Chd7 plays a critical role in controlling left-right symmetry during zebrafish somitogenesis.
Somitogenesis is a complex process during early vertebrate development involving interactions between many factors to form a bilateral somite series. A role for chromatin remodelers in somitogenesis has not yet been demonstrated. Here, we investigate the function of chromodomain helicase DNA binding protein 7 (chd7) during zebrafish somitogenesis. We show that Chd7 deficiency leads to asymmetric segmentation of the presomitic mesoderm (PSM), as revealed by expression of the somitogenesis genes, cdx1a, dlc, her7, mespa, and ripply1. Moreover, we show that abrogation of Chd7 results in the loss of asymmetric expression of spaw in the lateral plate mesoderm, which is consistent with more general laterality defects. Based on the observation that insufficient Chd7 leads to left-right asymmetry defects during PSM segmentation, and because CHD7 has been linked to human spinal deformities, we suggest that zebrafish chd7 morphants may be a good in vivo model to examine the pathophysiology of these diseases.


Determinants of normoglycemia and contribution to cardiovascular risk factors in a Chinese population: the Hong Kong Cardiovascular Risk Factor Study.
Glucose intolerance is clearly associated with increasing risk of cardiovascular disease, but the association among increasing glycemia and cardiovascular risk factors, angina and coronary heart disease in normoglycemic subjects is less clear, particularly in Chinese. A total of 2763 subjects were recruited and the prevalence of glucose intolerance investigated, using fasting or 2-h 75-g oral glucose tolerance test (OGTT), glucose levels. Subjects normoglycemic by both criteria were selected and the relationship between glycemia and cardiovascular risk factors investigated using analysis of variance and stepwise multiple linear regression analyses. 1931 (69.9%) subjects were normoglycemic by both tests. After adjustment for age and gender, quartiles of fasting and post-load glucose levels showed a clear positive relationship with cardiovascular risk factors, including obesity, blood pressure and lipid levels (p<0.001 for all). Additionally, other measures of glycemia and insulin resistance also dose-dependently increased with increasing fasting and post-load glucose levels (p<0.001 for all). Stepwise multiple regression showed that in females, age (standardised regression coefficient beta (beta)=0.23, p<0.001), insulin (beta=0.17, p<0.001), waist circumference (beta=0.11, p=0.007) were independently associated with fasting glucose levels; and body mass index (beta=0.17, p<0.001), age (beta=0.15, p<0.001) and triglycerides (beta=0.15, p<0.001) were independently associated with post-load glucose levels. In males, age (beta=0.19, p<0.001) and insulin (beta=0.18, p<0.001) were independently associated with fasting glucose levels; and waist circumference (beta=0.17, p<0.001), triglycerides (beta=0.16, p<0.001) and insulin (beta=0.12, p=0.001) were independently associated with post-load glucose levels.


Long-term follow-up after endovascular treatment of aortic coarctation with bare and covered Cheatham platinum stents.
Endovascular treatment of aortic coarctation (CoA) in children and adults frequently requires stent implantation. The aim of this study was to analyze long-term results after CoA treatment with bare and covered Cheatham-PlatinumTM (CP) stents in our institution and to derive recommendations for the differential use of these stent types. In this retrospective single institution study, 212 patients received endovascular CoA treatment with bare (n = 71) and covered (n = 141) CP stents between September 1999 and July 2021, respectively. The indications for treatment were native CoA in 110/212 patients (51.9%) and re-coarctation after primary surgical or interventional treatment in 102/212 patients (48.1%). Median patient age at endovascular CoA treatment was 18.8 years [IQR 11.9; 35.8]. Long-term follow-up was available in 158/212 patients (74.5%) with a median follow-up of 7.3 years [IQR 4.3; 12.6]. Procedural success was achieved in 187/212 (88.2%) patients. Survival rate was 98.1% after 5, and 95.6% after 10 and 15 years, respectively. The probability of freedom from re-intervention was 93.0% after 5, 82.3% after 10 and 77.8% after 15 years, respectively. Freedom from re-interventions (44/158, 27.8%) did not differ between patients who received bare or covered CP stents (p = 0.715). Multivariable risk factor analysis identified previous CoA surgery (HR: 2.0, 95% confidence interval (CI): 1.1-3,9, p = 0.029), postdilatation (HR: 2,9, 95% CI: 1.1-6.3, p = 0.028) and age at intervention (HR: 0.96, 95% CI: 0.94-0.99, p = 0.002) as independent risk factors for re-intervention. Peri-procedural complications occurred in 15/212 (7.1%) patients (dissection/thrombosis of vascular access vessel: n = 9; bleeding: n = 1; stent dislocation: n = 2; aortic dissection/aortic wall rupture: n = 3). Long-term complications were observed in 36 patients and included stent fracture (n = 19), aneurysm formation (n = 14), endoleak (n = 1) and subclavian artery stenosis (n = 2). Peri-procedural and long-term complications did not differ between patients who received CoA treatment with bare or covered CP stents (all p > 0.05). Endovascular treatment of CoA using bare or covered CP stents can be performed safely and effectively with excellent long-term results. Survival, re-intervention and complication rate did not significantly differ between both stent types. However, individual stent selection is advisable with regard to CoA morphology and severity as well as patient age.


Executive function deficits in pediatric cerebellar tumor survivors.
Besides motor function the cerebellum subserves frontal lobe functions. Thus, we investigated executive functions in pediatric posterior fossa tumor survivors. We tested information processing, aspects of attention, planning and intelligence in 42 pediatric posterior fossa tumor survivors (mean age 14.63 yrs, SD 5.03). Seventeen low-grade tumor patients (LGCT) were treated with surgery only and 25 high-grade tumors patients (HGCT) received postsurgical adjuvant treatment. We evaluated simple reaction time, executive functioning, i.e. visuospatial memory, inhibition, and mental flexibility using the Amsterdam Neuropsychological Tasks program, whereas forward thinking was assessed with the Tower of London-test. Intelligence was determined using the Wechsler Intelligence Scale. Ataxia was assessed with the International Cooperative Ataxia Rating Scale. About one third of each patient group showed forward thinking scores below one standard deviation of the norm. Impaired forward thinking correlated significantly with degree of ataxia (r = -0.39, p = 0.03) but not with fluid intelligence. Both patient groups exhibited executive function deficits in accuracy and reaction speed in more difficult tasks involving information speed and attention flexibility. Still, HGCT patients were significantly slower and committed more errors. Working memory was inferior in HGCT patients. Pediatric cerebellar tumor survivors with different disease and treatment related brain damage exhibit similar patterns of impairment in executive functioning, concerning forward thinking, inhibition and mental flexibility. The deficits are larger in high-grade tumor patients. The pattern of function loss seen in both groups is most probably due to comparable lesions to cerebro-cerebellar circuits that are known to modulate critical executive functions.


Capsular attachment to the distal radius for extracapsular placement of pins.
The aim of this study was to evaluate the anatomy of the wrist joint capsule on the distal radius. As such the extent of the joint capsule and the limits of attachment in relation to the articular surface were determined. Furthermore, the study also determined whether there was any reflection of the capsule onto the distal radius. Fifty cadaveric specimens, preserved according to Thiel's method, were assessed. After careful dissection the distance between the chondral line of the carpal articular surface and three defined points on each of the palmar and dorsal aspects of the radius were measured. In none of the specimens was there any variation in the course and extent of the joint capsule. Using external fixators for managing fractures of the distal radius, pins and wires can be placed subchondrally close to the articular capsule. The risk of intraarticular infection, due to pin tract infection in intraarticularly positioned pins, is very low.


Gender differences in right ventricular function in patients with non-ischaemic cardiomyopathy.
To evaluate sex-related differences in right ventricular (RV) function, assessed with cardiac magnetic resonance imaging, in patients with stable non-ischaemic dilated cardiomyopathy. Prospective multicentre study. We included 71 patients (38 men) and 14 healthy volunteers. Mean age was 60.9 ± 12.2 years. Men presented higher levels of haemoglobin and white blood cell counts than women, and performed better in cardiopulmonary stress testing. A total of 24 patients (12 women) presented severe left ventricular (LV) systolic dysfunction, 32 (13 female) moderate and 15 (8 women) mild LV systolic dysfunction. In the group with severe LV systolic dysfunction, average right ventricular ejection fraction (RVEF) was normal in women (52 ± 4 %), whereas it was reduced in men (39 ± 3 %) p = 0.035. Only one woman (8 %) had severe RV systolic dysfunction (RVEF < 35 %) compared with 6 men (50 %) p < 0.001. In patients with moderate and mild LV dysfunction , the mean RVEF was normal in both men and women. In the 14 healthy volunteers, the lowest value of RVEF was 48 % and mean RVEF was normal in women (56 ± 2 %) and in men (51 ± 1 %), p = 0.08. In patients with dilated cardiomyopathy, RV systolic dysfunction is found mainly in male patients with severe LV systolic dysfunction.


Acute kidney injury after allogeneic hematopoietic stem cell transplantation - Predictors and survival impact: A single center retrospective study.
Acute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. We performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. AKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. Patients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.


Insecticide susceptibility and detoxication enzyme activities among Coptotermes formosanus Shiraki workers sampled from different locations in New Orleans.
Coptotermes formosanus Shiraki worker termites were sampled from 20 locations in the City Park area of New Orleans, LA. The termites were subsequently assayed to determine their susceptibility to cypermethrin, chlordane and chlorpyrifos, and detoxication enzyme activity. Cypermethrin was most toxic against Formosan subterranean termite workers, chlorpyrifos exhibited intermediate toxicity and chlordane was least toxic. A comparison of insecticide susceptibility between the most and least tolerant colonies revealed 1.9-, 1.7- and 1.8-fold differences in susceptibility for cypermethrin, chlorpyrifos and chlordane, respectively. As with the bioassay data, although significant differences were noted, a great deal of overlap was observed among the colonies for total cytochrome P450 content (difference of 2.2-fold between high and low value) aldrin epoxidation (3.6-fold) and cytosolic esterase (3.9-fold) activity. No significant differences were observed among the colonies for methoxyresorufin O-demethylase or glutathione S-transferase activity. Conversely, microsomal esterase activity varied greatly; a 38-fold difference was observed between the most (Cf1776) and least (Cf1387) active colonies. However, no significant correlation was observed between insecticide susceptibility and microsomal esterase activity. In fact, no significant correlations were observed between any of the enzyme activities measured and insecticide susceptibility. These results are discussed in the context of insecticide selection and future control effectiveness.


Local metabolite accumulation augments passive muscle stretch-induced modulation of carotid-cardiac but not carotid-vasomotor baroreflex sensitivity in man.
We examined the effects of muscle mechanoreflex stimulation by passive calf muscle stretch, at rest and during concurrent muscle metaboreflex activation, on carotid baroreflex (CBR) sensitivity. Twelve subjects either performed 1.5 min one-legged isometric plantarflexion at 50% maximal voluntary contraction with their right or left calf [two ischaemic exercise (IE) trials, IER and IEL] or rested for 1.5 min [two ischaemic control (IC) trials, ICR and ICL]. Following exercise, blood pressure elevation was partly maintained by local circulatory occlusion (CO). 3.5 min of CO was followed by 3 min of CO with passive stretch (STR-CO) of the right calf in all trials. Carotid baroreflex function was assessed using rapid pulses of neck pressure from +40 to -80 mmHg. In all IC trials, stretch did not alter maximal gain of carotid-cardiac (CBR-HR) and carotid-vasomotor (CBR-MAP) baroreflex function curves. The CBR-HR curve was reset without change in maximal gain during STR-CO in the IEL trial. However, during the IER trial maximal gain of the CBR-HR curve was smaller than in all other trials (-0.34+/-0.04 beats min(-1) mmHg(-1) in IER versus -0.76+/-0.20, -0.94+/-0.14 and -0.66+/-0.18 beats min(-1) mmHg(-1) in ICR, IEL and ICL, respectively), and significantly smaller than in IEL (P<0.05). The CBR-MAP curves were reset from CO values by STR-CO in the IEL and IER trials with no changes in maximal gain. These results suggest that metabolite sensitization of stretch-sensitive muscle mechanoreceptive afferents modulates baroreflex control of heart rate but not blood pressure.


[A multidimensional questionnaire as a component of preventive geriatric assessment: comparison of self-assessment version with the interview version].
In an earlier study we have shown good internal consistency and test-retest-reliability of a newly developed German-language instrument in the interviewer-administered version. The aim of this study was to test the reliability of a self-administered version compared to the original interviewer-administered version of our newly developed German-language instrument. We recruited a group of 50 over 75-year-old community-dwelling persons in Hamburg, Germany (N = 25) and Berne, Switzerland (N = 25). The questionnaire contains items on: self-perceived health, chronic conditions, basic and instrumental activities of daily living, urinary incontinence, nutrition, recent falls, pain, the social support/network and preventive-care measures. In addition, the Functional Status Questionnaire, the Physical Activity Scale for the Elderly, the Geriatric Oral Health Assessment Index, the Visual Function Questionnaire, the Hearing Handicap Inventory for the Elderly and the Geriatric Depression Scale were administered. Cohen's Kappa (self-administered version compared to the interviewer-administered version) was good to excellent (0.69-1.0) with only three exceptions (physical activity kappa = 0.49, basic activities kappa = 0.54 and oral health kappa = 0.54). For the domains activities of daily living, oral health, visual function and depression the self-administered version detected significantly more problems than the interview. In the future the self-administered version of this assessment instrument can be used for various purposes, e.g. (annual) preventive geriatric assessment for outpatients and other community-dwelling persons and epidemiological studies in older persons.


Sorbinil does not prevent galactose-induced glomerular capillary basement membrane thickening in the rat.
We investigated the role of the polyol pathway in the pathogenesis of glomerular basement membrane thickening in galactosaemic rats, an animal model that develops basement membrane lesions comparable to those of human diabetic subjects. Normotensive Wistar-Kyoto rats fed a 30% galactose diet for nine months developed significant glomerular basement membrane thickening by comparison with rats on a control test diet (p = 0.008). However, addition of an aldose reductase inhibitor, sorbinil (250 mg/kg diet), to the galactose diet did not prevent the increase in glomerular basement membrane thickness. Furthermore, by using a quantitative electron microscopic immunogold technique, we examined biochemical alterations in the composition of glomerular basement membranes in this animal model. The labelling density (comparable to relative concentration) of collagen type IV in thickened glomerular basement membranes of galactosaemic animals was significantly increased by comparison to those of control rats (p = 0.015). However, there was no significant difference in labelling densities of laminin and heparan sulfate proteoglycan core protein of these animals. Thus, our results indicate that an increase in glomerular basement membrane thickness accompanied by an increase in the labelling density of collagen type IV occurs in the galactosaemic rats, but this thickening is not prevented by sorbinil at the dose used in this experiment. Our study raises the strong possibility that glomerular basement membrane thickening in galactosaemic rats may not be due to excessive polyol pathway activity.


Enhanced excretion of urinary leukotriene E4 in coronary artery disease and after coronary artery bypass surgery.
Excretion of leukotriene (LT) E4, the major urinary metabolite of cysteinyl leukotrienes in humans, is increased in patients with unstable angina and myocardial infarction, suggesting that cysteinyl leukotrienes are released into the circulation during episodes of myocardial ischaemia. Furthermore, leukotrienes are known to induce potent vasoconstrictive effects in human atherosclerotic coronary arteries and the saphenous vein. Accordingly, we measured urinary excretion of LTE4 in patients with stable coronary artery disease both before and after coronary artery bypass surgery, and in age-matched healthy controls, to study the relation between the systemic synthesis of cysteinyl leukotrienes and stable coronary artery disease, as well as the possible changes after bypass surgery. LTE4 was isolated from urine samples by solid-phase extraction, purified by reverse-phase high-performance liquid chromatography, and subsequently quantified by radioimmunoassay. In patients with coronary artery disease, preoperative urinary LTE4 levels were normally distributed on a log10 scale, with a genometric mean of 115 pmol/mmol creatinine (95% confidence interval 67-196) compared with 63.0 pmol/mmol creatinine (95% confidence interval 47.9-82.7) in healthy subjects (P < 0.05). Urinary LTE4 levels increased further in patients after coronary artery bypass surgery with levels peaking on the second day after surgery (266.2 pmol/mmol creatinine, 95% confidence interval 167.2-423.9) at significantly higher than preoperative levels (P < 0.02), and then decreasing by day 3. Levels of cysteinyl leukotrienes are raised in coronary artery disease patients both before and after coronary artery bypass surgery. As these mediators are capable of inducing potent vasoconstrictive effects on atherosclerotic coronary arteries and the saphenous vein, our results could have important clinical and possibly therapeutic implications.


Harnessing particle disintegration of cooked rice grains for predicting glycaemic index.
This study investigated the particle disintegration of cooked milled rice during in vitro digestion to identify its potential for rapidly predicting glycaemic index (GI). Milled grains and flour of rice with varying GI were cooked, stirred and subjected to digestion followed by kinetics analyses. Despite variations in physicochemical parameters (typically amylose content), flours showed a single-phase-digestion rate (k, ∼0.12 min-1) which did not vary significantly between varieties. In contrast, intact grains were disintegrated into small/intermediate (d < 30 μm, 30 < d < 300 μm) and large (d > 300 μm) particles. The small/intermediate particles comprising 50-70 % starch were initially-digested (0-20 min) at a fast k-f (∼0.05-0.10 min-1), which enabled to differentiate rice digestibility; whereas the large was latter-digested (20-180 min) at a slow k-s (∼0.04 min-1). The sum-ratio of disintegrated-particle 0-300 μm (Q-300) correlated positively with clinical GI values, allowing for a digestibility prediction of intact milled rice grain.


The science of CBT: toward a metacognitive model of change?
This article supports several aspects of the arguments by Hofmann, Asmundson, and Beck (2013--this issue) about the scientific basis of cognitive-behavioral therapy (CBT), for example, that CBT has a strong evidence base, and that studies of the mechanisms of change are warranted. This response discusses growth within the broad field of CBT, as well as the diverse research methods that are needed to explore both clinical efficacy and treatment mechanism questions. It is suggested that the field of CBT may be approaching a shift in emphasis from cognitive to metacognitive assessment and interventions. The article concludes with a statement of general support for further development of the field of CBT.


Inhibition of mouse trypsin isoforms by SPINK1 and effect of human pancreatitis-associated mutations.
Serine protease inhibitor Kazal type 1 (SPINK1) is a trypsin-selective inhibitor protein secreted by the exocrine pancreas. Loss-of-function SPINK1 mutations predispose to chronic pancreatitis through either reduced expression, secretion, or impaired trypsin inhibition. In this study, we aimed to characterize the inhibitory activity of mouse SPINK1 against cationic (T7) and anionic (T8, T9, T20) mouse trypsin isoforms. Kinetic measurements with a peptide substrate, and digestion experiments with β-casein indicated that the catalytic activity of all mouse trypsins is comparable. Human SPINK1 and its mouse ortholog inhibited mouse trypsins with comparable efficiency (KD range 0.7-2.2 pM), with the sole exception of T7 trypsin, which was inhibited less effectively by the human inhibitor (KD 21.9 pM). Characterization of four chronic pancreatitis-associated human SPINK1 mutations in the context of the mouse inhibitor revealed that the reactive-loop mutations R42N (human K41N) and I43M (human I42M) impaired SPINK1 binding to trypsin (KD 60 nM and 47.5 pM, respectively), whereas mutations D35S (human N34S) and A56S (human P55S) had no impact on trypsin inhibition. Our results confirmed that high-affinity trypsin inhibition by SPINK1 is conserved in the mouse, and the functional consequences of human pancreatitis-associated SPINK1 mutations can be replicated in the mouse inhibitor.


Scrotal hitch procedure to prevent apical necrosis of scroto-perineal flap for urethroplasty.
To present our experience with scrotal hitch technique to prevent necrosis of apex of scroto-perineal flap during two staged open urethroplasty for long segment complex anterior urethral strictures. Over the past 6 years, 22 patients underwent two-staged urethroplasty at our institution. All the strictures were laid open during first stage along with scrotal hitch. The stitch was removed after 7 days. The flap was healthy in all 22 patients at the time of second stage. Neo-meatal stenosis was not seen in any of the patients. One patient had local site collection, which was cured by topical antibiotics. This technique is simple, cost effective, which minimizes the drag over the flap by the shaft of the Foley catheter and thus prevents its pressure necrosis. The technique is particularly helpful in cases of thick, bulky scrotum and does not cause any morbidity, instead allows for early, comfortable ambulation and obviates the need of cumbersome scrotal supportive dressings.


Geographical disparities and determinants of infant mortality in Ethiopia: mapping and spatial analysis using EDHS data.
Infant mortality remains a public health challenge in Ethiopia. Exploring infant mortality will aid in tracking the progress toward achieving sustainable development goals. The study aimed to explore the geographical variations and associated factors of infant mortality in Ethiopia. A total of 11,023 infants from the 2016 Ethiopian Demographic and Health Survey (EDHS) data were extracted and included in the analysis. EDHS used a two-stage cluster sampling design with a census enumeration area as the primary sampling unit and households as the secondary sampling unit. Arc GIS software was used for spatial analysis using clusters for exploring geographical variations in infant mortality. A binary logistic regression was employed using R software to identify the significant determinants of infant mortality. The study revealed that the spatial distribution of infant mortality was non-random in the country. Infants whose mothers not receiving ANC (AOR = 1.45; 95%CI: 1.17, 1.79), not breastfed status (AOR = 3.94; 95%CI: 3.19, 4.81), poor wealth index (AOR = 1.36; 95%CI: 1.04, 1.77), male infants (AOR = 1.59; 95%CI: 1.29, 1.95), birth order of six or above (AOR = 3.11; 95%CI: 2.08, 4.62), small birth size (AOR = 1.27; 95%CI: 1.26, 1.60), birth spacing [(≤ 24 months (AOR = 2.29; 95%CI: 1.79, 2.92), 25-36 months (AOR = 1.16; 95%CI: 1.12, 1.49)], multiple births (AOR = 6.82; 95%CI: 4.76, 10.81), rural residence (AOR = 1.63; 95%CI: 1.05, 2.77) and regions [Afar (AOR = 1.54; 95%CI: 1.01, 2.36), Harari (AOR = 1.56; 95%CI: 1.04, 2.56), and Somali (AOR = 1.52; 95%CI: 1.03, 2.39)] were the determinants of infant death in Ethiopia. There is a great geographical disparity in infant mortality rates across regions. Afar, Harari, and Somali regions were verified as hot spot areas. ANC usage, breastfed status, wealth index, sex of the infant, birth order, birth size, birth spacing, birth type, residence, and region were the determinants of infant death in Ethiopia. Therefore, appropriate interventions need to be implemented in the hot spots to alleviate the risk factors for infant mortality.


Pulmonary reactions after exposure to 3-methylfuran vapour, a fungal metabolite.
A case of obstructive pulmonary reaction with flu-like symptoms after exposure to 3-methylfuran is described. This compound is produced by fungi, and can be found in buildings with mould growth. Previous studies have shown that exposure to the substance might increase the prevalence of respiratory symptoms, and is pneumotoxic to animals at high concentrations.


The effect of prior BCG vaccination on the clinical and radiographic presentation of tuberculosis meningitis in children in Istanbul, Turkey.
Department of Pediatrics, Istanbul University Faculty of Medicine, Istanbul, Turkey, between January 1984 and December 1996. To explore whether neonatal BCG vaccination offers any protective effect on clinical and laboratory profiles of central nervous system (CNS) tuberculosis in children. A retrospective review of cases of CNS tuberculosis diagnosed and treated in one institution. Of the 145 patients identified with CNS tuberculosis, 9.6% were vaccinated during the neonatal period. The rate of close contact with contagious pulmonary tuberculosis in family, age distribution, clinical findings and laboratory investigations on admission were not significantly different in vaccinated and non-vaccinated children. Although mortality rate in the vaccinated patients (8.3%) was found to be nearly half of that in the non-vaccinated group (15.1%), severe sequelae were significantly more frequent (P < 0.02) among the vaccinated patients; This study shows that neonatal BCG vaccine has little effect on the clinical findings of subsequent CNS tuberculosis, and that these children have typical presentations of tuberculosis disease.


Recognizing and treating upper extremity lymphedema in postmastectomy/lumpectomy patients: a guide for primary care providers.
To provide an overview of the lymphatics, physiology of lymphedema (LE), incidence, risks, and costs as well as a guide for the primary care provider on how to recognize the symptoms of LE, a review of current published treatment recommendations, and advice about making a referral to appropriate LE specialists. Selected studies on diagnosing and treating LE in breast cancer patients following mastectomy/lumpectomy and evidence-based treatment guidelines. LE is the most common complication related to breast cancer treatment with an occurrence estimated between 10% and 60% depending on the parameters used for measurement. Most commonly, LE occurs within the first 3 years after breast cancer treatment, but the remaining cases happen beyond this period of time and can occur after many years. This means that significant numbers of patients with LE can present to primary care clinicians. A patient who is treated for breast cancer will be followed for a time by the oncology team, but eventually, that patient will be discharged from the oncology practice and will be seen in primary care. Risk factors for developing LE include treatment-related (number of nodes removed and radiation to axilla), disease-related (stage and location of tumor), and patient-related (younger age, obesity, and comorbid conditions) factors. A systematic evaluation of any patient presenting with LE will assure accurate diagnosis and prompt treatment.


Toll-like receptor 4-mediated immune stress in pregnant rats activates STAT3 in the fetal brain: role of interleukin-6.
Prenatal exposure to pathogens induces long lasting effect on brain function and plasticity. It is unclear how maternal immune stress impacts fetal brain development. Immune challenged pregnant rats induce the production of inflammatory cytokines including tumor necrosis factor (TNF)α, interleukin (IL)1β, and IL-6. IL-6 crosses the placenta but its mechanism of action on fetal brain is unclear. Gestation day 15 (GD15) rats were given a single injection of lipopolysaccharide (LPS) (100 µg/kg) in the presence or the absence of an IL-6 neutralizing antibody (IL-6Ab, 10 µg/kg). The activation of the intracellular signal of IL-6; signal transducer and activator of transcription (STAT3) and levels of glucocorticoids (GCs) were monitored in fetal brains. LPS administration to GD15 rats significantly increased the phosphorylation levels of STAT3 in fetal brains. Such activation was blunted by IL-6Ab. LPS induced a significant rise in GCs in the plasma of dams but not in fetal brains. IL-6Ab significantly reduced LPS-induced GCs in maternal plasma. Toll-like receptor 4 (TLR4)-induced activation of the maternal innate immune system affects fetal brains likely via the mobilization of IL-6/STAT3 pathway. In contrast, TLR4-stimulated maternal GCs release is less likely to play a significant role in fetal brain development.


Impact of PGC-1α on the topology and rate of superoxide production by the mitochondrial electron transport chain.
Reactive oxygen species (ROS) play an important role in normal signaling events and excessive ROS are associated with many pathological conditions. The amount of ROS in cells is dependent on both the production of ROS by the mitochondrial electron transport chain and their removal by ROS-detoxifying enzymes. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of mitochondrial functions and a key regulator of the ROS-detoxifying program. However, the impact of PGC-1α on the topology and rate of superoxide production by the mitochondrial electron transport chain is not known. We report here, using mitochondria from muscle creatine kinase-PGC-1α transgenic mice, that PGC-1α does not affect the topology of ROS production, but increases the capacity of complexes I and III to generate ROS. These changes are associated with increased mitochondrial respiration and content of respiratory chain complexes. When normalizing ROS production to mitochondrial respiration, we find that PGC-1α preserves the percentage of free radical leak by the electron transport chain. Together, these data demonstrate that PGC-1α regulates the intrinsic properties of mitochondria in such a way as to preserve a tight coupling between mitochondrial respiration and ROS production.


Metropolitan area income inequality and self-rated health--a multi-level study.
We examined the association of income inequality measured at the metropolitan area (MA) and county levels with individual self-rated health. Individual-level data were drawn from 259,762 respondents to the March Current Population Survey in 1996 and 1998. Income inequality and average income were calculated from 1990 census data, the former using Gini coefficients. Multi-level logistic regression models were used. Controlling for sex, age, race, and individual-level household income, respondents living in high, medium-high, and medium-low income inequality MAs had odds ratios of fair/poor self-rated health of 1.20 (95% confidence interval 1.04-1.38), 1.07 (0.95-1.21), and 1.02 (0.91-1.15), respectively, compared to people living in the MAs with the lowest income inequality. However, we found only a small association of MA-level income inequality with fair/poor health when controlling further for average MA household income: odds ratios were 1.10 (0.95-1.28), 1.01 (0.89-1.14), and 1.00 (0.89-1.12), respectively. Likewise, we found only a small association of county-level income inequality with self-rated health although only 40.7% of the sample had an identified county on CPS data. Regarding the association of state-level income inequality with fair/poor health, we found the association to be considerably stronger among non-metropolitan (i.e. rural) compared to metropolitan residents.


Reaction times predict dynamic brain representations measured with MEG for only some object categorisation tasks.
Behavioural categorisation reaction times (RTs) provide a useful way to link behaviour to brain representations measured with neuroimaging. In this framework, objects are assumed to be represented in a multidimensional activation space, with the distances between object representations indicating their degree of neural similarity. Faster RTs have been reported to correlate with greater distances from a classification decision boundary for animacy. Objects inherently belong to more than one category, yet it is not known whether the RT-distance relationship, and its evolution over the time-course of the neural response, is similar across different categories. Here we used magnetoencephalography (MEG) to address this question. Our stimuli included typically animate and inanimate objects, as well as more ambiguous examples (i.e., robots and toys). We conducted four semantic categorisation tasks on the same stimulus set assessing animacy, living, moving, and human-similarity concepts, and linked the categorisation RTs to MEG time-series decoding data. Our results show a sustained RT-distance relationship throughout the time course of object processing for not only animacy, but also categorisation according to human-similarity. Interestingly, this sustained RT-distance relationship was not observed for the living and moving category organisations, despite comparable classification accuracy of the MEG data across all four category organisations. Our findings show that behavioural RTs predict representational distance for an organisational principle other than animacy, however further research is needed to determine why this relationship is observed only for some category organisations and not others.


Patients with New York Heart Association class III heart failure may benefit with high flow nasal cannula supportive therapy: high flow nasal cannula in heart failure.
High flow nasal cannula (HFNC) may decrease preload being associated with beneficial hemodynamic and respiratory effects in adults with heart failure. This is a sequential intervention prospective study including 10 adults with New York Heart Association (NYHA) class III and left ventricle ejection fraction 45% or less. High flow gas was administered (fraction of inspired oxygen, 0.21) through nasal cannula (Optiflow(TM); Fisher & Paykel, Auckland, New Zealand). Sequential echocardiographies were performed at baseline, using HFNC with 20 lpm and 40 lpm and post-HFNC. A reduction greater than 20% in the estimated inspiratory collapse of the inferior vena cava (IVC) from baseline was considered clinically significant. Ten patients were included, with median age of 57 (44-65) years; 6 (60%) were female, and 8 (80%) had dilated cardiomyopathy. Median IVC inspiratory significantly (P<.05) decreased from baseline (37%) to HFNC with 20 lpm (28%) and HFNC with 40 lpm (21%), representing mean attributable reductions of 20% (95% confidence interval, 6-55) and 53% (95% confidence interval, 36-67) from baseline. Changes in the IVC inspiratory collapse were reversible after HFNC withdrawal. Respiratory rate was significantly reduced from 23 breaths per minute at baseline to 17 breaths per minute at HFNC with 20 lpm and 13 breaths per minute at HFNC with 40 lpm. In contrast, no significant changes in other echocardiographic or clinical variables were documented. These findings suggest that patients with NYHA class III heart failure may benefit with HFNC supportive therapy.


The quality of VA mental health services.
This study examines whether male and female veterans differ on either subjective or objective measures of the quality of VA mental health care. The study sample were all discharged with a psychiatric diagnosis from a VA inpatient mental health program. Results indicate that women were less satisfied with inpatient care, but were mixed on their satisfaction with overall mental health care. Males and females did not differ on the quality of inpatient care, but women had significantly higher quality of outpatient care. These results not only highlight the need to stratify or adjust quality measures by gender, but also highlight the potential confounding effect of sub-group specific health behaviors on measures of quality.


A practical illustration of spatial smoothing methods for disconnected regions with INLA: spatial survey on overweight and obesity in Malaysia.
National prevalence could mask subnational heterogeneity in disease occurrence, and disease mapping is an important tool to illustrate the spatial pattern of disease. However, there is limited information on techniques for the specification of conditional autoregressive models in disease mapping involving disconnected regions. This study explores available techniques for producing district-level prevalence estimates for disconnected regions, using as an example childhood overweight in Malaysia, which consists of the Peninsular and Borneo regions separated by the South China Sea. We used data from Malaysia National Health and Morbidity Survey conducted in 2015. We adopted Bayesian hierarchical modelling using the integrated nested Laplace approximation (INLA) program in R-software to model the spatial distribution of overweight among 6301 children aged 5-17 years across 144 districts located in two disconnected regions. We illustrate different types of spatial models for prevalence mapping across disconnected regions, taking into account the survey design and adjusting for district-level demographic and socioeconomic covariates. The spatial model with split random effects and a common intercept has the lowest Deviance and Watanabe Information Criteria. There was evidence of a spatial pattern in the prevalence of childhood overweight across districts. An increasing trend in smoothed prevalence of overweight was observed when moving from the east to the west of the Peninsular and Borneo regions. The proportion of Bumiputera ethnicity in the district had a significant negative association with childhood overweight: the higher the proportion of Bumiputera ethnicity in the district, the lower the prevalence of childhood overweight. This study illustrates different available techniques for mapping prevalence across districts in disconnected regions using survey data. These techniques can be utilized to produce reliable subnational estimates for any areas that comprise of disconnected regions. Through the example, we learned that the best-fit model was the one that considered the separate variations of the individual regions. We discovered that the occurrence of childhood overweight in Malaysia followed a spatial pattern with an east-west gradient trend, and we identified districts with high prevalence of overweight. This information could help policy makers in making informed decisions for targeted public health interventions in high-risk areas.


A survey of chloroquine use for prevention and treatment of COVID-19 in Nigeria.
Rampant chloroquine/hydroxychloroquine poisoning in Nigerian hospitals following suggestions of its possible efficacy in the treatment and prevention of the newly emerged COVID-19 disease informed this survey. The aim of this study was to assess the knowledge, attitude and perception of the Nigerian populace on the use of chloroquine in the COVID-19 pandemic. This cross-sectional study was done by administering an electronic questionnaire created using Google Docs, through social media cascade methods including the WhatsApp application software to capture data on chloroquine use between April 20 and June 20, 2020. Six hundred and twenty-eight people responded to the questionnaire (response rate 99.2%, mean age 41.05 ± 12.3) from the six geopolitical zones in Nigeria with 556 (88.5%) having tertiary level education. Only 21 (3.3%) of the respondents took chloroquine for treatment or prevention. Respondents from the North-west geopolitical zones used chloroquine 5.8 (95% CI: 1.55, 21.52, p=0.02) more times than other zones while the age group 20-29 were 8.8 times more likely to use chloroquine than any other age group (95% CI: 3.53, 21.70, p = 0.00). Female respondents were 2.3 times more likely to use chloroquine than the males (OR 2.26 95% CI: 0.90-5.68; p=0.08) and those in the income bracket of N75,000-99,000, 2.5 times more than other income groups. Young adults, North-western geopolitical zone, and female gender should be target groups for education on rational chloroquine use. The danger of chloroquine overdose should be communicated to the general population in Nigeria.


An exploration of spatial auditory BCI paradigms with different sounds: music notes versus beeps.
Visual brain-computer interfaces (BCIs) are not suitable for people who cannot reliably maintain their eye gaze. Considering that this group usually maintains audition, an auditory based BCI may be a good choice for them. In this paper, we explore two auditory patterns: (1) a pattern utilizing symmetrical spatial cues with multiple frequency beeps [called the high low medium (HLM) pattern], and (2) a pattern utilizing non-symmetrical spatial cues with six tones derived from the diatonic scale [called the diatonic scale (DS) pattern]. These two patterns are compared to each other in terms of accuracy to determine which auditory pattern is better. The HLM pattern uses three different frequency beeps and has a symmetrical spatial distribution. The DS pattern uses six spoken stimuli, which are six notes solmizated as "do", "re", "mi", "fa", "sol" and "la", and derived from the diatonic scale. These six sounds are distributed to six, spatially distributed, speakers. Thus, we compare a BCI paradigm using beeps with another BCI paradigm using tones on the diatonic scale, when the stimuli are spatially distributed. Although no significant differences are found between the ERPs, the HLM pattern performs better than the DS pattern: the online accuracy achieved with the HLM pattern is significantly higher than that achieved with the DS pattern (p = 0.0028).


The incidence, risk factors and predictive nomograms for early death among patients with stage IV gastric cancer: a population-based study.
Although advances in the treatment of stage IV gastric cancer (GC) patients, some patients were observed to die within 3 months of initial diagnosis. The present study aimed to explore the early mortality and risk factors for stage IV GC and further develop nomograms. A total of 2,174 eligible stage IV GC patients were selected from the Surveillance, Epidemiology, and End Results database. Logistic regression analyses were used to determine the risk factors and develop the nomograms to predict all-cause early death and cancer-specific early death. The predictive performance of the nomograms was assessed by receiver operating characteristic curves (ROC), calibration plots and decision curve analyses (DCA) in both training and validation cohorts. Of 2,174 patients enrolled, 708 died within 3 months of initial diagnosis (n=668 for cancer-specific early death). Early mortality remained stable from 2010-2015. Non-Asian or Pacific Islander (API) race, poorer differentiation, middle sites of the stomach, no surgery, no radiotherapy, no chemotherapy, lung metastases and liver metastases were associated with high risk of both all-causes early death and cancer-specific early death. The nomograms constructed based on these factors showed favorable sensitivity, with the area under the ROC range of 0.816-0.847. The calibration curves and DCAs also exhibited adequate fit and ideal net benefit in prediction and clinical application. Approximately one-third of stage IV GC patients experienced early death. These associated risk factors and predictive nomograms may help clinicians identify the patients at high risk of early death and be the reference for treatment choices.


Integrated probabilistic-fuzzy synthetic evaluation of drinking water quality in rural and remote communities.
An integrated probabilistic-fuzzy synthetic evaluation (PFSE) approach was developed for assessing drinking water quality in rural and remote communities (RRCs) through the lens of health risks and aesthetic impacts. The probabilistic health risk assessment can handle aleatory uncertainty raised by the variation of contaminant concentrations, and fuzzy synthetic evaluation (FSE) can address vagueness and ambiguity in human perception of risks and aesthetic impacts. The PFSE approach was applied to five RRCs in British Columbia, Canada where different drinking water quality issues, including high metal(loids) concentrations, the presence of coliforms, and poor aesthetics were reported. Cancer, non-cancer, and microbial risks assessed, as well as both quantitative and qualitative aesthetic impact assessment outcomes, were aggregated into synthetic water quality indices for water quality ranking. The probabilistic health risk assessment results revealed significant health risks for a community with relatively high arsenic concentrations (mean value = 7.0 μg/L) in the water supply. The microbial risks were also found significant (disability-adjusted life years >1 × 10-6) for all communities because of the presence of coliforms in the water. The FSE results indicated that the drinking water quality of five RRCs was associated with high aggregated impacts, which concurred with the "poor" water quality ratings according to the Canadian Water Quality Index. The water quality of the five RRCs was ranked based on the synthetic water quality evaluation indices. The PFSE approach can help decision-makers prioritize RRCs in effective resource allocation for addressing drinking water quality issues.


Physical comorbidity of migraine and other headaches in US adolescents.
To examine the pattern and extent to which other physical conditions are comorbid with migraine and other headaches in youth in a representative sample of the US population. The National Comorbidity Survey-Adolescent Supplement is a face-to-face survey of adolescents aged 13-18 years in the continental US. Sufficient information to assess the International Headache Society's criteria for migraine with and without aura over the past 12 months was available in the diagnostic module. A caretaker/parental self-administered report was used to assess a broad range of other physical conditions. The sample for these analyses was 6843 adolescents with systematic caretaker/parent reports. Adolescents with any headaches reported higher rates of other neurologic conditions, including epilepsy (OR, 2.02; 95% CI, 1.04-3.94), persistent nightmares (OR, 2.28; 95% CI, 1.34-3.87), and motion sickness (OR, 1.6; 95% CI, 1.07-2.4), as well as abdominal complaints (OR, 2.36; 95% CI, 1.59-3.51). Asthma (OR, 2.22; 95% CI, 1.26-3.92) and seasonal allergies (OR, 1.66; 95% CI, 1.12-2.48) were more common in adolescents with migraines than in adolescents with nonspecific headaches. Adolescent migraine is associated with inflammatory conditions such as asthma and seasonal allergies, as well as with epilepsy, persistent nightmares, and motion sickness. Our findings suggest that comorbid medical conditions should be evaluated comprehensively in determining treatment options in youth with headache. Such comorbidity also could be an important source of the clinical and etiologic heterogeneity in migraine.


Indocyanine green fluorescence imaging for sentinel lymph node detection in colorectal cancer: A systematic review.
Indocyanine green fluorescence-imaging (ICG-FI) has emerged as a potential tool for increasing the accuracy of staging of patients with primary colorectal cancer (CRC) through the detection of sentinel lymph nodes (SLNs). Here, we report the results of a systematic review of the available literature in the clinical setting of ex vivo and in vivo ICG-FI for the detection of SLNs in primary colorectal cancer. PubMed, Scopus, and Cochrane literature databases were searched for original articles on the use of ICG in the setting of clinical studies of CRC. Eighty studies were identified and screened, 23 were assessed for eligibility and 10 were included for review. Both ex vivo and in vivo ICG-FI are reported to be feasible for the detection of SLNs in CRC. The reported sensitivity of both techniques remains low, varying from 0% to 100% for the in vivo technique and 57% for the ex vivo technique. ICG-FI has not yet been shown to perform better than the standard blue dye technique. In addition, large variability among reported studies in terms of techniques used (ICG dose, type of injection), type of pathologic analyses performed (HE, IHC, serial section), and definition of positive LN status for sensitivity calculations made them difficult to compare directly. ICG-FI is a promising technique for the detection of SLNs in the setting of CRC but more work needs to be done to clearly define protocols and indications for its use and to test its efficacy in larger patient populations.


Comparative Study of the Preparation of High-Molecular-Weight Fibroin by Degumming Silk with Several Neutral Proteases.
Removing sericin from the periphery of silk without damage to silk fibroin (SF) to obtain high-molecular-weight SF is a major challenge in the field of SF-based biomaterials. In this study, four neutral proteases, subtilisin, trypsin, bromelain and papain, were used to degum silk, and the degumming efficiency of the proteases and their influence on the molecular weight (MW) of regenerated silk fibroin were studied. The results indicated that all four neutral proteases could remove sericin from silk almost completely, and they caused less damage to SF fibers than Na2CO3 degumming did. The degumming efficiency of trypsin and papain was strong, but they caused relatively high damage to SF, whereas bromelain caused the least damage. The results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, gel permeation chromatography and shear viscosity showed that the MWs of regenerated SF derived from neutral protease degumming were significantly higher than that of SF derived from Na2CO3 degumming. The MW of regenerated SF derived from bromelain degumming was the highest, while the MWs of regenerated SF derived from papain and trypsin degumming were relatively low. This study provides an efficient and environmentally friendly biological degumming method for obtaining high-molecular-weight silk fibroin.


Alzheimer's disease. Involving nursing in the development and implementation of health care for patients and families.
This article focuses on integrating nurses into the development, implementation, and evaluation of clinical, inpatient, community-based, and in-home services for patients with Alzheimer's disease and for their families.


Oral surgery wait times in NHS secondary dental care in England: a five-year review.
Aims To report the oral surgery referral to treatment waiting times in hospitals in England and to identify any trends in the percentage of patients seen within 18 weeks.Materials and methods Data published by the NHS statistics team was analysed from 2016-2020.Results Pre-COVID-19, the best performing month was February 2016, with 91.5% of patients seen within 18 weeks. The worst performing month was September 2019, with 79.3% of patients seen within 18 weeks. Oral surgery was the worst performing speciality for 8% of months (4/50). Post-COVID-19, oral surgery was the worst performing speciality for 70% of months (7/10). In July 2020, the percentage of patients seen within 18 weeks of an oral surgery referral dropped to 24%.Discussion Over the last five years, there has been a steady decline in the number of patients who have been seen within 18 weeks of their oral surgery referral. There has also been an increase in oral surgery referrals to secondary care which needs to be addressed.Conclusion Improvements to undergraduate and postgraduate training, combined with enhanced commissioning of primary care services, is required.


The yellow nail syndrome in an 8-year-old girl.
Yellow nail syndrome is characterized by the triad of abnormally shaped, slow-growing, yellow nails, lymphedema, and chronic respiratory tract disease. Nail changes may precede the other features by several years. The syndrome is most often seen in middle-aged individuals and has not been documented in children under age 11 years. We cared for an 8-year-old girl with this disorder.


TEST performance of a myositis panel in a clinical immunology laboratory in New South Wales, Australia.
There is increasing recognition of a clinico-serological correlation between the idiopathic inflammatory myopathies and myositis-specific autoantibodies (MSA). We review the use of a line immunoassay-based myositis panel incorporating both MSA and myositis-associated autoantibodies (MAA) in a selected population of patients. A retrospective analysis of patients with myositis panel assays performed in 2013 were reviewed and compared against clinical diagnoses. A total of 96 patient samples were evaluated, the clinical indications include 60 patients with suspected idiopathic inflammatory myositis (IIM), 24 patients with suspected interstitial lung disease (ILD) and 12 patients with suspected systemic autoimmune disease (SAD). In the myositis group, there were 21 patients diagnosed with IIM and 18 patients diagnosed with IIM had a positive myositis panel. Of the 39 patients without IIM, nine of these patients had a positive myositis panel. In the ILD group, 10 of 24 patients had a positive myositis panel; of these, two were diagnosed anti-synthetase syndrome (ASS) and five patients with ILD. In the suspected SAD group, three had positive myositis panel and all did not appear associated with their final diagnoses. In patients with a clinical diagnosis of IIM or ILD-associated SAD, four patients with anti-PL-12 were detected, three patients with anti-signal recognition protein, two patients with anti-Jo-1, and two patients with anti-Mi2. The myositis panel is an objective investigative modality with a sensitivity of 80.00% and a specificity of 75.76% in a setting of high pretest clinical suspicion.


Pediatric norovirus GII.4 infections in Nicaragua, 1999-2015.
Investigate clinical and epidemiological factors of pediatric GII.4 norovirus infections in children with acute gastroenteritis (AGE) in Nicaragua between 1999 and 2015. We retrospectively analyzed laboratory and epidemiologic data from 1,790 children≤7years with AGE from 6 hospitals in Nicaragua (n=538), and 3 community clinics (n=919) and households (n=333) in León, between 1999 and 2015. Moreover, asymptomatic children from community clinics (n=162) and households (n=105) were enrolled. Norovirus was detected by real-time PCR and genotyped by sequencing the N-terminal and shell region of the capsid gene. Norovirus was found in 19% (n=338) and 12% (n=32) of children with and without AGE, respectively. In total, 20 genotypes including a tentatively new genotype were detected. Among children with AGE, the most common genotypes were GII.4 (53%), GII.14 (7%), GII.3 (6%) and GI.3 (6%). In contrast, only one (1.4%) GII.4 was found in asymptomatic children. The prevalence of GII.4 infections was significantly higher in children between 7 and 12months of age. The prevalence of GII.4 was lowest in households (38%), followed by community clinics (50%) and hospitals (75%). Several different GII.4 variants were detected and their emergence followed the global temporal trend. Overall our study found the predominance of pediatric GII.4 norovirus infections in Nicaragua mostly occurring in children between 7 and 12months of age, implicating GII.4 as the main norovirus vaccine target.


[Synthesis of Butyl 6alpha-Fluoro-11beta-hydroxy-16alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (Fluocortin Butylester) (author's transl)].
Among the metabolites of fluocortolone (1) there was found the alpha-keto acid 4a. This acid, as well as the esters 4b--4k were synthesized and the butyl ester 4c was chosen for local anti-inflammatory therapy.


A prospective one-year study of estrogen and progestin in postmenopausal women: effects on clinical symptoms and lipoprotein lipids.
Ninety-five healthy women who had been amenorrheic for at least 6 months were randomly assigned to one of four cyclic, sequential hormone regimens for 1 year. Groups A and C received 0.625 or 1.25 mg conjugated equine estrogen (Premarin), respectively, from days 1-25 and 5 mg medroxyprogesterone acetate (Provera) from days 15-25. Groups B and D were given 0.625 or 1.25 mg conjugated equine estrogen, respectively, from days 1-25 and placebo from days 15-25. Plasma estrone levels were physiologic after the lower dose of conjugated equine estrogen and supraphysiologic after ingestion of the higher dose. All four treatment regimens successfully controlled hot flushes, but patients who received 1.25 mg conjugated equine estrogen with or without medroxyprogesterone acetate had a higher energy level and a more enhanced sense of well-being (P less than .05). The four treatments all had favorable effects on lipid metabolism, albeit in a dose-related manner: After 1 year of treatment, high-density lipoprotein levels increased 4.3, 13.7, 13.4, and 19% in groups A, B, C, and D, respectively, compared with pre-treatment values. The high-density lipoprotein/low-density lipoprotein ratios, an antiatherogenic index, increased by 7.3, 13.6, 24, and 43% in groups A, B, C, and D, respectively. The findings of this study on the relative effects of different doses of oral estrogen and progestin, administered sequentially, on clinical symptoms and lipid metabolism provide guidelines for the treatment of postmenopausal women.


Effect of feeding a daily oral care chew on the composition of plaque microbiota in dogs.
The objective of this study was to investigate the influence of daily feeding of an oral care chew on the composition of canine supragingival plaque microbiota. Twelve beagle dogs were recruited to the randomized cross-over study. The dogs were fed one of two dietary regimes, both consisting of a commercially available wet and dry diet mix, either with or without daily supplementation with an oral care chew. After each 28-day test phase, supragingival plaque samples were collected and processed via Illumina sequencing to determine the microbiota composition. A comparative analysis of bacterial species associated with health and periodontal disease, identified from prior clinical studies, revealed differences between the dietary regimes. Consumption of the daily oral care chew, resulted in a significant increase in proportion of 6 health associated taxa but only 3 disease associated taxa compared to no chew. In contrast, 8 disease and 1 health associated taxa showed increased proportions for no chew versus the oral care chew. Daily feeding of the oral care chew tested in this study has therefore been shown to increase the proportion of health associated bacteria, over bacteria associated with periodontal disease, in supragingival plaque compared to no chew. By influencing plaque microbiota towards a bias for health associated bacteria, feeding of the oral care chew provides a means to reduce the prevalence of bacterial species shown to be associated with periodontal disease in dogs.


A practical guide to separate and concentrate ALNs and femtoplankton entities.
The development of new technologies of microscopy, flow cytometry and genomics has allowed a profound reconsideration of the diversity and ecological role of femtoplankton entities (i.e., viruses, vesicles, aster like nanoparticles -ALNs-). Among these, the discovery of ALNs, raise serious questions about their exact nature and their biological and environmental roles. The elaboration of a practical guide for the concentration and separation of femtoplankton entities, including ALNs, is necessary for a better understanding of their diversity, ontogeny, and ecology. Here, we propose a step-by-step procedure for the enrichment and isolation of femtoplankton entities and prokaryotes. The established protocol couples tangential flow filtration to differential centrifugation, leading to differentiate enriched samples (with different target entity contents), usable as a matrix for sorting by flow cytometry. All entities were identified, characterized and counted by transmission electron microscopy and flow cytometry. The procedure allows an efficient detection, concentration and separation of femtoplankton entities (up to purity rate of 92, 67, 81 and 85% for virus like particles, vesicles, prokaryotes and ALNs, respectively), and different morphotypes of ALNs into different fractions (up to 51, 72, 52, 40 and 79% of total ALNs for 20-, 11-, budding 11-, 5-10- and 4-armed ALNs, respectively).


Contextualized response of carbon-use efficiency to warming at the plant and ecosystem levels.
Carbon-use efficiency (CUE) has been widely used as a constant value in many earth system models to simulate how assimilated C is partitioned in ecosystems, to estimate ecosystem C budgets, and investigate C feedbacks to climate warming. Although correlative relationships from previous studies indicated that CUE could vary with temperature, and relying on a fixed CUE value could cause large uncertainty in model projections, however, due to the lack of manipulative experiment, it remains unclear how CUE at the plant (CUEp) and ecosystem (CUEe) levels respond to warming. Based on a 7-year manipulative warming experiment in an alpine meadow ecosystem on the Qinghai-Tibet Plateau, we quantitatively distinguished various C flux components of CUE, including gross ecosystem productivity, net primary productivity, net ecosystem productivity, ecosystem respiration, plant autotrophic respiration, and microbial heterotrophic respiration and explored how CUE at different levels responded to climate warming. We found large variations in both CUEp (0.60 to 0.77) and CUEe (from 0.38 to 0.59). The warming effect on CUEp was positively correlated with ambient soil water content (SWC) and the warming effect on CUEe was negatively correlated with ambient soil temperature (ST), but was positively correlated with warming-induced changes in ST. We also found that the direction and magnitude of the warming effects on different CUE components scaled differently with changes in the background environment, which explained the variation in CUE's warming response under environmental changes. Our new insights have important implications for reducing modelling uncertainty of ecosystem C budgets and improving our ability to predict ecosystem C-climate feedbacks under climate warming.


Risk analysis of COVID-19 hospitalization and critical care by race and region in the United States: a cohort study.
This study aimed to identify the current risk factors for coronavirus disease 2019 severity and examine its association with medication use. We used data from a large United States electronic health record database to conduct an anonymized cohort study of 171,491 patients with coronavirus disease 2019. The study was conducted from January 1, 2020, to August 27, 2021. Data on age, race, sex, history of diseases, and history of medication prescriptions were analyzed using the Cox proportional hazards model analysis to calculate hazard ratios for hospitalization and severe risk. Factors that increased the risk of hospitalization and critical care were age ≥ 65 years, male sex, type 2 diabetes, hypertension, interstitial pneumonia, and cardiovascular disease. In particular, age ≥ 65 years significantly increased the risk of hospitalization (hazard ratio, 2.81 [95% confidence interval, 2.58-3.07]; P < 0.001) and critical care (hazard ratio, 3.45 [2.88-4.14]; P < 0.001). In contrast, patients with hyperlipidemia had a reduced risk. However, patients with hyperlipidemia who were not taking statins had a significantly increased risk of hospitalization (hazard ratio, 1.24 [1.16-1.34]; P < 0.001). Sodium-glucose cotransporter-2 inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, glucocorticoids, and statins significantly reduced the risk of hospitalization and critical care. The risk of hospitalization and critical care increased in patients of all ethnicities with type 2 diabetes. The factors that significantly increased the risk of hospitalization in all regions were older age, hypertension, chronic obstructive pulmonary disease, and cardiovascular disease. This study identified factors that increase or reduce the risk of severe coronavirus disease. The provision of appropriate drug treatment and modification of lifestyle-related risk factors may reduce coronavirus disease severity.


Reduction of herpes simplex virus-type 2 plaque formation by urea.
The effect of urea on plaque formation by herpes simplex virus type 2 (HSV-2) was examined in two systems at concentrations within or approximating the range found in human urine. Approximately 7--10 mg urea/ml, added 2, 4, or 8 hours after infection, reduced plaque formation by 50% in African green monkey kidney cells. The growth of this system was affected slightly by continuous treatment with urea at 7--10 mg/ml. Plaque formation was reduced in the monkey kidney system, albeit diminishingly, even after addition of urea 12 hours after infection. In the human lung fibroblast system, urea at 10 mg/ml reduced plaque numbers by 50% but depressed the growth of cells completely.


The effect of arterial oxygen content on the results of radiation therapy for epidermoid bronchogenic carcinoma.
Anemia is believed to be an important prognostic factor in treating cancer patients by radiation therapy. One possible explanation for this is tumor oxygenation. With respect to tumor oxygenation, the arterial oxygen content (CaO2) may be of more importance than the hemoglobin (Hb) level. This study shows the relationship between the CaO2 and tumor response to radiation therapy. Forty-two patients with epidermoid bronchogenic carcinoma, treated by irradiation alone between April 1982 and March 1986, were reviewed. Regression of the tumor after radiation therapy was calculated as a percent change in the tumor area. Arterial oxygen partial pressure (PaO2), Hb level, and percent oxygen saturation of Hb in arterial blood (SaO2) were measured within 2 weeks of commencement of radiation therapy and the CaO2 was calculated. The rank correlation coefficients between the maximum percent regression of the tumor and the PaO2, the Hb level and the CaO2 were 0.36, 0.34, and 0.46, respectively. Statistical analyses of the data indicate that the group of patients with CaO2 over 14.5 ml/dl exhibited greater tumor regression and longer survival periods than the group of patients with CaO2 below 14.5 ml/dl. Similarly patients with PaO2 over 90 mmHg or Hb level over 11 g/dl, exhibited significantly greater tumor regression and longer survival periods than those with PaO2 below 90 mmHg and Hb level below 11 g/dl. There were no significant differences in the length of survival periods with respect solely to the Hb level or the PaO2. It was concluded that the CaO2 is more important than the Hb level in determining tumor response to radiation therapy. This is considered as important indirect evidence of the existence of hypoxic fractions of cells in human tumors.


Expression of the basal cell markers of taste buds in the anterior tongue and soft palate of the mouse embryo.
Although embryonic expression of Shh in the fungiform papilla placodes has a critical role in fungiform papilla patterning, it remains unclear whether its appearance indicates the differentiation of the basal cells of taste buds. To examine the embryonic development of the basal cells, the expression of Shh, Prox1, and Mash1 was determined in the anterior tongue and soft palate in mouse embryos by in situ hybridization. In the anterior tongue, Prox1 was coexpressed with Shh from the beginning of Shh expression in the fungiform papilla placodes at E12.5. Shh was expressed in the soft palate in a band-like pattern in the anteriormost region and in a punctate pattern in the posterior region at E14.5. The number (21.4 +/- 4.3, at E14.5) of locations where Shh was observed (i.e., spots) rapidly increased and reached a peak level (54.8 +/- 4.0 at E15.5). Also in the soft palate, Prox1 was coexpressed with Shh from the beginning of Shh expression. These results suggest that basal cell differentiation occurs synchronously with the patterning of Shh spots both in the anterior tongue and in the soft palate. In contrast, Mash1 expression lagged behind the expression of Shh and Prox1 and began after the number of Shh spots had reached its peak level in the soft palate. Furthermore, immunohistochemistry of PGP9.5 and Shh revealed that epithelial innervation slightly preceded Mash1 expression both in the tongue and in the soft palate. This is the first report describing the time courses of the embryonic expression of basal cell markers of taste buds.


High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation.
Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation. We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and analysed via population pharmacokinetic modelling. The concentration-time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2-22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199-267) and 521 L (95% CI 441-634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5-64.4). The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24.


Is there a place for ileal pouch-anal anastomosis in patients with Crohn's colitis?
It is generally agreed that ileal pouch-anal anastomosis (IPAA) is contraindicated in patients with Crohn's disease (CD), since recurrent disease will frequently necessitate pouch excision, thereby fostering to the ultimate development of a short bowel syndrome. For these reasons, patients with CD requiring coloproctectomy have up till now undergone definitive end ileostomy. However, when faced with the prospect of definitive ileostomy in young patients, the possibility to keep, even for a few years before the disease recurs, acceptable continence and defecation must be stressed. Although the failure rate is higher in patients with CD than in patients with ulcerative colitis, long-term results from recent reports, as well as from our own experience, demonstrated that in selected patients with CD (i.e. without anoperineal or ileal manifestations), pouch can be maintain in function in 55 to 90% of the patients. In these patients functional results are similar to those of patients with ulcerative colitis. In conclusion, unlike the authors who consider that IPPA is definitely contraindicated in CD, we believe that IPAA could be proposed for selected patients with CD for whom rectal resection is mandatory, as an alternative to coloproctectomy with definitive end ileostomy. The patients concerned are those with no history of anal manifestations and no evidence of small bowel involvement.


Biomaterials used in urology: current issues of biocompatibility, infection, and encrustation.
This review focuses on the biomaterials used in urology, in particular, the properties of urethral catheters and ureteral stents currently being used in clinical practice. The importance of biomaterial type, biocompatibility, and encrustations are discussed and explained. Current management of bacterial infection and the importance of biofilms are presented, with recommendations based on published information.


Zygomaticomaxillary complex fractures: finding the least complicated surgical approach (A Randomized Clinical Trial).
Many approaches have been suggested for management of zygomaticomaxillary fractures. Each approach has its own advantages and limitations. The study is intended to compare between the subtarsal approach, conventional transconjuctival approach and the Y- modification of the transconjuctival approach in the management of zygomatico-maxillay complex fractures. Twenty-four patients with age range of 20-50 years requiring open reduction and fixation of a fractured zygomatic complex were randomly divided into three equal groups. Group A: subtarsal approach group, group B: a conventional transconjunctival approach group and group C: Y- modification of the transconjunctival approach group. Intraoperative and postoperative parameters were evaluated. As for the exposure time, group C had the longest duration. Easy access to the site of fracture was reached in all groups with no statistically significant difference. During the first 24 h, the pain was only statistically significant between groups A and B with higher pain level in group A. After the first week, pain was significantly higher in groups A and C, with respect to group B. The least edema was observed in group B after 24 h, one week and four weeks postoperatively. Regarding ocular complications, wound healing and sensory nerve function, there was no statistically significant difference between the groups. Scarring was only noticeable in group A patients. The transconjunctival approach provides adequate exposure with excellent esthetics and minor complications. The Y-modification also delivers an esthetic access with inconspicuous scar to the frontozygomatic region. The trial has been registered on clinicaltrials.gov (ID: NCT05695872).


Inhibition of capillary morphogenesis and associated apoptosis by dominant negative mutant transforming growth factor-beta receptors.
Transforming growth factor-beta 1 (TGF-beta 1) induces angiogenesis in vivo and capillary morphogenesis in vitro. Two receptor serine/threonine kinases (types I and II) have been identified as signal transducing TGF-beta receptors. We explored the possibility of inhibiting TGF-beta-mediated events in glomerular capillary endothelial cells using a TGF-beta type II receptor (T beta R-II) transdominant negative mutant. A mutant TGF-beta type II receptor (T beta R-IIM), lacking the cytoplasmic serine/threonine kinase domain, was produced by polymerase chain reaction using rat T beta R-II cDNA as template. Since T beta R-II and TGF-beta type I receptor (T beta R-I) heterodimerize for signal transduction, the mutant receptor competes for binding to wild-type T beta R-I, hence acting in a dominant negative fashion. Glomerular capillary endothelial cells were stably transfected with T beta R-IIM, and four independent clones were expanded. That the T beta R-IIM mRNA was expressed was shown by reverse transcriptase-polymerase chain reaction, RNase protection assay, and Northern analysis. Presence of cell surface T beta R-IIM protein was shown by affinity cross-linking with 125I-TGF-beta 1. In wild-type endothelial cells, TGF-beta 1 (2 ng/ml) significantly inhibited [3H]thymidine incorporation to 63 +/- 10% of control (n = 4). In transfected endothelial cells carrying T beta R-IIM, TGF-beta 1 stimulated [3H]thymidine incorporation to 131 +/- 9% of control (n = 4, p < 0.005). Also, in wild-type endothelial cells, endogenous and exogenous TGF-beta 1 induced apoptosis and associated capillary formation. Both apoptosis and capillary formation were uniformly and entirely absent in transfected endothelial cells carrying T beta R-IIM. This represents the first demonstration that capillary morphogenesis in vitro is associated with apoptosis, and that interference with T beta R-II signaling inhibits this process in glomerular capillary endothelial cells.


Control of Intramolecular Hydrogen Bonding in a Conformation-Switchable Helical-Spring Polymer by Solvent and Temperature.
A substituted poly(phenylacetylene) derivative (PPAHB ) with two hydroxymethyl groups at the meta position of the side phenyl ring was examined as a conformation-switchable helical spring polymer that responds to solvent and heat stimuli in a precisely controlled manner. Intramolecular hydrogen bonds, which cause the helical structure of the polymer, were broken and re-formed by adjusting the hydrogen-bonding strength values (pKHB ) of various combinations of solvents or by varying the temperature. In this process, a reversible conformational change from cis-cisoid to cis-transoid, accompanied by a phase transition in the form of a helix-coil transformation occurred, with the polymer exhibiting critical changes of color fading and recovery in specific environments. These results demonstrate that PPAHB can be used as either a pKHB indicator or a thermometer. The color changes of the polymer solution are described in detail based on spectroscopic analyses and thermodynamic considerations.


Immunotropic Effects and Proposed Mechanism of Action for 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors (Statins).
Inhibitors of HMG-CoA reductase (statins) are the major group of lipid-lowering drugs. Along with hypocholesterolemic activity, statins exhibit anti-inflammatory and immunomodulatory properties that expand their clinical use, particularly, in the treatment of chronic inflammatory and autoimmune disorders. In this review, we critically analyze the data of statin effects on immune cells (e.g., monocytes and T cells) involved in the development of atherosclerosis and other chronic inflammatory diseases. We (i) discuss the properties of statins and routes of cell entry, as well as their major intracellular targets; (ii) evaluate the data on the effects of statins on the subset composition of circulatory monocytes, ability of monocytes to migrate to the site of inflammation (cell motility and expression of adhesion molecules and chemokine receptors), production of cytokines, matrix metalloproteinases, and reactive oxygen species by monocytes/macrophages, and antigen-presenting activity in peripheral blood monocyte-derived dendritic cells; and (iii) summarize the data on the regulation of proliferation and differentiation of various CD4+ T cell subsets (type 1/2/17 helper T cells and regulatory T cells) by statins.


Action of a cytotoxin from Pseudomonas aeruginosa on human leukemic cell lines. Increase in cell permeability to Ca2+ and Mn2+ and lack of stimulation of inositol lipid turnover.
Quin2 loaded human leukemic, JURKAT and K562 cells, were exposed to various doses of Pseudomonas aeruginosa cytotoxin. This cytotoxin induced an increase in quin2 fluorescence indicating an increase in the cytoplasmic free Ca2+ concentration. The rate of the fluorescence increase and the lag time before the response were dependent on the doses of the cytotoxin. Addition of MnCl2 to the cytotoxin-treated cells induced a decrease in the quin2 fluorescence at rates dependent on the doses of the cytotoxin. The cytotoxin did not stimulate the inositol lipid turnover in JURKAT cells, which was determined by the accumulation of [3H]inositol phosphates in myo-[2-3H]inositol-prelabeled cells in the presence of LiCl. These results indicate that the cytotoxin increases cell permeability to both Ca2+ and Mn2+ by direct breakdown of the permeability barrier of the plasma membrane.


Self-reported benefit and weakness after botulinum toxin in dystonia.
With this retrospective, single center, chart review study, we investigate the self-reported benefit and weakness after botulinum toxin injections in three different types of dystonia: focal hand dystonia (FHD), blepharospasm and cervical dystonia. We found that the benefit lasts significantly longer in FHD compared to the other two groups.


Assessment of genetic risk for improved clinical-neuropathological correlations.
In the clinical diagnosis of dementia with Lewy bodies, distinction from Alzheimer's disease is suboptimal and complicated by shared genetic risk factors and frequent co-pathology. In the present study we tested the ability of polygenic scores for Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease to differentiate individuals in a 2713-participant, pathologically defined sample. A dementia with Lewy bodies polygenic score that excluded apolipoprotein E due to its overlap with Alzheimer's disease risk was specifically associated with at least limbic (transitional) Lewy-related pathology and a pathological diagnosis of dementia with Lewy bodies. An Alzheimer's disease polygenic score was associated with neuritic plaques and neurofibrillary tangles but not Lewy-related pathology, and was most strongly associated with an Alzheimer's pathological diagnosis. Our results indicate that an assessment of genetic risk may be useful to clinically distinguish between Alzheimer's disease and dementia with Lewy bodies. Notably, we found no association with a Parkinson's disease polygenic score, which aligns with evidence that dementia with Lewy bodies has a distinct genetic signature that can be exploited to improve clinical diagnoses.


Motor Vehicle Registration Taxes (MVRT) across EU countries: MNEs' profitability and the role of market concentration.
This paper discusses the effects of one-off Motor Vehicle Registration Taxes (MVRT) and market concentration level on the profitability of multinational enterprises (MNEs) operating in the European Union motor vehicle industry. Our simple theoretical framework shows that firm profits depend on the demand function and therefore on taxes applied to prices. We overcome empirically the challenges of making informative theoretical predictions on the pass-through rate under imperfect competition. We find that MVRT,-both as ad valorem taxes and as specific taxes,-have a significant negative effect on MNEs' profitability. Our findings show a statistically significant positive effect of market concentration on profitability. Finally, our results suggest that the degree of competitiveness in the motor vehicle market moderates the effect of MVRT on firm profitability only in EU countries where the MVRT is an ad valorem tax, with the negative effect of the ad valorem MVRT becoming higher as the motor vehicle market becomes less competitive.


Immune-enhancing activity of polysaccharides isolated from Atractylodis macrocephalae Koidz.
This study evaluated the immune-enhancing activity of polysaccharides from the rhizoma of Atractylodis macrocephalae Koidz (RAMPS) in vitro. Lymphocyte proliferation, cell cycle distribution, and percentages of CD4(+) and CD8(+) cells were determined. Different concentrations of RAMPS were added to peripheral blood T lymphocytes. Results showed that RAMPStp and RAMPS60c could significantly enhance T lymphocyte proliferation individually or synergistically with phytohemagglutinin at most concentrations. The active sites of RAMPStp and RAMPS60c were then selected. Lymphocyte cell cycle distribution and percentages of CD4(+) and CD8(+) cells were determined by flow cytometry. At most time points, RAMPS60c and RAMPStp could promote lymphocytes enter into S and G2/M phases. RAMPStp and RAMPS60c effectively improved the percentages of CD4(+) and CD8(+) T cells. RAMPStp produced optimal effects. Therefore, RAMPStp could be used as a component of novel immunopotentiators.


Carbapenemase OXA-423: A Novel OXA-23 Variant in Acinetobacter baumannii.
A novel variant of OXA-23, named OXA-423, was identified in an Acinetobacter baumannii clinical isolate. The aim of this study was to analyse the resistance phenotype of OXA-423. The A. baumannii strain WY-0713 was isolated from an intensive care unit patient. PCR was used to detect the bla OXA-23-like genes. Amplifying, cloning and sequencing were performed for the complete bla OXA-23-like. The novel bla OXA-423 and its ancestor bla OXA-23 were cloned into the expression vector pET-28b(+), and transformed into E. coli Rosetta (DE3) for antibiotic susceptibility testing. SDS-PAGE, modified Hodge test and CarbaNP test were used for detecting the expression of OXA-423 and OXA-23. PCR screening of A. baumannii WY-0713 was positive for bla OXA-23-like genes. Sequencing of the PCR product identified a novel bla OXA-23-like, named bla OXA-423 which encoding OXA-423. OXA-423 differed from OXA-23 by a crucial amino acid substitution (Val128Ala). The V128A substitution was located at the conserved active-site motifs SAV of OXA-23. Antibiotic susceptibility testing performed using isogenic E. coli showed that the MICs of E. coli Rosetta (pET-OXA-423) for penicillins and carbapenems were lower (reduced MICs 4-fold to 16-fold) than that of E. coli Rosetta (pET-OXA-23). The MICs of cefotaxime, ceftazidime and aztreonam for both transformants remained the same as the acceptor strain. Moreover, OXA-423 was slightly inhibited by sulbactam, clavulanic acid and tazobactam. SDS-PAGE analysis showed that OXA-423 and OXA-23 were conspicuously expressed. Modified Hodge test and CarbaNP test were positive demonstrated both of them were functional. OXA-423, the first report of an amino acid substitution located at conserved active-site motifs of OXA-23, conferred lower MIC values of penicillins and carbapenems as compared with OXA-23, while without affecting the resistance profiles of expanded-spectrum cephalosporins and aztreonam.


Percutaneous aortic valve replacement: endovascular resection of human aortic valves in situ.
Transluminal in vitro resection of severely calcified human aortic valves has already been successfully carried out by our group. The aim of this study was to analyze endovascular laser-assisted resection of human aortic valves in situ in 10 human cadavers. After anterolateral minithoracotomy, the aortic valve isolation chamber system was inserted into the descending aorta and pushed forward transluminally into the aortic position to generate a separate operation space between the subvalvular and the proximal ascending aortic area. After deployment and sealing of the chamber, stable function with a continuous chamber lavage of 1.58 L/min saline solution was established (8/10 cases). The endoscopically guided laser fiber was delivered via the right carotid artery. After fixation of a leaflet by a forceps catheter, the native leaflets were resected each by a thulium:YAG laser with 20-W power rating. Macropathology and micropathology of surrounding anatomic structures were analyzed. The duration of transluminal positioning and deployment of the aortic valve isolation chamber took 7.3 +/- 5.8 minutes. Fluoroscopy confirmed sealed chambers. The resection was completed in all leaflets and took, on average, 6.0 +/- 3.5 minutes per leaflet. The aortic wall was moderately injured in 4 of 10 cases and the aortic annulus in two cases with one aortic wall perforation. The surrounding tissue, the coronary ostia, the mitral valve, and the left ventricular outflow tract remained unaffected. This study demonstrates the feasibility of endovascular resection of human aortic valves in situ. This is a subsequent step toward complete percutaneous replacement (resection and implantation) of human aortic valves.


Quality improvement in pharmacy: a prescription for change.
Quality improvement activities offer pharmacists opportunities for establishing their roles as clinical practitioners, documenting their contributions to quality-of-care improvement, and bringing recognition to pharmacy as a clinical profession. Unfortunately, pharmacists haven't yet recognized the importance of or need for these programs. Drug usage evaluations and quality improvement still are not considered a benefit or an opportunity but continue to be perceived as boring, tedious tasks that must be performed for the Joint Commission rather than the patient. The time has come to refocus our emphasis on what really matters. We need to build quality improvement programs not merely to placate the Joint Commission but to improve the quality of care for patients. We need to build quality improvement programs that extend to the grass roots level of every organization so that everyone is involved, participating, and committed to correcting patient-care problems. This commitment must become a routine habit, a daily acknowledgment, and an ongoing process. Clinical practitioners must become actively involved in quality improvement programs by developing valid, reliable indicators to help ensure safe, appropriate use of drugs. We need to develop a computer model to assist in data collection for drug usage evaluations and quality improvement projects. And we must create a multidisciplinary team of practitioners, including physicians, nurses, and pharmacists, to thoroughly evaluate and respond to this information. A successful team effort means everybody wins, and the biggest winner of all is--and must be--the patient.


Scaffold repositioning of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies.
The concept of "one target, one drug, one disease" is not always true, as compounds with previously described therapeutic applications can be useful to treat other maladies. For example, acridine derivatives have several potential therapeutic applications. In this way, identifying new potential targets for available drugs is crucial for the rational management of diseases. Computational methodologies are interesting tools in this field, as they use rational and direct methods. Thus, this study focused on identifying other rational targets for acridine derivatives by employing inverse virtual screening (IVS). This analysis revealed that chitinase enzymes can be potential targets for these compounds. Subsequently, we coupled molecular docking consensus analysis to screen the best chitinase inhibitor among acridine derivatives. We observed that 3 compounds displayed potential enhanced activity as fungal chitinase inhibitors, showing that compound 5 is the most active molecule, with an IC50 of 0.6 ng/µL. In addition, this compound demonstrated a good interaction with the active site of chitinases from Aspergillus fumigatus and Trichoderma harzianum. Additionally, molecular dynamics and free energy demonstrated complex stability for compound 5. Therefore, this study recommends IVS as a powerful tool for drug development. The potential applications are highlighted as this is the first report of spiro-acridine derivatives acting as chitinase inhibitors that can be potentially used as antifungal and antibacterial candidates.


Metabolic characteristics and pathogenesis of precocious puberty in girls: the role of perfluorinated compounds.
Precocious puberty (PP) in girls is traditionally defined as the onset of breast development before the age of 8 years. The specific biomarkers of premature thelarche (PT) and central precocious puberty (CPP) girls are uncertain, and little is known about their metabolic characteristics driven by perfluorinated compounds (PFCs) and clinical phenotype. This study aimed to screen specific biomarkers of PT and CPP and elucidate their underlying pathogenesis. The relationships of clinical phenotype-serum PFCs-metabolic characteristics were also explored to reveal the relationship between PFCs and the occurrence and development of PT and CPP. Nuclear magnetic resonance (NMR)-based cross-metabolomics strategy was performed on serum from 146 PP (including 30 CPP, 40 PT, and 76 unspecified PP) girls and 64 healthy girls (including 36 prepubertal and 28 adolescent). Specific biomarkers were screened by the uni- and multivariate statistical analyses. The relationships between serum PFCs and clinical phenotype were performed by correlation analysis and weighted gene co-expression network analysis to explore the link of clinical phenotype-PFCs-metabolic characteristics in PT and CPP. The disordered trend of pyruvate and butyrate metabolisms (metabolites mapped as formate, ethanol, and 3-hydroxybutyrate) were shared and kept almost consistent in PT and CPP. Eight and eleven specific biomarkers were screened for PT and CPP, respectively. The area under curve of specific biomarker combination was 0.721 in CPP vs. prepubertal, 0.972 in PT vs. prepubertal, 0.646 in CPP vs. prepubertal integrated adolescent, and 0.822 in PT vs. prepubertal integrated adolescent, respectively. Perfluoro-n-heptanoic acid and perfluoro-n-hexanoic acid were statistically different between PT and CPP. Estradiol and prolactin were significantly correlated with PFCs in CPP and PT. Clinical phenotypes and PFCs drive the metabolic characteristics and cause metabolic disturbances in CPP and PT. The elevation of formate, ethanol, and 3-hydroxybutyrate may serve as the early diagnostic indicator for PP in girls. But the stratification of PP still needs to be further determined based on the specific biomarkers. Specific biomarkers of CPP and PT exhibited good sensitivity and can facilitate the classification diagnosis of CPP and PT. PFC exposure is associated with endocrine homeostasis imbalance. PFC exposure and/or endocrine disturbance directly or indirectly drive metabolic changes and form overall metabolic network perturbations in CPP and PT.


Ephrin Ligands and Eph Receptors Show Regionally Restricted Expression in the Developing Palate and Tongue.
The Eph family receptor-interacting (ephrin) ligands and erythropoietin-producing hepatocellular carcinoma (Eph) receptors constitute the largest known family of receptor tyrosine kinases. Ephrin ligands and their receptors form an important cell communication system with widespread roles in normal physiology and disease pathogenesis. In order to investigate potential roles of the ephrin-Eph system during palatogenesis and tongue development, we have characterized the cellular mRNA expression of family members EphrinA1-A3, EphA1-A8, and EphrinB2, EphB1, EphB4 during murine embryogenesis between embryonic day 13.5-16.5 using radioactive in situ hybridization. With the exception of EphA6 and ephrinA3, all genes were regionally expressed during the process of palatogenesis, with restricted and often overlapping domains. Transcripts were identified in the palate epithelium, localized at the tip of the palatal shelves, in the mesenchyme and also confined to the medial epithelium seam. Numerous Eph transcripts were also identified during tongue development. In particular, EphA1 and EphA2 demonstrated a highly restricted and specific expression in the tongue epithelium at all stages examined, whereas EphA3 was strongly expressed in the lateral tongue mesenchyme. These results suggest regulatory roles for ephrin-EphA signaling in development of the murine palate and tongue.