'Absolute' inter-observer classifications agreement for proximal humeral fractures with a single shoulder anteroposterior X-ray.
Several studies have been carried out, and there is no classification for proximal humeral fractures (PHF) exempted from variability in interpretation and with questioned reliability. In the present study, we investigated the 'absolute diagnostic reliability' of the most currently used classifications for PHFs on a single anterior-posterior X-ray shoulder image. Six orthopaedic surgeons, with varying levels of experience in shoulder pathology, evaluated radiographs from 30 proximal humeral fractures, according to the 'absolute reliability' criteria. Each of the observers rated each fracture according to Neer, Müller/AO and Codman-Hertel's classification systems. The overall inter-observer agreement (κ) has been 0.297 (CI95% 0.280 to 0.314) for the Neer's classification system, 0.206 (CI95% 0.193 to 0.218) for the Müller/AO classification system, and 0.315 (CI95% 0.334 to 0.368) for the Codman-Hertel classification system. We found loss of agreement in Neer's classification as the study progressed, low agreement in the AO classification, and stable values in the different evaluations with the best degree of agreement for Codman-Hertel classification, with a moderate agreement in the second evaluation among the six evaluators. The Neer, AO, and Hertel-Codman classification systems for PHF with a single radiographic projection have a difficult interpretation for orthopaedic surgeons of varying levels of experience, and therefore substantial agreements are not obtained.


A Novel Approach to Screen for Somatosensory Evoked Potentials in Critical Care.
Somatosensory evoked potentials (SSEPs) help prognostication, particularly in patients with diffuse brain injury. However, use of SSEP is limited in critical care. We propose a novel, low-cost approach allowing acquisition of screening SSEP using widely available intensive care unit (ICU) equipment, specifically a peripheral "train-of-four" stimulator and standard electroencephalograph. The median nerve was stimulated using a train-of-four stimulator, and a standard 21-channel electroencephalograph was recorded to generate the screening SSEP. Generation of the SSEP was supported by visual inspection, univariate event-related potentials statistics, and a multivariate support vector machine (SVM) decoding algorithm. This approach was validated in 15 healthy volunteers and validated against standard SSEPs in 10 ICU patients. The ability of this approach to predict poor neurological outcome, defined as death, vegetative state, or severe disability at 6 months, was tested in an additional set of 39 ICU patients. In each of the healthy volunteers, both the univariate and the SVM methods reliably detected SSEP responses. In patients, when compared against the standard SSEP method, the univariate event-related potentials method matched in nine of ten patients (sensitivity = 94%, specificity = 100%), and the SVM had 100% sensitivity and specificity when compared with the standard method. For the 49 ICU patients, we performed both the univariate and the SVM methods: a bilateral absence of short latency responses (n = 8) predicted poor neurological outcome with 0% FPR (sensitivity = 21%, specificity = 100%). Somatosensory evoked potentials can reliably be recorded using the proposed approach. Given the very good but slightly lower sensitivity of absent SSEPs in the proposed screening approach, confirmation of absent SSEP responses using standard SSEP recordings is advised.


Transition from pediatric to adult care for adolescents and young adults with a disorder of sex development.
Over the past twenty years, there has been an increasing awareness of the transition to adult-oriented health care in adolescents and young adults with a chronic illness. While general guidelines for health care transition have been established, some have called for illness-specific guidelines which are tailored to the needs of specific illness populations. The current paper sought to outline illness-specific guidelines for health care transition in adolescents and young adults with disorders of sex development based upon the recent American Academy of Pediatrics guidelines. We also suggest indicators of successful transition for adolescents and young adults with disorders of sex development as well as areas for future research.


Accessing the position-specific 18O/16O ratios of lignin monomeric units from higher plants with highly selective hydrogenolysis followed by GC/Py/IRMS analysis.
The 18O/16O of lignin at bulk, molecular and positional levels can be used to extract valuable information about climate, plant growth environment, plant physiology, and plant metabolism. Access to the individual oxygen isotope compositions (δ18O) in the lignin monomeric units is, however, challenging as depolymerization of lignin to release the monomeric units may cause isotope fractionation. We have developed a novel method to measure the δ18O of the three oxygens (O-3, O-4 and O-5) attached to the aromatic ring of the monomeric units (bearing no oxygen in their side chains) releasable by highly selective W2C/AC (tungsten carbide supported by activated carbon)-catalyzed hydrogenolysis of lignin. O-4 is obtained by measuring the δ18O of H-type monomeric unit, while O-3 and O-5 can be calculated following isotope mass balance between H, G and S-type monomeric units measurable simultaneously with GC/Py/IRMS (gas chromatography-pyrolysis-isotope ratio mass spectrometry). The measurement precisions are better than 1.15 mUr and 4.15 mUr at molecular and positional levels, respectively. It was shown that there were a δ18OH > δ18OG > δ18OS isotopic order in the herbaceous plant lignin and an (inclusive) opposite order in woody plant lignin. Such differences in isotopic order is likely to be caused by the fact that both L-tyrosine, which carries an 18O-enriched leaf water signal, and L-phenylalanine, which carries mainly a molecular O2 isotopic signal, serve as the precursors for lignin biosynthesis in herbaceous plants while only the latter serves as precursor for lignin biosynthesis in woody plants. We have highlighted the potential application of such molecular and positional levels isotopic signals in plant physiological, metabolic, lignin biosynthetic and climate studies.


Schwannoma arising from the sublingual gland.
Sublingual gland tumors, especially mesenchymal tumors, are extremely rare. We describe the first reported case of schwannoma arising from the sublingual gland with details of the histopathologic and immunohistochemical features. A 70-year-old woman developed a painless swelling on the floor of the mouth. The excised material was sublingual gland tissue with an ovoid, grayish-yellow solid tumorous mass at the cut surface. The tumor was composed of proliferated spindle-shaped tumor cells exhibiting palisading patterns. In the center of the tumor, a small salivary gland component was recognized. Immunohistochemically, the tumor cells were strongly positive for S-100 protein but negative for neurofilament protein. The Ki-67 labeling index was 4.58. The clear presence of a remnant sublingual gland lobule in the present tumor provided convincing evidence that it was a schwannoma arising from the sublingual gland and thus the first of its type to be reported.


Effects of the polypeptide from peanut meal mixed fermentation on lipid metabolism and intestinal flora of hyperlipidemic mice.
Hyperlipidemia is one of the metabolic disorders posing great threat to human health. Our previous studies have shown that the nutritional properties of peanut meal after fermentation are markedly improved, and can effectively improve hyperlipidemia caused by high-fat diet in mice. In this study, in order to facilitate the further utilization of peanut meal, the effect of peanut polypeptide (PP) from peanut meal mixed fermentation on lipid metabolism in mice fed with high-fat diet (HFD) and its possible mechanism were investigated. Fifty male C57BL/6J mice were randomly divided into five groups: normal control group (N), high-fat model group (M), PP low-dose group (PL), PP high-dose group (PH), and atorvastatin positive control group (Y). The results show that PP supplementation can effectively reduce the body weight of mice, decrease the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and leptin levels (P < 0.05), increase the high-density lipoprotein cholesterol (HDL-C) levels (P < 0.05), up-regulate the expression levels of ileal tight junction proteins ZO-1 and occludin (P < 0.05), reduce the hepatocyte injury and lipid accumulation caused by high-fat diet and increase the species richness of intestinal flora. PP can significantly improve hyperlipidemia and regulate intestinal flora disorders caused by hyperlipidemia. The possible mechanism may be related to the reduction of serum leptin levels and up-regulating the expression levels of the ileal tight junction proteins ZO-1 and occludin. This study provides evidence for its regulatory role in lipid metabolism and intestinal function, and provides a research basis for the potential nutritional benefits of underutilized food by-products. © 2023 Society of Chemical Industry.


Use of retrievable compared to permanent inferior vena cava filters: a single-institution experience.
The purpose of this study was to review the use, safety, and efficacy of retrievable inferior vena cava (IVC) filters in their first 5 years of availability at our institution. Comparison was made with permanent filters placed in the same period. A retrospective review of IVC filter implantations was performed from September, 1999, to September, 2004, in our department. These included both retrievable and permanent filters. The Recovery nitinol and Günther tulip filters were used as retrievable filters. The frequency of retrievable filter used was calculated. Clinical data and technical data related to filter placement were reviewed. Outcomes, including pulmonary embolism, complications associated with placement, retrieval, or indwelling, were calculated. During the study period, 604 IVC filters were placed. Of these, 97 retrievable filters (16%) were placed in 96 patients. There were 53 Recovery filter and 44 Tulip filter insertions. Subjects were 59 women and 37 men; the mean age was 52 years, with a range of from 18 to 97 years. The placement of retrievable filters increased from 2% in year 1 to 32% in year 5 of the study period. The total implantation time for the permanent group was 145,450 days, with an average of 288 days (range, 33-1811 days). For the retrievable group, the total implantation time was 21,671 days, with an average of 226 days (range, 2-1217 days). Of 29 patients who returned for filter retrieval, the filter was successfully removed in 28. There were 14 of 14 successful Tulip filter retrievals and 14 of 15 successful Recovery filter retrievals. In one patient, after an indwelling period of 39 days, a Recovery nitinol filter could not be removed secondary to a large clot burden within the filter. For the filters that were removed, the mean dwell time was 50 days for the Tulip type and 20 days for the Recovery type. Over the follow-up period there was an overall PE incidence of 1.4% for the permanent group and 1% for the retrieval group. In conclusion, there was an increase in the use of retrievable filters over the study period and an overall increase in the total number of filters implanted. The increased use of these filters appeared to be due to expanded indications predicated by their retrievability. Placement and retrieval of these filters have a low risk of complications, and retrievable filters appeared effective, as there was low rate of clinically significant pulmonary embolism associated with these filters during their indwelling time.


Mitral valve diseases in Williams syndrome-case report and review of the literature.
Williams syndrome is a genetic syndrome involving an unusual facies, short stature, developmental delay and heart defects. There is a genetic marker for this disease. Williams syndrome is frequently associated with congenital heart defects. The most common cardiac diagnoses are supravalve aortic stenosis, supravalve pulmonic stenosis, and arterial hypertension. In contrast, the association of mitral valve prolapse with Williams syndrome is less well defined. We present a case of a 15-year-old girl with Williams syndrome who underwent successful mitral valve repair. Review of the echocardiographic database of our institution over a 10-year period identified 26 other patients with Williams syndrome. Overall, 10 of the 27 children with Williams syndrome had mitral valve disease (37%) including 9 patients with mitral valve prolapse and one with mitral insufficiency. In conclusion, patients with Williams syndrome should be examined for mitral valve disease. Mitral valve repair is feasible and may be considered in the growing child with Williams syndrome.


Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family.
Accumulating evidence suggests that various diseases, including many types of cancer, result from alteration of subcellular protein localization and compartmentalization. Therefore, it is worthwhile to expand our knowledge in subcellular trafficking of proteins, such as epidermal growth factor receptor (EGFR) and ErbB-2 of the receptor tyrosine kinases, which are highly expressed and activated in human malignancies and frequently correlated with poor prognosis. The well-characterized trafficking of cell surface EGFR is routed, via endocytosis and endosomal sorting, to either the lysosomes for degradation or back to the plasma membrane for recycling. A novel nuclear mode of EGFR signaling pathway has been gradually deciphered in which EGFR is shuttled from the cell surface to the nucleus after endocytosis, and there, it acts as a transcriptional regulator, transmits signals, and is involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, and chemo- and radio-resistance. Internalized EGFR can also be transported from the cell surface to several intracellular compartments, such as the Golgi apparatus, the endoplasmic reticulum, and the mitochondria, in addition to the nucleus. In this review, we will summarize the functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles. A better understanding of the molecular mechanism of EGFR trafficking will shed light on both the receptor biology and potential therapeutic targets of anti-EGFR therapies for clinical application.


Design of a multiplex quantitative reverse transcription-PCR system to simultaneously detect 16 pathogens associated with bovine respiratory and enteric diseases.
Bovine respiratory disease (BRD) and bovine enteric disease (BED) are two major diseases in cattle, resulting in severe economic losses in the dairy and beef industries. The two major diseases are associated with several factors such as viruses, bacteria, the health condition of the host and environmental factors. We aimed to design a new efficient diagnostic method, which rapidly detect causative pathogens, minimizing economic loss due to BRD and BED. We designed a multiplex quantitative reverse transcription-PCR (qRT-PCR) system for the simultaneous diagnosis of 16 pathogens, including 12 viruses and 4 bacteria related to BRD and BED, based on single qRT-PCR assays in previous studies. The designed multiplex qRT-PCR was highly sensitive and has minimal detection levels which will be no different from those of single qRT-PCR. Moreover, the multiplex qRT-PCR could more efficiently detect the causative pathogens than conventional RT-PCR in test using a part of BRD and BED clinical samples. Furthermore, our data revealed that the multiplex qRT-PCR had high performance in its specificity and reproducibility tests. Our system can effectively detect multiple BRD or BED related pathogens from each animal while testing several clinical samples via the multiplex qRT-PCR. It is more time-, cost- and labour-efficient than other diagnostic methods. Rapid detection of infected animals from the herd using our system will greatly contribute to infection control and prompt treatment in field.


The ataxia-ome: connecting disease proteins of the cerebellum.
In this issue of Cell, Lim et al. (2006) describe a protein-protein interaction network for inherited human ataxias, a group of diseases characterized by degeneration of cerebellar Purkinje cells. This protein interactome shows that the cerebellar ataxias not only share clinical and pathological characteristics but also have proteins, processes, and pathways in common.


An automatic neuron reconstruction system.
Most contemporary neuron tracing systems are semi-automatic; that is, an operator follows neuron branches in a microscope or on a data tablet and instructs a computer when to record a spatial sample. A list of such samples is then used to generate a display of the neuron and to summarize statistically its structure. The tracing is tedious, and the operator must make subjective decisions about point types, thus biasing the results. A fully automatic system in which the computer views the image through a television digitizing system has been constructed. The computer follows the fibers and recognizes branchpoints and fiber endings. The coordinates, types of points, and fiber diameters are recorded in computer memory. An operator is required only to start the tracing of a fiber and to help the computer when it becomes "confused". The results are mixed. The computer can follow fibers quite successfully and can determine branches and endings with some success, but the procedure is an order of magnitude more slow than that of a skilled operator using a well-designed semi-automatic system.


Molecular cloning, expression and mimicking antiviral activity analysis of retinoic acid-inducible gene-I in duck (Anas platyrhynchos).
Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Pattern recognition receptors(PRRs) of the innate immune system detected the dsRNA and initiate the antiviral responses. Retinoic acid-inducible gene I (RIG-I), a member of PRRs, plays an essential regulatory role in dsRNA-induced signalling. In this study, the full-length complementary DNA (cDNA) of duck RIG-I (duRIG-I) was cloned using the reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of the cDNA ends (RACE). The cDNA of duRIG-I contained 97-bp 5'UTR, 141-bp 3'-UTR and 2802 bp complete open-reading frame (ORF) encoding 933 amino acids. Multiple sequence alignments showed that duRIG-I shared high similarity with RIG-I from other vertebrates. Quantitative real-time PCR (qRT-PCR) analysis revealed that duRIG-I mRNA was expressed in all tested tissues, with high levels in the liver, heart, spleen, kidney and thymus, while lower in the duodenum. duRIG-I could be induced by treatment with poly(I:C). Further, overexpression of duRIG-I significantly activated the transcription of poly(I:C)-induced IFN-b, IRF7, TRIF, Mx, STAT1 and STAT2 mRNA, and duRIG-I knockdown showed the opposite results. Overall, our results suggested that duRIG-I could be an important receptor for mimicking antiviral state in duck, which warrant further studies to show the possible mechanism.


RALF-FERONIA Signaling: Linking Plant Immune Response with Cell Growth.
Plants perceive various external and internal signals to self-modulate biological processes through members of the receptor-like kinase (RLK) family, among which Catharanthus roseus receptor-like kinase 1-like (CrRLK1L) proteins with their ligands, rapid alkalinization factor (RALF) peptides, have attracted considerable interest. FERONIA (FER), a CrRLK1L member, was initially reported to act as a major plant cell growth modulator in distinct tissues. Subsequently, the RALF-FER pathway was confirmed to function as an essential regulator of plant stress responses, including but not limited to immune responses. Furthermore, the RALF-FER pathway modulates immune responses and cell growth in a context-specific manner, and the vital roles of this pathway are beginning to be appreciated in crop species. The recent remarkable advances in understanding the functions and molecular mechanisms of the RALF-FER pathway have also raised many interesting questions that need to be answered in the future. This review mainly focuses on the roles of FER and other CrRLK1L members in modulating immune responses in the context of cell growth in response to their RALF peptide ligands and presents a brief outlook for future research.


Diagnostic value of adenohypophyseal MRI features in female children with precocious puberty.
To evaluate the diagnostic value of adenohypophyseal magnetic resonance imaging (MRI) features for precocious puberty (PP) in female children and also to establish a non-invasive diagnostic approach in clinics. A total of 126 female children (37, 57, and 32 female children clinically diagnosed with central PP [CPP], incomplete PP [IPP], and controls, respectively) were enrolled in this study. Data were collected and analysed using analysis of variance. Pearson correlation and stepwise multivariate linear regression analysis were used to examine the association and build prediction models. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic efficacy. The values of adenohypophysis volume (aPV), adenohypophysis height (aPH), and signal-intensity ratio (SIR), height, weight, and seven laboratory testing characteristics were correlated closely with the activation status of the hypothalamic-pituitary-gonad axis in the different groups (all p<0.05). Model 1 including aPV, weight, and aPH and Model 2 including SIR, aPV, and height were built to obtain predicted luteinising hormone (LH; R2 = 0.271) and LH/follicle stimulating hormone (FSH; R2 = 0.311). ROC analysis showed the predicted LH, predicted LH/FSH, and aPV were the top 3 best predictors in distinguishing CPP from controls (AUC = 0.969, 0.949, and 0.938) while predicted LH/FSH was the best predictor in distinguishing CPP from IPP and controls (AUC = 0.829 and 0.828). The adenohypophysis volume itself and the prediction models including main adenohypophyseal MRI features increased diagnostic efficiency for PP and offered a non-invasive and credible diagnostic method.


Evolution of Liver Transplantation Over the Last 2 Decades Based on a Single-Center Experience of 300 Cases.
BACKGROUND Over the past 2 decades, there have been many medical advances in the field of liver transplantation. We conducted this study to evaluate the changes in liver transplantation over the last 2 decades. MATERIAL AND METHODS Three hundred cases of liver transplantation encountered between 1997 and 2019 in Nagasaki University Hospital were divided into 3 groups: Era 1 (cases no. 1-100), Era 2 (cases no. 101-200), and Era 3 (cases no. 201-300). Several items were compared among the groups. RESULTS There were no cases of deceased-donor liver transplantation in Era 1, 1 case in Era 2, and 12 cases in Era 3. The proportion of virus-related disease was significantly lower in Era 3 compared to other eras. In contrast, the proportion of alcoholic liver cirrhosis was significantly higher in Era 3 (27%) than Era 1 (7%) and Era 2 (10%) (P<0.01). In Era 1, the right lobe was selected most frequently, but in Eras 2 and 3, the left lobe was more frequently selected. CONCLUSIONS The evolution of the treatment and the transplant system in Japan is clearly reflected in the indications and types of donors for liver transplantation, even at a single center in Japan.


Effective connectivity between emotional and motor brain regions in people with psychogenic nonepileptic seizures (PNES).
To characterize the effective connectivity (EC) between the emotion and motor brain regions in patients with psychogenic nonepileptic seizures (PNES), based on resting-state spectral dynamic causal modeling (spDCM). Twenty-three patients with PNES and twenty-five healthy control (HC) subjects underwent resting-state fMRI scanning. The coupling parameters indicating the causal interactions between eight brain regions associated with emotion, executive control, and motion were estimated for both groups, using resting-state fMRI spDCM. Compared to the HC subjects, in patients with PNES: (i) the left insula (INS) and left and right inferior frontal gyri (IFG) are more inhibited by the amygdala (AMYG), anterior cingulate cortex (ACC), and precentral gyrus (PCG); (ii) the left AMYG has greater inhibitory effects on the INS, IFG, dorsolateral prefrontal cortex (DLPFC), PCG, and supplementary motor area (SMA); (iii) the left ACC has more inhibitory effects on the INS and IFG; (iv) the right ACC is more inhibited by the INS and IFG, and has a less inhibitory effect on the SMA and PCG; and (v) the left caudate (CAU) had increased inhibitory effects on the AMYG and IFG and a more excitatory effect on the SMA. Our results suggest that in patients with PNES, the emotion-processing regions have inhibitory effects on the executive control areas and motor regions. Our findings may provide further insight into the influence of emotional arousal on functional movements and the underlying mechanisms of involuntary movements during functional seizures. Furthermore, they may suggest that emotion regulation through cognitive behavioral psychotherapies can be a potentially effective treatment modality.


Evaluation of left ventricular diastolic function in patients with non-Q-wave myocardial infarction and its correlation with underlying coronary artery disease.
Left ventricular diastolic function was studied by Doppler echocardiography in 35 patients with non-Q-wave myocardial infarction, on the third and tenth day of hospitalization and six weeks after hospitalization and was correlated with electrocardiogram, serum enzyme values, and angiographic data. Normal diastolic function on the first echocardiographic study predicted (p = 0.0001) the existence of no or single-vessel disease, and excluded (p = 0.005) the presence of 3-vessel or left main disease, whereas an abnormal study on either the second or third echocardiographic discriminated (p = 0.0001), with higher sensitivity (80.97%, 92.31%, respectively), patients with 3-vessel or left main vessel disease.


The molecular phenotype of severe asthma in children.
Although the clinical attributes of severe asthma in children have been well described, the differentiating features of the lower airway inflammatory response are less understood. We sought to discriminate severe from moderate asthma in children by applying linear discriminant analysis, a supervised method of high-dimensional data reduction, to cytokines and chemokines measured in the bronchoalveolar lavage (BAL) fluid and alveolar macrophage (AM) lysate. Bronchoalveolar lavage fluid was available from 53 children with asthma (severe asthma, n = 31) undergoing bronchoscopy for clinical indications and 30 nonsmoking adults. Twenty-three cytokines and chemokines were measured by using bead-based multiplex assays. Linear discriminant analyses of the BAL fluid and AM analytes were performed to develop predictive models of severe asthma in children. Although univariate analysis of single analytes did not differentiate severe from moderate asthma in children, linear discriminant analyses allowed for near complete separation of the moderate and severe asthmatic groups. Significant correlations were also noted between several of the AM and BAL analytes measured. In the BAL fluid, IL-13 and IL-6 differentiated subjects with asthma from controls, whereas growth-related oncogene (CXCL1), RANTES (CCL5), IL-12, IFN-gamma, and IL-10 best characterized severe versus moderate asthma in children. In the AM lysate, IL-6 was the strongest discriminator of all the groups. Severe asthma in children is characterized by a distinct airway molecular phenotype that does not have a clear T(H)1 or T(H)2 pattern. Improved classification of children with severe asthma may assist with the development of targeted therapeutics for this group of children who are difficult to treat.


Melatonin-A Potent Therapeutic for Stroke and Stroke-Related Dementia.
Secreted by the pineal gland to regulate the circadian rhythm, melatonin is a powerful antioxidant that has been used to combat oxidative stress in the central nervous system. Melatonin-based therapies have been shown to provide neuroprotective effects in the setting of ischemic stroke by mitigating neuroinflammation and accelerating brain tissue restoration. Melatonin treatment includes injection of exogenous melatonin, pineal gland grafting and melatonin-mediated stem cell therapy. This review will discuss the current preclinical and clinical studies investigating melatonin-based therapeutics to treat stroke.


Assessing manual pursuit tracking in Parkinson's disease via linear dynamical systems.
Quantitative assessment of motor performance is important for diseases of motor control, such as Parkinson's disease (PD). Manual tracking tasks are well suited for motor assessment, as they can be performed concomitantly with brain mapping techniques. Here we propose utilizing second-order linear dynamical systems to assess manual pursuit tracking performance. With the desired trajectory as the input, and the subject's actual motor response as the output, a linear model characterized by natural frequency and damping ratio is identified for each subject. We applied this method to 10 PD subjects (on and off L: -dopa medication) and 10 normal subjects performing a multi-frequency sinusoidal tracking task. Model parameters were more sensitive than overall tracking errors in determining significant differences between groups. The effect of L: -dopa medication was to reduce the damping ratio and make the range in natural frequency across individuals approach that of normal subjects. We interpret the changes in damping ratio and natural frequency as possibly related to suppression of compensatory cerebellar activity and/or improvement of motor program selection, and the changes in natural frequency as an implicit strategy to maintain settling time in the face of reduce damping ratio. Our results suggest that simple linear dynamical system models can be a powerful method to assess tracking performance in Parkinson's disease because of the additional insight they can provide into neurological processes.


Ultrasound contrast agents nucleate inertial cavitation in vitro.
Some ultrasound contrast agents contain stable bodies of gas, and this study was undertaken to determine if these agents could provide nuclei for inertial cavitation. Inertial cavitation was detected and assessed by the measurement of the sonochemical hydrogen peroxide after exposure to 2.17-, 2.95- or 3.8-MHz ultrasound. A noncavitating system was obtained by removing cavitation nuclei from the rotating tube exposure chambers by vacuum degassing, and from the phosphate-buffered saline medium by filtering. Albunex added at 10-2, 10-3 or 10-4 dilutions, or Levovist added at 2 mg mL-1, 0.2 mg mL-1 or 0.02 mg mL-1 all initiated significant H2O2 production for 2.17-MHz ultrasound at 0.41 MPa or higher spatial peak pressure amplitude for 5 min exposure gated at 0.25 s on and off with 60-rpm rotation. Not rotating the tube virtually eliminated H2O2 production. For 2.5-min continuous exposure, both agents initiated significant H2O2 production for 2.95-MHz exposure at 0.58 MPa or higher, but not for 3.8-MHz exposure up to 1.16 MPa. Bubble-based ultrasound contrast agents therefore appear to be able to provide nuclei for inertial cavitation in the rotating tube exposure system.


Preliminary investigation on intrafamilial spread of hepatitis C virus (HCV).
To determine the risk of cohabitant HCV infection, we investigated the sera of 101 family members of 53 anti-HCV antibody positive chronic liver disease patients. Altogether 14.8% of the cohabitants were also anti-HCV antibody positive, compared to a prevalence of 1.4% in the general population. These results suggest that hepatitis-C-virus may spread by person-to-person infection.


The influence of patella alta on patellofemoral joint stress during normal and fast walking.
To determine if persons with patella alta exhibit elevated patellofemoral joint stress compared to pain-free controls during normal and fast walking speeds. Twenty-four subjects (13 patella alta, 11 pain-free controls) participated. Sagittal and axial magnetic resonance images of the knee were obtained to quantify subject specific knee extensor mechanics and patellofemoral joint contact area. Instrumented gait analysis was used to quantify knee joint kinematics and kinetics. MRI and gait data were used as input variables into a model of patellofemoral joint stress. Analysis of variance with repeated measures was used to compare group differences and group x gait speed interactions for each dependent variable during stance. During normal speed gait there were no group differences in peak knee flexion angle, knee extensor moment, joint reaction force, or stress. However, the patella alta group had significantly less contact area. During fast speed gait there were no group differences in peak knee flexion angle, knee extensor moment, or joint reaction force. However, the patella alta group demonstrated significantly less contact area and significantly greater stress compared to controls. Persons with patella alta demonstrated greater calculated patellofemoral stress during fast walking. This was the result of reductions in contact area as joint reaction forces were similar between groups. Persons with patella alta may be predisposed to patellofemoral dysfunction through elevations in joint stress. Therefore, treatments aimed at increasing the load-bearing surface area between the patella and femur, such as bracing, may be beneficial in this patient population.


Fibrous Clays in Dermopharmaceutical and Cosmetic Applications: Traditional and Emerging Perspectives.
Functionalization of natural clay minerals for high value-added pharmaceutical and cosmetic applications receives significant research attention worldwide attributable to a rising demand and ongoing search for green, efficient, economically sustainable and ecofriendly geomaterials. Fibrous clays, i.e. palygorskite and sepiolite, are naturally-occurring hydrated magnesium aluminum silicate clay minerals with 2:1 layer-chain microstructure and one-dimensional nanofibrous morphology. Due to their unique structural, textural and compatibility features, over the past decade, fibrous clays and their organic modified derivatives are increasingly used in the dermopharmaceutical and cosmetic fields as excipients, active agents or nanocarriers to develop novel skin delivery systems or to modify drug release profile for enhanced health effects. This comprehensive review presents the up-to-date information on fibrous clays used in topically-applied products for therapeutic and cosmetic purposes with the focus on their performance-related structural characteristics and the underlying mechanisms. The recent advancement of fibrous clay-based skin delivery systems was summarized in wide range of applications including pelotherapy, wound healing, antimicrobial action, coloration and UV protection. An overview of the commonly used topically-applied dosage forms (powders, hydrogels, films, peloids and Pickering emulsion) as well as the toxicological aspects was also included, which might provide guidance to the design and development of fibrous clay-based skin delivery systems.


Hematohidrosis of the mid-face and hands treated with oral oxybutynin.
Hematohidrosis is a rare condition characterized by blood in the sweat. We report a case of hematohidrosis of the mid-face and hands in a 13-year-old girl who was treated successfully with oral oxybutynin and discuss the therapeutic rationale.


Lysosomal Rag-ulation of mTOR complex 1 activity.
An amino acid-sensing pathway regulates mTOR complex 1 (mTORC1) activity and participates in nutrient control of cell metabolism and growth. Sancak et al. (2010) identify a lysosomal membrane-localized super-complex that drives amino acid-dependent mTORC1 activation.


Association of anthropometric parameters as a risk factor for development of diabetic retinopathy in patients with diabetes mellitus.
To study the relationship of body fat distribution in patients with diabetes mellitus (DM), and its long-term complications like diabetic retinopathy (DR), in Indian population. This was a prospective, cross-sectional observational study involving 1773 subjects diagnosed with DM and 1778 age and gender-matched individuals. The patients with DM were assessed for the presence and severity of DR. Severe non-proliferative DR and proliferative DR were categorised as sight threatening DR (STDR). Anthropometric parameters, i.e., neck circumference (NC); mid-upper arm circumference (MAC); waist circumference (WC); hip circumference (HC); mid-thigh circumference (MTC) and body mass index (BMI) were measured using standardised technique. The mean age was 59.33 ± 9.32 for DM group, and 66.03 ± 11.04 for non-DM group. DM group showed significantly greater NC, WC, and MTC and significantly reduced MAC and weight. HC and BMI were comparable between the groups. There was a significant positive correlation of MAC and WC (with any level of DR) and MAC, WC, and weight (for STDR); and a significant negative correlation of HC and MTC (with any level of DR) and NC, HC, MTC, and BMI (for STDR). Multiple logistic regression analysis confirmed that WC was the single most important predictor for any level of DR and STDR. Association of body fat distribution with DM and DR appears multifactorial. However, central obesity signified by waist circumference appears to be the significant risk related to the development of DR and STDR in Indian population.


Comparative evaluation of river chemical status based on WFD methodology and CCME water quality index.
The Water Framework Directive (WFD) methodology, proposed by the Ministry of Environment and Energy of Greece (WFD-MEEG), and the Canadian Council of Ministers of Environment Water Quality Index (CCME-WQI) are comparatively applied to evaluate the chemical status of a major transboundary river. Water quality parameters were monitored at 11 sites along the main stream of the river and its main tributaries, and at five sites in the reservoirs, on a monthly frequency, in the period from May 2008 to May 2009. Water temperature (T), dissolved oxygen (DO), pH, and electrical conductivity (EC) were measured in-situ, while water samples were collected for the determination of total suspended solids (TSS), biochemical oxygen demand (BOD), chemical oxygen demand (COD), nitrite-, nitrate- and ammonium-nitrogen, total Kjeldahl nitrogen (TKN), ortho-phosphates (OP), total phosphorus (TP), and chlorophyll-a (Chl-a). The water samples were also analyzed for the determination of seven heavy metals (i.e., Cd, Pb, Hg, Ni, Cr, Cu, Zn) and 33 priority substances, as listed in Annex II of EU Directive 2008/105/EC. The results showed that the physicochemical parameters (i.e., T, DO, pH, EC, inorganic nitrogen, TKN, OP, TP, TSS, and Chl-a) were within the natural range. The mean concentration of the measured heavy metals did not exceed the limits set by WHO (2003, 2017) for drinking water. Regarding the priority substances, some of them (i.e., anthracene, fluoranthene, and polyaromatic hydrocarbons) were measured in various stations at higher concentrations than the Annual Average Environmental Quality Standards (AA-EQS). Based on the WFD-MEEG methodology, the river water was in the 'good' quality class, while according to CCME-WQI the river quality ranged from 'marginal' to 'good' category. It seems that CCME-WQI is stricter than WFD-MEEG but could be a WQI appropriate for use.


1α,25-Dihydroxyvitamin D3 upregulates HIF-1 and TREM-1 via mTOR signaling.
Triggering receptor expressed on myeloid cells-1 (TREM-1) is induced by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) in human monocytes/macrophages and epithelial cells. However, little information is available regarding the mechanism of 1,25(OH)2D3-induced TREM-1 expression in human monocytes/macrophages. In this study, 1,25(OH)2D3 was shown to strongly upregulate hypoxia-inducible transcription factor (HIF) in PMA-differentiated U937 cells. However, HIF was not mainly involved in 1,25(OH)2D3-induced TREM-1 expression. Instead, 1,25(OH)2D3-induced expression of TREM-1 was inhibited by rapamycin, a specific inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, indicating the involvement of mTOR. Induction of HIF proteins by 1,25(OH)2D3 was also inhibited by rapamycin. In addition, 1,25(OH)2D3 induced the phosphorylation of p70S6 kinase, a target of mTOR complex 1 (mTORC1). Our results suggest that 1,25(OH)2D3 induces the expression of TREM-1 through the mTOR signaling pathway in human macrophages.


[A research pathway in care and relational touch].
Passionate about the relational dimension of care, this nurse-turned-researcher shares with us the key stages of her university career guided by the place of touch in the therapeutic relationship.


Endoscopic anatomy of the ulnar nerve: a useful adjunct to teaching anatomy.
There has been a shift away from gross anatomy teaching and hands-on cadaveric dissection. This has been replaced by a variety of teaching modalities including problem-based learning, models and prosections, and computer-assisted learning. We aim to pilot a technique of endoscopic visualisation of upper limb anatomy, to produce a video that can be incorporated into anatomy teaching and to assess the video qualitatively as an adjunct to anatomy teaching. A single, previously undissected, formalin preserved cadaver was used and views were obtained of the left arm. The video was shown to 10 surgical trainees who were then asked to complete appraisal forms anonymously. The endoscopic views were thought to be useful and helped the trainees to appreciate the in situ anatomy and potential sites of nerve compression. 70% of respondents would recommend the system to others. We feel this represents another method to help in the understanding of a complex area of anatomy in a way that is unique to endoscopy.


Collaborative testing in physical examination skills training and the autonomous motivation of students: a qualitative study.
Teaching methods that stimulate the active learning of students make a positive impact on several aspects of learning in higher education. Collaborative testing blended with teaching is one such method. At our medical school, a training session was designed using a collaborative testing format to engage medical students actively in the theoretical phase of a physical examination training, and this session was evaluated positively by our students. Therefore, we extended the use of the format and converted more of the training into collaborative testing sessions. The literature on collaborative testing and the theoretical framework underlying its motivational mechanisms is scarce; however, students have reported greater motivation. The aim of the current study was to investigate student perceptions of a collaborative testing format versus a traditional teaching format and their effects on student motivation. Year four medical students attended seven physical examination training sessions, of which three followed a collaborative testing format and four a traditional format. The students were asked to evaluate both formats through questionnaires comprised of two items that were answered on a five-point Likert scale and five open-ended essay questions. Content analysis was conducted on the qualitative data. The themes from this analysis were finalized through the consensus of the full research team. The quantitative data showed that 59 students (55%) preferred collaborative testing (agreed or strongly agreed), 40 students (37%) were neutral, and 8 students (8%) did not prefer collaborative testing (disagreed or strongly disagreed). The themes found for the collaborative testing format were: 'interaction', 'thinking for themselves', and 'active participation'. 'Interaction' and 'thinking for themselves' were mainly evaluated positively by the students. The most frequently mentioned theme for the traditional format was: 'the teacher explaining'. Students evaluated this theme both positively and negatively. The most frequently mentioned themes for the collaborative testing format, namely 'interaction', 'thinking for themselves', and 'active participation', fit within the framework of self-determination theory (SDT). Therefore, the collaborative testing format may support the fulfilment of the three basic psychological needs indicated in SDT: autonomy, competence, and relatedness. Thus, our findings provide initial support for the idea that the use of collaborative testing in medical education can foster the autonomous motivation of students.


The ethics of stem cells revisited.
Stem cells constitute one of the most promising tools for regenerative medicine. Thus, it seems morally compelling to explore all the sources that might provide us with them. However, some of these sources, such as somatic cell nuclear transfer, embryo destruction, or even induced pluripotency obtained by reprogramming have raised deep ethical issues. The aim of this paper is to reflect on the stem cell ethical debate at the current moment through an analysis of the academic literature. It will also provide an analysis of the ethical implications of the most relevant scientific advances that have happened in recent months or those which seem about to merge.


Low intake of essential amino acids and other risk factors of stunting among under-five children in Malang City, East Java, Indonesia.
The lack of energy-protein intake has been shown to increase the risk of stunting in under-five children. The quality of protein in food is assessed by the completeness of amino acid content. This study aims to determine the amount of essential amino acid (EAAs) intake and other risk factors of stunting among under-five children. A descriptive, case-control study was performed in the work area of Kedungkandang Health Center Malang. The subjects were 24-59 month-old children with a total of 23 stunted (height-for-age Z-score (HAZ) <-2 SD) and 57 normal children (HAZ ≥-2 SD). Furthermore, the data were collected using anthropometric measurement, validated and pre-tested questionnaires, which were analyzed using multiple logistic regression. The intake of all the nine EAAs in stunted children was lower than that of non-stunted children. However, only histidine, isoleucine, and methionine were significantly different (p<0.05). The significant risk factors of stunting include a family income per month fewer than the Regional Minimum Wages [OR=12.06, 95% CI 1.83-79.53], being underweight [OR=7.11, 95% CI 1.49-33.93], breastfeeding of less than 6 months [OR=5.34, 95% CI 1.28-22.20], and the lack of EAA methionine intake [OR=0.14, 95% CI 0.03-0.67]. Stunted children may not receive sufficient dietary intake of EAAs in their diet. Furthermore, the lack of EAAs intake, especially methionine, alongside low family income, underweight, lack of breastfeeding and variety in food consumption were the risk factors of stunting among under-five children in a selected Health Center in Malang City, Indonesia.


A case of overlap syndrome of systemic sclerosis and dermatomyositis with right ventricular dysplasia.
We report a 39-year-old woman with overlap syndrome of systemic sclerosis and dermatomyositis who died of congestive heart failure. The pathologic findings of the heart included contraction band necrosis and myocardial fibrosis. Unique was the finding of remarkable replacement of the right ventricle with fatty tissue.


'Digoxin conundrum - Time for validation?'
Despite no incontrovertible data, Digoxin use has been demonised. As a consequence, a lot of patients, stable on Digoxin, have been taken off it and offered alternative drugs. However, there is some light at the end of the tunnel for Digoxin, with the reporting of RATE-AF Trial at the recent European Society of Cardiology Congress. Compared to Bisoprolol, Digoxin use was associated with statistically significantly greater improvements in symptomatology and NT ProBNP levels making Digoxin a first line drug for rate control in permanent AF.


New-onset diabetes after renal transplantation.
Renal transplantation has important benefits in people with end-stage renal disease, with improvements in mortality, morbidity and quality of life. Whilst significant advances in transplantation techniques and immunosuppressive regimens have led to improvements in short-term outcomes, longer-term outcomes have not improved dramatically. New-onset diabetes after transplantation appears to be a major factor in morbidity and cardiovascular mortality in renal transplant recipients. The diagnosis of new-onset diabetes after renal transplantation has been hampered by a lack of clarity over diagnostic tests in early studies, although the use of the WHO criteria is now generally accepted. HbA1c may be useful diagnostically, but should probably be avoided in the first 3 months after transplantation. The pathogenesis of new-onset diabetes after renal transplantation is likely to be related to standard pathogenic factors in Type 2 diabetes (e.g. insulin resistance, β-cell failure, inflammation and genetic factors) as well as other factors, such as hepatitis C infection, and could be exacerbated by the use of immunosuppression (glucocorticoids and calcineurin inhibitors). Pre-transplant risk scores may help identify those people at risk of new-onset diabetes after renal transplantation. There are no randomized trials of treatment of new-onset diabetes after renal transplantation to determine whether intensive glucose control has an impact on cardiovascular or renal morbidity, therefore, treatment is guided by guidelines used in non-transplant diabetes. Many areas of uncertainty in the pathogenesis, diagnosis and management of new-onset diabetes after renal transplantation require further research.


Transformation of Wurtzite ZnO to a New Triclinic Nanoporous ZnO Phase via Hydrothermal Treatment with Metformin for Designing Proton Conducting Material.
Zinc oxide is one of the most widely studied semiconductor metal oxides, which predominantly crystallizes as hexagonal wurtzite and often cubic zinc-blende phases. Here we report the transformation of the highly stable wurtzite ZnO to a new triclinic phase NZO-2 by using metformin as a template during post-synthesis hydrothermal treatment. This crystalline phase of the material NZO-2 has been identified through the refinement of the powder XRD data. NZO-2 possesses porous rod like particle morphology consisting of the self-assembly of 3-7 nm size spherical nanoparticles and interparticle nanoscopic voids spaces. NZO-2 has been surface phosphorylated and the resulting material displayed good proton conductivity. Further, NZO-2 displayed ultra-low band gap of 1.74 eV, thereby responsible for red emission under high energy laser excitation and this may open new opportunities in optoelectronic application of ZnO.


Recent Advances in Bronchopulmonary Dysplasia.
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that occurs in preterm infants, usually those receiving substantial respiratory support with either mechanical ventilation or supplementation with oxygen. The pathogenesis of BPD is multifactorial, and the clinical phenotype is variable. BPD is associated with substantial mortality and short- and long-term morbidity. The incidence of BPD has remained stable or increased, as advances in neonatal care have led to improved survival of more extremely preterm infants. Extensive basic science, translational, and clinical research focusing on BPD has improved the current understanding of the factors that contribute to BPD pathogenesis. However, despite a better understanding of its pathophysiology, BPD continues to be challenging to prevent and manage adequately. The current review aims to provide a clinically useful synopsis of evidence on the prevention and management of BPD in preterm infants.


Steady-state study of horse-liver ADH: detection of two kinetically heterogeneous components.
New theoretical considerations and a new approximation strategy were applied to the kinetic analysis of the experimental relationship between the reaction velocity in the steady state and the concentrations of ethanol and NAD. It could be shown that horse-liver ADH consists of two kinetically heterogeneous components.


Endoscopic Ultrasound-Guided Fine Needle Aspiration of a PET/CT-Positive Small Hilar Lymph Node for the Diagnosis of Metastatic Merkel Cell Carcinoma.
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Screening of Microbial Fermentation Products for Anti-M. tuberculosis Activity.
Tuberculosis (TB), caused by M. tuberculosis (M.tb), is the leading infectious cause of mortality worldwide. The emergence of drug-resistant M.tb has made the control of TB more difficult. In our study, we investigated the ability of microorganism fermentation products from the soil to inhibit M.tb. We successfully identified four fermentation products (Micromonospora chokoriensis, Micromonospora purpureochromogenes, Micromonospora profundi, Streptomyces flavofungini) that inhibited the growth of M.tb in vitro and in intracellular bacteria at 25 μg/mL MIC. Importantly, the fermentation products decreased some essential gene expression levels for M.tb growth. Our data provide the possibility that microbial fermentation products have potential development value for anti-M.tb drugs.


Characterisation of copolymer, poly (hydroxybutyrate-co-hydroxyvalerate) (PHB-co-PHV) produced by Halomonas campisalis (MCM B-1027), its biodegradability and potential application.
Characterisation of polyhydroxyalkanoate (PHA) film produced by haloalkalitolerant Halomonas campisalis (MCM B-1027) in 14L SS fermenter revealed it to have composition of monomer units, HB:HV as 96:4 as analysed by (1)H NMR indicating the PHA as a co-polymer of PHB-co-PHV, molecular weight by gel permeation chromatography as 2.08 × 10(6), melting temperature 166.51°C, tensile strength 18.8 MPa; two relaxations namely beta transition corresponding to the glass rubber transition and alpha transition corresponding to crystalline relaxation by Dynamic Mechanical Thermal analysis and only one relaxation corresponding to MWS interfacial polarisation with activation energy of 129 kJ/mol by broadband dielectric spectroscopy. Optical microscopic studies showed typical Maltese-cross pattern of spherulites. The PHA film was found to be biodegradable by standard ASTM method as well as by soil burial method. The leak proof polymer bags prepared from the film could be used as a packaging material.


Immunological classification of T-cell acute lymphoblastic leukaemia using monoclonal antibodies.
We had been able to classify 70 cases of acute lymphoblastic leukemia (ALL) into different immunological subtypes based on surface marker analysis with the aid of a panel of monoclonal antibodies. The relative proportions of different ALL subclasses appears to be similar to those reported from Europe and the U.S.A. Our results also indicated that monoclonal antibodies OKT11, UCHT-2 and WT1 were very useful in defining pre-T or early T subtypes of ALL. The latter leukaemias lack most maturation-linked T-cell markers but share with the other T-ALL the characteristic of low density or undetectable insulin receptors.


Pancreatic endocrine function in cystic fibrosis.
To characterize pancreatic endocrine secretion and to examine interrelationships among alterations in alpha, beta, and pancreatic polypeptide cell function in patients with cystic fibrosis (CF), we studied 19 patients with exocrine insufficiency (EXO), including 9 receiving insulin therapy (EXO-IT); 10 patients with no exocrine insufficiency (NEXO); and 10 normal control subjects. First-phase C-peptide response to intravenously administered glucose was significantly impaired in CF patients with exocrine insufficiency (EXO-IT = 0.02 +/- 0.01; EXO = 0.11 +/- 0.02; NEXO = 0.25 +/- 0.05; control subjects = 0.30 +/- 0.04 nmol/L). Lowering fasting glucose levels with exogenous insulin administration in EXO-IT did not improve beta cell responsivity to glucose. The C-peptide response to arginine was less impaired (EXO-IT = 0.12 +/- 0.02; EXO = 0.15 +/- 0.02; NEXO = 0.23 +/- 0.06; control subjects = 0.28 +/- 0.04 nmol/L). Alpha cell function, measured as peak glucagon secretion in response to hypoglycemia, was diminished in EXO but not NEXO (EXO-IT = 21 +/- 10; EXO = 62 +/- 19; NEXO = 123 +/- 29; control subjects = 109 +/- 12 ng/L). Despite diminished glucagon response, EXO patients recovered normally from hypoglycemia. Peak pancreatic polypeptide response to hypoglycemia distinguished CF patients with exocrine insufficiency from those without exocrine insufficiency (EXO-IT = 3 +/- 2; EXO = 3 +/- 1; NEXO = 226 +/- 68; control subjects = 273 +/- 100 pmol/L). Thus CF patients with exocrine disease have less alpha, beta, and pancreatic polypeptide cell function than CF patients without exocrine disease. These data suggest either that exocrine disease causes endocrine dysfunction in CF or that a common pathogenic process simultaneously and independently impairs exocrine and endocrine function.


A Molecular Dynamics Study of Antimicrobial Peptide Interactions with the Lipopolysaccharides of the Outer Bacterial Membrane.
With rising bacterial resistance, antimicrobial peptides (AMPs) have been widely investigated as potential antibacterial molecules to replace conventional antibiotics. Our understanding of the molecular mechanisms for membrane disruption are largely based on AMP interactions with the inner phospholipid bilayers of both Gram-negative and Gram-positive bacteria. Mechanisms for AMP translocation across the outer membrane of Gram-negative bacteria composed of lipopolysaccharides and the asymmetric lipid bilayer are complicated by the secondary structure adopted by the peptide in the different membrane environments. We have employed atomistic molecular dynamics and umbrella-sampling simulations with an aggregate duration of [Formula: see text] 6 microseconds to obtain the free energy landscape of CM15 peptide translocating through the lipopolysaccharide region of Gram-negative bacteria, E. coli. The peptide has a favorable binding-free energy (- 130 kJ mol[Formula: see text]) in the O-antigen region with a large barrier (150 kJ mol[Formula: see text]) at the interface between the anionic core saccharides and upper bilayer leaflet made up of lipid-A molecules. Restraint-free molecular dynamics simulations show that the random coil structure is favored over the helix in both the extracellular aqueous region and the cation-rich core-saccharide regions of the outer membrane. The peptide and membrane properties are analyzed at each of the 100 ns duration of the umbrella-sampling windows to illustrate changes in peptide length, orientation, and hydration. Our study provides insights into the free energy landscape for the insertion of the AMP CM15 in the outer membrane of Gram-negative bacteria, and we discuss the implications of our findings with the broader question of how AMPs overcome this barrier during antimicrobial activity.


Effects of collagen matrix on proliferation and differentiation of vascular smooth muscle cells in vitro.
In an attempt to better define the relationship between collagen matrices and vascular smooth muscle cells in vitro, proliferation of smooth muscle cells was observed in the early stages of culture. Cells spread on collagen gels had a longer doubling time and less incorporation of [3H]thymidine into DNA on the first day of culture than did cells grown on a plastic substrate. Cells on collagen gels were more elongated than were those on the plastic substrate and showed a "hills and valleys" arrangement from the first day in culture on the collagen type III gel. All cells were identified as smooth muscle having definite microfilaments, dense bodies, and pinocytotic vesicles. They had a distinct actin filament running from end to end when labeled with nitrobenzoxadiazole-phallacidin. Cells on the collagen gels had a larger number of actin filaments traveling parallel to the direction of the major axis of their cytoplasm than did those on the glass substrate. Therefore, cultured smooth muscle cells in the more physiological environment for cells in vitro, i.e., on collagen gels, show a suppression of cellular proliferation and an enhancement of differentiation in the early stages of culture. The effects of collagens on the differentiation of cells vary with the collagen phenotype.


Anomalous Cis-Conformation Regioselectivity of Heterocycle-Fused Sc3 N@D3h -C78 Derivatives.
Endohedral clusterfullerenes exhibit unique chemical properties due to intramolecular electron transfer of the encaged metal cluster to the outer fullerene cages. We report the synthesis of two Sc3 N@D3h -C78 monoadducts 2 a and 2 b through the 1,3-dipolar reaction of Sc3 N@D3h -C78 with carbonyl ylide bearing anomalous cis-conformation regioselectivity. The molecular structures of these monoadducts are unambiguously confirmed by single-crystal X-ray crystallography, revealing that both 2 a and 2 b have cis-conformations with the furan moiety grafted via [6,6]-closed addition patterns. Under the same conditions, the control reaction of C60 with carbonyl ylide affords two monoadducts 3 a and 3 b, which exhibit cis- and trans-conformations, respectively, with [6,6]-closed addition patterns. According to theoretical calculations, the exclusive formation of the cis-only Sc3 N@D3h -C78 monoadducts is a consequence of conjunct effects of thermodynamic stability of adducts, the reactivity of the addition site, and the cis-dipole intermediate from trans 1.


Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel.
Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0-∞ of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10-7 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC0-∞ 3.9-fold; range 2.1-7.9-fold (P = 2·10-6 ), compared with ritonavir alone. Ritonavir decreased the AUC0-4h of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.


Differential expression of arc mRNA and other plasticity-related genes induced by nicotine in adolescent rat forebrain.
Relatively little attention has been focused on mechanisms related to neural plasticity and drug abuse in adolescence, compared with abundant research using adult animal models. As smoking is typically initiated in adolescence, an important question to address is whether the adolescent brain responds differently to nicotine compared with the adult. To investigate this question, we examined the expression of a number of early response genes (arc, c-fos and NGFI-B) that have been implicated in synaptic plasticity and addiction, following acute nicotine in adolescent and adult rats. Baseline expression of arc and c-fos was higher in adolescent brains compared with adults. Following acute nicotine treatment (0.1, 0.4mg/kg), we found a marked induction of arc mRNA in the prefrontal cortex of nicotine-treated adolescents compared with a less pronounced increase of arc in the adult. c-fos and NGFI-B were also upregulated by nicotine, but not in an age-related manner. In contrast, nicotine induced less arc, c-fos, and NGFI-B expression in the somatosensory cortex of adolescents compared with adults. A fourth gene, quinoid dihydropteridine reductase was expressed at lower levels in white matter of the adolescent forebrain compared with the adult, but was not affected by nicotine. These results suggest that in adolescence, the activity of specific early response genes is higher in brain regions critical for emotional regulation and decision-making. Further, nicotine affects key plasticity molecules in these areas in a manner different from the adult. Thus, adolescence may represent a neurobiologically vulnerable period with regard to nicotine exposure.


A long-term, comprehensive exercise program that incorporates a variety of physical activities improved the blood pressure, lipid and glucose metabolism, arterial stiffness, and balance of middle-aged and elderly Japanese.
A 6-month, twice-a-week exercise program emphasizing swimming was conducted for 11 men (57-73 years) and 24 women (51-68 years). The control group comprised 11 male (59-70 years) and 11 female (53-70) volunteers. The exercise program significantly improved the systolic and diastolic blood pressure (SBP/DBP) and lipid and glucose metabolism, with no change in the controls. Brachial-ankle pulse wave velocity (baPWV), as an index of systemic arterial stiffness, was measured during medical examinations before and after each exercise session using a volume-plethysmographic apparatus. SBP and DBP of the extremities were significantly decreased after exercise, but did not change in the controls. Average baPWV decreased significantly in the exercise group, from 1661±50 to 1581±40 cm per sec. No change was seen in the controls. The sway path of the center of balance was analyzed using a force plate. The length of postural sway, the length of postural sway per sec and the area of postural sway were measured with eyes open and eyes closed, and the rectangular area was calculated. The eyes open/eyes closed ratio (Romberg sign) was also calculated. All parameters of body sway were significantly lower after 6 months in the exercise group, with no change in the controls. The Romberg sign did not change for either group. In addition to promoting better health, as shown by the clinical data, this type of exercise program improves balance function, which could help prevent falls of the elderly.


Repair and healing of the divided digital flexor tendon.
A series of 275 repairs is reviewed. Primary or delayed primary repair of the divided digital flexor tendon is advocated. Preoperative splinting and careful operative technique to avoid damage to the blood supply of the divided tendon are necessary. The tendon repair is followed by closure of the fibrosynovial sheath and postoperative splintage. By this means acceptable results are obtained.


Aptamer-functionalized superporous hydrogels for sequestration and release of growth factors regulated via molecular recognition.
While the discovery of highly potent biologics has led to the development of promising therapies for various human diseases, biologics can cause severe toxicity if delivered inappropriately. Thus, great efforts have been made to synthesize polymeric systems for safe and efficient delivery of biologics. However, the application of polymeric delivery systems is often limited by problems such as harsh reaction conditions, low drug sequestration efficiency, and difficult drug release regulation. This study was aimed at developing a superporous material system with a hydrogel and an aptamer to overcome these challenges. The results have shown that the superporous hydrogel is capable of instantaneously and fully sequestering a large amount of growth factors, owing to the presence of superporous architectures and aptamers. Moreover, the sequestering and loading procedure does not involve any harsh conditions. The release kinetics of growth factors can be molecularly modulated by either changing the binding affinity of the aptamer or by using a triggering effector. Therefore, this study presents a promising superporous material for the delivery of highly potent biologics such as growth factors for clinical applications.


Trajectories of fear learning in healthy participants are able to distinguish groups that differ in individual characteristics, chronicity of fear and intrusions.
Studies on the development and treatment of anxiety disorders mostly focus on the comparison of predefined groups. An alternative approach is to use data-driven latent class growth analyses (LCGA) to determine differentiation between groups based on particular mechanistic factors. This study validated the use of LCGA on responses in a compact fear conditioning task and whether specific characteristics are associated with maladaptive fear learning trajectories. Healthy subjects (N = 300) completed a fear conditioning task that included uninstructed and instructed acquisition and extinction phases. Subjective fearfulness and US expectancy were used as outcome measures. Latent classes in the responses to the CS+ (coupled with a scream) and the CS- (control stimulus) were determined based on trajectories across the experimental phases. State and trait anxiety were measured during testing, and return of fear and intrusions were measured one and six weeks later. Fear learning trajectories of poor extinction in responding to the CS+ and generalization of fear to the CS- were associated with higher state and trait anxiety. Individuals belonging to these trajectories reported more intrusions, fear and had higher US expectancy ratings after 1 week. Only 56% of participants completed the six weeks follow-up measures. Fear learning trajectories are associated with individual characteristics, return of fear and intrusions. Next, this task will be implemented in clinical practice to assess its predictive power for the extent to which patients benefit from exposure treatments.


Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection.
BackgroundIntrauterine infection is a significant cause of early preterm birth. We have developed a fetal-neonatal model in the rhesus macaque to determine the impact of chronic intrauterine infection with Ureaplasma parvum on early neonatal reflexes and brain development.MethodsTime-mated, pregnant rhesus macaques were randomized to be inoculated with U. parvum (serovar 1; 105 c.f.u.) or control media at ~120 days' gestational age (dGA). Neonates were delivered by elective hysterotomy at 135-147 dGA (term=167d), stabilized, and cared for in our nonhuman primate neonatal intensive care unit. Neonatal reflex behaviors were assessed from birth, and fetal and postnatal brain magnetic resonance imaging (MRI) was performed.ResultsA total of 13 preterm and 5 term macaque infants were included in the study. Ten preterm infants survived to 6 months of age. U. parvum-infected preterm neonates required more intensive respiratory support than did control infants. MRI studies suggested a potential perturbation of brain growth and white matter maturation with exposure to intra-amniotic infection.ConclusionWe have demonstrated the feasibility of longitudinal fetal-neonatal studies in the preterm rhesus macaque after chronic intrauterine infection. Future studies will examine long-term neurobehavioral outcomes, cognitive development, neuropathology, and in vivo brain imaging to determine the safety of antenatal antibiotic treatment for intrauterine infection.


Characterization of biochemical properties of Bacillus subtilis RecQ helicase.
RecQ family helicases function as safeguards of the genome. Unlike Escherichia coli, the Gram-positive Bacillus subtilis bacterium possesses two RecQ-like homologues, RecQ[Bs] and RecS, which are required for the repair of DNA double-strand breaks. RecQ[Bs] also binds to the forked DNA to ensure a smooth progression of the cell cycle. Here we present the first biochemical analysis of recombinant RecQ[Bs]. RecQ[Bs] binds weakly to single-stranded DNA (ssDNA) and blunt-ended double-stranded DNA (dsDNA) but strongly to forked dsDNA. The protein exhibits a DNA-stimulated ATPase activity and ATP- and Mg(2+)-dependent DNA helicase activity with a 3' → 5' polarity. Molecular modeling shows that RecQ[Bs] shares high sequence and structure similarity with E. coli RecQ. Surprisingly, RecQ[Bs] resembles the truncated Saccharomyces cerevisiae Sgs1 and human RecQ helicases more than RecQ[Ec] with regard to its enzymatic activities. Specifically, RecQ[Bs] unwinds forked dsDNA and DNA duplexes with a 3'-overhang but is inactive on blunt-ended dsDNA and 5'-overhung duplexes. Interestingly, RecQ[Bs] unwinds blunt-ended DNA with structural features, including nicks, gaps, 5'-flaps, Kappa joints, synthetic replication forks, and Holliday junctions. We discuss these findings in the context of RecQ[Bs]'s possible functions in preserving genomic stability.


Role of muscle FOXO gene in exercise against the skeletal muscle and cardiac age-related defects and mortality caused by high-salt intake in Drosophila.
FOXO has long been associated with aging, exercise, and tissue homeostasis, but it remains unclear what the role is of the muscle FOXO gene in E against high-salt intake(HSI)-induced age-related defects of the skeletal muscle, heart, and mortality. In this research, overexpression and RNAi of the FOXO gene in the skeletal and heart muscle of Drosophila were constructed by building Mhc-GAL4/FOXO-UAS-overexpression and Mhc-GAL4/FOXO-UAS-RNAi system. The skeletal muscle and heart function, the balance of oxidation and antioxidant, and mitochondrial homeostasis were measured. The results showed that exercise reversed the age-related decline in climbing ability and downregulation of muscle FOXO expression induced by HSI. Muscle-specific FOXO-RNAi (FOXO-RNAi) and -overexpression (FOXO-OE) promoted or slowed the age-related decline in climbing ability, heart function, and skeletal muscle and heart structure damage, which was accompanied by the inhibition or activation of FOXO/PGC-1α/SDH and FOXO/SOD pathway activity, and oxidative stress (ROS) increased or decreased in both skeletal muscle and heart. The protective effect of exercise on the skeletal muscle and heart was blocked by FOXO-RNAi in aged HSI flies. FOXO-OE prolonged its lifespan, but it did not resist the HSI-induced lifespan shortening. Exercise did not improve HSI-induced lifespan shortening in FOXO-RNAi flies. Therefore, current results confirmed that the muscle FOXO gene played a vital role in exercise against age-related defects of the skeletal muscle and heart induced by HSI because it determined the activity of muscle FOXO/SOD and FOXO/PGC-1α/SDH pathways. The muscle FOXO gene also played an important role in exercise against HSI-induced mortality in aging flies.


Is it worth it? Carers' views and expectations of residential respite for people living with dementia during and beyond the COVID-19 pandemic.
The Covid-19 pandemic has taken a heavy toll on many people living with dementia and carers. Caring for a person living with dementia at home with limited avenues for support and a break challenged many carers. Care homes in England closed to visitors, with very few offering opportunities for a short-stay. We investigated impact of Covid-19 on views and expectations of carers of people living with dementia about residential respite. Qualitative interviews with 35 carers were conducted March-December 2020: 30 women and 5 men, with ages ranging 30-83 years. Interviews explored experiences, views of residential respite, and expectations post-Covid. Data were thematically analysed and salient concepts were drawn out and discussed within the research team and study advisers. Three themes were identified in transcripts, relating to impact of Covid-19 on views and expectations of respite: (1) Carers described regularly negotiating risks and stresses of Covid, weighing up how to prevent infection and changing family arrangements to facilitate caring; (2) Carers were balancing different needs, prioritising needs of their relatives while bearing the impact of cumulative caregiving responsibilities. (3) Uncertainty about future residential respite continued, in terms of availability, ongoing restrictions and trustworthy information sources. Residential respite is a positive, acceptable option for some carers to get a break from caring. Covid-19 may have heighted some of caregiving stressors and there may be an increased need for a break. Views of care homes developed during the pandemic suggest that individual confidence to use respite may need to be rebuilt.


The spatial configuration of biotic interactions shapes coexistence-area relationships in an annual plant community.
The increase of species richness with area is a universal phenomenon on Earth. However, this observation contrasts with our poor understanding of how these species-area relationships (SARs) emerge from the collective effects of area, spatial heterogeneity, and local interactions. By combining a structuralist approach with five years of empirical observations in a highly-diverse Mediterranean grassland, we show that spatial heterogeneity plays a little role in the accumulation of species richness with area in our system. Instead, as we increase the sampled area more species combinations are realized, and they coexist mainly due to direct pairwise interactions rather than by changes in single-species dominance or by indirect interactions. We also identify a small set of transient species with small population sizes that are consistently found across spatial scales. These findings empirically support the importance of the architecture of species interactions together with stochastic events for driving coexistence- and species-area relationships.


Clinical Features and Outcomes of Tubulointerstitial Nephritis and Uveitis Syndrome in Spain and Portugal: The IBERTINU Project.
To assess the clinical features, management and prognosis of patients diagnosed with tubulointerstitial nephritis and uveitis (TINU) syndrome in Spain and Portugal. Retrospective multicenter study, which included all patients diagnosed with TINU syndrome managed in 15 uveitis referral centers from Spain and Portugal. Forty-eight subjects with a mean age at diagnosis of 25.0 [14.8; 49.5] years were included. Both eyes were affected in 43 patients (89.6%). The visual outcome was favorable, but immunosuppressive systemic therapy (IST) was needed in 26 (54.16%) due to relapses. Renal function normalized in 35 patients (72.9%). HLA-DQB1*05 was the most common genetic typing (57.1%). The mean follow-up time was 22.5 [11.0; 48.0] months. Both visual and renal outcomes were favorable, although IST was frequently used. TINU is under- diagnosed, so further prospective studies would provide more knowledge about its recognition and management. TINU Syndrome is underdiagnosed because ocular and renal disease are asynchronous. Outcomes are favorable so it has to be highly suspected in cases of bilateral anterior uveitis. According to literature and our experience, systemic immunosuppressive therapy is often required because of ocular relapses.This study adds to the previous knowledge that HLA-DQB1*05 could be an important HLA type amongst the TINU Syndrome Iberian population. HLA typing should be assessed in these patients in order to describe its phenotype-genotype relationship better. A considerable number of patients in our series were diagnosed in their sixties, so TINU Syndrome should also be suspected in elderly patients.


Passive ankle dorsiflexion increases in patients after a regimen of tilt table-wedge board standing. A clinical report.
We monitored the result of a tilt table-wedge board routine on the passive ankle dorsiflexion of 20 patients consecutively to determine the effectiveness of the treatment. The calculated frequency of the treatment, which was applied for 30 minutes on each of 5 to 22 treatment days, ranged from 2.3 to 6.4 treatments a week. All patients demonstrated increased passive ankle dorsiflexion. The increases ranged from 3 to 17 degrees and occurred at a calculated rate of 0.11 to 1.0 degrees a day. We believe the treatment is an effective clinical method for increasing passive ankle dorsiflexion in neurologically involved patients.


Proviral integration site Mis-1 in rat thymomas corresponds to the pvt-1 translocation breakpoint in murine plasmacytomas.
Two loci independently implicated in T-and B-lymphocyte neoplasia are shown to be equivalent. The Mis-1 locus is a common proviral integration site in retrovirally induced rat T lymphomas, while the pvt-1 locus on murine chromosome 15 frequently translocates to the kappa locus in plasmacytomas bearing 6;15 translocations. By comparing cloned sequences, we show that pvt-1 is the murine homolog of Mis-1.


The effect of ara-C-induced inhibition of DNA synthesis on its cellular pharmacology.
The cytotoxicity of ara-C is believed to result from incorporation of ara-CTP into DNA and inhibition of DNA synthesis. Since complete inhibition of DNA synthesis would prevent further incorporation of ara-CTP, ara-C may have a self-limiting effect on its own cytotoxicity, particularly at the high concentrations typical of high-dose ara-C clinical protocols. In this study, the incorporation of [3H]-dThd and [3H]-ara-C into DNA were compared. Within 1 h of exposure of L5178Y cells to ara-C, the rate of [3H]-dThd incorporation into the acid-insoluble fraction was reduced by 98%. Despite this nearly complete block in [3H]-dThd incorporation, DNA synthesis was not completely inhibited since [3H]-ara-C continued to be incorporated for up to 6 h, although a plateau in ara-CDNA synthesis was observed between 2 and 3 h exposure when ara-CTP levels were maximal. The effect of ara-C on [3H]-dThd incorporation into DNA was due in part to an indirect effect of ara-C on the metabolism of intracellular [3H]-dThd to [3H]-dTTP. Within 30 min exposure to 10 microM ara-C, the rate of cellular [3H]-dTTP synthesis was slowed to only 15% of the control rate. This was not due to inhibition of [3H]-dThd transport, since the intracellular and extracellular concentrations of the nucleoside were equal. The effect of ara-C on [3H]-dTTP synthesis resulted from significant changes in deoxynucleoside 5'-triphosphate (dNTP) pools. dTTP, dATP, and dGTP levels were increased, whereas the dCTP concentration was decreased. When dThd kinase from L5178Y cells was assayed with increased dTTP levels induced by ara-C vs the dTTP level in control cells, its activity was reduced by 72%. Thus, the [3H]-dThd incorporation experiment overestimated the extent of inhibition of DNA synthesis by ara-C due to increased feedback inhibition of dThd kinase and increased competition for DNA polymerase between the elevated unlabeled dTTP pool and the decreased levels of [3H]-dTTP. In vitro assay of DNA polymerase in the presence of the ara-CTP concentration achieved after 0.5 or 3 h exposure to 10 microM ara-C (60 microM and 200 microM, respectively), plus the mixture of dNTPs found intracellularly at these times, resulted in 57% and 80% inhibition of the polymerase, respectively. This inhibition may account for the plateau in the accumulation of ara-CDNA that was observed at 3 h and suggests that ara-C incorporation may be self-limiting at high cellular concentrations of ara-CTP.(ABSTRACT TRUNCATED AT 400 WORDS)


Zig-zag technology adoption behavior among brick kiln owners in Pakistan.
This study uses the theory of planned behavior to examine the individual's intentions and zig-zag kiln technology adoption attitude in responding to carbon emissions in Pakistan. This study is based on cross-sectional data and a representative sample of 335 brick kilns owners from 11 districts of Punjab province of Pakistan is collected. Partial least squares structural equation modeling technique was used for the analysis. Results depicted that environmental concern and self-efficacy have a significant influence on attitude toward sustainable technology while subjective norms have a significant effect on intentions toward zig-zag kiln technology. A 1% increase in environmental concern and self-efficacy increases sustainable environmental technology by 24% and 58%, respectively. Furthermore, perceived behavioral control and intentions also significantly impact adoption attitude, and a 1% increase in perceived behavioral control and intentions increase the zig-zag kiln adoption attitude by 68% and 30%, respectively. Results depicted that adoption attitude is significantly determined by these explanatory variables. The study's findings provided new evidence for the government to place more emphasis on enhancing kiln owners' attitudes, social norms, and perceived behavioral control, which would lead towards the adoption of this new technique.


Reforms to the patented medicine prices review board and the introduction of new drugs in Canada: An observational study.
Innovative Medicines Canada has said that companies are delaying the introduction of new drugs into Canada in anticipation of changes in how the Patented Medicine Prices Review Board determines prices for patented medicine. This study investigates whether this claim is accurate. Delays in seeking approval for and marketing of new drugs were examined using linear regression analysis and comparing the time between approvals by Health Canada and approvals of the same drugs by the United States (US) Food and Drug Administration (FDA). Linear regression was also used to examine changes in the percent of drugs approved by the FDA and also approved by Health Canada and whether fewer drugs approved by Health Canada were being marketed. Approvals in Australia served as a control. There was no change in the difference in approval times between Health Canada and the FDA (p = 0.7073). Time between approval of new drugs and when they were marketed increased (p = 0.0002). Health Canada approved a smaller percent of drugs approved by the FDA (p = 0.0019) but the same trend was found in Australia. Fewer drugs approved in Canada were marketed (p = 0.0288). There is mixed evidence about whether drug companies are delaying or simply not introducing new drugs into Canada.


Clinical differences between late-onset and early-onset chronically hospitalized elderly schizophrenic patients in Taiwan.
To examine the clinical differences between late-onset schizophrenia (LOS) and early-onset schizophrenia (EOS) in Taiwanese elderly chronic hospitalized schizophrenic patients. By using a cross-sectional study method, we investigated all the hospitalized elderly schizophrenic patients in a general hospital's psychiatric ward during July-September 2007. All the subjects matched DSM-IV-TR diagnostic criteria and were aged 60 years or above. A total of 52 subjects were enrolled (LOS = 23, EOS = 29). Demographic data, illness history, and antipsychotic treatment record were documented; the positive and negative syndrome scale (PANSS), Center for Epidemiological Studies Depression scale (CES-D), mini-mental status examination (MMSE), activities of daily living rating scale for psychiatric patients (ADLRS), community self-sufficiency test (CST), clinical global impression (CGI), and general assessment of functioning scale (GAF) were administered. In our samples, a lower educational level was found to be more common in late-onset patients. In LOS, there was no significant increase in the severity of PANSS psychopathology except for greater thought disorder symptoms. Both LOS and EOS patients had similar cognitive and functioning impairment with poor global outcomes. There was a trend of low antipsychotic drug use in LOS. In Taiwan, elderly chronic inpatients LOS had greater thought disorders compared to findings in Western studies. Further large-scale longitudinal studies are needed to understand the factors related to these findings.


Touch gives new life: mechanosensation modulates spinal cord adult neurogenesis.
The ability to respond to a wide range of novel touch sensations and to habituate upon repeated exposures is fundamental for effective sensation. In this study we identified adult spinal cord neurogenesis as a potential novel player in the mechanism of tactile sensation. We demonstrate that a single exposure to a novel mechanosensory stimulus induced immediate proliferation of progenitor cells in the spinal dorsal horn, whereas repeated exposures to the same stimulus induced neuronal differentiation and survival. Most of the newly formed neurons differentiated toward a GABAergic fate. This touch-induced neurogenesis reflected the novelty of the stimuli, its diversity, as well as stimulus duration. Introducing adult neurogenesis as a potential mechanism of response to a novel stimulus and for habituation to repeated sensory exposures opens up potential new directions in treating hypersensitivity, pain and other mechanosensory disorders.


The DOMUS study protocol: a randomized clinical trial of accelerated transition from oncological treatment to specialized palliative care at home.
The focus of Specialized Palliative Care (SPC) is to improve care for patients with incurable diseases and their families, which includes the opportunity to make their own choice of place of care and ultimately place of death. The Danish Palliative Care Trial (DOMUS) aims to investigate whether an accelerated transition process from oncological treatment to continuing SPC at home for patients with incurable cancer results in more patients reaching their preferred place of care and death. The SPC in this trial is enriched with a manualized psychological intervention. DOMUS is a controlled randomized clinical trial with a balanced parallel-group randomization (1:1). The planned sample size is 340 in- and outpatients treated at the Department of Oncology at Copenhagen University Hospital. Patients are randomly assigned either to: a) standard care plus SPC enriched with a standardized psychological intervention for patients and caregivers at home or b) standard care alone. Inclusion criteria are incurable cancer with no or limited antineoplastic treatment options. Programs that facilitate transition from hospital treatment to SPC at home for patients with incurable cancer can be a powerful tool to improve patients' quality of life and support family/caregivers during the disease trajectory. The present study offers a model for achieving optimal delivery of palliative care in the patient's preferred place of care and attempt to clarify challenges. Clinicaltrials.gov Identifier: NCT01885637.


Endoscopic third ventriculostomy limited by artery of Percheron.
The irrigation of the thalamus depends mainly on the thalamoperforating arteries. There are many anatomical variations in these arteries, the best known being the artery of Percheron. We report a case of a 13-year-old male presented with headache and decline in his mental status. Imaging features showed obstructive hydrocephalus secondary to a mass at the level of the mesencephalon so an endoscopic third ventriculostomy was performed. During the procedure a thalamoperforating artery was encountered at the level of the tuber cinereum limiting the perforation of the third ventricle floor. The present case emphasizes the importance of knowing the anatomy of these arteries and the identification of their main variants during neurosurgical procedures.


The subcellular distribution of peptides immunoreactive for the amino-terminal of pro-cholecystokinin in rat brain.
Antiserum 1942 raised against the synthetic peptide V-9-M is specific for the amino-terminus of pro-cholecystokinin (pro-CCK). It detects three major peptides in whole rat brain extracts with molecular weights of about 13 000 (peak 1), 8000 (peak 2) and 2700 (peak 3), of which the major one is peak 3. Rat brain was found to contain large quantities of these V-9-M-like peptides. Subcellular fractionation of whole rat brain was performed to determine what cellular component was enriched in these peptides. The molecular weight of the V-9-M-like and CCK-8-like peptides enriched in various subcellular fractions has been determined by Sephadex G-50 chromatography. Primary subcellular fractionation experiments indicated a significant enrichment of V-9-M-like peptides in the mitochondrial pellet (P2), a lesser amount in the microsomal pellet (P3), and a slight enrichment in the soluble fraction (S3). Further purification of the P2 fraction demonstrated an increase of V-9-M-like immunoreactivity in purified synaptosomes. With the exception of the enrichment in the soluble fraction, V-9-M-like peptides follow a similar distribution to that of CCK-8-like peptides. Sephadex chromatography of P2 and P3 fractions indicates that the major form of V-9-M present is the peak 3 (2700) form. This V-9-M-like peptide may represent an intermediate in the processing of CCK, and its presence in synaptosomes may indicate that the proteolytic cleavage of pro-CCK into CCK 58 and peak 3 takes place in synaptic vesicles.


An automated PSRO-utilization review system.
A set of computer programs collects, processes, and reports Professional Standards Review Organization (PSRO) and utilization data for all patients at the Miami Heart Institute. They help reduce the time spent by physicians in PSRO and utilization review activities and ease the clerical work load required to comply with rules and guidelines. Daily printed reports provide attending physicians with their patient census and inform them of the next scheduled PSRO review dates for each of their patients. Reports are produced also for the Utilization Review Committee and the Institute's PSRO office. This set of programs is part of a comprehensive automated hospital information system and has been designed to respond rapidly to the frequent changes in regulations and policies dictated by the administering agency. The PSRO subsystem had been in uninterrupted operation for over 6 years and has mitigated escalating clerical and, therefore, health care costs. Physicians' acceptance of this subsystem had been adequate; however, developmental and maintenance costs are high in comparison with other applications within the hospital information system. This article describes the methodology used in complying with PSRO requirements. It does not attempt to evaluate the impact of PSRO on quality of care or length of hospital stay.


Environmental and genetic contributions to diabetes.
Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by persistent hyperglycemia. Its two most common forms are type 1 diabetes (T1D) and type 2 diabetes (T2D), for which genetic and environmental risk factors act in synergy. Because it occurs in children and involves infectious, autoimmune or toxic destruction of the insulin-secreting pancreatic beta-cells, type 1 diabetes has been called juvenile or insulin-deficient diabetes. In type 2, patients can still secrete some insulin but its effectiveness may be attenuated by 'insulin resistance.' There is also a group of rare forms of diabetes in the young which are inherited as monogenetic diseases. Whether one calls the underlying process 'genes vs. environment' or 'nature vs nurture', diabetes occurs at the interface of the two domains. Together with our genetic background we are born tabula rasa-a blank slate upon which the story of life, with all its environmental inputs will be written. There is one proviso: the influence of epigenetic inheritance must also be considered. Thus, in the creation of databases that include "big data" originating from genomic as well as exposome (defined as: the totality of environmental exposure from conception to death), a broad perspective is crucial as these factors act in concert in such chronic illnesses as diabetes that, for example, are likely to require adoption of an appropriate lifestyle change. Also, it is becoming increasingly evident that epigenetic factors can modulate the interplay between genes and environment. Consequently, throughout the life of an individual nature and nurture interact in a complex manner in the development of diabetes. This review addresses the question of the contribution of gene and environment and their interactions in the development of diabetes.


Genomic analysis of carbapenem-resistant Pseudomonas aeruginosa ST143 clone showing susceptibility to broad-spectrum cephalosporins.
Using whole-genome sequencing (WGS), we aimed to characterise a Pseudomonas aeruginosa ST143 clinical strain (Pb9) that presented resistance to meropenem and imipenem and susceptibility to piperacillin/tazobactam and broad-spectrum cephalosporins. The antimicrobial susceptibility profile was confirmed by broth microdilution. WGS was performed using an Illumina MiSeq platform to identify possible genetic determinants of β-lactam resistance. Transcription levels of chromosomally encoded efflux systems and oprD were evaluated by RT-qPCR. WGS analysis showed that no acquired carbapenemase-encoding gene was found in isolate Pb9, although mutations in the chromosomally encoded β-lactamase genes blaOXA-488, blaPIB-1 and blaPDC-5 were observed. In addition, we detected a premature stop codon in the major porin-encoding gene oprD coupled with hyperexpression of MexAB-OprM and MexEF-OprN. Our results suggest that the β-lactam resistance phenotype presented by strain Pb9 might be related to an association of OprD loss with hyperexpression of the efflux pump systems MexAB-OprM and MexEF-OprN. However, the contribution of OXA-488, PDC-5 and PIB-1 to this phenotype remains unclear and warrants further investigation.


Treatment of jaw fractures in small animals with parapulpar pin composite bridges.
This article describes a 5-year study of 73 cats that were surgically treated for mandibular fractures or combinations of fractures with luxation of the temporomandibular joint. Surgical technique and results are described in detail.