Comparative study on the mutagenicity of three structurally related substituted aniline mustards in the Salmonella/microsome assay.
The ortho, meta and para isomers of N,N-bis(2-chloroethyl)aminocinnamic acid were tested for their ability to mutate Salmonella typhimurium strains in the Salmonella/microsome mutagenicity test. The aim of the work was to establish a structure-activity relationship between these three isomers. The drugs were found to induce base-pair substitutions, causing dose-dependent increases in his+ revertants, in strains TA100 and TA1535. The study showed that the position of the substituent groups influenced the mutagenic activity of the compounds. The ortho isomer exhibited a poorer mutagenic effect than meta and this was found to be a weaker mutagen than para. The presence of metabolic activation enzymes in the test system induced a further increase in his+ revertants, in strains TA100 and TA1535, which is consistent with the findings for melphalan, a cancer chemotherapeutic agent with a chemical structure similar to that of the isomers tested.


Semiparametric copula-based analysis for treatment effects in the presence of treatment switching.
In controlled trials, "treatment switching" occurs when patients in one treatment group switch to alternative treatments during the trial, and poses challenges to treatment effect evaluation owing to crossover of the treatments groups. In this work, we assume that treatment switching can occur after some disease progression event and view the progression and death events as two semicompeting risks. The proposed model consists of a copula model for the joint distribution of time-to-progression (TTP) and overall survival (OS) up to the earlier of the two events, as well as a conditional hazard model for OS subsequent to progression. The copula model facilitates assessing the marginal distributions of TTP and OS separately from the association between the two events, and, in particular, the treatment effect on OS in the absence of treatment switching. The proposed conditional hazard model for death subsequent to progression allows us to assess the treatment switching (crossover) effect on OS given occurrence of progression and covariates. Semiparametric proportional hazards models are employed in the marginal models for TTP and OS. A nonparametric maximum likelihood procedure is developed for model inference, which is verified through asymptotic theory and simulation studies. The proposed analysis is applied to a lung cancer dataset to illustrate its real utility.


Surgical repair of ruptured thoracic and thoracoabdominal aortic aneurysms.
Rupture is the single most common cause of death in patients with thoracic aortic and thoracoabdominal aneurysm (TAA/TAAA) and is almost uniformly fatal. This was a retrospective review of patients admitted to a single practice with rupture of a TAA/TAAA between 1993 and 2000. Twenty-two consecutive patients with a leaking TAA/TAAA were identified. The aetiology of rupture was either secondary to a degenerative TAAA or a type B dissection. Seventeen patients underwent surgery; one had a Crawford extent I, seven an extent II, one an extent III and two an extent IV TAAA. Six patients had an acute type B dissection with rupture in the upper descending thoracic aorta. The 30-day survival rate was 88 per cent (15 of 17 patients). Actuarial survival at 1 year in patients who had surgery was 65 per cent. Survival at 1 year for all presenting patients who consented to surgery was 40 per cent. Median survival was greater than 36 months. As a result of improving medical care, more patients with a contained rupture of a TAA/TAAA may present for treatment. Surgery is complex and requires specialist teams for optimal care.


Motor improvement with bilateral subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive secondary parkinsonism.
At many centers, subthalamic nucleus (STN) deep brain stimulation (DBS) is not considered for patients with secondary forms of parkinsonism, due to higher expected rates of treatment failure. We present the case of a woman with secondary parkinsonism that developed following a Measles, Mumps, and Rubella (MMR) vaccination, who experienced sustained improvement in motor function following STN DBS. Despite the diagnosis of a secondary parkinsonism, this patient responded well to dopaminergic therapy, a good predictor of DBS outcome in patients with idiopathic Parkinson's disease. This case suggests that DBS may be considered in the setting of secondary parkinsonism if such patients have levodopa-responsive symptoms.


A crystalline hydrogen-bonded network with a poly-catenate topology.
A polycatenate network, whose rings are formed from metal-templated hemispheres linked by hydrogen bonds, is reported.


Zinc Attenuates Tubulointerstitial Fibrosis in Diabetic Nephropathy Via Inhibition of HIF Through PI-3K Signaling.
Evidence has demonstrated that hypoxia may have a central pathogenic mechanism in the development of diabetic nephropathy (DN). Epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in kidney is a contributor to the renal accumulation of matrix protein in DN and is highly associated with the progression of tubulointerstitial fibrosis. Zinc (Zn) has anti-fibrosis effects in liver and lungs. In the present study, we aimed to investigate the effect of Zn on renal tubulointerstitial fibrosis especially under hypoxic conditions and its association with DN. We found that Zn treatment blockaded tubular EMT and attenuated renal tubulointerstitial fibrosis by downregulation of hypoxia-inducible factor alpha (HIF-1α) in the kidneys of diabetic streptozotocin-treated mice. High glucose (HG)/hypoxic conditions stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker E-cadherin and ZO-1 while the increase in mesenchymal markers α-smooth muscle actin (α-SMA). Zn supplement mainly prevented HG/hypoxic-induced HIF-1α accumulation and EMT marker changes. In co-treatment Zn with PI3K/Akt/GSK-3β signaling pathway, inhibitor LY294002 prevented HG/hypoxic-induced HIF-1α increase and EMT changes, suggesting that Zn may mediate HG/hypoxic-induced EMT through PI3K/Akt/GSK-3β pathway. Therefore, we concluded that Zn had an important anti-fibrosis role under HG/hypoxic conditions, and a novel mechanism contributing to Zn protection on renal tubular epithelial cells from HG/hypoxia-induced EMT through activation of PI3K/Akt/GSK-3β signaling pathway, which subsequently leads to the downregulation of the expression of HIF-1α.


[Physicochemical and biological properties of an allergen from Trichomonas vaginalis].
The chemical and biological characterization of the preparation, found to be strictly specific, is presented. The allergen is nontoxic and has sensitizing properties. The active principle of the preparation is protein.


Single-incision Midurethral Sling by the Dynamic Intraoperative Standing Sling Technique as an Office-based Procedure: A Pilot Study.
To assess the safety, feasibility, and short-term success of placing Solyx (Boston Scientific, Marlborough, MA) single-incision midurethral sling (SIMUS) using the Dynamic Intraoperative Standing Sling Technique (DISST) in an office setting under local anesthesia. The safety and efficacy of the in-office Solyx DISST procedure for treatment of stress urinary incontinence was assessed 6 months from the procedure. Improvement in stress urinary incontinence was measured using validated questionnaires (Medical, Epidemiologic, and Social Aspects of Aging, MESA; Incontinence Impact Questionnaire-7, IIQ-7; Pelvic Organ Prolapse/Urinary Incontinence Sexual Function, PISQ-12) and by a negative standing provocative stress test. Postoperative complications were documented along with subjective pain diaries, return to work/activities, and overall satisfaction. From July 2019 through February 2020, 20 subjects underwent in-office Solyx procedure by the DISST technique. Six of the 20 (30%) subjects required intraoperative sling adjustments. There were no complications as related to the office-based procedure. Participants reported a favorable intraoperative experience. Subjects had excellent postoperative pain control and early return to work and normal activities. At 6 months, all 20 subjects had negative standing provocative stress tests, showed statistically significant improvements on MESA, IIQ-7, and PISQ-12, and reported high satisfaction and acceptance for the procedure and outcomes. There were no late (>6 weeks) complications associated with the Solyx procedure. It appears safe and feasible to perform Solyx SIMUS by the DISST method in the office. Subjects remained dry and reported excellent improvement in symptoms and quality of life 6 months from surgery.


Makeham's addition to the Gompertz law re-evaluated.
The Makeham parameter, a constant mortality rate independent of aging added to the Gompertz law of human mortality, is proposed to be a measure of the impact on mortality rate by extrinsic causes of mortality, with the effect of aging removed. A small intrinsic contribution to mortality, assumed to depend on the components involved in cellular function, is linked to the initial mortality rate of the Gompertz law. To avoid biased results and conclusions, the impact of extrinsic mortality should be eliminated from the Gompertz parameters.


A catalytic cleavage strategy for fluorometric determination of Hg(II) based on the use of a Mg(II)-dependent split DNAzyme and hairpins conjugated to gold nanoparticles.
A catalytic cleavage strategy was developed for the fluorometric determination of Hg(II). The method is based on the use of a Mg(II)-dependent split DNAzyme. Fluorophore labeled hairpins were conjugated to gold nanoparticles (AuNPs) upon which fluorescence is quenched. Thymine-Hg(II)-thymine (T-Hg(II)-T) interaction causes the two DNA sequences to form an entire enzyme-strand DNA (E-DNA). The E-DNA bind to the hairpins on the AuNPs to form a Mg(II)-dependent DNAzyme structure. The circular cleavage of hairpins results in a signal amplification and in the recovery of fluorescence. The assay has a limit of detection (LOD) as low as 80 pM of Hg(II). This LOD is comparable to those obtained with other amplification strategies. The method was successfully applied to the determination of Hg(II) in Chinese herbs (Atractylodes macrocephala Koidz). Graphical abstract Schematic of a catalytic cleavage strategy based on Mg(II)-dependent split DNAzyme for fluorometric determination of Hg(II).


PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer.
Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-line treatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020.


CNS determinants of sleep-related worsening of airway functions: implications for nocturnal asthma.
This review summarizes the recent neuroanatomical and physiological studies that form the neural basis for the state-dependent changes in airway resistance. Here, we review only the interactions between the brain regions generating quiet (non-rapid eye movement, NREM) and active (rapid eye movement, REM) sleep stages and CNS pathways controlling cholinergic outflow to the airways. During NREM and REM sleep, bronchoconstrictive responses are heightened and conductivity of the airways is lower as compared to the waking state. The decrease in conductivity of the lower airways parallels the sleep-induced decline in the discharge of brainstem monoaminergic cell groups and GABAergic neurons of the ventrolateral periaqueductal midbrain region, all of which provide inhibitory inputs to airway-related vagal preganglionic neurons (AVPNs). Withdrawal of central inhibitory influences to AVPNs results in a shift from inhibitory to excitatory transmission that leads to an increase in airway responsiveness, cholinergic outflow to the lower airways and consequently, bronchoconstriction. In healthy subjects, these changes are clinically unnoticed. However, in patients with bronchial asthma, sleep-related alterations in lung functions are troublesome, causing intensified bronchopulmonary symptoms (nocturnal asthma), frequent arousals, decreased quality of life, and increased mortality. Unquestionably, the studies revealing neural mechanisms that underlie sleep-related alterations of airway function will provide new directions in the treatment and prevention of sleep-induced worsening of airway diseases.


Prevalence of Sonographic Achilles Tendon, Patellar Tendon, and Plantar Fascia Abnormalities in Division I Collegiate Athletes From a Variety of Sports.
This study aimed to determine the prevalence of ultrasound abnormalities in the Achilles tendon, patellar tendon, and plantar fascia among a large cohort of collegiate student-athletes. Observational cross-sectional study. Three Division I institutions. 243 student-athletes participated in this study. Exclusion criteria included those younger than 18 years or who underwent prior surgery/amputation of structures, including anterior cruciate ligament (ACL) surgeries with patellar tendon grafts. Ultrasound examination of the Achilles tendon, patellar tendon, and plantar fascia of each leg was performed. An experienced sonographer reviewed each tendon video in a blinded manner, with a separate experienced sonographer separately reviewing to establish inter-rater reliability. The primary outcome measured was the presence of any sonographic abnormality including hypoechogenicity, thickening, or neovascularity. Ultrasound abnormalities were identified in 10.1%, 37.2%, and 3.9% of all Achilles tendons, patellar tendons, and plantar fasciae, respectively. Abnormalities were significantly associated with the presence of concurrent pain for all structures (P < 0.01). Specifically, athletes with sonographic abnormalities were approximately 4 times [relative risk (RR) = 4.25; 95% confidence interval (CI), 2.05-8.84], 6 times (RR = 5.69; 95% CI, 2.31-14.00), and 5 times (RR = 5.17; 95% CI, 1.76-15.25) more likely to self-report pain in the Achilles tendon, patellar tendon, and plantar fascia, respectively. This multi-institutional study completed at 3 Division I institutions is the largest study of its kind to identify the prevalence of sonographic abnormalities in the Achilles tendon, patellar tendon, and plantar fascia among collegiate student-athletes of various sports.


Sex Differences Associated With Circulating PCSK9 in Patients Presenting With Acute Myocardial Infarction.
A limited number of studies have explored whether the role of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in the pathogenesis of acute myocardial infarction (AMI) is sex specific. The purpose of the present study was to examine sex differences in plasma PCSK9 in Chinese patients with AMI. In this study, a total of 281 records from patients presenting with AMI were analyzed.We compared hospital data and plasma PCSK9 levels by sex difference for inpatients presenting with AMI. After 1 year of follow-up, major adverse cardiac events(MACE) were recorded. A Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. We found that, compared with male groups, PCSK9 levels were higher in female patients not only for overall patients with AMI but also for patients with ST-elevation myocardial infarction (STEMI) (median: 273.6 [215.6-366.8] vs. 325.1 [247.5-445.3] ng/ml, P = 0.0136; 273.4 [215.6-369.7] vs. 317.1 [249.6-450.1], P = 0.0275, respectively). The cumulative incidence of cardiac death and 1-year MACE were significantly higher in the female group compared with male group (10% vs. 2.74%, P = 0.025; 15% vs. 4.11%, P = 0.0054, respectively). On multivariate Cox regression analysis, female sex, total triglyceride, glycosylated hemoglobin A, and homocysteic acid were independent risk factors of 1-year MACE. There was no significant correlation between PCSK9 and 1-year MACE in total AMI patients. In conclusion, PCSK9 levels and 1-year MACE were higher in women with AMI than in men with AMI, however, female sex but not PCSK9 were significant correlated with the 1-year MACE. The clinical implications of this finding are worthy of further investigations and must be confirmed in larger cohorts.


Clinical and laboratory evaluation of the immune system.
An attempt has been made to provide the reader with an overview of the immune system and its clinical and laboratory evaluation. The assessment of this activity is aided by the realization that certain defects predispose the host to certain types of infection; historically then, one has a clue to the nature of the defect. Simple laboratory tests are available at most hospital and commercial laboratories, and many immune defects can be delineated through these techniques. Additionally, more sophisticated laboratory techniques are obtainable at specialized centers, although many of these studies are of research importance only. It is probable that over the next several years, newer technologies will permit an even more precise evaluation of the immune network and its defects.


Effects of voluntary and forced exercise on lordosis behavior in female rats.
We measured sexual behavior (lordosis) in ovariectomized, steroid-treated, exercising female rats. When estradiol-treated animals exercised voluntarily, lordosis was directly related to the amount of exercise. Forced exercise (swimming) following treatment with estradiol 17 beta and progesterone significantly increased lordosis scores but only after animals swam for 2.5 hr per day. Lordosis behavior returned to baseline levels 7 weeks after forced exercise was stopped. Circulating levels of estrogen and progesterone measured immediately after behavioral testing did not differ between animals forced to exercise and their controls. The mechanisms responsible for the increase in lordosis behavior following exercise are unclear. It is possible that a change in body composition, a change in neural sensitivity to gonadal steroids, and/or changes in pituitary or adrenal function contribute to the increased lordosis behavior in exercised animals.


UDP-glucuronosyltransferase 1A6 is the major isozyme responsible for protocatechuic aldehyde glucuronidation in human liver microsomes.
Glucuronidation is an important pathway in the metabolism of protocatechuic aldehyde (3,4-dihydroxybenzaldehyde, PAL). However, the metabolites and primary UDP-glucuronosyltransferase (UGT) isozymes responsible for PAL glucuronidation remain to be determined in human. Here, we characterized PAL glucuronidation by human liver microsomes (HLMs), human intestine microsomes (HIMs), and 12 recombinant UGT (rUGT) isozymes to identify what kinds of metabolites are present and which human UGT isozymes are involved. Two metabolites (M-1 and M-2) were detected in reactions catalyzed by HLMs, HIMs, rUGT1A6, and rUGT1A9 and were identified as monoglucuronides by liquid chromatography-mass spectrometry. A kinetic study showed that PAL glucuronidation by rUGT1A6, rUGT1A9, HIMs, and HLMs followed Michaelis-Menten kinetics. The K(m) values of HLMs, HIMs, rUGT1A6, and rUGT1A9 for PAL glucuronidation were as follows: 432.7 +/- 24.5, 626.9 +/- 49.2, 367.5 +/- 25.1, and 379.9 +/- 42.5 microM for M-1 and 336.7 +/- 15.3, 494.3 +/- 48.7, 211.4 +/- 13.4, and 238.5 +/- 26.2 microM for M-2, respectively. The PAL glucuronidation activity was significantly correlated with UGT1A6 activity rather than with UGT1A9 activity from 15 individual HLMs. A chemical inhibition study showed that the IC(50) for phenylbutazone inhibition of PAL glucuronidation was similar in HLMs (61.9 +/- 7.9 microM) compared with rUGT1A6 (45.3 +/- 7.7 microM). In contrast, androsterone inhibited rUGT1A9-catalyzed and HLM-catalyzed PAL glucuronidation with IC(50) values of 27.1 +/- 3.8 and > 500 microM, respectively. In combination, we identified UGT1A6 as the major isozyme responsible for PAL glucuronidation in HLMs.


Evaluation of an Abnormal Liver Panel After Liver Transplantation.
Abnormal liver tests are common after liver transplantation. The differential diagnosis depends on the clinical context, particularly the time course, pattern and degree of elevation, and donor and recipient factors. The perioperative period has distinct causes compared with months and years after transplant, including ischemia-reperfusion injury, vascular thrombosis, and primary graft nonfunction. Etiologies seen beyond the perioperative period include biliary complications, rejection, infection, recurrent disease, and non-transplant-specific causes. The evaluation begins with a liver ultrasound with Doppler as well as appropriate laboratory testing and culminates in a liver biopsy if the imaging and laboratory testing is unrevealing.


Sex Differences in the Circumstances Leading to Falls: Evidence From Real-Life Falls Captured on Video in Long-Term Care.
Falls are a major health concern for older adults. Understanding sex differences in fall circumstances may guide the design of fall management plans specifically to men and women. In this study, analyzed real-life falls captured on video to compare scenarios leading to falls between men and women in 2 long-term care (LTC) facilities. Prospective cohort study. A total of 529 participants residing in 2 LTC facilities in British Columbia, Canada. Between 2008 and 2016, we video-captured 1738 falls experienced by 231 men and 298 women (mean age = 83 ± 9 years). Each video was analyzed to determine the causes of imbalance and the activities at time of falling. Using generalized estimating equation models, we examined how fall circumstances associated with age, sex, and health status. Men were more likely than women to fall from loss of support with an external object (odds ratio 1.37; 95% confidence interval 1.08-1.73) and less likely to fall from tripping (0.72; 0.54-0.96). Men were more likely to fall while seated (1.42; 1.07-1.87) or while rising (1.49; 1.11-1.99), and less likely to fall while walking (0.61; 0.50-0.75). After adjusting for age and health status, sex remained significantly associated with loss of support and walking. Furthermore, regardless of sex, falls from loss of support were more common among individuals who were less independent in activities of daily living, who used more medications, and who used diuretic. Individuals with independent activities of daily living and intact cognition were more likely to fall while walking, but less likely to fall while seated or while rising. Our results elucidate differences between older men and women in the scenarios that lead to falls, to inform sex-specific fall prevention strategies in the LTC setting.


Principles of pre-operative fluid therapy and resuscitation.
The pre-operative preparation of a patient for elective surgery requires correction of all major electrolyte abnormalities, osmolality and body fluid compartment excesses of deficits. For the emergency surgical procedure however, only stability of the cardiovascular system is required before the induction of anaesthesia. To facilitate rapid correction of the abnormal haemodynamic state a set of physiological principles are described which aim to simplify therapy.


Unusual cause of neck pain: septic arthritis of a cervical facet.
Neck pain is a common cause for presentation to an emergency department. Most causes are benign and often secondary to arthritis or injuries. We present a case of septic cervical facet arthritis, a very rare cause of neck pain. The clinical presentation of septic cervical facet arthritis includes fever, neck pain that is often unilateral that is worse with movement, nerve root symptoms, and radiation of pain to the shoulder. Consequences may be severe and include joint destruction and infection progression. Symptoms may be indolent, and a high index of suspicion is necessary to make this diagnosis.


Antifungal activity of Mahonia aquifolium extract and its major protoberberine alkaloids.
The crude extract of Mahonia aquifolium (Berberidaceae) stem bark and its components berberine, palmatine and jatrorrhizine were screened for their inhibitory activity against a variety of dermatophytes and two Candida species of human origin using the in vitro dilution agar plate method. Jatrorrhizine was found to be the most effective against all fungal species tested (MIC ranges from 62.5 to 125 micro g/mL), while the crude extract, berberine, and palmatine exhibited only marginal activity (MIC 500 to >/= 1000 micro g/mL). Dermatophytes were more susceptible to jatrorrhizine than yeasts, and Scopulariopsis brevicaulis appeared the least sensitive species to all the compounds tested. The effects of the alkaloids were compared with those of fluconazole and bifonazole for which the MIC ranges were 12.5 to >100 micro g/mL. Our results suggest that jatrorrhizine may serve as a leading compound for further studies to develop new antifungal agents with highly potent antifungal activity and low host toxicity.


The dorsomedial hypothalamus and the response to stress: part renaissance, part revolution.
Emotional stress provokes a stereotyped pattern of autonomic and endocrine changes that is highly conserved across diverse mammalian species. Nearly 50 years ago, a specific region of the hypothalamus, the hypothalamic defense area, was defined by the discovery that electrical stimulation in this area evoked changes that replicated this pattern. Attention later shifted to the hypothalamic paraventricular nucleus (PVN) owing to (1) elucidation of its role as the final common pathway mediating activation of the hypothalamic-pituitary-adrenal (HPA) axis, a defining feature of the stress response and (2) the finding that the PVN was the principal location of hypothalamic neurons that project directly to spinal autonomic regions. Consequently, a primary role for the PVN as the hypothalamic center integrating the autonomic and endocrine response to stress was inferred. However, our findings indicate that neurons in the nearby dorsomedial hypothalamus (DMH)--a region originally included in the hypothalamic defense area--and not in the PVN play a key role in the cardiovascular changes associated with emotional or exteroceptive stress. Indeed, excitation of neurons in the parvocellular PVN and consequent recruitment of the HPA axis that occurs in exteroceptive stress is also signaled from the DMH. Thus, the DMH may represent a higher order hypothalamic center responsible for integrating autonomic, endocrine and even behavioral responses to emotional stress.


Potential of TiO2 with Various Au Nanoparticles for Catalyzing Mesotrione Removal from Wastewaters under Sunlight.
Nowadays, great focus is given to the contamination of surface and groundwater because of the extensive usage of pesticides in agriculture. The improvements of commercial catalyst TiO2 activity using different Au nanoparticles were investigated for mesotrione photocatalytic degradation under simulated sunlight. The selected system was 2.43 × 10-3% Au-S-CH2-CH2-OH/TiO2 (0.5 g/L) that was studied by transmission electron microscopy and ultraviolet-visible (UV-Vis) spectroscopy. It was found that TiO2 particles size was ~20 nm and ~50 nm, respectively. The Au nanoparticles were below 10 nm and were well distributed within the framework of TiO2. For 2.43 × 10-3% Au-S-CH2-CH2-OH/TiO2 (0.5 g/L), band gap energy was 2.45 eV. In comparison to the pure TiO2, addition of Au nanoparticles generally enhanced photocatalytic removal of mesotrione. By examining the degree of mineralization, it was found that 2.43 × 10-3% Au-S-CH2-CH2-OH/TiO2 (0.5 g/L) system was the most efficient for the removal of the mesotrione and intermediates. The effect of tert-butanol, NaF and ethylenediaminetetraacetic acid disodium salt on the transformation rate suggested that the relative contribution of various reactive species changed in following order: h+ > ●OHads > ●OHbulk. Finally, several intermediates that were formed during the photocatalytic treatment of mesotrione were identified.


Pregnancy in women with gliomas: a case-series and review of the literature.
The occurrence of pregnancy in women with brain tumors confronts both patients and physicians with difficult decision making at each stage of pregnancy. We studied the course of events of nine pregnancies in seven women with low-grade glioma in our hospital over a 10 year period. Five patients had a surgical resection, one a biopsy and one woman was followed by wait-and-see policy before pregnancy. In two women, a therapeutic abortion was carried out in the first trimester because of signs of progression, necessitating surgical removal of the tumor. In the other five women pregnancy had an uncomplicated course. Based on a literature review, we found 28 women diagnosed with a known glioma before becoming pregnant. All pregnancies but one, were uneventful and all women had a normal delivery, including the seven cases with exposure to chemotherapy and in whom healthy babies were born. A total of 75 pregnant women were identified in whom new onset glioma developed, which was high-grade in 56 %, and becoming symptomatic in 51 % during the third trimester, usually by focal neurological deficits. We conclude that in relation to pregnancy, low-grade gliomas are more often seen in women already known with a brain tumor, while high-grade gliomas represent more frequently a new onset phenomenon. Based on these observations, guidelines are given on initiation of antitumor therapy during pregnancy, seizure management, counseling on therapeutic abortion, and on the timing and choice of obstetrical interventions.


Trends in Gestational Weight Gain in Louisiana, March 2019 to March 2022.
Average gestational weight gain (GWG) increased during the COVID-19 pandemic, but it is not known whether this trend has continued. To examine patterns of GWG during the COVID-19 pandemic by delivery and conception timing through the second year of the pandemic. This cohort study is a retrospective review of birth certificate and delivery records from 2019 to 2022. Electronic health records were from the largest delivery hospital in Louisiana. Participants included all individuals giving birth from March 2019 to March 2022. Data analysis was performed from October 2022 to July 2023. Delivery date (cross-sectionally) and conception before the pandemic (March 2019 to March 2020) and during the peak pandemic (March 2020 to March 2021) and late pandemic (March 2021 to March 2022). The primary outcome was GWG (total GWG and adherence to the 2009 Institute of Medicine recommendations) analyzed using linear and log-linear regression with control for covariates. Among 23 012 total deliveries (8763 Black individuals [38.1%]; 11 774 White individuals [51.2%]; mean [SD] maternal age, 28.9 [5.6] years), 3182 individuals (42.0%) exceeded the recommended weight gain in the year proceeding the pandemic, 3400 (45.4%) exceeded recommendations during the peak pandemic, and 3273 (44.0%) exceeded recommendations in the late pandemic. Compared with those who delivered before the pandemic (reference), participants had higher total GWG if they delivered peak or late pandemic (adjusted β [SE], 0.38 [0.12] kg vs 0.19 [0.12] kg; P = .007). When cohorts were defined by conception date, participants who conceived before the pandemic but delivered after the pandemic started had higher GWG compared with those whose entire pregnancy occurred before the pandemic (adjusted β [SE], 0.51 [0.16] kg). GWG was lower in the pregnancies conceived after the pandemic started and the late pandemic (adjusted β [SE], 0.29 [0.12] kg vs 0.003 [0.14] kg; P = .003) but these participants began pregnancy at a slightly higher weight. Examining mean GWG month by month suggested a small decrease for March 2020, followed by increased mean GWG for the following year. Individuals with 2 pregnancies (1289 individuals) were less likely to gain weight above the recommended guidelines compared with their prepandemic pregnancy, but this association was attenuated after adjustment. In this cohort, individuals with critical time points of their pregnancy during the COVID-19 pandemic gained more weight compared with the previous year. The increased GWG leveled off as the pandemic progressed but individuals were slightly heavier beginning pregnancy.


Research Publications from the ATS MECOR Program in Turkiye.
The American Thoracic Society (ATS) Methods in Epidemiologic, Clinical, and Operations Research (MECOR) Program aims to build research capacity in low and middle-income countries. MECOR has three levels, during which students learn to develop a research protocol and write a manuscript. MECOR Turkiye has been offered every year since 2008. The aim of this paper is to report the number and impact of published articles generated from research questions developed by students in levels 1, 2, and 3 of the ATS MECOR Program in Turkiye between 2008 and 2018. We collected the research questions developed in all levels of the ATS MECOR Program in Turkiye between 2008 and 2018. We searched Google Scholar, PubMed, Web of Science, and ResearchGate in April 2022 to see how many of these research questions were published as articles and, if published, in which journals. Of the 176 research questions collected, 49 had been developed in level 1, 82 had been developed in level 2, and 45 had been developed in level 3. Of those 176 research questions, 55 (31.3%) generated articles that were accepted for publication. The frequency of published articles based on MECOR-developed research questions increased linearly as the course level in which they were developed increased (18.4% in level 1, 30% in level 2, 46.7% in level 3; P = 0.012; linear-by-linear association, P = 0.003). The median time from the development of the research question to publication was three years overall and did not differ significantly among the course levels (P = 0.36). Of the research questions developed, 43 were published in Science Citation Index or Science Citation Index Expanded-indexed journals. Acceptance of an article for publication is one way to measure the impact of the ATS MECOR Program. Our data describe significant research output among our participants, which increases with their length of participation in the program.


Attenuation of bovine herpesvirus type 1 by deletion of its glycoprotein G and tk genes and protection against virulent viral challenge.
To develop a novel vaccine against infectious bovine rhinotracheitis (IBR), a bovine herpesvirus-1 (BoHV-1) mutant was constructed by deleting the genes for glycoprotein G (gG) and thymidine kinase (tk) through homologous recombination. The resulting sequences for both genes were shown to be correct and a gG expression defect was also confirmed. A parallel study of the BoHV-1 gG(-)/tk(-), gE(-)/tk(-) mutants and wild type (wt) in 31 calves was performed at three different doses, 4×10(5)PFU, 4×10(6)PFU and 4×10(7)PFU. Compared to wt BoHV-1, inoculation of BoHV-1 gG(-)/tk(-) and gE(-)/tk(-) produced no clinical signs and the virus was not reactivated by dexamethasone (dex). Inoculation of BoHV-1 gG(-)/tk(-) at the doses of 4×10(6) and 4×10(7)PFU provided full clinical protection for the cattle against wt BoHV-1 challenge at 4×10(7)PFU/calf. Although the mutants were associated with significantly lower levels of serum neutralizing antibody, interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) than wt BoHV-1 on days 3, 5 and 7 after immunization, stimulation of IFN-β by BoHV-1 gG(-)/tk(-) was significantly higher than that of wt BoHV-1 and gE(-)/tk(-) on days 3 and 5. We conclude that BoHV-1 gG(-)/tk(-) was attenuated adequately and that it maintains the ability to stimulate immune protection. Therefore, it may be a promising candidate for a marker vaccine against IBR.


Evaluation of Evidence-Based Guidelines for Fever Management in Critically Ill Adult Patients With Brain Injury.
The aim of this study was to evaluate the effectiveness of evidence-based guidelines for fever management of critically ill adult patients with brain injury. We used a pretest-posttest design with 48 patients 19 years or older admitted to an intensive care unit after surgery for brain injury. We applied evidence-based guidelines only to an experimental group of 24 patients and compared with 24 control patients who did not receive evidence-based guidelines. Experimental and control groups were matched 1:1 using the Acute Physiology and Chronic Health Evaluation II score. Data included the proportion of patients with reduced fever and time to normalized temperature. The proportion of patients whose temperature fell to normal after fever was 4.5 times higher in the experimental group than in the control group. The time it took the patients' highest fever to fall to normal during their intensive care unit stay was 4.84 times faster in the experimental group than in the control group (hazard ratio, 4.84; 95% confidence interval, 1.79-13.11; P = .002). Evidence-based guidelines for fever management in patients with a brain injury can be used in nursing practice with rapid response, improving healthcare efficiency and contributing to better outcomes for critically ill patients.


Effects of procaine-induced cardioplegia on myocardial ischemia, myocardial edema, and postarrest ventricular function. A comparison with potassium-induced cardioplegia and hypothermia.
The extent of myocardial protection afforded by a procaine cardioplegic solution during cardiac ischemia has been evaluated and compared with the protection seen using a potassium cardioplegic solution. An isolated cat heart model was employed, and ventricular function parameters, intramyocardial gas tensions, and postischemic myocardial edema were measured and compared following 60 minutes of induced ischemia at 37 degrees C. and 27 degrees C. There was no significant improvement in recovery of postarrest ventricular function when procaine cardioplegia was used during normothermic ischemia. When used at 27 degrees C., however, both cardioplegic solutions were associated with significantly better recovery of postarrest ventricular function, although there was less myocardial edema formation in the potassium-treated hearts. Results of this study indicate that procaine-induced cardioplegia provides myocardial protection during anoxic cardiac arrest which is additive to that afforded by hypothermia alone. In addition, procaine cardioplegia results in postarrest functional recovery which is similar to that seen with potassium cardioplegia.


Negotiating sexual and gender diversity in rural and peri-urban KwaZulu-Natal, South Africa.
A noticeable tendency in the first generation of scholarship on sexual orientation and gender identity/expression (SOGIE) in Africa has been the focus on urban or modern institutional settings. A dominant theme is to document people's struggles against stigma, fear and violence to better inform interventions to strengthen human rights and sexual health for all. In some cases, unintentionally, the impression conveyed of Africa is of a continent with cultures that are uniformly, hostile to SOGIE rights. The present study arises from a large survey among boys and men in KwaZulu-Natal, South Africa that problematises that impression. The study revealed unexpectedly high levels of same-sex sexual experience among boys and men in a mostly rural, culturally conservative setting. Following from that revelation, we conducted in-depth interviews to gain insight into their lives. Informants did indeed recount many incidents of discrimination and violence and admitted to sometimes severe emotional health problems. Yet they also spoke of finding love, acceptance, allies, resources, humour and hope for the future. In this paper, we tease out key themes from the interviews in relation to trends in the scholarship.


Overview: hypertension and atherosclerosis.
Many large-scale trials of drug treatment for hypertension have shown an apparent lack of benefit with regard to the incidence of complications related to atherosclerosis. Recent experimental evidence has contributed to an understanding of the pathogenesis of hypertensive vascular disease, although exact mechanisms by which hypertension and antihypertensive drugs influence the atherosclerotic process are still poorly defined. In animal models, hypertension appears to induce a sequence of changes in endothelial cells, smooth muscle cells, and endothelial permeability. However, increased lipid deposition in the intima and acceleration of atherosclerosis appear to require elevation of plasma lipid levels. Some beta-blockers have been found to retard the development of atherosclerosis in the cholesterol-fed rabbit model. The clinical applicability of these interesting research findings awaits further investigation.


From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy.
The term "propagon" is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various "tauopathies" that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer's disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer's pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer's disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.


A novel injectable phospholipid gel co-loaded with doxorubicin and bromotetrandrine for resistant breast cancer treatment by intratumoral injection.
Systemically administered anticancer treatments were greatly limited by extensive side effects mainly due to nonspecific distributions in vivo, and multidrug resistance in various tumors. A phospholipids-based in situ-forming gel platform has been developed for the concurrent delivery of doxorubicin (DOX) and bromotetrandrin (W198). Phospholipid gel containing DOX and W198 remained in a solution (sol) state before injection and underwent rapid gelation after injection in vivo. The release of DOX and W198 from phospholipid gel (PG) was sustained in vitro for over 20 days (d). DOX and W198 from PG achieved prolonged release for over two weeks in rats via subcutaneous injection. Compared with repeated injections of free drug, eliminated cardiac toxicity and less bone marrow inhibition were observed for DOX and W198-loaded PG (DOX/W198-PG) in normal rats via subcutaneous injection. Also, a single intratumoral injection of DOX/W198-PG in the resistant MCF-7/Adr xenograft-bearing mice showed much better antitumor efficacy compared to other treatment groups. In sum, DOX/W198-PG was well demonstrated to achieve sustained drug release both in vitro and in vivo with eliminated toxicity and improved antitumor efficacy by reversing the multidrug resistance in breast cancers.


Uterine artery Doppler velocimetry for the detection of adverse obstetric outcomes in patients with elevated mid-trimester beta-human chorionic gonadotrophin.
The aim of this study is to review the clinical usefulness of Doppler velocimetry of the uterine artery for the detection of adverse obstetric outcome in a population of women with elevated mid-trimester serum beta-human chorionic gonadotrophin (betahCG). Women with an unexplained elevated mid-trimester betahCG level (> or = 4.0 multiples of the median) are offered uterine artery Doppler assessment at 22-24 weeks of gestation. We have audited the clinical usefulness of this practice by reviewing the prevalence of the adverse outcomes of gestational hypertension, intrauterine growth restriction (IUGR) and preterm birth and the predictive capacity of the test when applied to this subgroup of high-risk patients. Sixty-two women had an elevated serum betahCG and underwent Doppler study of uterine artery flow velocity waveform. Notching afforded better predictive utility for any outcome than the resistance index alone or in combination with notching. For a composite adverse outcome of any or all of gestational hypertension, birthweight < or = 10th centile, and preterm delivery, the presence of a uterine notch alone had sensitivity of 30.7% and specificity of 93.8%. For the identification of severe fetal growth restriction (< 5th centile) and/or preeclampsia, the presence of a notch offered a sensitivity of 50%, specificity of 96.3%, a positive likelihood ratio of 13.5, and a negative likelihood ratio of 0.5. The identification of uterine artery notching by means of Doppler ultrasound as a component of the surveillance of women with unexplained elevated betahCG levels significantly improves the prediction of preeclampsia and/or severe IUGR, although the low prevalence of 13% of these adverse outcomes limits the usefulness of the test in routine clinical practice.


The Nature of Attachment Relationships and Grief Responses in Older Adults: An Attachment Path Model of Grief.
Various researchers have theorized that bereaved adults who report non-secure attachment are at higher risk of pathological grief. Yet past findings on avoidant attachment representations and grief have yielded limited and contradictory outcomes. Little research has been conducted with older adults to identify the psychological processes that mediate between self-reported attachment representations and the patterns of grief. To examine the impacts of avoidant attachment and anxious attachment dimensions on emotion and non-acceptance, in response to the loss of a conjugal partner, and the mediating effect of yearning thoughts. Men (N = 21) and women (N = 68) aged 60 years and above who had lost a partner within the last 12 to 72 months were invited to participate. Participants rated their levels of yearning thoughts about the deceased, emotions and non-acceptance on the Texas Revised Inventory of Grief (TRIG-Present), and their type and level of general romantic attachment on the Experiences In Close Relationship questionnaire (ECR). Structural equation modelling (SEM) indicated that individuals who reported higher levels of avoidant attachment reported less emotional responses and less non-acceptance. SEM also showed that individuals who reported higher levels of anxious attachment reported greater emotional responses and greater non-acceptance. SEM further indicated that these relationships were mediated by yearning thoughts. People adopt different grief coping patterns according to their self-reported attachment representations, with the nature of their yearning thoughts influencing the process. Grief therapy may be organized according to individual differences in attachment representations.


Haemostatic fleece (TachoComb) to prevent intrapleural adhesions after thoracotomy: a rat model.
Postoperative adhesion is a complication common to all surgical subspecialties. TachoComb is a collagen fleece with properties well suited to the prevention of adhesion. This preclinical study was performed to evaluate the efficacy and mechanism of action of TachoComb in the prevention of adhesion following pleural injury during thoracic surgery. Rats (n = 72) were randomised to receive saline or TachoComb following pleural injury. The macroscopic severity of adhesion formation and histological changes were assessed following euthanasia at time points up to 28 weeks post-operation. Levels of the biochemical markers t-PA, PAI-1 and bFGF were measured in intrapleural lavage fluid. The severity of adhesion was lower in TachoComb-treated animals compared with control animals at all time points (mean adhesion score: 1.4 vs. 4 at week 28 post-operation; P < 0.01). Regeneration of the mesothelial cell stratum occurred faster in TachoComb-treated animals, and a significantly lower PAI-1 activity was observed (14.32 vs. 23.28 U/ml; P < 0.01). TachoComb is effective in the prevention of adhesion following thoracic surgery, both by acting as a physical barrier and by inhibiting PAI-1 activity.


Viruses of the white root rot fungus, Rosellinia necatrix.
Rosellinia necatrix is a filamentous ascomycete that is pathogenic to a wide range of perennial plants worldwide. An extensive search for double-stranded RNA of a large collection of field isolates led to the detection of a variety of viruses. Since the first identification of a reovirus in this fungus in 2002, several novel viruses have been molecularly characterized that include members of at least five virus families. While some cause phenotypic alterations, many others show latent infections. Viruses attenuating the virulence of a host fungus to its plant hosts attract much attention as agents for virocontrol (biological control using viruses) of the fungus, one of which is currently being tested in experimental fields. Like the Cryphonectria parasitica/viruses, the R. necatrix/viruses have emerged as an amenable system for studying virus/host and virus/virus interactions. Several techniques have recently been developed that enhance the investigation of virus etiology, replication, and symptom induction in this mycovirus/fungal host system.


Low C3 in cirrhotic ascites predisposes to spontaneous bacterial peritonitis.
The risk of developing spontaneous bacterial peritonitis (SBP) in relation to the concentration of C3 in ascitic fluid (AF) has been studied prospectively in 33 patients with cirrhosis of the liver, seven of whom had one or more episodes of SBP during hospitalization. C3 concentrations in the AF of patients who developed infection (9.0 +/- 2.67 mg/dl) were significantly lower than in those who did not (18.26 +/- 8.11 mg/dl) (P less than 0.01). C4 concentrations were similar in both groups. A direct correlation was found between AF C3 and total protein concentrations (P less than 0.001). We conclude that a low C3 concentration in AF may predispose to SBP.


Antioxidant Activity of Blackthorn (Prunus spinosa L.) Fruit Extract and Cytotoxic Effects on Various Cancer Cell Lines.
Blackthorn (Prunus spinosa L. (Rosaceae) is a shrup whose fruits are consumed as food in Turkey. This study was aimed to evaluate antioxidant activity of methanol extract of P. spinosa and its cytotoxic effects on cancer cell lines. Methanol extract of P. spinosa fruit was evaluated for its in vitro cytotoxic activity on multiform (GBM) brain cancer (LN229, U87 and T98G) and pancreas cancer (PANC-1 and AsPC-1) cell lines. Cell viability assays were performed by calculating the percentage of viable cells using a luminescence system, and spectrophotometrically. measuring its antioxidant ABTS and DPPH radical scavenging activities. Differences were considered as statistically significant at p*<0.001 and p**<0.0005 according to unpaired student t-test. Methanol extract of P. spinosa fruit showed 2548±18 mg GAE/100 g correspon-ding to the total phenolic content, and moderate antioxidant activity (0.1896±0.1143 and 0.0729±0.0348) by ABTS� and DPPH� assays. To the best of our knowledge, after evaluating the results of brain and pancreas cancer cell lines, significant cytotoxic activities with 50-63% cell viability of GBM brain cancer cells were determined while no cytotoxicity was observed on pancreas cancer cell lines, PANC-1; and AsPC-1. The results of this study showed that the methanol extract of P. spinosa fruit has significant antioxidant capacity and leads to statistically significant decreased viability on glioblastoma brain cancer cells.


Listeria monocytogenes and its products as agents for cancer immunotherapy.
This review covers the use of Listeria monocytogenes and its virulence factors as cancer immunotherapeutics. We describe their development as vectors to carry protein tumor antigen and eukaryotic DNA plasmids to antigen-presenting cells and efforts to harness their tumor-homing properties. We also describe their use as vectors of angiogenic molecules to induce an immune response that will destroy tumor vasculature. The background knowledge necessary to understand the biology behind the rationale to develop Listeria as a vaccine vector for tumor immunotherapy is included as well as a brief summary of the major therapies that have used this approach thus far.


Comparison of ultrasound and manometric sphincter length and incontinence scores.
Fecal incontinence can be assessed by a wide variety of means that vary in their clinical relevance. This study assesses the correlation between two methods of recording sphincter length and incontinence scores. A retrospective review of results from 1999 to 2001 of 137 patients with fecal incontinence was undertaken on patients who had both ultrasound and manometric assessment. Incontinence scores, ultrasonic sphincter length, and manometrically derived sphincter length were recorded. The data were analyzed using the Spearman rank correlation coefficient (r(s)) for nonparametric data. There was negative correlation between incontinence scores and manometric sphincter length (r(s) = -0.27; P = 0.002) but not with ultrasonic length (r(s) = -0.08; P = 0.38). There was correlation between manometric and ultrasonic lengths (r(s) = 0.21; P = 0.02). In males, all three correlated but none of the values were significant (n = 12). Internal and external sphincter defects had no effect on correlation coefficients. Given that all measurements include a degree of subjectivity, manometry more closely correlates with the fecal incontinence scores than ultrasound measurements. There seems to be little benefit in measuring the sphincter length with ultrasound. Manometric sphincter length measurement seems to have a role in assessing patients with fecal incontinence.


Plasminogen activators in rat neural tissues during development and in Wallerian degeneration.
The fibrinolytic activity of blood is caused by plasminogen activators (PA) converting plasminogen to plasmin, the active fibrinolytic protease. PA activity in rat neural tissues was studied by Todd's fibrin slide technique. Cryostat sections overlayed with a film of plasminogen and fibrin were incubated for 60-90 min. PA activity was related to the size of the zone of fibrinolysis surrounding the sections. No lysis occurred with fibrin alone. In rats perfused with saline prior to decapitation the size of the zone of lysis was approximately the same as in non-perfused animals. PA activity was compared in the following tissues: adult (2-3 month) cerebellum and 6-14-day postnatal cerebellum; normal sciatic nerve and transected sciatic nerve 1-9 weeks after operation (in these experiments the sciatic nerve was crushed on the left side, on the right side it was transected and the stumps were tightly ligated to prevent regeneration); normal optic nerves and optic nerves undergoing Wallerian degeneration 1-2 weeks after enucleation of the eye. As compared to normal cerebellum PA activity was increased in 6-14-day cerebellum. PA activity was also markedly increased in both crushed and ligated sciatic nerves 1-4 weeks after operation while no differences were observed between normal sciatic nerves and sciatic nerves 9 weeks after ligation. The zone of fibrinolysis surrounding normal optic nerves and the optic nerves of blinded rats was approximately the same. It is proposed that the fibrinolytic system may be relevant to the problem of CNS regeneration.


A probe of the human plasmin-alpha 2-macroglobulin interaction utilizing monoclonal antibodies to human plasmin.
These experiments have shown that alpha 2M may have a bait region capable of accommodating proteases of a far greater molecular weight than previously recognized, since antibody-plasmin complexes apparently become entrapped. In the case of large proteases, however, it now appears that a portion of these molecules is not enclosed. Clearly, in the case of plasmin, the K1-4 region remains outside the molecular trap.


Analysis of sleep and stress profiles from biomedical signal processing in wearable devices.
The present paper describes procedures for the evaluation of sleep quality and for stress management based on the analysis of the HRV and respiration signals. The analysis is though for a device aimed to provide support to people who want to develop a healthier lifestyle, with major focus on cardiovascular disease prevention.


Hyaluronic acid tethered pH-responsive alloy-drug nanoconjugates for multimodal therapy of glioblastoma: An intranasal route approach.
In the present investigation, FePt alloy nanoparticles were synthesized with controlled size and elemental composition followed by surface modification using (3-Aminopropyl) triethoxysilane (APTES). Lenalidomide was covalently bound to FePt-NH2 by pH sensitive hydrazone bonding. Hyaluronic acid was conjugated to amino groups of APTES while lactoferrin (Lf) was directly conjugated to excess carboxylic group present on hyaluronic acid (HA) to form surface modified pH sensitive alloy-drug nanoconjugates (SPANs). The multifunctional nanoconjugates were characterized and evaluated using extensive in vitro and in vivo techniques. The nanoconjugates demonstrated excellent heating ability on exposure to alternating magnetic field and near-infrared laser irradiation. The acidic microenvironment of lysozome triggered release of LND from SPANs. Owing to leaching of Fe and Pt contents, SPANs demonstrated ability to generate reactive oxygen species (ROS) in U87MG cell line which further enhanced therapeutic effect of SPANs. Significant difference in cell viability suppression was observed in in vitro photothermal, chemo-photothermal and chemo-magnetophotothermal killing of cancer cells using SPANs in U87MG cell lines. Significant difference in heating ability and cell cytotoxicity of SPANs in comparison to alternative magnetic field and NIR irradiation was observed for DUAL-mode exposure of SPANs. The results of cellular internalization study showed efficient internalization of SPANs inside U87MG cells. The in vivo results (both qualitative and quantitative) confirmed enhanced uptake of SPANs in brain after intranasal administration with enhanced nasal and mucus penetration owing to presence of Lf. No significant interaction was observed with ECM and mucin due to presence of carboxyl group on SPANs.


The utility and the safety of EUS-guided FNA in the evaluation of duplication cysts.
Diagnosis of a foregut duplication cyst is of great clinical impact. A definitive diagnosis of a foregut duplication cyst can avert the need for major thoracic surgery in the otherwise asymptomatic individual. This study sought to evaluate the safety and the utility of EUS and EUS-guided FNA (EUS-FNA) in the diagnosis of foregut duplication cysts. Over a period of 4 years, 4771 patients underwent EUS for various indications at two EUS referral centers. EUS findings were consistent with a mediastinal cyst in 30 cases. EUS-FNA was performed in 22 patients. A definitive diagnosis was established based on cytology, surgical pathology, and/or clinical follow-up. FNA was done with 22-gauge needles and antibiotic prophylaxis. The appearance of cyst contents on EUS ranged from completely anechoic (23 cases) to hypoechoic (7 cases). Hypoechoic cystic lesions contained echogenic foci. All anechoic lesions were confirmed as benign duplication cysts based on cytology, pathology, and clinical follow-up. Hypoechoic cystic lesions were confirmed to be benign duplication cysts in 4 cases. Three cases proved to be malignant or granulomatous necrotizing lymph nodes. No periprocedural complications occurred. Variation exists in the EUS appearance of benign mediastinal cysts. EUS-FNA of mediastinal cysts with smaller-gauge needles, and antibiotic prophylaxis appears safe and can provide a definitive diagnosis in atypical mediastinal cystic lesions.


Home environment and noise disturbance in a national sample of multi-family buildings in Sweden-associations with medical symptoms.
Poor acoustic conditions at home can have negative health impact. The aim was to investigate home environment factors and medical symptoms associated with noise disturbance. All adults (≥18 y) registered in selected apartments in Sweden were invited to participate in a questionnaire survey including medical questions and personal factors. Totally 5775 adults participated (response rate 46%). Information on home environment was obtained through an indoor environment questionnaire. Two-level logistic regression models (individual, municipality) were performed to estimate associations. Totally 11.9% reported noise disturbance in general at home. Noise disturbance from voice/radio/TV/music/similar sounds from neighbours (13.2%), scraping sound/footsteps/thumping from neighbours (16.5%) and road traffic (16.1%) were common. Younger age and smoking were related to more noise disturbance and more medical symptoms. Noise disturbance was related to tiredness, headache and difficulty concentrating (OR = 1.70-8.19). Renting the apartment (OR = 2.53) and living above ground floor (OR = 1.37) were related to more noise disturbance in general. Living in newer buildings (constructed from 1986 to 2005) was related to less noise disturbance in general (OR = 0.40-0.59). A warmer climate (OR = 1.95), higher municipality population density (OR = 1.24), a longer living time (OR = 1.34), construction year (1961-1975) (OR = 2.42), renting (OR = 1.80-2.32), living above ground floor (OR = 1.45) and having a bathroom fan (OR = 1.84) were associated with increased noise disturbance from neighbours. Factors associated with increased noise disturbance from installations or ventilation/fans/heat pumps included a warmer climate, higher municipality population density, construction year (1961-1995), renting and any mechanical ventilation. Higher municipality population density, construction year (especially 1961-1985) and renting were associated with more noise disturbance from traffic (OR = 1.77-3.92). Renting the apartment (OR = 1.73) and living above ground floor (OR = 1.60) were related to more severe traffic noise disturbances. Noise disturbance in general was partly a mediator of the effects of old buildings, renting the apartment and lack of mechanical ventilation on medical symptoms (% of total effect mediated by noise disturbance: 19-44.8%). Noise disturbance can be associated medical symptoms. Younger age, smoking, a warmer climate, higher municipality population density and different building factors (e.g. renting the apartment, construction period 1961-1985) can be associated with noise disturbance.


On the development of mycobacterial infections II. Changing mycobacterial infection spectrum in the Cologne area 1983-1993.
The overall detection rate of mycobacteria in the Cologne area did not change between 1983 and 1993. But a significant shift of the rate of Mycobacterium tuberculosis to nontuberculous mycobacteria, especially Mycobacterium avium-intracellulare complex, could be observed. Whereas the portion of Mycobacterium tuberculosis fell during these years from about 90% to 50-70% the portion of Mycobacterium avium-intracellulare increased steadily from 0 to 23% of all mycobacteria positive patients. The portion of tuberculosis patients positive for HIV remained constantly at 5-7% until 1992. Whether the 10% in 1993 signalizes a definitive increase remains to be proven. HIV positive patients with the diagnosis mycobacteria show another development. Whereas Mycobacterium tuberculosis is isolated constantly from about 2-3% of all HIV positive patients, the Mycobacterium avium-intracellulare complex increased from 0 to 10%. As methodical factors play a special role in the diagnostic procedure of mycobacteria, we evaluated some of the newer techniques for our routine laboratory: The well-known high sensitivity and specificity of the DNA probes (Gen-probe system) was confirmed, and by the radiometric culture system, in fact, the ubiquitous mycobacteria were detected much better. Otherwise from one third of special materials Mycobacterium tuberculosis and Mycobacterium bovis grew only on the conventional solid media. The susceptibility testing of 925 Mycobacterium tuberculosis strains revealed a rate of 10% (95 strains) with resistance to one antituberculotic drug only and 3% (29 strains) with resistance to two or more drugs. Only 0.9% (8 strains) were resistant to isoniacid and rifampicin (multidrug-resistant strains) indicating that drug resistance of Mycobacterium tuberculosis is still no serious problem in our region.


The response of suprachiasmatic neurons of the rat hypothalamus to photic and nicotinic stimuli.
Single neurons in the suprachiasmatic nucleus (SCN) and surrounding hypothalamic nuclei of the rat were characterized functionally and pharmacologically. Photically responsive neurons of the SCN typically exhibited a similar response to intravenous nicotine. The response to nicotine was antagonized by the nicotinic blocker, mecamylamine. Nicotinic blockade either eliminated or even reversed the sign of the photic response during subsequent photic stimulation. This constellation of results was not seen in neurons of adjacent hypothalamic regions.


Biology of neuroblastomas that were found by mass screening at 6 months of age in Japan.
Mass screening (MS) of neuroblastoma has been carried out by measuring the urinary catecholamine metabolites in infants at the age of 6 months in Japan. We assessed the incidence of neuroblastoma that may be a target for MS by studying tumor biology. FISH on chromosome 1 and MYCN analysis was performed on 453 patients that were classified into three clinical groups (287 infants found by MS, 51 infants < 12 months diagnosed clinically, and 115 children >or=12 months diagnosed clinically). The relationship between the biological types of tumors and the clinical outcome was examined. Type 1 (trisomy 1 and normal MYCN), type 2 (disomy 1/tetrasomy 1 and normal MYCN), and type 3 (disomy 1/tetrasomy 1 and amplified MYCN) tumors were found in 88.2%, 10.5%, and 1.4% of infants found by MS, in 68.0%, 24.0%, and 8.0% of infants diagnosed clinically, and in 23.4%, 42.3%, and 34.2% of children diagnosed clinically (P < 0.001). Infants with type 1 tumors found by MS or diagnosed clinically had earlier stages of the disease (P < 0.0001 and P = 0.0005) and better overall survival (P < 0.001 and P = 0.005) than children with type 1 tumors diagnosed clinically. Infants with type 2 tumors found by MS, had earlier stages (P = 0.06 and P < 0.0001) and better overall survival (P = 0.014 and P < 0.001) than infants or children with type 2 tumors diagnosed clinically. All three clinical groups of patients with type 3 tumors had advanced stages and dismal prognoses. About 12% of tumors found by MS showed unfavorable biological (types 2 and 3) characteristics.


Evaluation of anti-angiogenic agent F16 for targeting glioblastoma xenograft tumors.
Glioblastoma Multiforme (GBM) is one of the most aggressive and lethal types of all cancers, with an average 5-year survival rate of 5%. Since GBM tumors are highly vascularized tumors, and their growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors were considered as one of the promising approaches. In this context, intensive preclinical evaluation of a novel small molecule named F16 has exhibited potent anti-angiogenic and anti-tumor activities by selectively antagonizing Vascular Endothelial Growth Factor Receptor (VEGFR). Also, recent pharmacokinetic evaluation of F16 with tissue distribution analysis has shown that this molecule is transported across the blood-brain barrier (BBB) and accumulates in the brain regions with no signs of neurotoxicity. Therefore, further studies were conducted to determine the efficacy of F16 in delaying glioblastoma progression via inhibiting tumor angiogenesis. Our in vitro studies have clearly demonstrated the ability of F16 to inhibit migration and invasion of U87MG cells and also confirmed a potent cytotoxic effect against these cells in comparison to Temozolomide (TMZ). Our in vivo studies with the subcutaneously implanted (s.c.) xenograft tumor model and in vitro studies have clearly demonstrated the ability of F16 to delay tumor growth and inhibit migration and invasion.


Spectroscopic analysis of the effect of glycation on casein structure and aggregation and its dependence on lactose concentration.
In order to study the effect of glycation on the molecular structure of casein (CN), three groups of simulated milk powders with different lactose (Lac) contents, CN:Lac = 1:1.5, 1:2, and 1:2.5 (m:m), were constructed. The glycation level and the structural changes of CN were analyzed by multiple spectra. The results showed that the interaction between Lac and CN molecules was based on the dynamic quenching of collision. A higher quenching constant, KSV, means that the 1:1.5 group showed more distinct glycation levels. In addition, CN glycation reduced the aggregation of casein micelles caused by heating treatment and repaired the structural damage of CN induced during the heating process. There was no positive correlation found between Lac content and protein glycation; thus, decreasing the Lac content of milk powder is not likely to be an effective method to prolong storage stability.


Inhibition of VEGF expression in cancer cells and endothelial cell differentiation by synthetic stilbene derivatives.
We here report the synthesis of several stilbene derivatives. They show a measurable inhibitory effect on angiogenesis, some of them to a higher degree than resveratrol. Test methods included cell proliferation and tube formation assays using bovine aorta endothelial cells. In addition, it has been confirmed through the reverse transcriptase/polymerase chain reaction experiment that these stilbene derivatives downregulate the expression of the gene related to the production of the angiogenesis factor VEGF in cancer cells.


1,25-Dihydroxycholecalciferol modulates 3H-thymidine incorporation in FRTL5 cells.
1,25-dihydroxycholecalciferol (1,25(OH)2D3) possesses proliferation and differentiation modulating effects in many cell types in vitro. We studied the effect of 1,25(OH)2D3 on 3H-thymidine incorporation in FRTL5 cells, a cultured rat thyroid follicular cell line. 1,25(OH)2D3 alone at 10(-11) and 10(-9) M exerted no effect on 3H-thymidine incorporation. However, at 10(-7) M, 1,25(OH)2D3 slightly enhanced 3H-thymidine incorporation. In the presence of 5% calf serum, 1,25(OH)2D3 increased 3H-thymidine incorporation induced by calf serum in a dose-dependent manner. 1,25(OH)2D3 also enhanced 3H-thymidine incorporation induced by PMA, an extrinsic stimulator of protein kinase C, without directly affecting PMA-induced protein kinase C translocation. In contrast to the stimulatory effects of 1,25(OH)2D3 on the calf serum and PMA-induced 3H-thymidine incorporation, 1,25(OH)2D3 inhibited the increase in 3H-thymidine incorporation induced by TSH in a dose-dependent manner. This effect of 1,25(OH)2D3 on TSH-induced 3H-thymidine incorporation may be, in part, due to post-cAMP pathways since 1,25(OH)2D3 also inhibited the increase in 3H-thymidine incorporation induced by Bu2cAMP without affecting the TSH-induced increase in cAMP. The stimulatory effect of insulin on 3H-thymidine incorporation, a cAMP-independent process, was also inhibited by 1,25(OH)2D3. We conclude that 1,25(OH)2D3 affects 3H-thymidine incorporation in FRTL5 cells raising the possibility of a physiologic role for 1,25(OH)2D3 in the growth and function of thyroid follicular cells.


LncRNA XIST Prevents Tendon Adhesion and Promotes Tendon Repair Through the miR-26a-5p/COX2 Pathway.
Tendon adhesion is the biggest obstacle to repair of tendon injury. Long-chain non-coding RNA X-inactive specific transcript (lncRNA XIST) is highly expressed in populations at high risk of tendon injury. However, whether XIST participates in tendon injury and the specific mechanism remain unknown. Here, we aimed to explore the effects and underlying mechanism of XIST in tendon injury. A mouse model of tendon injury was constructed by the transection method in vivo. XIST and COX2 were highly expressed in tendon tissues of mice with tendon injury, while miR-26a-5p was lowly expressed. Fibroblasts were isolated from tendon injury mice. Overexpression of XIST promoted fibroblast proliferation and upregulated α-SMA and Collagen I protein expression, while silencing XIST indicated the opposite effects. Further dual-luciferase reporter gene assay and RIP assay verified a targeting relationship between XIST and miR-26a-5p, as well as miR-26a-5p and COX2, and XIST targeted miR-26a-5p to act on COX2 expression. miR-26a-5p inhibition and COX2 overexpression reversed the decrease in fibroblast proliferation and the downregulation of α-SMA and Collagen I expression caused by XIST silencing, while interference with si-COX2 eliminated the effects of miR-26a-5p inhibitor. This study revealed that XIST promoted fibroblast proliferation and the formation of tendon adhesion through miR-26a-5p/COX2 pathway, suggesting that XIST/miR-26a-5p/COX2 may be a potential target for the treatment of tendon injury.


Radiation effects in fluoroscopically guided cardiac interventions--keeping them under control.
It would appear that a significant number of cardiologists are unaware that skin injuries ranging from erythema to telangiectasia or even dermal necrosis can be caused by the procedures they perform. Conditions that have been reported to be associated with radiation-induced skin injuries include: the high values of the exposure factors required with thick patients; prolonged or multiple procedures; elevated radiosensitivity of some patients (ataxia telangiectasia); connective tissue disease and diabetes mellitus. The total number of reported severe injuries worldwide so far is 100-200, or over 200 when all degrees of skin injuries are included, but the real number may be substantially larger since initial symptoms often appear only weeks after the procedure and the cardiologist may not be notified, unless a procedure for systematic follow up is in place. Besides skin injuries, patients-more so, the younger ones-incur a risk of radiation-induced cancer at some stage in the future. Experience shows that, with awareness of radiation safety aspects, proper equipment performance, the use of proper techniques, and the monitoring of patient doses, severe skin injuries should not occur in patients undergoing 5-10 PTCA-s. However, for those patients whose radiation doses approach the thresholds for radiation injuries a systematic follow up is required. These issues are addressed here.


Regulation of ER-mitochondria contacts by Parkin via Mfn2.
Parkin, an E3 ubiquitin ligase and a Parkinson's disease (PD) related gene, translocates to impaired mitochondria and drives their elimination via autophagy, a process known as mitophagy. Mitochondrial pro-fusion protein Mitofusins (Mfn1 and Mfn2) were found to be a target for Parkin mediated ubiquitination. Mfns are transmembrane GTPase embedded in the outer membrane of mitochondria, which are required on adjacent mitochondria to mediate fusion. In mammals, Mfn2 also forms complexes that are capable of tethering mitochondria to endoplasmic reticulum (ER), a structural feature essential for mitochondrial energy metabolism, calcium (Ca2+) transfer between the organelles and Ca2+ dependent cell death. Despite its fundamental physiological role, the molecular mechanisms that control ER-mitochondria cross talk are obscure. Ubiquitination has recently emerged as a powerful tool to modulate protein function, via regulation of protein subcellular localization and protein ability to interact with other proteins. Ubiquitination is also a reversible mechanism, which can be actively controlled by opposing ubiquitination-deubiquitination events. In this work we found that in Parkin deficient cells and parkin mutant human fibroblasts, the tether between ER and mitochondria is decreased. We identified the site of Parkin dependent ubiquitination and showed that the non-ubiquitinatable Mfn2 mutant fails to restore ER-mitochondria physical and functional interaction. Finally, we took advantage of an established in vivo model of PD to demonstrate that manipulation of ER-mitochondria tethering by expressing an ER-mitochondria synthetic linker is sufficient to rescue the locomotor deficit associated to an in vivo Drosophila model of PD.


Demonstration of a training response by the Canadian home fitness test.
The relative merits of the Astrand nomogram and the CHFT formula for prediction of maximum oxygen intake (VO2max) have been tested in 35 men and women during performance of the advanced version of the Canadian Home Fitness Test in a laboratory setting. Prior to training, systematic errors relative to direct treadmill measurements of maximum oxygen intake were Astrand-10.1% (male) and-1.4% (female), and CHFT 5.6% (male), and 2.2% (female), the error of the Astrand procedure being statistically significant for the men. Training was effected by a walk/jog prescription or rope-skipping and calisthenics. Following training, data analysis indicated that the CHFT prediction formula distinguished quite well between the behaviour of experimental and control subjects. The Astrand procedure showed a greater increment in VO2(max) than the CHFT formula for the experimental subjects (significantly so in the women), but it also predicted a large and spurious change in many of the controls, so that in the men responses did not differ between trained and control subjects. Further comparisons suggested that the CHFT procedure gave a closer approximation to direct treadmill estimates of training response than did the Astrand nomogram.


Modulation of TGF-β/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model.
Diabetic patients experience exaggerated intimal hyperplasia after endovascular procedures. Recently it has been shown that circulating smooth muscle progenitor cells (SPC) contribute to intimal hyperplasia. We hypothesized that SPC differentiation would be increased in diabetes and focused on modulation of TGF-β/BMP-6 signaling as potential underlying mechanism. We isolated SPC from C57Bl/6 mice with streptozotocin-induced diabetes and controls. SPC differentiation was evaluated by immunofluorescent staining for αSMA and collagen Type I. SPC mRNA expression of TGF-β and BMP-6 was quantified using real-time PCR. Intima formation was assessed in cuffed femoral arteries. Homing of bone marrow derived cells to cuffed arterial segments was evaluated in animals transplanted with bone marrow from GFP-transgenic mice. We observed that SPC differentiation was accelerated and numeric outgrowth increased in diabetic animals (24.6 ± 8.8 vs 8.3 ± 1.9 per HPF after 10 days, p < 0.05). Quantitative real-time PCR showed increased expression of TGF-β and decreased expression of the BMP-6 in diabetic SPC. SPC were MAC-3 positive, indicative of monocytic lineage. Intima formation in cuffed arterial segments was increased in diabetic mice (intima/media ratio 0.68 ± 0.15 vs 0.29 ± 0.06, p < 0.05). In GFP-chimeric mice, bone marrow derived cells were observed in the neointima (4.4 ± 3.3 cells per section) and particularly in the adventitia (43.6 ± 9.3 cells per section). GFP-positive cells were in part MAC-3 positive, but rarely expressed α-SMA. In conclusion, in a diabetic mouse model, SPC levels are increased and SPC TGF-β/BMP-6 expression is modulated. Altered TGF-β/BMP-6 expression is known to regulate smooth muscle cell differentiation and may facilitate SPC differentiation. This may contribute to exaggerated intimal hyperplasia in diabetes as bone marrow derived cells home to sites of neointima formation.


Molecular aspects of osteopathy in type 1 Gaucher disease: correlation between genetics and bone density.
Bone-related complications in Gaucher disease are considered to be poorly responsive to specific enzyme replacement therapy. Polymorphisms of candidate genes associated with low bone density were investigated to see whether they are correlated with bone mineral density (BMD) and bone involvement in Gaucher disease. Genotyping for polymorphisms in candidate genes (interleukins 1alpha and 1beta, interleukin-1 receptor antagonist; cytochrome P450; collagen 1A1; low-density Lipoprotein Receptor; bone morphogenic protein 4; vitamin D receptor; and estrogen receptor 2beta) were performed using standard methodologies. BMD was measured by dual energy X-ray absorptiometry (DXA). One hundred and ninety-four patients and 100 controls were genotyped for the above polymorphisms. Thirteen haplotypes were obtained, with several correlations with BMD in patients; also, a haplotype (T889-T3954-C511-240VNTR of IL1) was significantly correlated with T-scores and Z-score for femur neck and lumbar spine (p = 0.01) in patients. Haplotypes of bone-specific candidate genes associated with BMD may predict severity of these features in Gaucher disease.


Right ventricular inflow obstruction from massive fungal vegetation presenting as neonatal circulatory collapse.
Occurrence of neonatal circulatory collapse imposes effective differential diagnosis and expeditious therapeutic intervention. We report a case of neonatal cardiogenic shock, caused by a massive intra-cardiac fungal vegetation.


Strain-induced water dissociation on supported ultrathin oxide films.
Controlling the dissociation of single water molecule on an insulating surface plays a crucial role in many catalytic reactions. In this work, we have identified the enhanced chemical reactivity of ultrathin MgO(100) films deposited on Mo(100) substrate that causes water dissociation. We reveal that the ability to split water on insulating surface closely depends on the lattice mismatch between ultrathin films and the underlying substrate, and substrate-induced in-plane tensile strain dramatically results in water dissociation on MgO(100). Three dissociative adsorption configurations of water with lower energy are predicted, and the structural transition going from molecular form to dissociative form is almost barrierless. Our results provide an effective avenue to achieve water dissociation at the single-molecule level and shed light on how to tune the chemical reactions of insulating surfaces by choosing the suitable substrates.


The relationship between ATP hydrolysis and active force in compressed and swollen skinned muscle fibers of the rabbit.
We investigated whether the inhibition of force generation observed in compressed muscle fibers is accompanied by a coupled reduction in hydrolytic activity. Isometric force and rates of ATP hydrolysis (ATPase) were measured as functions of the relative width of chemically skinned skeletal muscle fiber segments immersed in relaxing (pCa greater than 8) and activating (pCa 4.9) salt solutions. Osmotic radial compression of the fiber segment was produced (with little or no affect on striation spacing) by adding Dextran T500 to the bathing media. ADP as a product of ATP hydrolysis in fibers undergoing 10-15 min contractions was measured using high pressure liquid chromatography. Compression of the (initially swollen) fiber segment with dextran produced a slight (4%) increase in average active force and then, with further compression, a sharp decrease (with maximum around in situ width). With compression, the average ATPase of the fiber decreased monotonically, and with extreme compression (with 0.22 g dextran per ml), ATPase fell to a fifth of its level determined in dextran-free solution while force was abolished. The time course of active force development was described by the sum of two exponential functions, the faster of which characterized the rate of rise. Fiber compression (0.14 g dextran per ml) reduced the rate of rise of force ten-fold compared to that in dextran-free solution. Hindrance of cross movement is proposed to account for the inhibition of active force generation and (coupled) ATPase in compressed fibers.


Recovery of OATP1B Activity after Living Kidney Transplantation in Patients with End-Stage Renal Disease.
Recently, several studies have shown that renal failure decreases the metabolic clearance of drugs and the transportation capability of some drug transporters. However, whether organic anion transporting polypeptide (OATP)1B activities decrease in renal failure remains unknown. In this study, we measured plasma concentrations of coproporphyrin-I (CP-I), a specific endogenous OATP1B probe, in patients with end stage renal disease before and after living kidney transplantation and evaluated the effect of renal function on OATP1B activity. This prospective study recruited 13 patients with end-stage renal disease. Plasma CP-I concentrations were measured before and 7, 14, 30 and 90 days after living kidney transplantation. Plasma CP-I concentrations decreased over time after living kidney transplantation and showed significant difference on day 90 compared with before living kidney transplantation [1.12 ± 0.59 vs 0.65 ± 0.27 ng/mL, p < 0.05 (95% CI of difference - 0.927, -0.013)]. A significant negative correlation was observed between estimated glomerular filtration rate and plasma CP-I concentration (r = -0.30, p < 0.05), suggesting recovery of OATP1B activity with improvement in renal function. OATP1B activity may decrease in renal failure and dose adjustment of OATP1B substrates may be needed in patients with renal failure.


A Practical Tool for Risk-Based In-use Compatibility Assessments.
In drug development, in-use compatibility studies are crucial steps to ensure that the critical quality attributes of the drug product are maintained when in contact with administration components. But once the drug is in clinical trials, unanticipated variations in these components can stretch limited resources and lengthen timelines to market, as these changes must be assessed and approved to ensure continued patient safety. It's desirable to use a science-based risk evaluation to determine the extent of data and testing needed in these situations, but there is no standard for how such evaluations are done. We have developed an Excel™-based semi-quantitative risk assessment tool to determine whether in-use testing is needed when drug delivery sites or components are changed during a clinical trial. We developed the tool based on our multi-company experience with compatibility studies for many types of drug products targeted for various geographic regions. We have employed the tool as a means to expedite decision-making and, if appropriate, reduce testing in low-risk situations. The tool can save significant time and effort (our estimate is approximately at least 6-9 months off the development cycle) and can minimize pitfalls in clinical administration. While we have designed the tool for our drug products and for use with parenteral dosing regimens, the tool can be adapted for other situations as needed. It will be especially useful for companies with more limited resources.


Purification, properties, and mode of action of hemicellulase I produced by Ceratocystis paradoxa.
A culture isolate (CP2) of the fungal plant pathogen Ceratocystis paradoxa produces at least five extra-cellular hemicellulases when grown on a medium containing a commercial hemicellulose as inducer. One of the five enzymes, hemicellulase I (HC-I), was purified by ammonium sulphate preceipitation, ion-exchange chromatography (DEAE-Sephadex and then Cellex-CM), and iso-electric focusing at pH 3-10 and 8-10. HC-I behaves as a single protein on a electrophoresis at pH 6.0 and 8.4. The enzyme degrades hemicellulose B (an arabino-4-O-methylglucurono-xylan) and arabinoxylanto arabinose, xylose, xylobiose (Xyl2; beta-D-Xylp-(1 leads to 4)-D-Xyl), and a mixture of arabinose-xylose and xylose oligosaccharides (AraXyln and Xyln, where n=3, 4, or 5). The enzyme is deduced to be an endo-enzyme. Xylotetraose (Xyl4) was the lowest homologue of the xylose oligosaccharides attacked, yielding xylobiose and xylotriose (Xyl3) only. A mechanism is postulated for this reaction. AraXyl5 were slowly hydrolysed to arabinose and the respective xylose saccharide (Xyl2-Xyl5), and thence to Xyl2 and Xyl3. Hydrolysis of the arabinofuranosyl linkage probably does not occur at the same active site as for the xylose oligosaccharides. Hemicellulose B fractions from different sources appeared to be degraded by HC-I. The enzyme showed optimum activity at pH 5.5 and 40 degrees, and Km was 4.24 mg of hemicellulose/ml.


Cardiovascular Dysfunction in Intrauterine Growth Restriction.
We highlight important new findings on cardiovascular dysfunction in intrauterine growth restriction. Intrauterine growth restriction (IUGR) is a multifactorial condition which negatively impacts neonatal growth during pregnancy and is associated with health problems during the lifespan. It affects 5-15% of all pregnancies in the USA and Europe with varying percentages in developing countries. Epidemiological studies have reported that IUGR is associated with the pathogenesis of hypertension, activation of the renin-angiotensin system (RAS), disruption in placental-mTORC and TGFβ signaling cascades, and endothelial dysfunction in IUGR fetuses, children, adolescents, and adults resulting in the development of cardiovascular diseases (CVD). Experimental studies are needed to investigate therapeutic measures to treat increased blood pressure (BP) and long-term CVD problems in people affected by IUGR. We outline the mechanisms mediating fetal programming of hypertension in developing CVD. We have reviewed findings from different experimental models focusing on recent studies that demonstrate CVD in IUGR.


Historic evolution of population exposure to heatwaves in Xinjiang Uygur Autonomous Region, China.
Heatwaves have pronounced impacts on human health and the environment on a global scale. Although the characteristics of heatwaves has been well documented, there still remains a lack of dynamic studies of population exposure to heatwaves (PEH), particularly in the arid regions. In this study, we analyzed the spatio-temporal evolution characteristics of heatwaves and PEH in Xinjiang using the daily maximum temperature (Tmax), relative humidity (RH), and high-resolution gridded population datasets. The results revealed that the heatwaves in Xinjiang occur more continually and intensely from 1961 to 2020. Furthermore, there is substantial spatial heterogeneity of heatwaves with eastern part of the Tarim Basin, Turpan, and Hami been the most prone areas. The PEH in Xinjiang showed an increasing trend with high areas mainly in Kashgar, Aksu, Turpan, and Hotan. The increase in PEH is mainly contributed from population growth, climate change and their interaction. From 2001 to 2020, the climate effect contribution decreased by 8.5%, the contribution rate of population and interaction effects increased by 3.3% and 5.2%, respectively. This work provides a scientific basis for the development of policies to improve the resilience against hazards in arid regions.


Risks of Developing Diabetes and Hyperglycemic Crisis Following Carbon Monoxide Poisoning: A Study Incorporating Epidemiologic Analysis and Animal Experiment.
Carbon monoxide (CO) poisoning may damage the pancreas, but the effects of CO poisoning on the development of diabetes and on existing diabetes remain unclear. We conducted a study incorporating data from epidemiologic analyses and animal experiments to clarify these issues. Using the National Health Insurance Database of Taiwan, we identified CO poisoning patients diagnosed between 2002 and 2016 (CO poisoning cohort) together with references without CO poisoning who were matched by age, sex, and index date at a 1:3 ratio. We followed participants until 2017 and compared the risks of diabetes and hyperglycemic crisis between two cohorts using Cox proportional hazards regressions. In addition, a rat model was used to assess glucose and insulin levels in blood as well as pathological changes in the pancreas and hypothalamus following CO poisoning. Among participants without diabetes history, 29,141 in the CO poisoning cohort had a higher risk for developing diabetes than the 87,423 in the comparison cohort after adjusting for potential confounders (adjusted hazard ratio [AHR]=1.23; 95% confidence interval [CI]: 1.18-1.28). Among participants with diabetes history, 2302 in the CO poisoning cohort had a higher risk for developing hyperglycemic crisis than the 6906 in participants without CO poisoning (AHR = 2.12; 95% CI: 1.52-2.96). In the rat model, CO poisoning led to increased glucose and decreased insulin in blood and damages to pancreas and hypothalamus. Our epidemiological study revealed that CO poisoning increased the risks of diabetes and hyperglycemic crisis, which might be attributable to damages in the pancreas and hypothalamus as shown in the animal experiments.


The movement of potassium ions during electrical activity, and the kinetics of the recovery process, in the non-myelinated fibres of the garfish olfactory nerve.
1. An electrophysiological study was made with the sucrose gap of the compound action potential of the non-myelinated fibres of the garfish olfactory nerve at temperatures between 8 and 22 degrees C. The efflux of 42K with stimulation, and the post-tetanic hyperpolarization following a period of repetitive stimulation, were also studied. 2. At 22 degrees C the compound action potential (at zero conduction distance) reached its peak in about 5 msec and lasted about 12 msec; the conduction velocity was 19.4 cm/sec. The corresponding extrapolated values at 0 degrees C were: time to peak, 16 msec; duration, 37 msec; conduction velocity, 4.2 cm/sec. 3. The rate constant for resting potassium efflux (kr) was 0.0108 min-1 at 22 degrees C and 0.00489 min-1 at 0 degrees C. 4. The extra fractional loss of potassium with stimulation (ks) was 2.02 x 10(-4) impulse-1 at 22 degrees C and 4.41 x 10(-4) impulse-1 at 0 degrees C. 5. Raising the external potassium concentration, or addition of ouabain (1 mM), raised the resting rate of efflux of potassium. 6. The post-tetanic hyperpolarization, which reflects the electrogenic extrusion of sodium ions, indicated a rate constant for active sodium efflux at 22 degrees C of 0.47 min=1. 7. The rate constant was decreased by a 10 degrees C fall in temperature by a factor of 1.73. 8. Increasing the external potassium concentration increased the rate constant, apparently by potassium combining with some site with an equilibrium dissociation constant of 1.2 mMM. 9. The rate constant was decreased slightly in acidic solutions and increased slightly in alkaline solutions. 10. 14C-labelled ouabain was found to bind to the garfish olfactory nerve with an equilibrium dissociation constant of about 0.5 muM. The maximum saturable binding capacity, 22.3 p-mole/mg dry, suggests that there are about 350 sodium pumping sites per square micron membrane.


Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients.
Embryonic stem cells hold great promise for various diseases because of their unlimited capacity for self-renewal and ability to differentiate into any cell type in the body. However, despite over 3 decades of research, there have been no reports on the safety and potential efficacy of pluripotent stem cell progeny in Asian patients with any disease. Here, we report the safety and tolerability of subretinal transplantation of human embryonic-stem-cell (hESC)-derived retinal pigment epithelium in four Asian patients: two with dry age-related macular degeneration and two with Stargardt macular dystrophy. They were followed for 1 year. There was no evidence of adverse proliferation, tumorigenicity, ectopic tissue formation, or other serious safety issues related to the transplanted cells. Visual acuity improved 9-19 letters in three patients and remained stable (+1 letter) in one patient. The results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine.