A new method for tracking poultry litter in the Potomac Basin headwaters of West Virginia.
To validate the distribution of a poultry litter-specific marker gene in faecally contaminated environmental waters of an intensive poultry litter rearing region. A TaqMan(®)-based qPCR assay for Brevibacterium sp. LA35 16S rRNA (LA35 gene), which was previously shown to be associated with poultry litter and faeces, was tested on 126 nontarget faecal samples and 28 poultry litter and faecal samples. The TaqMan assay was sensitive (76%) and specific (100%) to the LA35 gene and exhibited a detection limit for poultry litter in water samples that is sufficiently low (2.5 × 10(-2) mg litter l(-1)) to be applicable for environmental monitoring. The LA35 gene was detected in 43% of water samples (n = 30) collected in an intensive poultry rearing region of West Virginia which drains to the Chesapeake Bay. The poultry-specific TaqMan qPCR method for the LA35 gene is more specific than previously published methods and can be used to identify regions impacted by poultry rearing activities. The LA35 gene appears to have a broad geographical distribution as it has been found in poultry litter and faeces from Delaware and West Virginia, in this study and from Arkansas, Georgia, Florida, Minnesota, Oklahoma and Utah previously.


Incidence and Associated Risk Factors of Venous Thromboembolism After Open and Laparoscopic Nephrectomy in Patients Administered Short-period Thromboprophylaxis: A Danish Nationwide Population-based Cohort Study.
To report the incidence of venous thromboembolism (VTE) after nephrectomy in Denmark and explore associated risk factors. A nationwide population-based retrospective cohort study was performed. All nephrectomies from January 2010 to August 2018 were assessed for postoperative VTE events. Univariable and multivariable analyses were used to evaluate the odds ratio (OR) of clinical variables' effect on postoperative VTEs, within 4 weeks and 4 months after nephrectomy. In 5213 nephrectomized patients, postoperative VTE incidence was 1% and 2% within 4 weeks and 4 months, respectively. Multivariable analyses revealed that predictors of postoperative VTE within 4 months were: open nephrectomy (OR 2.5, P = .001), history of VTE (OR 13.3, P <.001), length of hospital stay (OR 0.98, P = .02), and lymph node dissection (OR 2.0, P = .04). Limitations included the retrospective and registry-based study design and absence of individual patient data on patient body mass index and length of surgery. For nephrectomy, postoperative VTE is rare. Open nephrectomy, history of VTE, length of hospital stay, and lymph node dissection are important risk factors which should be evaluated when tailoring VTE prophylaxis regimens.


Effects of mitragynine on viability, proliferation, and migration of C6 rat glioma, SH-SY5Y human neuroblastoma, and HT22 immortalized mouse hippocampal neuron cell lines.
Mitragynine (MG) is an indole alkaloid found in the extract of Mitragyna speciosa Korth native to Southeast Asia. Although MG is known for its pain-relieving and psychoactive effects, reports have suggested that it has therapeutic potential against neoplasms and psychiatric disorders. However, no evidence currently exists to support the effect of MG on brain tumors. This study aimed to investigate the antitumor effects of MG in C6 rat glioma and SH-SY5Y human neuroblastoma tumor cell lines compared with those in the non-tumor HT22 mouse hippocampal neuronal cell line. MTT assay for cell viability, clonogenic and wound healing assays for cell migration, Hoechst 33342/propidium iodide staining for nuclear morphology, and cell cycle distribution using flow cytometry were performed. MG at 125.47 μM (50 μg/ml) significantly reduced the viability of all cell lines, and the clonogenicity of C6 glioma cells began decreasing at 75.28 μM (30 μg/ml) of MG. Cell migration was inhibited in C6 and HT22 cells treated with 75.28 μM (30 μg/ml) of MG. Apoptotic nuclear condensation and fragmentation were observed in all cell lines treated with 125.47 μM (50 μg/ml) MG, whereas late-phase apoptotic cells were predominant in the group treated with 250.94 μM (100 μg/ml) of MG. The cell cycle assay results suggest that MG arrested the S phase in the C6 cell line and the G2/M phase in the HT22 cell lines. This study showed that MG induces cell death and cell cycle arrest, disrupting cell migration and reducing the clonogenicity of brain tumor cells.


Training of Dental Professionals in Motivational Interviewing can Heighten Interdental Cleaning Self-Efficacy in Periodontal Patients.
The success of periodontal therapy depends on the adherence of patients to professional recommendations. The aim of this study was to investigate the influence of a workshop in motivational interviewing (MI) on non-surgical periodontal treatment performed by dental students. In the experimental group patients with periodontitis were treated by students trained in MI, while in the control group patients were treated by students who had not been trained in MI. Clinical oral parameters were assessed by a blinded periodontist in addition to the evaluation of psychological questionnaires given before and after the non-surgical periodontal treatment (6 months). Conversations between patients and students were recorded and rated with the Motivational Treatment Integrity Code (MITI-d) by a blinded psychologist. There were 73 patients in the MI group and 99 patients in the control group. The MI group showed significantly higher scores in the MITI-d analysis. Regression analysis showed that there were no significant differences between groups with regard to plaque level, gingival bleeding, pocket depth reduction or bleeding upon probing. However, patients in the MI-group showed significantly higher interdental cleaning self-efficacy than patients in the control group (MI = 19.57 ± 4.7; control = 17.38 ± 6.01; p = 0.016). Teaching MI to dental students resulted in a significant improvement in the self-efficacy of interdental cleaning in patients compared to a control group of non-trained students, but no improvement in other aspects of non-surgical periodontal therapy. The study also showed that an 8-h workshop with supervision significantly improved the MI-compliant conversations of dental students without requiring more conversation time.


[Cardiovascular risks of corticosteroids].
Prolonged use of glucocorticoids is associated with an increase in cardiovascular morbidity and mortality: hypertension and atheroma mainly. Severe cardiovascular complications of pulse corticosteroids are related to underlying comobidities and require some precautions. There are probably individual factors of complications associated with polymorphisms of the glucocorticoid receptor. Without clearly established recommendations concerning prevention of cardiovascular risk, screening and treatment of risk factors during treatment is the best prevention possible. Screening and treatment of cardiovascular complications require a just prescription and appropriate surveillance.


A dermatology-psychiatry liaison clinic.
A dermatology-psychiatry liaison clinic at Stanford University is described. The clinic provides an opportunity for dermatology residents to learn about the psychological aspects of the specialty and to witness at first hand technics of interviewing, strategic questioning, and listening.


[Study of Vibrio cholerae fractions. II. A comparison of the immunochemical and biological properties of preparations of alkaline extracts (vibrionin) and the endotoxin of Vibrio cholerae].
Comparative study of immuno-chemical and biological properties of vibrionin and cholera vibrio endotoxin showed vibrionin to contain up to 73.5% of protein, whereas endotoxin preparations contained only 25% of protein. Use of disc electrophoresis in polyacrylamide gel permitted to determine the relative electrophoretic mobility of the protein component bands of both preparations. Residual quantities of O-antigenic cholera vibrio determinants were revealed serologically in the vibrionin preparations. Study of biological properties of vibrionin (cholera allergen) demonstrated a possibility of using vibrionin in the capacity of a new bacterial allergen.


Partially overlapping territories of nerves to hindlimb foot skin demonstrated by plasma extravasation to antidromic C-fiber stimulation in the rat.
The innervation territories of the cutaneous nerves to the hindfoot were examined in the rat. Plasma extravasation of Evans blue to antidromic stimulation of C-fibers in the saphenous, sural, peroneal and tibial nerves was the means to determine the innervation areas. A high degree of bilateral symmetry was found for the territory of each nerve in individual rats. Stimulation of pairs of nerves, one on each side, that innervate neighboring skin regions revealed the existence of overlapping territories for all pairs of nerves. The area of overlap was greatest on the toes and just proximal to the toes on the dorsum of the foot, whereas overlap on the volar aspect of the foot was minimal. The need to consider the existence of overlapping cutaneous innervation in normal animals in studies involving collateral sprouting after nerve injuries is discussed.


Regulation of blood oxygen transport in hibernating mammals.
Along with the periodic reductions in O2 requirements of mammalian hibernators during winter, the O2 affinity of the blood of mammalian hibernators is seasonally regulated to help match O2 supply to consumption, contributing to limit tissue oxidative stress, particularly at arousals. Specifically, mammalian hibernators consistently show an overall increase in the blood-O2 affinity, which causes a decreased O2 unloading to tissues, while having similar or lower tissue O2 tensions during hibernation. This overview explores how the decreased body temperature and concentration of red blood cell 2,3-diphosphoglycerate (DPG) that occur in hibernation contribute separately or in combination to the concurrent increase in the O2 affinity of the hemoglobin, the O2 carrier protein of the blood. Most mammalian hemoglobins are responsive to changes in DPG concentrations, including that of the hibernating brown bear, although the smaller hibernators, such as golden-mantled ground squirrel, chipmunks, and dormice, have hemoglobins with low sensitivity to DPG. While the effect of DPG on oxygenation may vary, the decrease in body temperature invariably increases hemoglobin's O2 affinity in all hibernating species. However, the temperature sensitivity of hemoglobin oxygenation is low in hibernators compared to human, apparently due in part to endothermic allosteric quaternary transition in ground squirrels and dissociation of chloride ions in brown bears. A low heat of blood oxygenation in temporal heterotherms, like hibernators, may thus contribute to reduce heat loss, as found in regional heterotherms, like polar mammals, although the significance would be low in winter hibernation.


Analysis of Iron Complexes of Tannic Acid and Other Related Polyphenols as Revealed by Spectroscopic Techniques: Implications in the Identification and Characterization of Iron Gall Inks in Historical Manuscripts.
In this work, a structural analysis of the polyphenol complexes with iron and copper at several conditions is reported. The investigated polyphenols were tannic acid, gallic acid, pyrogallol, and syringic acid, being components and molecular models of the gallnuts usually employed in the past in fabrication of iron gall inks (IGIs). Commercial tannic acid extracted from gallnuts, which is a complex mixture of different gallotannins and simpler galloylglucoses, was also employed in this analysis. This analysis comprised the use of Raman, Fourier-transform infrared (FTIR), UV-vis absorption, and fluorescence spectroscopy. The complexation of iron with these molecules leads to a strong change in color due to the deep restructuring of the polyphenol that can be clearly seen by Raman and FTIR spectra. Three main Raman bands appeared at 1450-1490 cm-1 (ν1), 1320-1345 cm-1 (ν2), and 400-650 cm-1 (ν3), which are characteristic of the metal complexes. The structural changes of the polyphenol complexes with iron were also investigated at different pHs and different polyphenol/iron stoichiometries. Other effects of the interaction of polyphenols with iron are the pH decrease of the mixture upon metal complexation and fluorescence quenching induced by the interaction of iron. This quenching is important since it facilitates the Raman inspection of manuscripts since polyphenols show a strong fluorescence emission that overlaps the Raman spectrum. Furthermore, DFT calculations were performed for the first time on the gallic acid complex with iron in order to elaborate a detailed assignment of the vibrational modes of polyphenols and their metal complexes, something that was missed in previous applications of Raman to IGIs.


Carry on With Raja Ravi Varma, Mary Cassatt, and Renoir.
Raja Ravi Varma's painting "There Comes Papa" depicts his daughter carrying her son astride her hip. The positive implication of the posture of the hips of the child while being carried in this manner on acetabular development is discussed.


Clinical features and pharmacologic treatment of Paget's disease.
Paget's disease of the bone is characterized by a focal increase in the rate of bone turnover, which goes through phases of activity and quiescence. Most patients are asymptomatic. The two cardinal features are pain and deformities, and many complications may arise. Diphosphonates and calcitonin are the main therapeutic modalities.


Characteristics and Dynamics of Smile in Patients With Skeletal Class II Malocclusion Versus Class I Malocclusion Using Still Digital Video Captures: A Three-Group, Cross-Sectional, Comparative Study.
Background Smiling is one of the effective ways for people to express their feelings. It is an integral part of the diagnosis and planning and a key point of the treatment objectives in orthodontic care. Many factors are associated with a pleasant smile, such as correct anatomy, gingival health, and teeth proportion. Therefore, different malocclusion classes can affect the characteristics of smile esthetics. This study aimed to evaluate the effect of skeletal class II malocclusion on the characteristics and dynamics of the smile in the sagittal and frontal planes. Methodology The study sample included 60 patients comprising three groups of malocclusion classes, namely, Class I, Class II division 1, and Class II division 2. A video recording was taken for 5-10 seconds for each patient using a specific camera mounted at a fixed distance from the imaged face. Two facial expressions were captured for each patient, one representing the lips at rest and the second representing the unrestricted natural smile. The facial still images were derived from the streaming video recording, and two images were chosen for each plane (the frontal plane and the sagittal plane) for each patient. In total, 12 variables were assessed on these captured images. One-way analysis of variance (ANOVA) was used to detect significant differences between the three groups. Results There were statistically significant differences in some of the measured variables. The mean values of thickness of the upper lip, commissure height, gum width, maxillary incisor display, and interlabial gap were greater in the Class II division 1 group than in the other two groups. The proclined incisors were evident in the Class II division 1 group, while the retroclined incisors were evident in the Class II division 2 group. Conclusions The skeletal Class II malocclusion influences the characteristics of the smile, either assessed on the anterior or lateral imaging angles, in addition to its influence on the resting position of the lips. Orthodontists should always analyze patients' facial expressions, including those related to the upper and lower lips at rest and when patients smile naturally. Depending on the results of this analysis, treatment planning could be built to improve the characteristics of the natural smile in patients with Class I and Class II malocclusions.


Predictor of massive bleeding following stent placement for malignant oesophageal stricture/fistulae: a multicentre study.
To evaluate retrospectively the incidence and predictors of massive bleeding after stent placement for malignant oesophageal stricture/fistulae. This retrospective study comprised 519 patients with malignant oesophageal stricture/fistulae that were successfully treated with stent placement at three hospitals. The patients were divided into two groups based on the occurrence of massive bleeding. Univariate and multivariate analysis was performed to evaluate predictive factors of massive bleeding. Massive bleeding occurred in 54 of 519 patients 1-37 days following stent placement. All of the patients who developed massive bleeding died within 24 hours of the event. Univariate analysis showed massive bleeding was associated with the presence of a concomitant tracheal stent (p<0.001), the existence of concomitant oesophageal fistulae (p<0.001), and prior radiotherapy (p<0.001). Multivariate analysis exhibited that concomitant tracheal stent insertion (odds ratio [OR], 23.134; 95% confidence interval [CI], 9.523-56.199; p<0.001), the presence of oesophageal fistulae (OR, 3.724; 95% CI, 1.677-8.269; p=0.001), and prior radiotherapy (OR, 13.310; 95% CI, 5.464-32.421; p<0.001) were predictors of massive bleeding following stenting. The presence of oesophageal fistulae, prior radiotherapy, and concomitant tracheal stent are important factors contributing to bleeding after stenting.


KATP channel blocking actions of quaternary ions play no role in their antiproliferative action on mouse leukaemia and rat vascular smooth muscle cells in vitro.
1. The aim of the present study was to investigate the possibility that, in the two cell lines examined, alterations in cell growth caused by lipophilic quaternary ions may involve KATP channels. We examined the effect of tetraphenylphosphonium (TPP), tetraphenylboron (TPB), rhodamine 123, dequalinium chloride (DECA) and the non-quaternary ion cisplatin on the proliferation of L1210 mouse leukaemia cells and rat smooth muscle cells in vitro. The KATP channel opener levcromakalim (LKM) and the KATP channel antagonist glibenclamide were also tested. 2. From growth-inhibition studies, the rank order of potency (based on pIC50 values) using L1210 leukaemia cells was: DECA (6.61) > cisplatin (6.09) = rhodamine 123 (6.01) > TPP (5.61) > TPB (4.25). Levcromakalim and glibenclamide were found to be inactive at the maximum concentrations used (100 mumol/L). A different rank order of potency was obtained in rat aortic smooth muscle cells: cisplatin (6.33) > DECA (5.67) > TPP (4.96) > rhodamine 123 (4.1). Tetraphenylboron (30 mumol/L), LKM (100 mumol/L) and glibenclamide (100 mumol/L) were found to be inactive. 3. When the negatively charged TPB (30 mumol/L) was combined with some of the active agents, the potency of the active agents was increased. Thus, in L1210 cells, rhodamine 123, DECA and TPP were all more potent at inhibiting cell growth in the presence of TPB. Tetraphenylboron had no effect on cisplatin in this cell line. In rat smooth muscle cells, TPB (30 mumol/L) potentiated the effect of rhodamine 123 but had no effect on the actions of cisplatin, DECA or TPP. 4. In functional studies, rhodamine 123 was a weak antagonist of the vasorelaxant responses to the KATP channel opener LKM in the porcine right circumflex artery in vitro. The pKB value obtained for rhodamine 123 at 100 mumol/L was 4.95. Dequalinium chloride was inactive. 5. We found no correlation between the actions of the compounds tested to antagonise KATP channels and their ability to inhibit cell proliferation. In addition, compounds known to regulate KATP channel activity failed to influence proliferative rates. These results suggest that KATP channels are not involved in the antiproliferative action of TPP and other quaternary ions in the two cell lines studied.


The role of maladaptive personality traits on psychological stress the mediating effects of COVID-19-related worries and emotional dysregulation.
There is increasing evidence that dysfunctional personality traits, related to psychological maladjustment and psychopathology, can play an important role in a person's ability to cope with major stressful events. Relatively little is known about the specific effect of the emotional component on the relationship between maladaptive personality traits and psychological stress. Therefore, the aim of the present study was to investigate the relationship between the maladaptive personality traits of psychoticism, detachment, and negative affect, and psychological stress, considering the effects of COVID-19-related worries and emotional dysregulation. An online survey was administered to 1172 adult participants. A series of path analysis models showed that maladaptive personality traits (psychoticism, detachment, and negative affect) are related to psychological stress. COVID-19-related worries and emotional dysregulation partially explained this association. The results suggest that in the early months of 2022, during the reduction of government restrictions, although the world population was no longer in nationwide lockdown, the COVID-19-related emotional component could still explain, at least in part, the association between maladaptive personality traits and psychological stress.


Perceived deprivation, restrained eating and susceptibility to weight gain.
Perceived deprivation describes a feeling of not eating what or as much as one would like, despite being in energy balance. This construct was previously found to correlate with the Restraint Scale in obese binge eaters and current dieters [Timmerman, G. M., & Gregg, E. K. (2003). Dieting, perceived deprivation, and preoccupation with food. Western Journal of Nursing Research, 25(4), 405-418]. The current study examined perceived deprivation and restraint in 66 normal weight college females with no history of eating disorders. Perceived deprivation was significantly correlated with restraint generally and with dietary concern in particular; this relationship was due to perceived limits on what, rather than how much, food was eaten. This relationship may have important implications for understanding the motivation underlying restrained eaters' aberrant eating behaviors and the nature of their susceptibility to weight gain.


Doppler evaluation of pediatric goiter: effect of mandatory iodination.
The aim of this study was to evaluate the hemodynamic status of the thyroid in children with goiter after the use of iodinated dietary salt for 3 years in a region of endemic iodine deficiency. Sixty-six children between 7 and 12 years of age were included in the study. Three groups were constituted according to sonographically measured thyroid volume and urinary iodine excretion levels. Group 1 included 11 children with thyroid volumes greater than the 97th percentile according to age and sex criteria suggested by the World Health Organization International Council for Control of Iodine Deficiency Disorders and urinary iodine level lower than 100 microg/l. Group 2 included 30 children with thyroid volumes greater than the 97th percentile and urinary iodine level equal to or higher than 100 microg/l. The control group included 25 children who had normal thyroid volume and urinary iodine level. All children were examined by thyroid duplex sonography. Peak systolic velocity (PSV) and resistance index (RI) were measured in the inferior thyroid artery bilaterally. PSV in group 1 was significantly higher than in group 2 and in the control group (P < 0.05 and P < 0.01, respectively). There was no significant difference between the PSV of group 2 and the control group. The RI in groups 1 and 2 was significantly lower than in the control group (P < 0.01 and P < 0.01, respectively). There was no significant difference between the RIs of group 1 and group 2. These findings suggest an effect of iodination on thyroid hemodynamics before the size of the hyperplastic thyroid returned to normal, in keeping with normalization of the urinary iodine level.


High b-value diffusion tractography: Abnormal axonal network organization associated with medication-refractory epilepsy.
Diffusion magnetic resonance imaging (dMRI) tractography has played a critical role in characterizing patterns of aberrant brain network reorganization among patients with epilepsy. However, the accuracy of dMRI tractography is hampered by the complex biophysical properties of white matter tissue. High b-value diffusion imaging overcomes this limitation by better isolating axonal pathways. In this study, we introduce tractography derived from fiber ball imaging (FBI), a high b-value approach which excludes non-axonal signals, to identify atypical neuronal networks in patients with epilepsy. Specifically, we compared network properties obtained from multiple diffusion tractography approaches (diffusion tensor imaging, diffusion kurtosis imaging, FBI) in order to assess the pathophysiological relevance of network rearrangement in medication-responsive vs. medication-refractory adults with focal epilepsy. We show that drug-resistant epilepsy is associated with increased global network segregation detected by FBI-based tractography. We propose exploring FBI as a clinically feasible alternative to quantify topological changes that could be used to track disease progression and inform on clinical outcomes.


Membrane-active substituted triazines as antibacterial agents against Staphylococcus aureus with potential for low drug resistance and broad activity.
A library of new naphthalimide-triazine analogues was synthesized as broad-spectrum antibacterial agents to overcome drug resistance. Bioactivity assay reveals that derivative 8e, with benzylamine in its structure, exhibits strong antibacterial properties against multi-drug resistance Staphylococcus aureus at a concentration of 1.56 μg/ml. It was also found to be better than chloromycin and amoxicillin. The active compound 8e efficiently inhibits the development of drug resistance within 11 passages. In addition, compound 8e inhibits the formation of biofilms in S. aureus and acts rapidly in bactericidal efficacy. Furthermore, mechanistic studies reveal that compound 8e effectively destroys the cytoplasmic membrane of bacteria, leading to leakage of intercellular protein content and loss in metabolic activity. Compound 8e binds to HSA readily with a binding constant of 1.32 × 105 M-1, indicating that the compound could be delivered to the target site effectively. Compound 8e can also form a supramolecular complex with DNA to obstruct DNA replications. These results suggest that analogue 8e could be further developed as a potential antibacterial agent. Furthermore, the cytotoxicity of all the synthesized compounds was evaluated against 60 human cancer cell lines to test their potential for anticancer agents.


High prevalence of multidrug-resistant tuberculosis, Swaziland, 2009-2010.
In Africa, although emergence of multidrug-resistant (MDR) tuberculosis (TB) represents a serious threat in countries severely affected by the HIV epidemic, most countries lack drug-resistant TB data. This finding was particularly true in the Kingdom of Swaziland, which has the world's highest HIV and TB prevalences. Therefore, we conducted a national survey in 2009-2010 to measure prevalence of drug-resistant TB. Of 988 patients screened, 420 new case-patients and 420 previously treated case-patients met the study criteria. Among culture-positive patients, 15.3% new case-patients and 49.5% previously treated case-patients harbored drug-resistant strains. MDR TB prevalence was 7.7% and 33.8% among new case-patients and previously treated case-patients, respectively. HIV infection and past TB treatment were independently associated with MDR TB. The findings assert the need for wide-scale intervention in resource-limited contexts such as Swaziland, where diagnostic and treatment facilities and health personnel are lacking.


[Not Available].
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat pain and inflammation in osteoarthritis and rheumatoid arthritis. However, their long-term use is often limited by gastrointestinal mucosal injury and complications like bleeding, ulceration and perforation. Hence, the hope evolved that selective COX-2 inhibitors, a newly developed class of anti-inflammatory drugs, may be equally effective but better tolerated than nonselective NSAIDs. However, this enthusiasm was partly dampened by the fact that the exclusive use of selective COX-2 inhibitors is probably not justified. Particularly in patients treated with low-dose of aspirin for cardiovascular prophylaxis, the COX-2 inhibitors seem to have no obvious advantages over conventional NSAIDs. Furthermore, use of COX-2 inhibitors has recently been associated with enhanced cardiovascular risk. There is some evidence that COX-2 inhibitors may act via COX independent pathways and might be used for indications other than arthritic pain and inflammation.


Mean glomerular volume and rate of development of diabetic nephropathy.
We studied kidney glomerular structure and function in two groups of type I (insulin-dependent) diabetic subjects with 14-16 yr (group 1, n = 16) and 24-26 yr (group 2, n = 13) duration of diabetes and compared them to a group of 18 nondiabetic subjects with similar age ranges. Within each diabetic group, subjects were selected for normal kidney function (urinary albumin excretion less than 40 mg/24 h, normal blood pressure, creatinine clearance greater than 90 ml.min-1.1.73 m-2) or for nephropathy (urinary albumin excretion greater than 200 mg/24 h). Morphometric analysis of glomeruli revealed a significantly larger mean glomerular volume in subjects with nephropathy (group 2). Mesangial volumes were significantly greater in the nephropathic than the normoalbuminuric diabetic subjects in each group, but filtration surface per glomerulus was constant among all subjects. The percentage of sclerosed glomeruli was also significantly increased in the nephropathic subjects compared with the subjects with normal kidney function, in whom sclerosed glomeruli did not exceed 8%. In addition, there was a significant correlation between percentage of globally sclerosed glomeruli and glomerular volume in group 2 (rs = .79, P less than .01) but not group 1 (rs = -.20, NS) subjects. Thus, glomerular size or individual capacity for glomerular expansion may determine the rate of progression of the loss of kidney function in subjects destined to develop diabetic nephropathy.


The Natural Product Resveratrol Inhibits Yeast Cell Separation by Extensively Modulating the Transcriptional Landscape and Reprogramming the Intracellular Metabolome.
An increasing number of studies have shown that the promising compound resveratrol treats multiple diseases, such as cancer and aging; however, the resveratrol mode-of-action (MoA) remains largely unknown. Here, by virtue of multiple omics approaches, we adopted fission yeast as a model system with the goal of dissecting the common MoA of the anti-proliferative activity of resveratrol. We found that the anti-proliferative activity of resveratrol is mainly due to its unique role of inhibiting the separation of sister cells, similar phenotype with the C2H2 zinc finger transcription factor Ace2 knock-out strain. Microarray analysis shown that resveratrol has extensive impact on the fission yeast transcription levels. Among the changed gene's list, 40% of up-regulated genes are Core Environmental Stress Responses genes, and 57% of the down-regulated genes are periodically expressed. Moreover, resveratrol leverages the metabolome, which unbalances the intracellular pool sizes of several classes of amino acids, nucleosides, sugars and lipids, thus reflecting the remodulated metabolic networks. The complexity of the resveratrol MoA displayed in previous reports and our work demonstrates that multiple omics approaches must be applied together to obtain a complete picture of resveratrol's anti-proliferative function.


[Fetal heart rate variation in magnetocardiography and cardiotocography--a direct comparison of the two methods].
Heart rate variability (HRV) is becoming increasingly important in the analysis of prepartal cardiotocography (CTG). Dawes and Redmann have developed a computer algorithm which can calculate short-term variability on the basis of CTG data. In dealing with artefacts, CTG monitors average heart rate values over several beats which makes the use of standard measures of HRV such as the root mean square of successive differences (RMSSD) inappropriate. Fetal magnetocardiography (FMCG) enables the registration of signals similar to the electrocardiogram and this permits the precise determination of heart beat duration and, in consequence, of measures of fetal HRV. In this study we applied both methods--CTG and FMCG--sequentially and simultaneously in healthy pregnancies. Fetal short-term HRV was estimated on the basis of RMSSD values for both methods. The RMSSD values of the FMCG data were generally higher and showed a wider dynamic range than those of the CTG. The direct comparison of the simultaneously acquired data demonstrated that the data processing of the CTG signal leads to a suppression of essential aspects of short-term HRV. FMCG permits a substantially more differentiated examination of fetal HRV and offers new possibilities in the analysis of fetal cardiac activity.


Ex vivo comparison of the biomechanical properties of hand-sewn and stapled jejunoileal anastomoses in horses.
To compare bursting strength, construction time, and anastomotic dimensions of 4 jejunoileal anastomotic techniques. Experimental ex vivo study. Adult horses (n = 12). Jejunoileal anastomoses were constructed from harvested ileal and distal jejunal segments using a single-layer Lembert technique (1HS), double-layer simple continuous/Cushing technique (2HS), stapled side-to-side technique (SS), or stapled functional end-to-end technique (FEE). Anastomotic construction time was recorded. Bursting pressures (BP), bursting wall tension (BWT), percentage of mean anastomotic luminal diameter reduction, percentage of luminal diameter reduction relative to adjacent ileal and jejunal diameters and stomal length, were calculated. FEE had the shortest construction time. BP of 1HS and 2HS was significantly higher than FEE and SS (P < .001), which were not different from each other (P = .67). There were no significant differences in BP (P = .25) and BWT (P = .21) between 1HS and 2HS. Mean luminal diameter reduction was less for 1HS (25.1%) than for 2HS (34.8%), however, not statistically different (P = .12). Luminal diameter reduction relative to ileal diameter was significantly less for 1HS (15.2%) than for 2HS (28.47%; P = .012). Luminal diameter reduction relative to jejunal diameter was less for 1HS (32.4%) than 2HS (44.6%) but not statistically different; P = .07). Stomal length was significantly larger for SS (9.93 cm) than FEE (7.32 cm; P = .0002). 1HS and 2HS jejunoileal anastomosis are equal in strength; however, 1HS results in less relative luminal diameter reduction. SS and FEE have comparable strength but fail at significantly lower BPs than hand-sewn jejunoileal anastomoses.


Urinary excretion of cocaine and benzoylecgonine following oral ingestion in a single subject.
A 25 mg oral dose of cocaine HCl given to a single volunteer resulted in a peak urinary cocaine concentration of 269 ng/mL at 1 h, and a peak benzoylecgonine concentration of 7,940 ng/mL at 12 h. Urine benzoylecgonine concentrations remained in excess of 300 ng/mL for 48 h. We conclude that small, oral doses of cocaine, potentially undetectable to the user, may cause positive urine test results for at least 48 h using routine detection methods.


Catecholaminergic effects on ventricular repolarization during inhibition of the rapid component of the delayed rectifier potassium current in a perfused heart model.
To determine the catecholaminergic effects on the duration of ventricular repolarization during inhibition of the rapid component of the delayed rectifier potassium current (I(Kr)). Isolated perfused heart model. University research center. Eighteen male Dunkin-Hartley guinea pigs. Hearts were excised and perfused in a retrograde manner at a constant aortic pressure of 60 mm Hg and temperature of 37 degrees C. Thirteen hearts were administered sparfloxacin 20 microg/ml (an I(Kr) inhibitor) in a buffered solution; the remaining five hearts were perfused with only the buffered solution to act as controls for potential time-dependent changes in action potential duration (APD). Immediately after the sparfloxacin infusion, six of the 13 hearts were administered a bolus catecholamine infusion of an epinephrine 10 nM-norepinephrine 6 nM admixture; 10 minutes after the start of the first catecholamine infusion, these hearts received another bolus infusion of an epinephrine 5 nM-norepinephrine 3 nM admixture. The other seven hearts were administered only a buffered solution. Hearts were paced (240 beats/min), and left ventricular monophasic action potentials were recorded for determination of APD at 90% and 30% repolarization (APD(90) and APD(30), respectively). The APD(90) and APD(30) increased in all 13 hearts exposed to sparfloxacin. The mean +/- SD APD(90) increase from baseline at 15 minutes was 4.2 +/- 2.5% relative to the five control hearts. In the presence of I(Kr) inhibition, the epinephrine 5 nM-norepinephrine 3 nM and epinephrine 10 nM-norepinephrine 6 nM admixtures altered APD(90), with a mean +/- SD maximum increase in APD(90) of 3.1 +/- 1.2% and 4.5 +/- 3.6%, respectively. This corresponded to a statistically significant increase in APD(90) and APD(30) 2 minutes after the catecholamine infusion in the presence of I(Kr) inhibition. A net prolongation of ventricular repolarization was observed after a catecholamine surge in the presence of mild I(Kr) inhibition. This suggests that counteracting mechanisms may contribute to the apparent arrhythmogenic substrate during nonspecific adrenergic receptor activation in the presence of I(Kr) inhibition.


Development and validation of a novel personalized electronic patient-reported outcome measure to assess quality of life (Q-LIFE): a prospective observational study in people with Cystic Fibrosis.
Generic and disease-specific patient-reported outcome measures (PROMs) may lack relevance and sensitivity on a patient-level in chronic diseases with differential disease expression and high individual variability, such as Cystic Fibrosis (CF). This study aimed to develop and validate a novel personalized electronic PROM (ePROM) that captures relevant aspects of quality of life in individuals with CF. The Q-Life app was developed as a short personalized ePROM to assess individual quality of life. Psychometric properties were assessed in a single-center cross-sectional study between September 2019 and September 2021 and in a prospective cohort study between September 2021 and September 2022. Combined studies included 223 participants (median age: 24 years, IQR: 19.0-32.5 years, range: 12.0-58.0 years). Internal consistency (Cronbach's alpha: 0.83-0.90) and test-retest reliability (intraclass correlation coefficient: 0.90; 95% CI: 0.65-0.92; p < 0.001) of quality of life (Q-Life) scores were strong. Q-Life scores were associated with overall Cystic Fibrosis Questionnaire-Revised (CFQ-R) scores (ρ = 0.71; p < 0.001), CFQ-R respiratory domain scores (ρ = 0.57; p < 0.001) and forced expiratory volume in 1s (ρ = 0.41; p < 0.001). Furthermore, Q-Life scores improved from 65.0 (IQR: 45.0-63.3) at baseline to 84.2 (IQR: 75.0-95.0) and 87.5 (IQR: 75.0-100.0) after 3 and 6 months of elexacaftor/tezacaftor/ivacaftor treatment (change: 20.8; 95% CI: 17.5-25.0; p < 0.001), comparable to CFQ-R respiratory domain scores (change: 22.2, 95% CI: 19.4-25.0, p < 0.001). The Q-Life app is a reliable, valid and sensitive personalized ePROM to measure all aspects of quality of life that really matter to individuals with Cystic Fibrosis. This patient-centered approach could provide important advantages over generic and disease-specific PROMs in the era of personalized medicine and value-based healthcare. Dutch Cystic Fibrosis Foundation, Health-Holland.


Personality characteristics of cocaine and alcohol abusers: more alike than different.
Although there is extensive literature describing the characteristics of individuals entering treatment for alcoholism, few research reports are available describing the personality characteristics of individuals addicted to cocaine. Forty-four matched patient pairs, one member of each pair who abused cocaine and the other alcohol, were compared on the basis of their Minnesota Multiphasic Personality Inventory (MMPI) profiles. The subjects were matched on the basis of age, sex, and race from a larger population entering an inpatient addiction treatment center. Statistical analysis revealed more similarities than differences between the two groups, with the average profile type for both cocaine and alcohol abusers being 4-2. These results are discussed in the context of previous reports of psychopathology among cocaine abusers and personality theories of drug choice. The number of different code types within each substance abuse group is also reported and the concept of profile heterogeneity supported. Profile subtypes among cocaine patients are described clinically along with their implications for treatment.


Comparison of prone transpsoas lateral lumbar interbody fusion and transforaminal lumbar interbody fusion for degenerative lumbar spine disease: A retrospective radiographic propensity score-matched analysis.
This is the first study to compare the prone transpsoas (PTP) approach for lateral lumbar interbody fusion (LLIF) and transforaminal lumbar interbody fusion (TLIF) through an analysis of radiographic and clinical outcomes. A retrospective chart review of data for patients who underwent the PTP approach or TLIF for degenerative lumbar spine disease was conducted. Propensity score matching was completed through the utilization of a linear regression model with the classification of surgery (PTP vs. TLIF) being used as the indicator (dependent variable) and the radiographic outcomes as covariates (independent variables). Both cohorts (PTP and TLIF) were propensity score matched according to preoperative radiographic parameters using a 1-to-1 ratio to the nearest neighbor. Eleven patients in the TLIF group were matched to an equal number of patients in the PTP group who had similar propensity scores to perform a thorough analysis of clinical and radiographic outcomes. The PTP approach significantly improved the lumbar lordosis angle, pelvic tilt, and the pelvic incidence minus lumbar lordosis value when compared to TLIF (p < 0.05). Clinically, the PTP group improved significantly in terms of the Oswestry Disability Index (p < 0.05). That approach also significantly minimized blood loss and hospital stay (p < 0.05). Furthermore, significantly more cages were placed anteriorly in the PTP group than in the TLIF group (p < 0.05). However, the PTP group had a significantly longer duration of radiation exposure (p < 0.05). The PTP approach resulted in greater improvement in postoperative radiographic measurements as well as patient-reported outcomes.


Pathologist's role in identifying cardiac defects-a fetal autopsy series.
Major cardiac abnormalities can lead to miscarriages and is also an important indication of medical termination of pregnancy. The present study aims: (1) To determine the spectrum of cardiac anomalies in fetal autopsies, (2) To correlate the autopsy findings with prenatal imaging studies. Fetal autopsies with cardiac anomalies were retrospectively analyzed over a period of five years. Autopsy diagnoses were correlated with prenatal ultrasound and echocardiogram findings. Of the 177 fetal autopsies, 40 (22.5%) cases with cardiac defects were identified. Among these cases, 11 (27.5%) showed only cardiac defects and associated extracardiac malformations were seen in 29 cases (72.5%). Septal defects (45%) were the most frequent cardiac defect followed by left ventricular outflow tract obstruction. Agreement with prenatal imaging and autopsy findings was seen in 65% of cases. There was 100% concordance between autopsy and echocardiogram wherever available. Cardiac malformation forms a significant subset of fetal congenital anomalies. Meticulous examination and following sequential segmental analysis during autopsy are essential in identifying complex cardiac and additional extra cardiac defects in the fetuses. Fetal autopsy plays a vital role in confirming and/or refuting the imaging findings and could be the steppingstone in understanding the pathogenesis of cardiac abnormalities.


Accelerating code to function: sizing up the protein production line.
High-throughput biology has been pioneered by genomics through the application of robotics to expedite DNA-sequencing projects. Advances in high-throughput protein methods are needed to drive the protein production line for high-throughput structural and functional analysis of newly discovered genes. This will require the development and application of a variety of recombinant-protein expression systems to produce the diversity of proteins from both humans and model organisms.


Role of sigma factors in controlling global gene expression in light/dark transitions in the cyanobacterium Synechocystis sp. strain PCC 6803.
We report on differential gene expression in the cyanobacterium Synechocystis sp. strain PCC 6803 after light-dark transitions in wild-type, DeltasigB, and DeltasigD strains. We also studied the effect of day length in the presence of glucose on a DeltasigB DeltasigE mutant. Our results indicated that the absence of SigB or SigD predominately altered gene expression in the dark or in the light, respectively. In the light, approximately 350 genes displayed transcript levels in the DeltasigD strain that were different from those of the wild type, with over 200 of these up-regulated in the mutant. In the dark, removal of SigB altered more than 150 genes, and the levels of 136 of these were increased in the mutant compared to those in the wild type. The removal of both SigB and SigE had a major impact on gene expression under mixotrophic growth conditions and resulted in the inability of cells to grow in the presence of glucose with 8-h light and 16-h dark cycles. Our results indicated the importance of group II sigma factors in the global regulation of transcription in this organism and are best explained by using the sigma cycle paradigm with the stochastic release model described previously (R. A. Mooney, S. A. Darst, and R. Landick, Mol. Cell 20:335-345, 2005). We combined our results with the total protein levels of the sigma factors in the light and dark as calculated previously (S. Imamura, S. Yoshihara, S. Nakano, N. Shiozaki, A. Yamada, K. Tanaka, H. Takahashi, M. Asayama, and M. Shirai, J. Mol. Biol. 325:857-872, 2003; S. Imamura, M. Asayama, H. Takahashi, K. Tanaka, H. Takahashi, and M. Shirai, FEBS Lett. 554:357-362, 2003). Thus, we concluded that the control of global transcription is based on the amount of the various sigma factors present and able to bind RNA polymerase.


Simultaneous determination of 5-hydroxytryptophan and 3-O-methyldopa in dried blood spot by UPLC-MS/MS: A useful tool for the diagnosis of L-amino acid decarboxylase deficiency.
5-hydroxytryptophan (5HTP) and 3-O-methyldopa (3OMD) are CSF diagnostic biomarkers of the defect of aromatic L-amino acid decarboxylase (AADC), a rare inherited disorder of neurotransmitter synthesis which, if untreated, results in severely disabling neurological impairment. In the last few years, different methods to detect 3OMD in dried blood spot (DBS) were published. We developed and validated a fast and specific diagnostic tool to detect 5HTP alongside 3OMD. After extraction from DBS, 3OMD and 5HTP were separated by ultra-performance liquid chromatography (UPLC) and detected by tandem mass spectrometry (MS/MS). Instrument parameters were optimized to obtain the best sensitivity and specificity. Chromatographic separation was accomplished in 13 min. The limit of detection was 2.4 and 1.4 nmol/L of blood for 3OMD and 5HTP respectively, and response was linear over the blood range of 25-5000 nmol/L. Between-run imprecision was less than 9% for 3OMD and <13% for 5HTP. An age-specific continuous reference range was established, revealing a marked and continuous 3OMD decline with aging. The effect of age on 5HTP was less evident, showing only a slight decrease with age after the first week of life. A marked increase of both 3OMD and 5HTP was found in four patients affected by AADC deficiency (1780.6 ± 773.1 nmol/L, rv 71.0-144.9; and 94.8 ± 19.0 nmol/L, rv 15.2-42.8, respectively) while an isolated increase of 3OMD (6159.6 ± 3449.1 nmol/L, rv 73.2-192.2) was detected in three subjects affected by inherited disorders of dopamine synthesis under levodopa/carbidopa treatment (a marginal increase of 5HTP was detected in one of them). Simultaneous measurement of 5HTP and 3OMD in DBS leads to an improvement in specificity and sensitivity for the biochemical diagnosis of AADC deficiency.


Subtunical total reduction clitoroplasty: a safe modification of existing techniques.
Subtunical resection of hypertrophied cavernous tissue of the enlarged clitoris allows for maintenance of an intact blood supply to the glans and is an alternative safe method of diminishing shaft and glans size.


Functional tuftsin binding sites on macrophage-like tumor line P388D1 and on bone marrow cells differentiated in vitro into mononuclear phagocytes.
Mouse bone marrow cells, differentiated in vitro into mononuclear phagocytes (BMDMP), posess functional tuftsin binding sites, i.e. both tuftsin binding capacity and augmented phagocytic response related to tuftsin binding. The binding capacity of BMDMP was shown to be higher by a factor of about three than that exhibited by mouse monocytes and by normal, thioglycollate and Corynebacterium parvum induced peritoneal macrophages. The relatively high binding capacity did not depend on experimental variations in the in vitro culture of these populations (i.e. length of in vitro cultivation, source of serum or presence of conditioned medium leading to cell proliferation). The macrophage-like line, P388D1, was also shown to possess functional tuftsin binding sites and its binding capacity was comparable to that of the peritoneal macrophage populations.


Genome-based analysis of non-ribosomal peptide synthetase and type-I polyketide synthase gene clusters in all type strains of the genus Herbidospora.
The genus Herbidospora comprises actinomycetes belonging to the family Streptosporangiaceae and currently contains five recognized species. Although other genera of this family often produce bioactive secondary metabolites, Herbidospora strains have not yet been reported to produce secondary metabolites. In the present study, to assess their potential as secondary metabolite producers, we sequenced the whole genomes of the five type strains and searched for the presence of their non-ribosomal peptide synthetase (NRPS) and type-I polyketide synthase (PKS) gene clusters. These clusters are involved in the major secondary metabolite-synthetic pathways in actinomycetes. The genome sizes of Herbidospora cretacea NBRC 15474(T), Herbidospora mongoliensis NBRC 105882(T), Herbidospora yilanensis NBRC 106371(T), Herbidospora daliensis NBRC 106372(T) and Herbidospora sakaeratensis NBRC 102641(T) were 8.3, 9.0, 7.9, 8.5 and 8.6 Mb, respectively. They contained 15-18 modular NRPS and PKS gene clusters. Thirty-two NRPS and PKS pathways were identified, among which 9 pathways were conserved in all 5 strains, 8 were shared in 2-4 strains, and the remaining 15 were strain-specific. We predicted the chemical backbone structures of non-ribosomal peptides and polyketides synthesized by these gene clusters, based on module number and domain organization of NRPSs and PKSs. The relationship between 16S rRNA gene sequence-based phylogeny of the five strains and the distribution of their NRPS and PKS gene clusters were also discussed. The genomes of Herbidospora strains carry as many NRPS and PKS gene clusters, whose products are yet to be isolated, as those of Streptomyces. Herbidospora members should synthesize large and diverse metabolites, many of whose chemical structures are yet to be reported. In addition to those conserved within this genus, each strain possesses many strain-specific gene clusters, suggesting the diversity of these pathways. This diversity could be accounted for by genus-level vertical inheritance and recent acquisition of these gene clusters during evolution. This genome analysis suggested that Herbidospora strains are an untapped and attractive source of novel secondary metabolites.


Digital PCR for noninvasive detection of aneuploidy: power analysis equations for feasibility.
To determine the feasibility of digital PCR analysis for noninvasive prenatal diagnosis of trisomy 21. Through power equations, we modeled the number of wells necessary to determine the feasibility of digital PCR as a practical method for trisomy 21 risk assessment. The number of wells needed is a direct correlate of the ability to isolate free fetal DNA. If a 20% fetal DNA enhancement can be achieved, then 2,609 counts would be sufficient to achieve a 99% detection rate for a 1% false-positive rate and potentially feasible with readily available plates. However, if only a 2% increase is seen, then 220,816 counts will be necessary, and over 110,000 would be needed just to achieve 95% for a 5% false-positive rate - both far beyond current commercially available technology. There are several noninvasive prenatal diagnostic methods which may reach commercialization; all have differing potential advantages and disadvantages. Digital PCR is potentially a cheaper methodology for trisomy 21, but it is too early to determine the optimal method.


[Training of healthcare professionals in clinical hypnosis: A qualitative study].
Training in clinical hypnosis leads to important transformations in healthcare professionals, in their professional practices as well as in their personal lives. The objective of this study was to explore how health professionals experience the transformations that result from such a training. Semi-structured interviews with health professionals from France and Europe were conducted. The qualitative method used was Interpretative Phenomenological Analysis. Purposive sampling required to include participants from different professions, experience and regions of origin. They had already completed training in clinical hypnosis at different teaching institutions. Ten participants were included. The analysis showed four meta-themes of experience. First, it revealed participants' motivations for training in clinical hypnosis as one's desire to improve one's practice, leading to extraordinary discoveries, at a particular timing in their life. Second, participants described that hypnosis sometimes set the ground for a relationship verging on the more "intimate", therefore requiring greater caution so as not to disrupt the patient/healthcare professional relationship. Third, some participants experienced unforeseen personal fulfilment, better self-regulation of emotions and improved quality of life as well as greater comfort at the workplace. Finally, this study shed light on two limitations of training in clinical hypnosis as it can sometimes generate stress for the participants and/or result in bring about potential harmful effects: one of the risks being that the trainer might cross some ethical lines. The level of personal change experienced by the participants is similar to some changes induced by personal psychotherapy. For several participants, issues of power and vulnerability in the relationship using hypnosis were associated with a feeling of instability during the training. In hypnosis, the management of an asymmetrical relationship involves a two-way risk: vulnerability of the hypnotized person to the all-powerful relationship of their therapist as well as destabilization of therapists by the reduction of power asymmetry during hypnotic work with their patients.


ADOPT: intrinsic protein disorder prediction through deep bidirectional transformers.
Intrinsically disordered proteins (IDPs) are important for a broad range of biological functions and are involved in many diseases. An understanding of intrinsic disorder is key to develop compounds that target IDPs. Experimental characterization of IDPs is hindered by the very fact that they are highly dynamic. Computational methods that predict disorder from the amino acid sequence have been proposed. Here, we present ADOPT (Attention DisOrder PredicTor), a new predictor of protein disorder. ADOPT is composed of a self-supervised encoder and a supervised disorder predictor. The former is based on a deep bidirectional transformer, which extracts dense residue-level representations from Facebook's Evolutionary Scale Modeling library. The latter uses a database of nuclear magnetic resonance chemical shifts, constructed to ensure balanced amounts of disordered and ordered residues, as a training and a test dataset for protein disorder. ADOPT predicts whether a protein or a specific region is disordered with better performance than the best existing predictors and faster than most other proposed methods (a few seconds per sequence). We identify the features that are relevant for the prediction performance and show that good performance can already be gained with <100 features. ADOPT is available as a stand-alone package at https://github.com/PeptoneLtd/ADOPT and as a web server at https://adopt.peptone.io/.


Trends in the utilization of acupuncture among children in Taiwan from 2002 to 2011: a nationwide population-based study.
In recent years, acupuncture has been increasingly integrated into pediatric care worldwide. However, recent epidemiological studies about pediatric users of acupuncture are lacking. The current study aimed to fill the gap and carry out the large-scale investigation on the basis of the pediatric population in Taiwan. We conducted a nationwide population-based study to investigate the utilization of acupuncture in Taiwan. We analyzed data from the Longitudinal Health Insurance Database 2000 (LHID 2000). The datasets contained all original claims data for 1 million beneficiaries who were randomly sampled from the registry of all beneficiaries enrolled in the Taiwan's National Health Insurance Program from January 1, 2000 to December 31, 2011. Children younger than 18 years old were enrolled into our study for analysis. The demographic data, treatment modalities and distributions by disease categories of the pediatric acupuncture users were analyzed by descriptive statistics. Logistic regression analysis was used to investigate the trends in acupuncture use over time. The one-year prevalence of pediatric acupuncture users increased from 1.78% in 2002 to 5.34% in 2011. Acupuncture use significantly increased each year (p-value< 0.0001). Patients who were male, of greater age, resided in highly urbanized areas and suffered from injury or disorders of the musculoskeletal system were more likely to accept acupuncture treatment. Infantile cerebral palsy and psychoses were the top two health issues among those receiving complex acupuncture treatment. Older (> 9 years old) children tended to receive acupuncture treatment due to injury and musculoskeletal system disorders more than younger (≤9 years old) children. Our study revealed that the utilization of acupuncture in pediatrics became increasingly popular year by year in Taiwan from 2002 to 2011. The results of this study may provide some valuable information for further clinical practice and acupuncture research, as well as to the government and societies concerning pediatric health care.


Increased blood-brain barrier permeability to water in the aging brain detected using noninvasive multi-TE ASL MRI.
A fundamental goal in the drive to understand and find better treatments for dementia is the identification of the factors that render the aging brain vulnerable to neurodegenerative disease. Recent evidence indicates the integrity of the blood-brain barrier (BBB) to be an important component of functional failure underlying age-related cognitive decline. Practical and sensitive measurement is necessary, therefore, to support diagnostic and therapeutic strategies targeted at maintaining BBB integrity in aging patients. Here, we investigated changes in BBB permeability to endogenous blood water in the aging brain. A multiple-echo-time arterial spin-labeling MRI technique, implemented on a 9.4T Bruker imaging system, was applied to 7- and 27-month-old mice to measure changes in water permeability across the BBB with aging. We observed that BBB water permeability was 32% faster in aged mice. This occurred along with a 2.1-fold increase in mRNA expression of aquaporin-4 water channels and a 7.1-fold decrease in mRNA expression of α-syntrophin protein, which anchors aquaporin-4 to the BBB. Age-related changes to water permeability across the BBB can be captured using noninvasive noncontrast MRI techniques.


Relative Telomere Length Change in Colorectal Carcinoma and Its Association with Tumor Characteristics, Gene Expression and Microsatellite Instability.
We compared tumor and adjacent normal tissue samples from 165 colorectal carcinoma (CRC) patients to study change in relative telomere length (RTL) and its association with different histological and molecular features. To measure RTL, we used a Luminex-based assay. We observed shorter RTL in the CRC tissue compared to paired normal tissue (RTL 0.722 ± SD 0.277 vs. 0.809 ± SD 0.242, p = 0.00012). This magnitude of RTL shortening (by ~0.08) in tumor tissue is equivalent to RTL shortening seen in human leukocytes over 10 years of aging measured by the same assay. RTL was shorter in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. RTL shortening was more prominent in low-grade CRC and in the presence of microsatellite instability (MSI). In a subset of patients, we also examined differential gene expression of (a) telomere-related genes, (b) genes in selected cancer-related pathways and (c) genes at the genome-wide level in CRC tissues to determine the association between gene expression and RTL changes. RTL shortening in CRC was associated with (a) upregulation of DNA replication genes, cyclin dependent-kinase genes (anti-tumor suppressor) and (b) downregulation of "caspase executor", reducing apoptosis.


Posterior predictive checking of multiple imputation models.
Multiple imputation is gaining popularity as a strategy for handling missing data, but there is a scarcity of tools for checking imputation models, a critical step in model fitting. Posterior predictive checking (PPC) has been recommended as an imputation diagnostic. PPC involves simulating "replicated" data from the posterior predictive distribution of the model under scrutiny. Model fit is assessed by examining whether the analysis from the observed data appears typical of results obtained from the replicates produced by the model. A proposed diagnostic measure is the posterior predictive "p-value", an extreme value of which (i.e., a value close to 0 or 1) suggests a misfit between the model and the data. The aim of this study was to evaluate the performance of the posterior predictive p-value as an imputation diagnostic. Using simulation methods, we deliberately misspecified imputation models to determine whether posterior predictive p-values were effective in identifying these problems. When estimating the regression parameter of interest, we found that more extreme p-values were associated with poorer imputation model performance, although the results highlighted that traditional thresholds for classical p-values do not apply in this context. A shortcoming of the PPC method was its reduced ability to detect misspecified models with increasing amounts of missing data. Despite the limitations of posterior predictive p-values, they appear to have a valuable place in the imputer's toolkit. In addition to automated checking using p-values, we recommend imputers perform graphical checks and examine other summaries of the test quantity distribution.


Lead poisoning from use of bronze drinking vessels during the late Chinese Shang dynasty: an in vitro experiment.
Bronze drinking vessels famous for their intricate carvings and used by the aristocracy in the Chinese Shang dynasty (1555-1145 BCE) are known to have been fabricated with alloys containing soft metallic lead. The contribution of lead leaching from such vessels into the fermented grain wines drunk by the Chinese nobility in ancient times has not been previously estimated. Three bronze vessels containing 8% lead by weight were fabricated to resemble the late Shang bronze goblets. Shaoxing drinking rice wine was purchased locally and placed in the vessels, using a white grape wine and water as comparisons. Sampling was performed at baseline, 2 min, and then at days 1, 2, 4, and 7. Lead concentrations in the liquid matrix were measured using atomic absorption spectroscopy. Significant amounts of lead leached into the liquid within one day: 13,900 μg/L in water, 45,900 μg/L in rice wine, and 116,000 μg/L in white wine. Lead continued to leach into both the grape and rice wines with the passage of time. Significant lead contamination of Shaoxing rice wine was detected when it was left in bronze goblets fabricated to resemble the Shang dynasty vessels. If a liter of contaminated wine was drunk daily, the daily intake of lead could have been as high as 85 mg. Such a high degree of contamination could cause chronic lead poisoning, affecting the health of the Shang nobility who used bronze beverage containers, before lead was excluded from the manufacture of bronze.


Impact of early blood pressure variability on stroke outcomes after thrombolysis: the SAMURAI rt-PA Registry.
The present study determines associations between early blood pressure (BP) variability and stroke outcomes after intravenous thrombolysis. In 527 stroke patients receiving intravenous alteplase (0.6 mg/kg), BP was measured 8 times within the first 25 hours. BP variability was determined as ΔBP (maximum-minimum), standard deviation (SD), coefficient of variation, and successive variation. The systolic BP course was lower among patients with modified Rankin Scale (mRS) 0 to 1 than those without (P<0.001). Most of systolic BP variability profiles were significantly associated with outcomes. Adjusted odds ratios (95% confidence interval) per 10 mm Hg (or 10% for coefficient of variation) on symptomatic intracerebral hemorrhage were as follows: ΔBP, 1.33 (1.08-1.66); SD, 2.52 (1.26-5.12); coefficient of variation, 3.15 (1.12-8.84); and successive variation, 1.82 (1.04-3.10). The respective values were 0.88 (0.77-0.99), 0.73 (0.48-1.09), 0.77 (0.43-1.34), and 0.76 (0.56-1.03) for 3-month mRS 0 to 1; and 1.40 (1.14-1.75), 2.85 (1.47-5.65), 4.67 (1.78-12.6), and 1.99 (1.20-3.25) for death. Initial BP values before thrombolysis were not associated with any outcomes. Early systolic BP variability was positively associated with symptomatic intracerebral hemorrhage and death after intravenous thrombolysis.


Safe technique for aortic anastomosis in orthotopic canine cardiac transplantation.
In canine orthotopic transplantation, bleeding from the aortic suture line is often encountered, leading to the failure of the experiment. A new method for canine aortic anastomosis is described that is safe, simple to perform, and reproducible.


Characteristics of the nascent and non-nascent small DNA molecules found in Escherichia coli.
We have purified nascent DNA molecules from Escherichia coli pulse-labeled with 5-bromo[6-3H]deoxyuridine by repeated chromatography on nitrocellulose and isopycnic centrifugation in CsCl. The nascent molecules were labeled with 32P either at their 5' ends using polynucleotide kinase or at their 3' ends using terminal transferase. Compared to the non-nascent DNA of normal density, the nascent dense DNA contained a higher proportion of molecules terminated at their 5' ends with ribonucleotides. Exposure of the dense DNA to alkali generated 5' OH termini quantitatively equivalent to the number of molecules bearing 5' ribonucleotides. Experiments designed (1) to detect structures at the 5' ends of phosphatase-treated nascent DNA molecules that caused them to be resistant to hydrolysis by spleen exonuclease or (2) to detect polypeptides that were associated covalently with small DNA molecules and could be iodinated with the Bolton-Hunter reagent did not yield positive results. We conclude that many, if not all, of the intermediates in E. coli DNA replication are initiated with one or more ribonucleotides. The nascent molecules are outnumbered by small non-nascent DNA molecules in the cell, many of which appear to become slightly longer when cells are pulsed with thymidine. Many of the non-nascent DNA molecules behave as if they were self-complementary or crosslinked.


E1784K, the most common Brugada syndrome and long-QT syndrome type 3 mutant, disrupts sodium channel inactivation through two separate mechanisms.
Inheritable and de novo variants in the cardiac voltage-gated sodium channel, Nav1.5, are responsible for both long-QT syndrome type 3 (LQT3) and Brugada syndrome type 1 (BrS1). Interestingly, a subset of Nav1.5 variants can cause both LQT3 and BrS1. Many of these variants are found in channel structures that form the channel fast inactivation machinery, altering the rate, voltage dependence, and completeness of the fast inactivation process. We used a series of mutants at position 1784 to show that the most common inheritable Nav1.5 variant, E1784K, alters fast inactivation through two separable mechanisms: (1) a charge-dependent interaction that increases the noninactivating current characteristic of E1784K; and (2) a hyperpolarized voltage dependence and accelerated rate of fast inactivation that decreases the peak sodium current. Using a homology model built on the NavPaS structure, we find that the charge-dependent interaction is between E1784 and K1493 in the DIII-DIV linker of the channel, five residues downstream of the putative inactivation gate. This interaction can be disrupted by a positive charge at position 1784 and rescued with the K1493E/E1784K double mutant that abolishes the noninactivating current. However, the double mutant does not restore either the voltage dependence or rates of fast inactivation. Conversely, a mutant at the bottom of DIVS4, K1641D, causes a hyperpolarizing shift in the voltage dependence of fast inactivation and accelerates the rate of fast inactivation without causing an increase in noninactivating current. These findings provide novel mechanistic insights into how the most common inheritable arrhythmogenic mixed syndrome variant, E1784K, simultaneously decreases transient sodium currents and increases noninactivating currents, leading to both BrS1 and LQT3.


Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients.
Patients with coronary heart disease or equivalent risk received a single dose of 30, 100, 300, or 500 mg of unformulated D-4F (n = 8, each dose) or placebo (n = 8) under fasting conditions. An additional 10 patients received 500 mg (n = 8) or placebo (n = 2) with a low-fat meal. There were no significant trends in any safety parameter. D-4F was detectable in plasma at all doses with a T(max) of 30 min, 1 h, and 2 h for 30, 100, and > or = 300 mg, respectively. The area under the curve((0-t)) was 27.81 ng/hr/ml and 54.71 ng/hr/ml for the 300 mg and 500 mg dose groups, respectively, and 17.96 ng/hr/ml for the 500 mg dose given with food. HDL from each time point for each subject was tested for its ability to inhibit LDL-induced monocyte chemotactic activity in cultures of human aortic endothelial cells. The values obtained were normalized to 1.0 for LDL alone to obtain the HDL inflammatory index. This index significantly improved at 4 h at the 300 mg dose and at 2 h at the 500 mg dose compared with placebo (P < 0.05). There were no changes in plasma lipid or lipoprotein levels. We conclude that unformulated D-4F has low bioavailability that is improved under fasting conditions, and that a single dose of D-4F is safe and well tolerated and may improve the HDL anti-inflammatory index.


Psychometric properties of the Chinese version of the pediatric quality of life inventory 4.0 Generic core scales among children with short stature.
The quality of life in children with short stature was rarely studied in China, so we explore these children's quality of life and psychometric properties of the Chinese version of the Pediatric Quality of Life Inventory 4.0(PedsQL4.0) Generic Core Scales among children with short stature. A total of 201 children aged 8 ~ 18 years from the short stature clinic and other clinics of capital institute of pediatrics attended this study. The questionnaires include demographic information and PedsQL4.0 generic core scales. According to children's height, we divided them into three groups: short stature, normal short and normal group, then compared the score of scales by the height category. Moreover, we analyzed the reliability and validity of PedsQL4.0 generic core scales in these 201 children. The child self-report total PedsQL mean score, for the short stature, normal short and normal groups were 77.77 ± 9.69, 83.50 ± 8.56 and 87.36 ± 7.23; the parent-proxy total PedsQL mean score were 77.62 ± 10.50, 82.69 ± 8.35 and 84.91 ± 9.96 respectively. Both for children self- and parent proxy-reports, the Cronbach's α coefficients of total scale, psychosocial health and social functioning ranged between 0.74 and 0.80, it ranged between 0.51 and 0.66 in other dimensions. For child self-reports, the correlation coefficients of 17 items' scores (total 23 items) with the scores of dimensions they belong to were above 0.5, with the highest 0.759; the other 6 items' correlation coefficients were below 0.5, with the lowest 0.280. For parent proxy-reports, the correlation coefficients of 19 items' scores with the scores of dimension they belong to were above 0.5, with the highest 0.793, the other 4 items' below 0.5 with the lowest 0.243. The quality of life in children with short stature is worse than their normal peers by Peds QL4.0 generic core scales, the statues of their quality of life was positively related to their stature.


Vitamin D status and surgical outcomes: a systematic review.
The importance of vitamin D for musculoskeletal health has long been recognized, and awareness of significant extra-skeletal effects in health and disease is rapidly emerging. Although it has been possible for many decades to quantify serum markers of vitamin D deficiency, and to correct deficiency at low cost and with high safety, the influence of vitamin D status on post-surgical outcomes has only recently been identified as a research topic of interest. To the present, these data have not been the subject matter of formal review. Accordingly, we conducted a systematic review to assess the association between perioperative vitamin D status and outcomes after surgery. The databases of PubMed, Ovid MEDLINE, EMBASE, AMED, CINAHL (EBSCOHost), The Cochrane Databases of Systematic Review, and PROSPERO were searched through December, 2014 for studies relating to vitamin D and surgery. The initial search yielded 90 manuscripts. After applying exclusion criteria, 31 studies were eligible for inclusion. Fifteen studies employed prospective observational designs, 3 used prospective randomized protocols, and 13 report retrospective database interrogations. The main finding of the present review is that 26 of 31 studies (84%) report at least one statistically significant worse outcome in patients with low vitamin D status. Five of 31 studies (16%) found no association. In conclusion, this review supports the hypothesis that hypovitaminosis D is associated with adverse outcomes after diverse surgical procedures. Future studies should focus on additional surgeries and outcomes, and on the role of vitamin D supplementation in the improvement of patient safety in participants with low vitamin D status at the time of surgery.


Acquisition of resistance to vemurafenib leads to interleukin-10 production through an aberrant activation of Akt in a melanoma cell line.
Serine/threonine-protein kinase B-Raf (BRAF) inhibitors are very effective in treating melanoma with BRAF mutations. BRAF inhibitors suppress aberrant growth of melanoma cells caused by BRAF mutations. BRAF mutations reportedly result in melanoma cells releasing immunosuppressive factors, and BRAF inhibitors elicit anti-melanoma immune responses by reducing such factors. However, immunological characteristics of tumor cells that acquire resistance to BRAF inhibitors remain unknown. Here, we compared immunological characteristics between a melanoma cell line and its vemurafenib-resistant subline. No differences were observed in the status of BRAF mutations, expression of surface molecules related to antitumor T-cell responses or recognition by human leukocyte antigen-A*0201-matched melanoma-specific cytotoxic T lymphocytes in a short-term co-culture assay. However, resistant tumor cells released high amounts of interleukin-10 depending on aberrant activation of Akt signaling, and dendritic cell functions were considerably suppressed by culture supernatants of the resistant cells. Our findings demonstrated a novel immunological mechanism contributing to tumor growth owing to drug resistance to BRAF inhibitors.


Accuracy evaluation of objective refraction using the wavefront aberrometer in pseudophakic eyes.
To evaluate the accuracy of wavefront-derived objective refraction in pseudophakic eyes. Retrospective case series. A total of 356 eyes (356 patients) that underwent phacoemulsification and posterior chamber intraocular lens implantation were included. Noncycloplegic subjective manifest refraction (MR) and objective refraction results from the wavefront aberrometer were obtained and compared. Subgroup analysis of objective refraction at 2.6-mm zone was performed based on axial length (AL) and average keratometry. The biases (at the 2.6-mm, 3-mm, and 4-mm zones) were - 0.29 ± 0.37 D, - 0.53 ± 0.41 D, and - 0.51 ± 0.60 D for sphere; - 0.27 ± 0.36 D, - 0.52 ± 0.38 D, and - 0.53 ± 0.51 D for spherical equivalent (SE); 0.03 ± 0.20 D, 0.03 ± 0.22 D, and 0.04 ± 0.27 D for J0; and 0.01 ± 0.16 D, 0.03 ± 0.22 D, and 0.01 ± 0.22 D for J45, respectively. Objective refraction for sphere, SE, and J0 (at 2.6 mm, 3 mm, and 4 mm) was significantly different from MR (P < 0.05), while J45 values were equal. The objective refraction at 2.6 mm was the most accurate in short eyes (≤ 22.5 mm) with a minimum bias for SE (- 0.15 ± 0.28 D) and highest percentage of SE within ± 0.25 to ± 0.75 D of MR. However, there was no difference between the keratometry subgroups. The wavefront aberrometer achieved the best accuracy at 2.6 mm in pseudophakic eyes with short AL. It still needs modification to be used as a substitute for MR in such patients.


The cingulate cortex and spatial neglect.
Spatial neglect is asymmetric attention, orienting, and action causing functional disability. It is linked to higher-order cortical sensory processing; however, spatial motor "Aiming" processing is critical to fundamental, adaptive environmental movement and daily life function. The cingulate cortex, in particular the anterior cingulate and anterior midcingulate cortex, is strongly linked to spatial Aiming deficits and likely to predict daily life disability in spatial neglect. The authors review the impact and mechanisms of spatial neglect and then describe specific symptoms associated with spatial neglect that are theoretically linked to cingulate cortical functions or associated with lesions extending to cingulate regions in a well-characterized spatial neglect cohort. The treatment implications for a link between cingulate cortex spatial Aiming neglect and therapies that improve spatial action, arousal, and persistence are discussed. Clinicians may want to consider theoretically motivated treatments targeted at specific symptoms as well as use treatments supported for spatial neglect based on unselected and uncharacterized groups.


[Surgical treatment of axillary hidradenitis suppurativa].
Hidradenitis suppurativa is a chronic inflammatory disease of the cutis with furuncles, fistulas and abscesses, mostly located in the groin and axillary regions. A conservative treatment can not prevent a recurrence. We report on 16 patients with axillary hidradenitis suppurativa. The inflammatory region was excised, followed by immediate coverage with a transposition flap according to Limberg. Postoperatively, all patients received antibiotic treatment. After 2 weeks, physiotherapy was begun. All wounds healed primarily. Functional and aesthetic results were very satisfactory. Movement of the shoulder showed no restrictions. There was no major complication. The recurrence rate was low. Only radical debridement prevents a recurrence. The therapy of choice is radical excision of the affected region and immediate coverage by a transposition flap. Open granulation or split-skin grafting are inferior compared with a primary closure by transposition flap. Using the Limberg flap the donor site can be closed primarily.


Host nuclear abnormalities and depletion of nuclear antigens induced in Trichinella spiralis-infected muscle cells by the anthelmintic mebendazole.
Infection by the parasitic nematode Trichinella spiralis induces cell cycle repositioning (chronic suspension in apparent G2/M) and genetic reprogramming in differentiated mammalian skeletal muscle cells. These changes occur in association with dramatic enlargement of infected host cell nuclei (as large as 17 microm in diameter) and nucleoli. Nuclear antigens (NA) that colocalize with host chromatin have been detected by antibodies to T. spiralis antigens, but the functions of these NA are unresolved. Mebendazole (MBZ) preferentially binds parasite versus host beta-tubulins, is implicated in inhibiting secretion in nematodes and induces cytoplasmic changes in muscle cells infected with T. spiralis. These infected cell changes might be indirect via MBZ inhibition of parasite secretions. This effect would have implications for host/parasite interactions and was evaluated here. MBZ treatment of chronically infected mice caused: (1) a significant deformation of host nuclei and diminution of nucleoli by 4 and 6 days of treatment (dot), respectively; (2) a reduction of nuclear lamins A/C in infected cell nuclei that was concomitant with nuclear deformation; and (3) significant reductions in total RNA, general protein and acid phosphatase activity levels. These changes were associated with the depletion of NA from host nuclei detected by 4 dot. However, DNA content of infected cell nuclei was not detectably reduced and muscle gene expression was not reactivated. The cellular changes documented are likely to account for previously described cytoplasmic alterations induced by MBZ. Concomitant depletion of NA from infected cell nuclei suggests a role of these products in regulating nuclear functions of host cells.


High-Dose Inactivated Influenza Vaccine Quadrivalent for Older Adults.
To review the efficacy and safety of the high-dose inactivated influenza vaccine quadrivalent (HD-IIV4) in the prevention of influenza in older adults. A literature search was performed using PubMed and Google Scholar with the search terms high-dose, influenza vaccine, and quadrivalent. Other resources included the Centers for Disease Control and Prevention (CDC), the prescribing information, and the manufacturer's website. All relevant English-language articles of studies assessing the efficacy and safety of HD-IIV4 were included. HD-IIV4 is licensed by the Food and Drug Administration for the prevention of influenza in adults aged 65 years and older. The safety and immunogenicity of HD-IIV4 was demonstrated in a phase 3 trial, and the efficacy of the trivalent formulation (HD-IIV3) was demonstrated in a phase 3b-4 trial. HD-IIV4 carries a warning regarding the occurrence of Guillain-Barré syndrome. Adverse reactions, including injection-site pain and myalgia, were reported more frequently with HD-IIV4 than with HD-IIV3. Although the CDC recommends any age-appropriate influenza vaccine for adults aged 65 years and older, HD-IIV4 was associated with improved immunogenicity against the added B strain and HD-IIV3 provided better protection against influenza than the standard-dose vaccine. Other influenza vaccines have weaker evidence of efficacy in older adults. Therefore, HDIIV4 should be recommended as the vaccine of choice in adults aged 65 years and older. HD-IIV4 has proven immunogenic, safe, and effective in preventing influenza in older adults and should be recommended as the vaccine of choice in this patient population.


MDR tuberculosis in elderly.
Tuberculosis is very common in young population, but it has emerged in a significant number in geriatric/elderly population (>60 Yrs. of age) as the population is ageing. Most cases of TB in the elderly are linked to the reactivation of lesions that have remained dormant. The awakening of these lesions is attributable to changes in the immune system related to senescence. Mortality rate from tuberculosis remains higher in elderly patients. Diagnosis is difficult as symptoms of active TB are nonspecific and less pronounced in the elderly. MDR TB is known to occur in poorly compliant patients (non-adherence) and this can be a major issue in elderly due to loss of independence and frailty resulting in treatment failure. Multidisciplinary management, involving geriatricians and infectious disease specialists is essential throughout care to optimize a favourable outcome in these vulnerable patients.


Does imprint cytology of brain tumours improve intraoperative diagnoses?
To evaluate the diagnostic accuracy using frozen sections only and a combination of imprint cytology and frozen sections. After introduction of imprint cytology as a supplement to frozen sections in 1999, 153 patients with brain tumours underwent stereotactic or open surgery. An equal number of cases prior to 1999 were chosen for comparison. Intraoperative diagnoses were compared with final diagnoses based on paraffin sections of the same tissue samples. The number of delayed intraoperative diagnoses was noted in each patient group. The combined use of the two techniques improved intraoperative diagnostic accuracy from 87 to 91% while the delayed intraoperative diagnoses were significantly reduced from 30 to 8. The choice of surgical procedure did not affect the outcome of the pathological investigations. A combination of frozen sections and imprints significantly reduced the number of delayed intraoperative diagnoses. Intraoperative diagnostic accuracy was improved, although not to a statistically significant level. Choice of surgical procedure did not affect the diagnostic outcome.


Low-dose intravenous midazolam reduces etomidate-induced myoclonus: a prospective, randomized study in patients undergoing elective cardioversion.
Myoclonic movements are a common problem in unpremedicated patients during induction of anesthesia with etomidate. In a double-blind fashion, 40 patients (ASA physical status III-IV) scheduled for elective cardioversion were randomly assigned to receive either 0.015 mg/kg midazolam or placebo 90 s before the injection of 0.3 mg/kg etomidate. Myoclonic movements and sedation were recorded on a scale between 0 and 3. Pulse oximetry, noninvasive arterial blood pressure, and heart rate were recorded during the study period. Two patients (10%) in the midazolam group had myoclonic movements after the administration of etomidate, whereas 10 of the 20 patients (50%) receiving placebo experienced such movements (P = 0.006). No other differences were found between the groups; in particular, there was no difference in recovery 5 min after the administration of etomidate. IV midazolam 0.015 mg/kg administered 90 s before induction of anesthesia with etomidate is effective in reducing myoclonic movements and does not prolong recovery in unpremedicated patients after short procedures.


Binding of human factor VIII to phospholipid vesicles.
Factor VIII, a protein cofactor involved in blood coagulation, functions in vitro on a phospholipid membrane surface to greatly increase the rate of factor X activation by factor IXa. Using gel filtration, rapid sedimentation, and resonance energy transfer we have studied the interaction of recombinant-derived human factor VIII with small and large unilamellar phospholipid vesicles composed of phosphatidylserine and phosphatidylcholine. Resonance energy transfer, from intrinsic fluorophores in factor VIII to dansyl-phosphatidylethanolamine incorporated into vesicles, has been adapted for quantitative equilibrium measurements. Factor VIII binds rapidly and reversibly to small and large vesicles. At 8 degrees C the interaction of factor VIII with small vesicles fits a simple bimolecular model with a KD of 2 nM and a phospholipid binding site defined by 180 phospholipid monomers. At 25 degrees C the binding of factor VIII to small vesicles containing 20% phosphatidylserine can be described by an apparent KD of 4 nM; the phospholipid/protein ratio at saturation was 170. Binding to large vesicles was demonstrated with a KD of 2 nM and a phospholipid/protein ratio at saturation of 385. Binding was dependent upon the phosphatidylserine mole fraction and was nonlinear from 0 to 30% phosphatidylserine content. A direct comparison of factor VIII and factor V binding indicated that the affinity of factor V to phospholipid vesicles was equivalent to that of factor VIII and that the phosphatidylserine requirement was lower. A model is proposed to explain the nonlinear phosphatidylserine dependence of binding for factor VIII.


Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating β-Hydroxybutyrate-activated Citrate Synthase.
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended in the AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (60% calories from lard) + N [w] -nitro- l -arginine methyl ester ( l -NAME-0.5 g/L) (2 Hit) in male Sprague Dawley rats to effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing β-hydroxybutyric acid (β-OHB) levels, directing the activation of citrate synthase, reducing acetyl coenzyme A (acetyl-CoA) pools, modulating adenosine 5'-triphosphate production, and increasing the expression of mitochondrial oxidative phosphorylation system complexes I-V. In addition, following clinical DAPA therapy, the blood levels of β-OHB and citrate synthase increased and the levels of acetyl-CoA in the blood of HFpEF patients decreased. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.


Effect of tetrandrine on micronucleus formation and sister-chromatid exchange in both in vitro and in vivo assays.
The genotoxicity of tetrandrine, a drug potentially useful for the treatment of silicosis, was studied using the micronucleus and the sister-chromatid exchange (SCE) assay systems. Cultured Chinese hamster lung (V79) cells were used for the in vitro micronucleus and sister-chromatid exchange studies. Mouse bone marrow was used for the in vivo micronucleus assay and mouse spleen cells for the in vivo/in vitro sister-chromatid exchange analysis. The results show that SCE levels in V79 and in spleen cells were significantly elevated by treatment with tetrandrine at doses above 0.08 mg/ml and 100 mg/kg bw, respectively. Increased tetradrine-induced SCE in vitro was metabolic activation dependent. Tetrandrine failed to induce micronuclei at any of the doses tested. A decrease of replicative index with an increase in the concentration of tetrandrine was found both in vitro and in vivo. These results indicate that tetrandrine is a weak indirect-acting genotoxicant.


The Thrombostat system. A useful method to test antiplatelet drugs and diets.
The use of platelet inhibitory drugs, like aspirin, has resulted in a significant reduction of thrombotic complications in primary and secondary prevention of heart attacks. To find more effective substances or better drug combinations, inhibition of primary hemostasis in vitro (Thrombostat system) was investigated, with different drugs and fish diet, using small samples (1 ml) of anticoagulated (Na- citrate 3.8%, 1/9) human blood. 1. In the presence of 1 mM aspirin, which had no effect on bleeding volume, only 0.6 nM iloprost were necessary to show a 50% inhibition, in contrast to 2.5 nM without aspirin. 2. At aspirin concentrations of 1 mM, 50% inhibition of primary hemostasis could be achieved with 20 microM SIN-1, or with 7 microM SIN-1 together with iloprost (500 pM). The same effect was seen only with very high doses of SIN-1 (1000 microM) alone. 3. For 50% inhibition of primary hemostasis in vitro, RGDS concentrations were reduced from 250 microM to 160 microM when blood was pretreated with 1 mM aspirin and to 75 microM when 500 pM iloprost were added additionally. 4. Japanese fishermen (eating 270 g fish/day) demonstrated significantly longer in-vivo bleeding times and in-vitro bleeding volumes (6.49 min/224 microliters), respectively, as compared to Japanese farmers (90 g fish/day, 4.85 min/137 microliters). 5. In Japanese subjects in-vivo bleeding times correlated with in-vitro bleeding volumes (0.69). The Thrombostat system proved to be a sensitive method to detect synergistic effects of various antiplatelet drugs in vitro and of a platelet inhibitory diet ex vivo.


Stepwise conversion of flavonoids by engineered dioxygenases and dehydrogenase: Characterization of novel biotransformation products.
Flavonoids are a large group of plant secondary metabolites that exert various biological and pharmacological effects. In this context, the generation of derivatives is of considerable interest. The introduction of hydroxy groups is of particular relevance, as they are known to be involved in many of the biological interactions and furthermore enable additional modifications, such as glycosylations. Bacterial aryl-hydroxylating dioxygenases (ARHDOs) have proven to be very useful for the conversion of aromatic structures into versatile building blocks for different kinds of derivatizations. Such enzymes have been used with varying success for the oxidation of flavonoids. In order to find better ARHDOs for the hydroxylation of such substrates, we carried out biotransformation trials with a collection of hybrid ARHDOs of different origin, using resting cells of recombinant strains. This identified enzymes able to transform all of the flavonoids examined, typically in yields above 50%. It also showed that moderately reactive substituents of flavonoids, such as hydroxy or amino groups, can lead to spontaneous follow-up reactions with the dienediol structures generated by dioxygenation. A report of flavanone epoxidation, a reaction never before observed to be catalyzed by an ARHDO, is challenged by our results. All ARHDOs examined converted this substrate into a dehydrogenase-transformable dihydrodiol. All dihydrodiols obtained by dioxygenation of the examined flavonoids were successfully re-aromatized into catechols by a bacterial dehydrogenase. These metabolites were usually stable. However, the catechols formed from flavanone and 2'-hydroxy-chalcone, respectively, were interconvertible under mild conditions. Altogether, we isolated and characterized 13 compounds that have not previously been described. The biotransformations reported here give access to novel flavonoid derivatives that may be applied for biological screens as well as for further modification, such as glycodiversification.


The Use of Feedback in Improving the Knowledge, Attitudes and Skills of Medical Students: a Systematic Review and Meta-analysis of Randomized Controlled Trials.
This study aims to investigate the effectiveness of the use of different feedback modalities in improving the knowledge, attitudes, and skills of medical students compared to students receiving no feedback or unstructured feedback. A systematic review and meta-analysis of randomized controlled trials was conducted based on a search of the Cochrane, ERIC, PubMed, Scopus, and Web of Science databases. A total of 26 studies were included for the systematic review and 13 for the meta-analysis. The meta-analysis revealed that the use of feedback was associated with better results compared to control groups (SMD = 0.80 [0.56-1.04], p < 0.001), and also when only high-quality studies were included (SMD = 0.86 [0.56-1.16], p < 0.001). Our findings revealed high heterogeneity in the use of feedback in medical education. However, the results of most of the studies and of the meta-analysis were positive, showing that feedback had a positive influence on the education-learning process of the students. PROSPERO registration: CRD42018112688.