regurgitation and left atrial hypertension and emergent coil embolization. Hemodynamics dramatically improved after embolization. The postoperative period was uneventful, and the infant was released from the hospital on the 14th day.


Steatocholecystitis: the influence of obesity and dietary carbohydrates.
We have recently demonstrated that obese and lean mice fed a high fat diet have increased gallbladder wall fat and decreased gallbladder contractility, cholecystosteatosis. Animal and human data also suggest that diets high in refined carbohydrates lead to gallstone formation. However, no data are available on the role of dietary carbohydrates on gallbladder wall fat and inflammation. Therefore, we tested the hypothesis that both obesity and dietary carbohydrates would increase gallbladder fat and cytokines, steatocholecystitis. At 8 wk of age, 47 lean and 22 obese female mice were fed a 45% carbohydrate (CHO) diet while an equal number of lean and obese mice were fed a 75% CHO diet for 4 wk. All mice underwent cholecystectomy, and the gallbladders were snap-frozen. Individual and total lipids were measured by gas chromatography. Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 were measured by enzyme-linked immunosorbent assay. Data were analyzed by analysis of variance and Tukey test. Gallbladder total fat, triglycerides, and cholesterol were maximum (P < 0.001) in obese mice on the 75% CHO diet. Gallbladder TNF-alpha and IL-1beta as well as serum cholesterol levels showed a similar pattern (P < 0.001). Gallbladder saturated free fatty acids and IL-6 levels were highest (P < 0.001) in obese mice on the 45% CHO diet. These data suggest that (1) both obesity and dietary carbohydrates increase gallbladder total fat, triglycerides, cholesterol, TNF-alpha, and IL-1beta and (2) obesity also increases gallbladder free fatty acids and IL-6. Therefore, we conclude that obesity is associated with steatocholecystitis and that a high carbohydrate diet exacerbates this phenomenon.


[Bladder located gastric heterotopy: a case report confronting embryology to histopathology].
We report a case of bladder located gastric heterotopy, which has never been described, to our mind in the scientific literature. We discuss the diagnosis and the physiopathological mechanisms that may have been involved in the genesis of such a lesion.


Surface Modification of Nanoparticles Enhances Drug Delivery to the Brain and Improves Survival in a Glioblastoma Multiforme Murine Model.
Glioblastoma multiforme (GBM) is the most malignant type of brain tumor and has an extremely poor prognosis. Current treatment protocols lack favorable outcomes, and alternative treatments with superior efficacy are needed. In this study, we demonstrate that loading paclitaxel (PTX) in a polymeric, nanoparticulate delivery system is capable of improving its brain accumulation and therapeutic activity. We independently incorporated two different positively charged surface modifiers, poly(amidoamine) (PAMAM) and poly(ethylenimine) (PEI), onto poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG), PLGA-PEG, nanoparticles (NPs) using a modified nanoprecipitation technique that assures the formation of nanosized particles while exposing the positively charged polymer on the surface. The prepared NPs underwent comprehensive analyses of their size, charge, in vitro permeability against a BBB cell line, and in vivo biodistribution. Our results demonstrated the successful fabrication of positively charged NPs using PAMAM or PEI. Importantly, significant improvement in brain accumulation (in vivo) was associated with NPs containing PAMAM compared to unmodified NPs or NPs containing PEI. Finally, the efficacy of PAMAM-modified NPs loaded with PTX was evaluated with orthotopic human GBM xenografts in a mouse model, and the data demonstrated improved survival and equivalent safety compared to soluble PTX. Our data substantiate the importance of surface chemistry on the magnitude of NP accumulation in the brain and pave the way for further in vivo evaluation of chemotherapeutic drugs against GBM that have previously been overlooked because of their limited ability to cross the BBB.


Short open reading frame genes in innate immunity: from discovery to characterization.
Next-generation sequencing (NGS) technologies have greatly expanded the size of the known transcriptome. Many newly discovered transcripts are classified as long noncoding RNAs (lncRNAs) which are assumed to affect phenotype through sequence and structure and not via translated protein products despite the vast majority of them harboring short open reading frames (sORFs). Recent advances have demonstrated that the noncoding designation is incorrect in many cases and that sORF-encoded peptides (SEPs) translated from these transcripts are important contributors to diverse biological processes. Interest in SEPs is at an early stage and there is evidence for the existence of thousands of SEPs that are yet unstudied. We hope to pique interest in investigating this unexplored proteome by providing a discussion of SEP characterization generally and describing specific discoveries in innate immunity.


Long noncoding RNA BFAL1 mediates enterotoxigenic Bacteroides fragilis-related carcinogenesis in colorectal cancer via the RHEB/mTOR pathway.
Long noncoding RNAs (lncRNAs) contribute to many steps in carcinogenesis and often serve as biomarkers or therapeutic targets for tumor diagnosis and therapy. Although the role of lncRNAs in tumor formation is becoming clear, whether lncRNAs mediate gut microbiota-induced colorectal cancer (CRC) is largely unknown. Enterotoxigenic Bacteroides fragilis (ETBF) is a well-known tumor-inducing bacterium in the human gut; however, its tumorigenic effect remains to be explored. In the present study, we revealed the mechanism by which a lncRNA participates in gut bacteria-induced carcinogenesis: Bacteroides fragilis-associated lncRNA1 (BFAL1) in CRC tissues mediates ETBF carcinogenesis. BFAL1 was highly expressed in CRC tissues compared with that in adjacent normal tissues. In vitro, BFAL1 was upregulated in ETBF-treated CRC cells. Mechanistically, ETBF promoted tumor growth via BFAL1 by activating the Ras homolog, which is the MTORC1 binding/mammalian target of the rapamycin (RHEB/mTOR) pathway. Furthermore, BFAL1 regulated RHEB expression by competitively sponging microRNAs miR-155-5p and miR-200a-3p. Clinically, both high expression of BFAL1 and high abundance of ETBF in CRC tissues predicted poor outcomes for patients with CRC. Thus, BFAL1 is a mediator of ETBF-induced carcinogenesis and may be a potential therapeutic target for ETBF-induced CRC.


[Comparison of photodynamic effect with respect to human and rabbit erythrocytes].
Parameters of photoinduced lysis are studied for human and rabbit erythrocytes (photosensibilizer--Radachlorin, the light source--Shuttle HeNe lazer, lambda = 633 nm). The higher sensitivity to irradiation is revealed for rabbit erythrocytes. Treatment of erythrocytes with trypsin showed the surface proteins in human cells to produce a protective effect. Trypsynization of rabbit erythrocytes produced the opposite action--the rate of photohemolysis increased. Results of the study indicate the differences in sensitivity to the photoinduced lysis of erythrocytes of different species and participation of erythrocytes proteins in the effect of photohemolysis.


Isolated acetabular revision after total hip arthroplasty: results at 5-9 years of follow-up.
The purpose of the study was to determine whether isolated revision of the acetabular component can be successfully performed without disturbing the femoral stem and to determine the fate of the unrevised femoral stem following revision. Fifty-seven hips in 55 patients underwent isolated acetabular revision without removal of the femoral component. Thirty-three hips with minimal acetabular deficiency required no bone grafting; the remaining 24 hips were treated by morselized or structural allograft in addition to a new acetabular component. Twenty-two of these 24 hips demonstrated incorporation of the bone graft. A mean follow-up of 5.8 (5-9) years, all femoral and acetabular components were judged to be stable and well fixed.


Biological assay of luteinizing hormone-releasing hormone (gonadorelin).
The abilities of luteinizing hormone releasing hormone (LHRH) to stimulate the release of luteinizing hormone (LH) in vitro from dispersed pituitary cells or from segments of adenohypophysial tissue have both been exploited in an attempt to develop biological assays for its determination. Columns of dispersed adenohypophysial cells were highly sensitive to LHRH. The responses appeared to be specific, but the marked continual variation in their magnitude rendered the system nonprecise. Pituitary segments were less sensitive to LHRH than the dispersed cells. However, their responsiveness was increased by pretreatment ('priming') with the releasing hormone. Over a wide range of doses, there was a linear relationship between the LH released by 'primed' segments and the logarithm of the concentration of LHRH. The dose-response lines of hypothalamic extracts were parallel with those of the synthetic peptide. The method using segments is accurate, specific, and precise and fulfils the essential requirements of a biological assay.


Longitudinal study of non-cavitated carious lesion progression in the primary dentition.
This study reports changes in non-cavitated tooth surface diagnoses after a 4-year period. Dental examinations were conducted for Iowa Fluoride Study cohort children who had non-cavitated lesions in the primary dentition and were also examined an average of 4 years later in the mixed dentition. Comparison of fluoride exposures, socioeconomic factors, and beverage consumption patterns were made between children who had lesions progress and those who did not. Of 129 non-cavitated pit and fissure lesions in the first exams, 40 (31%) progressed to either frank decay or filled status, while among 132 noncavitated smooth surface lesions, 7 (5%) were filled and none had frank decay in the second exam. No fluoride, socioeconomic status or beverage variables were significantly associated with lesion progression. Non-cavitated smooth surface lesions rarely progressed in this age group, but nearly one-third of pit and fissure lesions progressed.


A case of distal limb arterial tortuosity and dilation: observations and potential clinical significance.
Arterial tortuosity describes variation via bending of the arterial wall and has been noted in several arteries throughout the body. Tortuous blood vessels can cause nerve compression, as well as present difficulties to surgeons and radiologists. Here we present an unusual case of multi-vessel arterial tortuosity discovered in 78-year-old Hispanic male cadaver, independent of systemic pathology. The left ulnar and right tibial arteries were dissected, and using calibrated digital callipers, their external and internal diameters were measured both at the origin site and at the site of greatest dilation. Both wall thickness and the number of inflection points were also measured. Six bends were noticed in the ulnar artery and its diameter measured 8.11 mm at its widest, with a wall thickness of 0.88 mm. On the lower extremity, the right tibial artery had three bends and its diameter measured 4.86 mm at its widest, with a wall thickness of 1.32 mm. This uncommon tortuosity is not only more prone to laceration during surgery, but the bending and thickening can be mistaken for tumours. Finally, fluid dynamics can be altered, resulting in an impact on blood pressure in the extremities. Thus, raising awareness is crucial to prevent both symptoms and iatrogenic complications.


Myocardial imaging in a patient with reproducible variant angina.
A unique case is presented of variant angina pectoris with reproducible chest pain and S-T segment elevation in the immediate postexercise period and with normal coronary arteries. Coronary arterial spasm was deomnstrated with arteriography after intravenous administration of ergonivine maleate. Thallium-201 imaging during the pain reproducibility demonstrated malperfusion in the region supplied by the artery with documented spasm.