Trends in diagnostic imaging utilization in a university hospital in Turkey.
The aim of this study was to evaluate utilization trends of the diagnostic imaging examinations during the past decade in a university hospital in Turkey. Patient registries of a university hospital were used for the years 1995 and 2003. The data set consisted of patients' admissions, social security status, and diagnostic imaging tests. When compared with 1995 data, the total number of diagnostic imaging examinations and patient admissions increased 65.9 percent and 81.6 percent, respectively, in the year 2003. Although the total number of diagnostic imaging tests decreased 9.0 percent, there was a 145.4 percent increase in magnetic resonance imaging (MRI) examinations. Nevertheless, radiological diagnostic procedures consisted of 12.8 percent of the total hospital revenues in 1995 and 9.4 percent in 2003. This study shows that approximately one third of inpatients underwent MRI and computed tomography examinations in 2003. The utilization rates of diagnostic imaging procedures, especially new technologies, need to be considered carefully with respect to appropriateness of procedures and planning of services.


Enlarging pigmented patches on the hand.
This case illustrates the clinical and pathological features of Tinea nigra. Awareness of the characteristic features of this cutaneous infection, especially in areas where the organism is endemic, can ultimately lead clinicians to the appropriate diagnosis. If Tinea nigra should be considered in the differential diagnosis of palmoplantar pigmentation, potassium hydroxide (KOH) preparation may facilitate the diagnosis.


Reversal of xylazine sedation in dogs.
Intramuscular injections of atipamezole (200 micrograms/kg), doxapram (2.5 mg/kg) and saline (0.1 ml/kg) were compared for their ability to reverse xylazine sedation in dogs. Atipamezole effectively reversed the sedative effects and partially reversed the cardiopulmonary effects of xylazine. Doxapram did not arouse the dogs as much as atipamezole, but it shortened the time taken for them to stand although the dogs were still ataxic.


Rifampicin kinetics in undernutrition.
Rifampicin 10 mg/kg was administered as a single dose to eight undernourished subjects, 10 well nourished subjects and 10 undernourished patients on continuous antituberculosis therapy as a single dose. The area under plasma time concentration (AUC0----infinity) and the peak concentration were significantly reduced in both the undernourished groups. The apparent oral and renal clearances were increased in both the undernourished groups. The (AUC0----infinity) was reduced in undernourished due to reduced absorption and/or changes in total body clearance or disposition. The plasma protein binding of the drug was significantly reduced in the undernourished resulting in increased free drug concentration. This might be sufficient to ensure adequate therapeutic efficacy. Therefore alteration in dosage regimes are not necessary in the undernourished.


[Intracellular immunoglobulins in lymphogranulomatosis].
In 27 cases of malignant lymphogranulomatosis investigations were made on the intracellular presence of severe chains of immunoglobulins (IgM, IgG, IgA) in plasma cells and prestages of plasma cells or in atypical cells (Sternberg-Reed, mirror picture, and Hodgkin cells) by using the immunoperoxidase method. In 7 cases an intensive intracellular colouring of IgG could be observed, with immature prestages of plasma cells being present simultaneously (plasmoblasts, immunoblasts). In 16 cases IgG was slightly marked only, no plasma cells being present. With regard to the first group the development of atypical cells in these cases may be supposed to be connected with the presence of precursors of plasma cells.


Wiring taste receptor cells to the central gustatory system.
Taste receptor cells in the tongue are epithelial in nature and turnover frequently. Taste receptor cell-associated neurons carrying bitter, sweet, or sour signals never turnover and are hardwired to specific gustatory centers in the brain. How can ever-changing bitter or sweet receptors find never-changing neurons that must match the specificity of the signal? This article reviews a recent paper published in Nature (Lee, MacPherson, Parada, Zuker, & Ryba, , 548:330-333) that identified two molecules belonging to the semaphorin axon guidance family of molecules (SEMA3A and SEMA7A) that help maintain the "labeled line principle" between peripheral bitter or sweet receptors and their respective central projection area in the gustatory center.


[Effect of pre-transplant donor specific antibody on antibody-mediated rejection and graft dysfunction].
To explore the effect of pre-transplant donor specific antibody (DSA) on antibody-mediated rejection (AMR) and function of transplanted kidney. A total of 88 cases of renal transplant recipients were selected. Before surgery, DSA was examined by Luminex liquid phase chip in renal transplant recipients. The recipients were divided into a DSA positive group (n=20) and a DSA negative group (n=68). The follow-up time was 2 years. After the operation, the pathologic morphology of the transplanted kidney was evaluated and classified according to the Banff 2005 standard. The situation for the transplanted kidney was evaluated. The incidence of AMR in the DSA positive group and negative group was 20% and 1.5%, respectively, with significant difference between them (P<0.01). The incidence of graft loss in the DSA positive group and negative group was 15% and 1.5%, respectively, with significant difference between them (P<0.05). The pre-transplant DSA associated with AMR at multiple mean fluorescence intensity (MFI) was obvious different from that without AMR (P<0.01). Receiver operating characteristic (ROC) curves showed that the maximal MFI threshold for recipients with AMR was 7909.5 after renal transplantation. There was no significant difference in the delayed recovery of renal graft function (DGF) between the 2 groups (P>0.05). The detection of DSA level before renal transplantation can predict the risk of AMR and the function of transplanted kidney. The MFI intercept point of the highest DSA (MFI> 7909.5) can be used to predict the risk of AMR.


The biology of leptin and its implications in breast cancer: a general view.
Obesity is a world health problem that increases the risk for developing type 2 diabetes, cardiovascular disease, fatty liver, and some types of cancer. In postmenopausal women, it represents an important risk factor for the development of breast cancer (BC). Leptin is an adipokine that is secreted by fatty tissue, and high leptin levels are observed both in mouse models of obesity and in obese subjects. High levels of leptin promote the proliferation and progression of various types of cancer, including BC. This review provides a general overview of the biology of leptin, important laboratory studies, and animal and clinical models that have provided evidence for an active role of leptin in the proliferation, progression, and survival of mammary tumors. Finally, this review addresses the most recent studies on the use of leptin receptor antagonists as a novel therapeutic treatment for BC.


[Measurement of residual gastric volume: in search of better evidence].
Measurement of residual gastric volume is a frequent practice in chronic patients, but there is lack of consensus on the convenience of reintroducing or discarding aspirated gastric content (AGC). Determine the grade of scientific evidence on the efficacy of two interventions -reintroduction/rejection- of AGC in chronic patients. Systematic review of the evidence available on the convenience of reintroducing or discarding ACG. a) establishment of inclusion/exclusion criteria; b) determination of the search strategy (keywords and itineraries); c) dumping of databases: MEDLINE, CINAHL, CUIDEN, IME, SCIELO and COCHRANE. Search for indirect method and manual dumping of indexes; d) independent and contrasted critical reading, using the CASPe template; and e) contrast of critical analysis results. Search itineraries generate more than 800 references that once purged make it possible to select 54. After reading them, only 4 really focused on the questions related with the reintroduction/rejection of AGC: 2 revisions, 1 observational study and a random clinical trial with a small sample. Meta-analysis techniques could not be used due to the heterogeneity of these studies. Thus, the results of the study were analyzed separately. Using this procedure, a final result was obtained that showed a low grade of scientific evidence. There is limited scientific evidence on the convenience, safety and benefits of both interventions. It is difficult to establish a care protocol, so that we suggest performing an experimental study to establish the indications and contraindications of both interventions.


Perception of Time in Music in Patients with Parkinson's Disease-The Processing of Musical Syntax Compensates for Rhythmic Deficits.
Objective: Perception of time as well as rhythm in musical structures rely on complex brain mechanisms and require an extended network of multiple neural sources. They are therefore sensitive to impairment. Several psychophysical studies have shown that patients with Parkinson's disease (PD) have deficits in perceiving time and rhythms due to a malfunction of the basal ganglia (BG) network. Method: In this study we investigated the time perception of PD patients during music perception by assessing their just noticeable difference (JND) in the time perception of a complex musical Gestalt. We applied a temporal discrimination task using a short melody with a clear beat-based rhythm. Among the subjects, 26 patients under L-Dopa administration and 21 age-matched controls had to detect an artificially delayed time interval in the range between 80 and 300 ms in the middle of the musical period. We analyzed the data by (a) calculating the detection threshold directly, (b) by extrapolating the JNDs, (c) relating it to musical expertise. Results: Patients differed from controls in the detection of time-intervals between 220 and 300 ms (*p = 0.0200, n = 47). Furthermore, this deficit depended on the severity of the disease (*p = 0.0452; n = 47). Surprisingly, PD patients did not show any deficit of their JND compared to healthy controls, although the results showed a trend (*p = 0.0565, n = 40). Furthermore, no significant difference of the JND was found according to the severity of the disease. Additionally, musically trained persons seemed to have lower thresholds in detecting deviations in time and syntactic structures of music (*p = 0.0343, n = 39). Conclusion: As an explanation of these results, we would like to propose the hypothesis of a time-syntax-congruency in music perception suggesting that processing of time and rhythm is a Gestalt process and that cortical areas involved in processing of musical syntax may compensate for impaired BG circuits that are responsible for time processing and rhythm perception. This mechanism may emerge more strongly as the deficits in time processing and rhythm perception progress. Furthermore, we presume that top-down-bottom-up-processes interfere additionally and interact in this context of compensation.


Role of VEGF I/D variant in suspectibility to odontogenic cyst formation.
Odontogenic cysts, are located in the jawbones, filled with fluid surrounded by epithelial lining and fibrous connective tissue. Vascular endothelial growth factor (VEGF) can induce physiological and pathological angiogenesis and is an endothelial cell-specific mitogen. The aim of the present study was to investigate whether any possible association between the VEGF insertion/deletion (I/D) variant and odontogenic cyst in Turkish population. Clinical information and venous blood samples were collected from 62 odontogenic cyst patients and 98 healthy controls. DNA was isolated from peripheral blood leukocytes. Genotyping of the VEGF I/D variant was done by the polymerase chain reaction (PCR) method. There was a statistically differece in terms of VEGF I/D allele frequencies between patients and controls. VEGF I/D variant I allele frequency was more prevalant in patients compared to controls (p = 0.006411, OR: 2.08, 95%Cl: 1.322-3.272). A statistically significant association was observed when the patients were compared with the controls according to D/D + I/D versus I/I genotype (p = 0.0508, OR: 1.925, 95%Cl: 0.872-4.246). The genotype distribution of VEGF I/D was not statistically different between patients and controls (p > 0.05). For the first time, our results provided evidence supporting the odontogenic cyst formation associated with the I/D variant at the promoter region of the VEGF gene in a group of Turkish population. Although it was seen in our study that the I/D variant in the promoter region of the VEGF gene supports odontogenic cyst formation, large-scale studies are needed to elucidate the effect of this variant on odontogenic cysts.


A qualitative exploration into the long-term perspectives of patients receiving critical care diaries across the United Kingdom.
Increasing evidence suggests the use of a diary with entries by nurses, doctors, AHPs and the patient's family can potentially help by "filling in the gaps" and help the patient make sense of a time that they have forgotten or feel confused and have fears about. A qualitative exploration of the impact of diaries on critical care patients around the United Kingdom in order to describe the long-term effects of patient diaries. In-depth qualitative interviews, using principles of grounded theory, via telephone and email were undertaken. The sample included former patients who responded via adverts on critical care charity/support websites. People who had diaries in the previous 1-3 years were asked about their experiences. Eight people who had been patients in various critical care units across the United Kingdom and who had a critical care diary were interviewed. All reported value in having diaries, however, participants reported needing support when first receiving the diary to understand events that took place in critical care. Diaries can offer a means of filing the gaps for patients who struggle with coming to terms with their critical care recovery, but should be given to patients with forethought and subsequent support.


Computer Vision Technology for Monitoring of Indoor and Outdoor Environments and HVAC Equipment: A Review.
Artificial intelligence technologies such as computer vision (CV), machine learning, Internet of Things (IoT), and robotics have advanced rapidly in recent years. The new technologies provide non-contact measurements in three areas: indoor environmental monitoring, outdoor environ-mental monitoring, and equipment monitoring. This paper summarizes the specific applications of non-contact measurement based on infrared images and visible images in the areas of personnel skin temperature, position posture, the urban physical environment, building construction safety, and equipment operation status. At the same time, the challenges and opportunities associated with the application of CV technology are anticipated.


HPV prevalence and genotype distribution among women in Shandong Province, China: Analysis of 94,489 HPV genotyping results from Shandong's largest independent pathology laboratory.
Data regarding human papillomavirus (HPV) prevalence and genotype distribution are limited in Shandong Province, China. Therefore, we investigated the recent HPV prevalence and genotype distribution among females in Shandong and aimed to provide comprehensive data to guide HPV-based cervical cancer screening and HPV vaccination for this population of Chinese women. HPV testing results of 94,489 females were retrospectively reviewed and extracted from the database of Jinan KingMed Diagnostics, the largest independent pathology laboratory in Shandong Province, China. HPV was detected by a HPV genotyping panel from January 2011 to June 2017. The overall prevalence, age-specific prevalence, and genotype distribution were analyzed. A total of 26,839 cases (28.4%) were HPV-positive, with 4.3% positive for low- or undetermined-risk HPV (lr-/urHPV)-only, 18.1% positive for high-risk HPV (hrHPV)-only, and 6.1% positive for mixed lr-/urHPV and hrHPV infections. Single HPV infections accounted for 62.8%, while the rest were multiple HPV infections of two or more genotypes. HPV16 (5.8%), HPV52 (5.1%), HPV58 (3.5%), HPV51 (2.6%), and HPV56 (2.3%) were the five most common hrHPV genotypes; while HPV81 (2.8%), HPV53 (2.8%), and HPV6 (2.3%) were the three most common lr-/urHPV genotypes. HPV18 (1.7%) was only the ninth most common hrHPV genotype. HPV16 but not HPV52 was more common in single infections than in multiple infections. The distribution of both mixed lr-/urHPV and hrHPV as well as overall HPV infections demonstrated a bimodal pattern across age groups, of which the first peak appeared in the younger group and the second peak was found in older women. A similar age-specific distribution was observed in multiple infections of three or more subtypes as well. Moreover, the proportion of mixed lr-/urHPV and hrHPV infection significantly increased, while those of lr-/urHPV-only and hrHPV-only infections declined as the number of co-infections increased during the study period. This large daily clinical practice report shows that HPV prevalence and genotype distribution are different in this population, who had limited cervical cancer screening service, compared to those in developed countries. Therefore, different strategies should be developed for HPV-based cervical cancer screening and vaccine-based HPV prevention in Shandong Province.


Vitamin D Deficiency and Its Determinants in Adults: A Sample from Community-Based Settings in the United Arab Emirates.
Background. Vitamin D deficiency (VDD) is a public health concern in adults worldwide. This study aims to explore the extent of VDD and its associated factors among adults in the United Arab Emirates (UAE). Subjects and Methods. Quantitative, cross-sectional research was used to assess VDD and its associated factors in 216 adults recruited from randomly selected community-based healthcare settings over a six-month period. Recent values of vitamin D and glycated hemoglobin (HbA1c) were abstracted from medical records, followed by interviews with participants to obtain information on factors related to VDD and other covariates and to measure their heights and weights. Results. A total of 74% of participants demonstrated VDD (vitamin D serum level ≤ 30 nmol/L). Emirati participants had higher odds of having VDD compared to non-Emiratis (OR: 2.95; 95% CI: 1.58-5.52), with also significantly increased odds of the condition appearing in older, less educated, and employed adults. Diabetes type 2 (HbA1c ≥ 6.5%), depression, and obesity were significantly associated with an increased likelihood of VDD after accounting for other covariates. Conclusion. VDD is a significant problem for UAE adults and requires attention by public health policy makers. Diabetes, obesity, and depression need to be considered when screening for vitamin D.


Pressure, Peptides, and a Piezolyte: Structural Analysis of the Effects of Pressure and Trimethylamine-N-oxide on the Peptide Solvation Shell.
The osmolyte trimethylamine-N-oxide (TMAO) is able to increase the thermodynamic stability of folded proteins, counteracting pressure denaturation. Herein, we report experimental solubility data on penta-alanine (pAla) in aqueous TMAO solutions (at pH = 7 and pH = 13) together with molecular simulation data for pAla, penta-serine (pSer), and an elastin-like peptide (ELP) sequence (VPGVG) under varying pH and pressure conditions. The effect of the peptide end groups on TMAO-peptide interactions is investigated by comparing the solvation of zwitterionic and negatively charged pentamers with the solvation of pentamers with charge-neutral C- and N-termini and linear, virtually infinite, peptide chains stretched across the periodic boundaries of the simulation cell. The experiments and simulations consistently show that TMAO is net-depleted from the pAla-water interface, but local accumulation of TMAO is observed just outside the first hydration shell of the peptide. While the same observations are also made in the simulations of the zwitterionic pentamers (Ala, Ser, and ELP) and virtually infinite peptide chains (Ala and ELP), weak preferential binding of TMAO is instead observed for pAla with neutral end groups at a 1 M TMAO concentration and for an ELP pentamer with capped neutral end groups at a 0.55 M TMAO concentration studied in previous work (Y.-T. Liao et al. Proc. Natl. Acad. Sci. USA, 2017, 114, 2479-2484). The above observations made at 1 bar ambient pressure remain qualitatively unchanged at 500 bar and 2 kbar. Local accumulation of TMAO correlates with a reduction in the total number of peptide-solvent hydrogen bonds, independent of the peptide's primary sequence and the applied pressure. By weakening water hydrogen bonds with the protein backbone, TMAO indirectly contributes to stabilizing internal hydrogen bonds in proteins, thus providing a protein stabilization mechanism beyond net depletion.


In situ examination of osteoblast biomineralization on sulfonated polystyrene-modified substrates using Fourier transform infrared microspectroscopy.
Osteoporosis is a skeletal disorder that is characterized by the loss of bone mineral density (BMD) resulting in increased risk of fracture. However, it has been shown that BMD is not the only indicator of fracture risk, as the strength of bone depends on a number of factors, including bone mass, architecture and material properties. Physiological mineral deposition requires the formation of a properly developed extracellular matrix (ECM), which recruits calcium and phosphate ions into the synthesis of apatite crystals. Temporal and spatial compositional and structural changes of biological apatite greatly depend on the properties of the crystals initially formed. As such, Fourier-transform infrared microspectroscopy (FTIRM) is capable of examining adaptive remodeling by providing compositional information such as the level of mineralization and carbonate substitution, as well as quality and perfection of the mineral phase. The objective of this study was to evaluate the in vitro mineralization development of MC3T3-E1 murine calvarial preosteoblasts cultured on different substrata by comparing FTIRM measurements from two subclones (mineralizing subclone 4 and nonmineralizing subclone 24) maintained in culture for up to 21 days. The results showed that modulation of the substrate surface using a thin coating of sulfonated polystyrene (SPS) provided favorable conditions for the development of a mineralizable ECM and that the mineral formed by the osteoblasts was similar to that of fully mineralized bone tissue. Specifically, the mineralizing subclone produced significantly more mineral phosphate when cultured on SPS-coated substrates for 21 days, compared to the same culture on bare substrates. In contrast, the level of mineralization in nonmineralizing subclone was low on both SPS-coated and uncoated substrates. The mineralizing subclone also produced comparable amounts of collagen on both substrates; however, mineralization was significantly higher in the SPS culture. The nonmineralizing subclone produced comparable amounts of collagen on day 1 but much less on day 21. Collagen maturity ratio increased in the mineralizing subclone from day 1 to day 21, but remained unchanged in the nonmineralizing subclone. These results suggest that SPS-treatment of the substrate surface may alter collagen remodeling; however, other factors may also influence osteoblast mineralization in the long term.


A typical migraine susceptibility region localizes to chromosome 1q31.
Migraine (with and without aura) is a prevalent neurovascular disease that shows strong familial aggregation, although the number of genes involved and the mode of inheritance is not clear. Some insight into the disease has been gained from genetic studies into a rare and very severe migraine subtype known as familial hemiplegic migraine (FHM). In this study, we took a family-based linkage and association approach to investigate the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chrlq31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned approximately 18 cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782 (P=0.00004). Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P=0.008). Utilising the independent sample of 82 pedigrees, we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 [global chi2 (5) of 15.00, P=0.010] in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers. However, overall they provide good evidence for the existence of a typical migraine locus near these markers on Chrlq3l, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine.


Isolation and characterization of temperature-sensitive mutants of adenovirus type 7.
Fifty temperature-sensitive mutants, which replicate at 32 degrees C but not at 39.5 degrees C, were isolated after mutagenesis of the vaccine strain of adenovirus type 7 with hydroxylamine (mutation frequency of 9.0%) or nitrous acid (mutation frequency of 3.8%). Intratypic complementation analyses separated 46 of these mutants into seven groups. Intertypic complementation tests with temperature-sensitive mutants of adenovirus type 5 showed that the mutant in complementation group A failed to complement H5ts125 (a DNA-binding protein mutant), that mutants in group B and C did not complement adenovirus type 5 hexon mutants, and that none of the mutants was defective in fiber production. Further phenotypic characterization showed that at the nonpermissive temperature the mutant in group A failed to make immunologically reactive DNA-binding protein, mutants in groups B and C were defective in transport of trimeric hexons to the nucleus, mutants in groups D, E, and F assembled empty capsids, and mutants in group G assembled DNA-containing capsids as well as empty capsids. The mutants of the complementation groups were physically mapped by marker rescue, and the mutations were localized between the following map coordinates: groups B and C between 50.4 and 60.2 map units (m.u.), groups D and E between 29.6 and 36.7 m.u., and group G between 36.7 and 42.0 m.u. or 44.0 and 47.0 m.u. The mutant in group A proved to be a double mutant.


Evaluation of objective visual quality in dry eye disease and corneal nerve changes.
To explore objective visual quality in dry eye diseases (DED) and the correlation between corneal nerves and objective visual quality. Ninety-eight eyes of 49 patients with DED were included. Each patient was evaluated with the ocular surface disease index (OSDI), eyelid margin signs and meibomian gland assessments; corneal staining; tear film breakup time (TBUT); tear meniscus height (TMH); in vivo confocal microscopic (IVCM); objective visual quality including the objective scatter index (OSI), mean objective scattering index (mOSI), modulation transfer function (MTF) cutoff value and Strehl ratio. A significant correlation was found between the OSDI and mOSI (r = 0.422, p = 0.005), MTF cutoff value (r = - 0.355, p = 0.020), and Strehl ratio (r = - 0.446, p = 0.003). The OSI was significantly correlated with TBUTf (r = - 0.213, p = 0.042). The mOSI, MTF cutoff value, Strehl ratio were correlated with eyelid margin signs and meibomian assessments. Additionally, there was a statistically significant correlation between corneal nerve length and the mOSI (r = - 0.239, p = 0.037), OSI (r = - 0.294, p = 0.028), MTF cutoff value(r = 0.282, p = 0.012), and Strehl ratio (r = 0.299, p = 0.008). Our study explored that objective visual quality was correlated with clinical symptoms and signs in DED patients. Furthermore, for the first time, our study explored the relationship between corneal nerves and objective visual quality and discovered that longer and wider corneal nerves were associated with better objective visual quality, which suggested that nerve changes may be a factor that related to poor visual quality in DED patients.


Phosphoinositides regulate P2X4 ATP-gated channels through direct interactions.
P2X receptors are ATP-gated nonselective cation channels highly permeable to calcium that contribute to nociception and inflammatory responses. The P2X(4) subtype, upregulated in activated microglia, is thought to play a critical role in the development of tactile allodynia following peripheral nerve injury. Posttranslational regulation of P2X(4) function is crucial to the cellular mechanisms of neuropathic pain, however it remains poorly understood. Here, we show that the phosphoinositides PI(4,5)P(2) (PIP(2)) and PI(3,4,5)P(3) (PIP(3)), products of phosphorylation by wortmannin-sensitive phosphatidylinositol 4-kinases and phosphatidylinositol 3-kinases, can modulate the function of native and recombinant P2X(4) receptor channels. In BV-2 microglial cells, depleting the intracellular levels of PIP(2) and PIP(3) with wortmannin significantly decreased P2X(4) current amplitude and P2X(4)-mediated calcium entry measured in patch clamp recordings and ratiometric ion imaging, respectively. Wortmannin-induced depletion of phosphoinositides in Xenopus oocytes decreased the current amplitude of P2X(4) responses by converting ATP into a partial agonist. It also decreased their recovery from desensitization and affected their kinetics. Injection of phosphoinositides in wortmannin-treated oocytes reversed these effects and application of PIP(2) on excised inside-out macropatches rescued P2X(4) currents from rundown. Moreover, we report the direct interaction of phospholipids with the proximal C-terminal domain of P2X(4) subunit (Cys(360)-Val(375)) using an in vitro binding assay. These results demonstrate novel regulatory roles of the major signaling phosphoinositides PIP(2) and PIP(3) on P2X(4) function through direct channel-lipid interactions.


Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy.
Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.


A new mouse T-cell receptor alpha chain variable region family.
Sequence analysis of the rearranged T-cell receptor alpha chain gene segments from an influenza reactive T-cell clone T2.5-5 and a hemin chloride reactive T-cell hybrid SJL-HE-1.1 have revealed a previously undescribed V alpha gene family. We have designated this family V alpha 15. Southern hybridization analysis has indicated that this family most probably contains only two members, and that these are conserved in each of six mouse strains representing three previously described V alpha haplotypes: V alpha a, V alpha b, and V alpha c.


Changes of fractional anisotropy and RGMa in crossed cerebellar diaschisis induced by middle cerebral artery occlusion.
Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the associated supratentorial region. The aim of the present study was to analyze the changes in fractional anisotropy (FA) in CCD induced by middle cerebral artery occlusion (MCAO) using magnetic resonance-diffusion tensor imaging (MR-DTI). Furthermore, the role of repulsive guidance molecule a (RGMa) in CCD was assessed by measuring RGMa expression using histochemical analysis. In the present study, the cerebellar hemisphere was serially scanned with T2-weighted, serial diffusion-weighted and diffusion tensor (DT) imaging using a 3.0T GE Signa HDxt Scanner to analyze the changes in FA over 72 h. Subsequently, immunohistochemistry analyses of the corresponding cerebellar hemisphere sections were performed to assess the expression of RGMa. Results indicated that FA of both sides of the cerebellar hemisphere, particularly that of the contralateral cerebellar hemisphere (right side) derived from DTI, was reduced during the 72-h time period following MCAO, and the decrease was maximal and statistically significant at 12 h (P<0.05). Immunohistochemistry analysis revealed a significant increase in the expression of RGMa protein in the affected region of the contralateral cerebellar hemisphere (right side) at 24 h following MCAO injury (P<0.05). Furthermore, the expression of RGMa and FA was negatively correlated in MCAO (P<0.05). The results suggest that MR-DTI is an important assessment to evaluate changes of FA in CCD induced by MCAO. Furthermore, the present results suggest that RGMa, which was negatively correlated with FA in MCAO rats, may serve an important role in CCD.


Comparative mapping in farm animals.
This paper summarises the current status of comparative mapping in farm animals. For most of the major farm animal species, a wide range of genomic tools are now available to create high-resolution genetic and physical maps of the genome. For many farm animals, the use of radiation hybrid panels and sequence data from expressed sequence tag (EST) projects has accelerated the development of high-resolution comparative maps, with human--the model species for farm animals. These tools and comparative maps are being used to map and identify the genes at the loci for simple and complex traits. The development of detailed physical maps in farm animals based on radiation hybrid panels and bacterial artificial chromosome (BAC) contigs provides a direct link between the 'information-poor' maps of farm animals and the 'information-rich' genomes of human and other model organisms.


Task-specific design of a hierarchical porous aromatic framework as an ultrastable platform for large-sized catalytic active site binding.
An amine-tagged hierarchical porous aromatic framework PAF70-NH2 with ultra-stability and narrowly distributed mesopores was synthesized. PAF70-NH2 has high potential for covalently immobilizing a relatively large-sized catalyst inside its pores. This work gave a perfect example of using PAF70-NH2 as a platform for completely recyclable heterogeneous organocatalysis.


Cold Shock as a Screen for Genes Involved in Cold Acclimatization in Neurospora crassa.
When subjected to rapid drops of temperature (cold shock), Neurospora responds with a temporary shift in its morphology. This report is the first to examine this response genetically. We report here the results of a screen of selected mutants from the Neurospora knockout library for alterations in their morphological response to cold shock. Three groups of knockouts were selected to be subject to this screen: genes previously suspected to be involved in hyphal development as well as knockouts resulting in morphological changes; transcription factors; and genes homologous to E. coli genes known to alter their expression in response to cold shock. A total of 344 knockout strains were subjected to cold shock. Of those, 118 strains were identified with altered responses. We report here the cold shock morphologies and GO categorizations of strains subjected to this screen. Of strains with knockouts in genes associated with hyphal growth or morphology, 33 of 131 tested (25%) showed an altered response to cold shock. Of strains with knockouts in transcription factor genes, 30 of 145 (20%) showed an altered response to cold shock. Of strains with knockouts in genes homologous to E. coli genes which display altered levels of transcription in response to cold shock, a total of 55 of 68 tested (81%) showed an altered cold shock response. This suggests that the response to cold shock in these two organisms is largely shared in common.


Quantum phases of dipolar rotors on two-dimensional lattices.
The quantum phase transitions of dipoles confined to the vertices of two-dimensional lattices of square and triangular geometry is studied using path integral ground state quantum Monte Carlo. We analyze the phase diagram as a function of the strength of both the dipolar interaction and a transverse electric field. The study reveals the existence of a class of orientational phases of quantum dipolar rotors whose properties are determined by the ratios between the strength of the anisotropic dipole-dipole interaction, the strength of the applied transverse field, and the rotational constant. For the triangular lattice, the generic orientationally disordered phase found at zero and weak values of both dipolar interaction strength and applied field is found to show a transition to a phase characterized by net polarization in the lattice plane as the strength of the dipole-dipole interaction is increased, independent of the strength of the applied transverse field, in addition to the expected transition to a transverse polarized phase as the electric field strength increases. The square lattice is also found to exhibit a transition from a disordered phase to an ordered phase as the dipole-dipole interaction strength is increased, as well as the expected transition to a transverse polarized phase as the electric field strength increases. In contrast to the situation with a triangular lattice, on square lattices, the ordered phase at high dipole-dipole interaction strength possesses a striped ordering. The properties of these quantum dipolar rotor phases are dominated by the anisotropy of the interaction and provide useful models for developing quantum phases beyond the well-known paradigms of spin Hamiltonian models, implementing in particular a novel physical realization of a quantum rotor-like Hamiltonian that possesses an anisotropic long range interaction.


Effects and mechanisms of total glucosides of paeony on adjuvant arthritis in rats.
Total glucosides of paeony (TGP) is the major active constituent of Paeonia lactiflora Pall. The present study was carried out to investigate the effects of TGP on adjuvant arthritis (AA) of rat and its possible mechanisms. AA was induced by metatarsal footpad injection with complete Freund's adjuvant in male Sprague-Dawley rats. The secondary inflammatory reaction was evaluated by hind paw swelling, polyarthritis index. Activity of interleukin-1 (IL-1) was detected by Con A-induced thymocytes proliferation of C57BL/6J mice assay. The tumor necrosis factor alpha (TNFalpha), prostaglandin E(2) (PGE(2)) and cyclic adenosine monophosphate (cAMP) levels in synoviocytes were assessed by radioimmunoassay (RIA). PGE(2) receptors, EP2 and EP4, were analyzed by Western blot analysis. The level of IL-6 was measured by ELISA. Intragastric administration of TGP (50,100 mg/kg) significantly decreased secondary inflammatory reaction in AA rats. Suppressing the activity of IL-1 and TNFalpha, decreased PGE(2) and increased cAMP levels in synoviocytes of AA rats were observed after administration of TGP. In the immunoblot analysis, TGP could up-regulate the expression of EP2 and EP4. These results showed TGP significantly inhibited the progression of AA, and the inhibitory effects might be associated with its ability to mediate the level of cAMP and inhibit the production of IL-1, TNFalpha, IL-6 and PGE(2) from activated synoviocytes.


Postoperative Load Bearing in Periprosthetic Femoral Fractures Around Hip Arthroplasty: A Survey Among Orthopedic Surgeons in the Netherlands.
Permissive weight bearing (PWB) has relatively recently been implemented to optimize rapid clinical recovery and restoration of function in patients suffering lower extremity fractures. PWB shows outcome advantages in this patient category. Currently, there are no decisive recommendations on postoperative load-bearing management after surgically treated periprosthetic femoral fractures (PPFF) around hip arthroplasty. The objective is to investigate the current postoperative practice of weight-bearing instructions for patients with surgically treated PPFF, accounting for differences in types of periprosthetic fractures and treatment options among Dutch orthopedic surgeons. An online survey was distributed among the members of the hip and trauma working groups of the Dutch Orthopedic Association. The response rate was 13% (n=75). The main finding was that postoperative load bearing regimes in Vancouver A, B, and C PPFFs differed greatly among Dutch orthopedic surgeons, and there was no decisive guideline or consensus in postoperative load bearing regimes after surgically treated PPFF was used in the Netherlands. In the absence of decisive guidelines or consensus, more research is needed to explore the efficacy of PWB after surgically treated PPFF.


Is prevention of suicide worth less? A comparison of the value per statistical life.
This paper compares the value per statistical life (VSL) in the context of suicide prevention to that of prevention of traffic fatalities. We conducted a contingent valuation survey with questions on willingness to pay (WTP) in both contexts by administering a web questionnaire to 1038 individuals aged 18 to 80. We conjectured that WTP for a given impact on the number of fatalities would be lower for suicide prevention because suicide, at least to some degree, is the result of individuals' own decisions. However, this hypothesis was not supported by the within- or between-sample estimates of WTP or by responses to direct questions. Hence, no support is provided for the use of a lower valuation of the impact of suicide prevention than for risk-reducing programs in other fields, such as traffic safety. This implies that the same VSL should be used for evaluating suicide prevention interventions and for risk-reducing programs in other policy areas and funds for the prevention of fatalities should be directed to the area with the lowest cost per life saved.


Endoscopic tattoo: the importance and need for standardised guidelines and protocol.
Preoperative endoscopic tattoo is becoming more important with the advent of minimally invasive surgery. Current practices are variable and are operator-dependent. There are no evidence-based guidelines to aid endoscopists in clinical practice. Furthermore, there are still a number of issues with endoscopic tattoo including poor intraoperative visualisation, complications from tattooing and inaccurate documentation leading to the need for intraoperative endoscopy, prolonged operative time and reoperation due to lack of oncologic resection. This review aims to collate and summarise evidence for the best practice of endoscopic tattoo for colorectal lesions in order to provide guidance for endoscopists.


Role of intracellular infections in premature childbirth.
Vaginal Smear taken by sterile Folkman spoon from 15 women with premature birth was studied. The study was performed by the direct immune fluorescence method with the luminescence microscope. We aimed to study the effect of intracellular infections: ureaplasma urealitikum, mycoplasma hominis, Chlamydia trachomatis, herpes simplex virus of I and II type and cytomegalovirus. Intracellular infections were detected in at about 82% of cases, which included mono infections with cytomegalovirus and in 9 cases in the form of bi-component associations. The obtained results may be interesting from the etiologic point of view of premature births in Georgian population.


Group A Streptococcus pharyngitis and pharyngeal carriage: A meta-analysis.
Antibiotic treatment of Group A Streptococcus (GAS) pharyngitis is important in acute rheumatic fever (ARF) prevention, however clinical guidelines for prescription vary. GAS carriers with acute viral infections may receive antibiotics unnecessarily. This review assessed the prevalence of GAS pharyngitis and carriage in different settings. A random-effects meta-analysis was performed. Prevalence estimates for GAS+ve pharyngitis, serologically-confirmed GAS pharyngitis and asymptomatic pharyngeal carriage were generated. Findings were stratified by age group, recruitment method and country income level. Medline and EMBASE databases were searched for relevant literature published between 1 January 1946 and 7 April 2017. Studies reporting prevalence data on GAS+ve or serologically-confirmed GAS pharyngitis that stated participants exhibited symptoms of pharyngitis or upper respiratory tract infection (URTI) were included. Included studies reporting the prevalence of asymptomatic GAS carriage needed to state participants were asymptomatic. 285 eligible studies were identified. The prevalence of GAS+ve pharyngitis was 24.1% (95% CI: 22.6-25.6%) in clinical settings (which used 'passive recruitment' methods), but less in sore throat management programmes (which used 'active recruitment', 10.0%, 8.1-12.4%). GAS+ve pharyngitis was more prevalent in high-income countries (24.3%, 22.6-26.1%) compared with low/middle-income countries (17.6%, 14.9-20.7%). In clinical settings, approximately 10% of children swabbed with a sore throat have serologically-confirmed GAS pharyngitis, but this increases to around 50-60% when the child is GAS culture-positive. The prevalence of serologically-confirmed GAS pharyngitis was 10.3% (6.6-15.7%) in children from high-income countries and their asymptomatic GAS carriage prevalence was 10.5% (8.4-12.9%). A lower carriage prevalence was detected in children from low/middle income countries (5.9%, 4.3-8.1%). In active sore throat management programmes, if the prevalence of GAS detection approaches the asymptomatic carriage rate (around 6-11%), there may be little benefit from antibiotic treatment as the majority of culture-positive patients are likely carriers.


Bioactive Segetane, Ingenane, and Jatrophane Diterpenes from Euphorbia taurinensis.
A novel segetane (1: ) and jatrophane diterpene (2: ), together with five known diterpenoids possessing segetane (3: ), jatrophane (4: ), and ingenane skeletons (5 - 7: ), were isolated from the methanol extract of Euphorbia taurinensis All. The structure elucidation of the compounds was performed by means of extensive spectroscopic analysis, including HRESIMS and 1D (1H, J-modulated spin-echo carbon experiment) and 2D (HSQC, HMBC, COSY, NOESY) NMR experiments. The multidrug resistance reversing and cytotoxic effects of five diterpenes (1, 4: - 7: ) were studied on the L5178 mouse lymphoma cell line using rhodamine 123 accumulation and the MTT cell viability assay. Segetane and jatrophane diterpenes had no cytotoxic activity on the sensitive parent and multidrug resistance cells, while ingenane diterpenes showed a cytotoxic effect on both cell lines. Ingenanes 6: and 7: and segetane 1: demonstrated the remarkable multidrug resistance modulating effect at 20 µM.


High molecular weight opioid-containing proteins in striatum.
Striatal extracts of guinea pigs, rats, and cattle were found to contain two large proteins (greater than 40,000 and greater than 100,000 daltons) that on treatment with trypsin yield opioid peptides differing chromatographically from the opioid nonapeptide generated by trypsin digestion of endorphins, beta-lipotropin, or pro-opiocortin. Furthermore, the large opioid proteins found in the pituitary do not appear to be present in the striatum. These and other findings indicate that the striatal enkephalins are produced via a pathway from the one deduced from studies on the pituitary.


"When I was no longer able to see and walk, that is when I was affected most": experiences of disability in people living with HIV in South Africa.
HIV-related disability is an emerging issue in countries where HIV is endemic. This study aimed to understand experiences of disability in patients living with HIV in South Africa using the International Classification of Functioning, Disability and Health (ICF) as a guiding framework. In-depth interviews were conducted with 19 HIV-positive people receiving ART through a public hospital in KwaZulu-Natal. Data were analyzed using collaborative qualitative content analysis. Participants described a variety of impairments related to mental, sensory, neuromusculoskeletal, skin, cardiovascular, digestive or reproductive systems. A tenuous relationship was evident between HIV and mental health impairments and the experience of other disabilities. Impairments affected participants' activity levels, especially mobility, domestic life, self-care and ability to work. Activity limitations affecting livelihood were often of more concern to participants than the impairments. Furthermore, women and men appeared to experience disability related to activities relevant to gendered norms in their cultural context. More understanding of the intersections among HIV, disability, gender and livelihood is needed. To respond to the increased need to manage disability within HIV care in Africa, HIV programs should include rehabilitative approaches, address concerns related to livelihoods in households with disability and consider gender differences in the experience of disability. HIV, its opportunistic infections and the treatments associated to them are related to health conditions and impairments that have the potential to develop into disability. Rehabilitation professionals in HIV endemic countries have therefore a larger and changing number of people living with HIV and need to consider the impact of the disease on the rehabilitation process. Mental health issues and disability might be interrelated and affect antiretroviral treatment (ART) adherence. Hence, rehabilitation has to use a holistic approach and integrate different therapy approaches (e.g. physiotherapy and mental health). The experience of living with HIV and developing disability has unreflected gender dynamics that need to be considered in rehabilitative care. Hence, the rehabilitation process has to consider the cultural realities and gendered experience of the condition. The study highlights the interrelationship between disability levels, the influence of environmental and social factors, and the changing experience related to gender. Hence, rehabilitation professionals in resource-poor settings have to go beyond the clinical response and therapy approaches in order to improve the activity and participation of people with disabilities and those living with HIV in their homes and communities. Community or home-based care might be avenues to further explore.


Constituent ratio of motor fibers from the C5-C7 spinal nerves in the radial nerve is greater in pup rats than in adult rats.
Clinically, injuries of C5-C7 of the brachial plexus cause falling of the wrist and fingers in infants but not in adults unless 4 consecutive spinal nerves are injured. The purpose of this study was to compare the constituent difference of spinal nerves in the radial nerve between pup and adult rats.A group of 16 pup rats and a group of 16 adult rats were each divided into 2 groups of 8 (P1 and A1 groups, C5-C6 were divided; P2 and A2 groups, C5-C7 were divided]). A nerve conduction study and histological examination were performed to evaluate radial nerve innervation to the extensor digitorum communis muscle after dividing the spinal nerves. Retrograde tracing with 5% cholera toxin B for anterior horn motoneurons of the spinal cord innervating the radial nerve was performed in 8 pup rats and 8 adult rats. Results showed that the division of C5-C7 caused more significant damage to radial nerve innervation to the extensor digitorum communis in pups than in adults, although the division of C5-C6 did not. In pups, the percentages (median with interquartile) of anterior horn motoneurons of the spinal cord innervating the radial nerve were 36.4 (28.3-38.5) in C5-C6, 28.1 (24.5-32.5) in C7, and 37.5 (36.5-39.3) in C8-T1. In adults, they were 24.2 (23.6-27.8) in C5-C6, 21.8 (19.5-26.3) in C7, and 50.7 (48.7-55.5) C8-T1.This study implies that C7 innervation in the radial nerve in humans may be more critical to the function of this nerve in infants than in adults.


One size (doesn't) fit all: new metaphors for and practices of scaling from indigenous peoples of the Northwest Amazon.
Ten years of field research and collaborative development of programs for early childhood in the Upper Rio Negro region of the Amazon provide the authors with new metaphors for achieving wider social impact and new frames to add to the international debate on 'scaling' social change initiatives. Using anthropology and ethno-ontology to think questions of universal and particular, center and periphery, the article reflects on the dangers of monolithic scaling to cultural diversity and future innovation. Instead of the metaphor of scaling - adopted in the discourse of public policy and international development from the Fordist or Taylorist efficiency of the economy of scale - indigenous people speak of exchange, sharing, and transformation. These ideas seek to connect local and decolonized models and value the diversity of local knowledges, epistemologies, and practices around early childhood development. Based on the expansion of the CanalCanoa project among diverse indigenous communities, the paper proposes a flexible and bottom-up model of achieving impact at scale through empowering local actors to teach each other and establish local criteria of learning and evaluation.


Interactions of spin waves with a magnetic vortex.
We have investigated azimuthal spin-wave modes in magnetic vortex structures using time-resolved Kerr microscopy. Spatially resolved phase and amplitude spectra of ferromagnetic disks with diameters from 5 microm down to 500 nm reveal that the lowest order azimuthal spin-wave mode splits into a doublet as the disk size decreases. We demonstrate that the splitting is due to the coupling between spin waves and the gyrotropic motion of the vortex core.


Endothelin 1 impairs oxygen delivery in livers from LPS-primed animals.
Endothelin 1 (ET-1) is a potent vasoactive peptide that acts at sinusoidal and extrasinusoidal sites in the liver. Sensitivity to ET-1 increases in LPS-primed animals and is associated with impaired liver microcirculation in these animals. We hypothesized that LPS priming leads to an exacerbation in the impaired oxygen delivery in response to intraportal infusion of ET-1. Rats were studied 24 h after LPS injection (1 mg/kg, i.p.). Surface PO2 was determined using a recently developed technology of O2 mapping. The baseline portal pressure was higher in LPS-primed animals (P < 0.05), and increased to'similar magnitude as sham animals after a 10-min infusion of ET-1. The resultant portal pressure remained elevated in LPS compared to sham animals. There was no significant difference in baseline mean arterial pressure, and no significant systemic response to ET-1 in either group. In contrast to the macrohemodynamic, the decrease in tissue surface PO2 in response to ET-1 infusion was potentiated by LPS treatment (increased from baseline levels 33.8+/-9 to 46.8+/-8.3 in sham; 42.3+/-9.1 to 69+/-6.5 gray scale units in LPS; P < 0.01, sham vs. LPS) at end of infusion of ET-1 for 10 min. This indicates tissue hypoxia in response to ET-1, which is exacerbated in livers from LPS-primed animals compared to sham. Frequency distribution analysis showed a shift in mode from lower intensity (higher PO2) to areas with higher fluorescent intensity ranges (lower PO2), indicating areas with shut down in perfusion in LPS-treated animals. In the whole liver, ET-1 suppressed oxygen consumption, and this response was potentiated by LPS pretreatment. We propose that ET-1 impairs oxygen delivery in the liver during endotoxemia, resulting in areas of focal hypoxia. This response is possibly due to potentiated action of ET-1 at both sinusoidal and extrasinusoidal sites in the liver during endotoxemia.


The effect of past and current dietary Zn intake on Zn absorption and endogenous excretion in the rat.
Effects of previous dietary Zn (or body Zn stores) and current dietary Zn intake on absorption and endogenous excretion of Zn were studied by using radioisotope dilution. Rats were fed diets containing 1.5, 12.6 or 50.3 mg Zn/kg for 19 d (dietary period I). Total body Zn in the three groups was 1870 +/- 340, 3953 +/- 698 and 4126 +/- 844 micrograms Zn/rat. Each group was divided into four subgroups fed 3.6, 12.6, 20.5 or 50.3 mg Zn/kg diet for 3 wk (dietary period II). Rats were injected intramuscularly with 65Zn after 7 d of dietary period II. True absorption and endogenous excretion were calculated by isotope dilution. Zinc intake, urinary and fecal excretion, balance and percent Zn absorption were significantly affected only by dietary Zn in dietary period II (P less than 0.01). Endogenous excretion was affected by both past dietary Zn deficiency (body Zn stores) and by dietary Zn in dietary period II (P = 0.0001). Total body Zn at the end of the experiment was significantly affected by both periods of dietary treatment (P less than 0.001), but total body Zn concentration was affected only by the final dietary treatment (P less than 0.05). These results show that Zn absorption is affected by the current diet, but that turnover of Zn (endogenous excretion) is regulated by both current Zn intake and past Zn intake, probably through an effect on body Zn stores.


First Reported Case of Dulaglutide-Induced Acute Pancreatitis With Normal Serum Lipase Level.
Dulaglutide is being extensively used for non-insulin-dependent diabetes mellitus and congestive heart failure and is also being used as an off-label weight loss aid. Due to its wide use, we had to shed some light on this rare finding of normal lipase level in a patient with signs and symptoms suggestive of acute pancreatitis. A high index of clinical suspicion for acute pancreatitis despite normal lipase should warrant a low threshold for radiological imaging to rule it out.


Health-related knowledge on hypertension among the Portuguese population: results from a population-based survey.
Adequate knowledge on hypertension has been shown to improve awareness, adherence to treatment and control of the disease. We aimed to estimate the health-related knowledge about hypertension among the Portuguese population. A representative sample of Portuguese-speaking dwellers in mainland Portugal (n = 1624), aged 16 to 79 years, was evaluated through face-to-face interviews conducted using a structured questionnaire. Health literacy was evaluated using the instrument Newest Vital Sign. The mean prevalence of hypertension in the Portuguese population estimated by the participants in this study was 45.4%. Salt intake and poor diet were reported as main causes of hypertension by 27.5% and 21.5% of the participants, respectively, whereas more than 85% acknowledged myocardial infarction and stroke as its main consequences. However, 31.2% of the participants were not able to identify a cause for high blood pressure, especially the older and those with worse scores for health literacy. The accurate interpretation of blood pressure values diminished with the increase of systolic and diastolic blood pressure figures provided as examples for interpretation, from approximately 80% for 95/60 mmHg to 50% for 180/100 mmHg. Women and participants with greater levels of education or a previous diagnosis of hypertension tended to interpret blood pressure values correctly more often. This study provided a quantitative estimate of the gaps in health-related knowledge about hypertension among the general population. Understanding the barriers that hinder the achievement of health-related knowledge on hypertension is expected to contribute for the global improvement of prevention and management of hypertension.


Tooth dimensions in hypodontia patients, their unaffected relatives and a control group measured by a new image analysis system.
Tooth dimensions were compared between index patients with severe hypodontia (six or more congenitally missing teeth), their relatives with a full complement of teeth, and a control group. The groups consisted of 12 index cases (seven females and five males), 21 relatives without hypodontia (13 females and eight males), and a control group of 10 males and 10 females with complete dentitions, and no family history of hypodontia. All formed teeth were imaged buccally and occlusally from study models, with a digital camera linked to a computer. The images were acquired and measured using Adobe Photoshop and Image Pro Plus, respectively. Mesiodistal, buccolingual, or occlusogingival area and perimeter measurements were determined from each image. In the index hypodontia group tooth dimensions were significantly smaller (P < 0.001, Bonferroni corrected level) for maxillary and mandibular canines, and first premolars for all dimensions from the buccal view, and for maxillary and mandibular canines and first premolars, maxillary central incisors, maxillary first molars, mandibular lateral incisors, and mandibular second premolars for all dimensions from the occlusal view. In the relatives without hypodontia compared with the control group, mesiodistal dimensions from the buccal view were significantly smaller (P < 0.001) for the central incisors and maxillary first and second premolars, and for the maxillary and mandibular first premolars for all dimensions from the occlusal view. There was a trend for the tooth dimensions of all teeth in the index group to be smaller compared with the control group. The tooth dimensions of the relatives without hypodontia also tended to be smaller than the control group, but were larger than those of the index cases.


Visualization of polymer chain conformations in amorphous polyisocyanide Langmuir-Blodgett films by atomic force microscopy.
Polymer Langmuir monolayers are an ideal model for two-dimensional (2D) polymer chains, but our understanding of them is still limited. Using atomic force microscopy, we have for the first time successfully visualized the polymer chain packings in amorphous polyisocyanide monolayers deposited on mica. The long polymer chains, which were partially forced to form hairpin-like conformations, were sophisticatedly packed in the 2D film without any chain stacking. The trend of the persistent lengths of the polymers in the 2D films fairly corresponded to those of 3D chains in solution. The molecular-level information provided by direct observations such as these will improve our understanding of polymers in 2D space.


Endocrine-specific NIR fluorophores for adrenal gland targeting.
The adrenal glands (AGs) are relatively small yet require definitive identification during their resection, or more commonly their avoidance. To enable image-guided surgery involving the AGs, we have developed novel near-infrared (NIR) fluorophores that target the AGs after a single intravenous injection, which provided dual-NIR image-guided resection or avoidance of the AGs during both open and minimally-invasive surgery.


Radiotherapy-induced mesorectum alterations: histological evaluation of 90 consecutive cases.
In order to identify the radiotherapy-induced histological modifications in the mesorectum, we reviewed the surgical specimens of 90 rectal resections comprehensive of the total mesorectal excision (23 cases radiologically classified as cT2N0M0 and 67 as cT3N0M0). All patients were preoperative treated with radiotherapy: 20 with 50 Gy, 20 with 20 Gy and 50 Gy irradiation associated to FOLFOX scheme chemotherapy. Routine hematoxylin and eosin stained serial slides at 5 mm of intervals were obtained from surgical specimens and included the tumor site and the adjacent irradiated mucosa, the submucosa and the muscular layers of the rectal wall and the mesorectal adipose tissue, completely removed until to the mesorectal fascia. Ten subjects (eight cT2N0M0 and two cT3N0M0), who did not received preoperative oncological treatments were adopted as controls. Histologically, examination revealed fibrosis of the adipose tissue in 86 cases (95%), vascular damage including vasculities and fibrotic thickening wall of arteries and veins in 46 cases (51%), sclero-hyalinosis of lymph nodes with pericapsular fibrosis in 22 cases (23%) and perineural deposition of fibrosis in 12 (13%). These findings were ubiquitously observed in the whole mesorectum. Fibrosis of the adipose tissue and vasculitis were mainly associated to the combination of 50 Gy radiations plus chemotherapy (p < 0.05). The detection of histopathological alterations in the mesorectum can give reason of the well-known postoperative complications and long-term sequels.


[Giant non-functioning adrenocortical carcinoma effectively treated with preoperative transarterial embolization: a case report].
An 80-year-old women consulted a physician because of weight loss and slight fever. Since a large retroperitoneal tumor was found, the patient was referred to our hospital. Based on abdominal computed tomography, magnetic resonance imaging and blood tests, preoperative diagnosis was non-functioning left adrenal tumor, 13 cm in diameter. Preoperative abdominal angiography revealed that the tumor was supplied blood by the left adrenal artery, left renal artery through left renal upper segment, splenic artery, pancreas tail artery, and middle colic artery. We performed transcatheter arterial embolization (TAE) of some of these tumor-supplying vessels. Three days after the TAE, adrenalectomy was performed without blood transfusion. Histopathological examination of the tumor was adrenocortical carcinoma of low grade malignancy.


Bone ingrowth into dynamically loaded porous-coated intramedullary nails.
Research to determine whether porous-coated Vitallium intramedullary rods could be used to bridge segmental defects in long bones was performed using rabbit tibias as a suitable model for human bone growth. One-centimeter segments of the midshaft of tibias of mature rabbits were removed surgically and replaced with equal-sized segments of Silastic tubing to maintain leg length. A coated rod was inserted through the proximal tibial segment, through the tubing, and into the distal bone segment. The legs were taken out of plaster at 3 weeks, and x-rays were taken periodically until sacrifice. At sacrifice, 30 weeks postoperatively, the mechanical properties of both tibias from each rabbit were measured destructively in a torsional testing machine. The load at failure of the tibia with the segmental defect averaged 90% of the contralateral control tibia. Rod pullout data and electron-probe x-ray micro-analysis indicated that a substantial rod-endosteal bone bond existed due to ingrowth into the porous coating. The torsional data may have been somewhat obscured by the presence of bony callus which grew over the Silastic tubing and bridged the segmental defect exosteally in every case.


Immunocytochemical Labeling of Rhabdomeric Proteins in Drosophila Photoreceptor Cells Is Compromised by a Light-dependent Technical Artifact.
Drosophila photoreceptor cells are employed as a model system for studying membrane protein transport. Phototransduction proteins like rhodopsin and the light-activated TRPL ion channel are transported within the photoreceptor cell, and they change their subcellular distribution in a light-dependent way. Investigating the transport mechanisms for rhodopsin and ion channels requires accurate histochemical methods for protein localization. By using immunocytochemistry the light-triggered translocation of TRPL has been described as a two-stage process. In stage 1, TRPL accumulates at the rhabdomere base and the adjacent stalk membrane a few minutes after onset of illumination and is internalized in stage 2 by endocytosis after prolonged light exposure. Here, we show that a commonly observed crescent shaped antibody labeling pattern suggesting a fast translocation of rhodopsin, TRP, and TRPL to the rhabdomere base is a light-dependent antibody staining artifact. This artifact is most probably caused by the profound structural changes in the microvillar membranes of rhabdomeres that result from activation of the signaling cascade. By using alternative labeling methods, either eGFP-tags or the self-labeling SNAP-tag, we show that light activation of TRPL transport indeed results in fast changes of the TRPL distribution in the rhabdomere but not in the way described previously.


Childhood encephalitis in Crete, Greece.
This study included all 18 cases of children hospitalized for encephalitis in the referral university hospital of Heraklion, Crete, Greece, during the 5-year period from 2000 to 2004. Encephalitis was attributed to viral infection (echovirus, herpes simplex virus 1, varicella-zoster virus, cytomegalovirus, and influenza A) in eight children and to bacteria (Mycoplasma pneumoniae, group A beta-hemolytic streptococcus, and Rickettsia typhi) in a further five cases. Multiple hyperintense brain lesions on magnetic resonance imaging (MRI) were associated with a severe clinical presentation but not with a guarded long-term outcome. Five children still presented with mild to moderate sequelae after 1.5 to 5.3 (median 4.0) years. Our findings confirm the elimination of measles, mumps, and rubella-associated encephalitis in the postvaccine era. MRI appeared to be of great diagnostic value. Although no fatalities were observed, deficits did persist in several patients.


Synthesis of (-)-oxycodone.
Our novel synthetic route to (-)-oxycodone, a semisynthetic opioid analgesic, features a palladium-catalyzed direct intramolecular arylation of an aryl bromide, oxidative dearomatization of a dihydrophenanthrenol, formation of a benzylic quaternary carbon by an intramolecular Michael addition of a malonate moiety, and construction of the morphinan skeleton via a Hofmann rearrangement/lactamization cascade.


Scanning molecular sieve chromatography of interacting protein systems. III. Effect of kinetic parameters on the large zone boundary profiles for local equilibration between mobile and stationary phases.
Large zone reaction boundary profiles for molecular sieve chromatography as affected by kinetic parameters have been simulated for local equilibration between the mobile and stationary phases. Our studies of monomer-dimer and monomer-tetramer systems indicate that in a slowly equilibrating system, the kinetic controls operating between the mobile and stationary phases contribute most significantly to the overall boundary profile. In a rapidly equilibrating system, however, the kinetic parameters k(ij) and k(ji) operating in the mobile phase are the principal determinants of the reaction boundary, while the kinetic effects of k(ii) and k-(ii) between the mobile and stationary phases are minimal.


Nuclear, Chloroplast, and Mitochondrial Genome Sequences of the Prospective Microalgal Biofuel Strain Picochlorum soloecismus.
Picochlorum soloecismus is a halotolerant, fast-growing, and moderate-lipid-producing microalga that is being evaluated as a renewable feedstock for biofuel production. Herein, we report on an improved high-quality draft assembly and annotation for the nuclear, chloroplast, and mitochondrial genomes of P. soloecismus DOE 101.


NLRC5 interacts with RIG-I to induce a robust antiviral response against influenza virus infection.
The NLR protein, NLRC5 is an important regulator of MHC class I gene expression, however, the role of NLRC5 in other innate immune responses is less well defined. In the present study, we report that NLRC5 binds RIG-I and that this interaction is critical for robust antiviral responses against influenza virus. Overexpression of NLRC5 in the human lung epithelial cell line, A549, and normal human bronchial epithelial cells resulted in impaired replication of influenza virus A/Puerto Rico/8/34 virus (PR8) and enhanced IFN-β expression. Influenza virus leads to induction of IFN-β that drives RIG-I and NLRC5 expression in host cells. Our results suggest that NLRC5 extends and stabilizes influenza virus induced RIG-I expression and delays expression of the viral inhibitor protein NS1. We show that NS1 binds to NLRC5 to suppress its function. Interaction domain mapping revealed that NLRC5 interacts with RIG-I via its N-terminal death domain and that NLRC5 enhanced antiviral activity in an leucine-rich repeat domain independent manner. Taken together, our findings identify a novel role for NLRC5 in RIG-I-mediated antiviral host responses against influenza virus infection, distinguished from the role of NLRC5 in MHC class I gene regulation.


The Occurrence of Some Nonblood Protozoan Parasites in Wild and Domestic Mammals in South Africa.
Relatively little is known about protozoan parasites in African animals. Here we investigated the occurrence of protozoan parasites in mammals from South Africa. Oocysts of protozoan parasites were detected in 13 of 56 (23%) fecal samples using conventional microscopic examination methods. Cryptosporidium spp. and Cystoisospora spp. were detected in eight (14%) and five (9%) samples, respectively. Mixed parasitic infection of Cryptosporidium spp. and Cystoisospora spp. was recorded in banded mongoose ( Mungos mungo). Cryptosporidium spp. was detected for the first time in cheetah ( Acinonyx jubatus), spotted hyena ( Crocuta crocuta), and African polecat ( Ictonyx striatus). Antibodies to Toxoplasma gondii and Neospora caninum were not detected by enzyme-linked immunosorbent assay in any of 32 sera tested. We detected T. gondii by PCR in tissues of five of 243 (2%) animals: domestic dog ( Canis lupus familiaris), gerbil ( Gerbilliscus spp.), greater kudu ( Tragelaphus strepsiceros), honey badger ( Mellivora capensis), and white-tailed mongoose ( Ichneumia albicauda). Our isolation of T. gondii from white-tailed mongoose and honey badger was a unique finding. All tissue samples were negative for N. caninum. The study increases our knowledge on the occurrence of protozoan parasites in populations of wild and domestic animals in South Africa.


X-linked female band heterotopia-male lissencephaly syndrome.
We report a family with band heterotopia in a mother and daughter and lissencephaly in a son (X-linked inheritance pattern). Postmortem examination of the boy revealed classical lissencephaly and, among other findings, simplified and discontinuous inferior olives without inferior olivary heterotopia. The absence of inferior olivary heterotopia may distinguish X-linked lissencephaly from other conditions with classic lissencephaly such as Miller-Dieker syndrome.


Exposure to maternal odor enhances intake of a taste that mimicks the sensory attributes of ethanol.
Early exposure to ethanol increases subsequent acceptance of this drug. Little attention, however, has been devoted to the interaction of the taste of the drug with other, familiar or non-familiar, odors contingent with ethanol access, particularly early in ontogeny. This study assessed the influence of exposure to maternal odor on intake and grasp responses to an artificial nipple providing a solution (a sucrose-quinine mix) that emulates the taste of alcohol, in 4-day-old rat pups. The results showed that the mother's odor enhanced intake from and seeking responses to an artificial nipple that provided the solution that mimicked the taste of alcohol (Experiment 1). This pattern of results was not evoked by the odor of an unrelated dam (Experiment 2), nor was it observed when the nipple delivered water. The main new finding of the present study is that 4-day-old rats tested in the presence of the mother (and hence exposed to her odor cues) exhibited enhanced seeking and intake of a solution that mimics the chemosensory properties of ethanol.


Geometrical optics, electrostatics, and nanophotonic resonances in absorbing nanowire arrays.
Semiconductor nanowire arrays have shown promise for next-generation photovoltaics and photodetection, but enhanced understanding of the light-nanowire interaction is still needed. Here, we study theoretically the absorption of light in an array of vertical InP nanowires by moving continuously, first from the electrostatic limit to the nanophotonic regime and then to the geometrical optics limit. We show how the absorption per volume of semiconductor material in the array can be varied by a factor of 200, ranging from 10 times weaker to 20 times stronger than in a bulk semiconductor sample.


Biomarkers for psoriasis skin lesions.
Psoriasis is a common, chronic skin disease, whose diagnosis is based mainly on clinical features but, in some cases, can be difficult. As the exact diagnosis of psoriasis and the differential diagnosis with other diseases are crucial for the therapeutic choice, several studies investigated the relevance of some genes and proteins as potential specific skin biomarkers. Despite a large number of reports, none of them has been tested in large studies and thus achieved regulatory approval and clinical application. Authors give an overview on the skin biomarkers (BMs) in psoriasis, distinguishing inflammatory and epidermal biomarkers, highlighting the most distinctive skin psoriasis BMs, that can help physicians and pathologists to recognize psoriasis among "psoriasiform dermatitis".


Dabigatran-Associated Intracranial Hemorrhage: Literature Review and Institutional Experience.
Dabigatran etexilate is an oral direct thrombin inhibitor approved for prevention of stroke and systemic embolization in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. Although dabigatran has a favorable safety profile, predictable pharmacokinetics, fewer drug interactions than warfarin, and does not require monitoring, clinical data regarding dabigatran reversal are limited. In addition, currently available laboratory assays allow measurement of the presence, but not extent, of dabigatran-associated anticoagulation. Patient age, renal function, weight, concurrent drug therapy, adherence, and concomitant disease states can affect dabigatran's efficacy and safety. Management of dabigatran-related intracranial hemorrhage must be approached on a case-by-case basis and include assessment of degree of anticoagulation, severity of hemorrhage, renal function, timing of last dabigatran dose, and risk of thromboembolic events. Initial management includes dabigatran discontinuation and general supportive measures. Oral activated charcoal should be administered in those who ingested dabigatran within 2 hours. Four-factor prothrombin complex concentrates (4PCCs), activated PCC, or recombinant activated factor VII use may be reasonable but is not evidence based. Reserve fresh frozen plasma for patients with dilutional coagulopathy. If readily available, hemodialysis should be considered, particularly in patients with advanced kidney injury or excessive risk of thromboembolic events. More clinical studies are needed to determine a standardized approach to treating dabigatran-associated intracranial hemorrhage. Institutional protocol development will facilitate safe, efficacious, and timely use of the limited management options.


Get the most from your data: a propensity score model comparison on real-life data.
In the past, the propensity score has been in the middle of several discussions in terms of its abilities and limitations. With a comprehensive review and a practical example, this study examines the effect of propensity score analysis of real-life data and introduces a simple and effective clinical approach. After the authors reviewed current publications, they applied their insights to the data of a nonrandomized clinical trial in bariatric surgery. This study examined weight loss in 173 patients where 127 patients received Roux-en-Y gastric bypass surgery and 46 patients sleeve gastrectomy. Both groups underwent analysis in terms of their covariate distribution using Mann-Whitney U and χ (2) testing. Mean differences within excess weight loss in native data were examined with Student's t-test. Three propensity score models were defined and matching was performed. Covariate distribution and mean differences in excess weight loss were checked with Mann-Whitney U and χ (2) testing. Native data implied a significant difference in excess weight loss. The propensity score models did not confirm this difference. All models proved that both surgical procedures were equal, due to their weight-loss induction. Covariate distribution improved after the matching procedure in terms of an equal distribution. It seemed that a practical clinical approach with outcome-related covariates as a propensity score base is the ideal midpoint between an equal distribution in covariates and an acceptable loss of data. Nevertheless, propensity score models designed with clinical intent seemed to be absolutely suitable for overcoming heterogeneity in covariate distribution.


Structural Changes Following Velopharyngeal Resistance Training (Continuous Positive Airway Pressure Therapy): A Preliminary Report.
To evaluate the feasibility/effectiveness of using magnetic resonance imaging (MRI) to document velopharyngeal (VP) structural changes induced by continuous positive airway pressure (CPAP) therapy. Changes in velar length and thickness, levator veli palatini (LVP) length and thickness, velar volume, and intravelar muscular proportion along the course of CPAP therapy participation (Pre-CPAP, Post-CPAP, and withdrawal). Velar and LVP lengths remained nearly the same, with the median changes (Δ) less than 0.6%, across repeated conditions. Although varying in magnitudes of change, median velar volume (Δ4%), velar thickness (Δ20%), LVP thickness (Δ17%), and intravelar muscular proportion (Δ10%) illustrated a consistent pattern of increases following the 8-week CPAP therapy. These VP structural measurements slightly decreased but remained above the pretraining condition after 8-week detraining. This report successfully demonstrated that MRI is a viable tool to document CPAP therapy-induced VP structural changes while providing preliminary empirical data.


Fixed-Dose Triple Combination of Antihypertensive Drugs Improves Blood Pressure Control: From Clinical Trials to Clinical Practice.
Blood pressure (BP) control is the main clinical goal in the management of hypertensive patients; however, BP in most of these patients remains uncontrolled, despite the widespread availability of antihypertensive drugs as free-combination therapy. This study compared the efficacy of a fixed-dose triple combination (FDTC) of antihypertensive drugs with that of a free combination of three antihypertensives in patients with uncontrolled hypertension. Ninety-two patients (mean age 60.8 ± 12.1, 58.0% male) with uncontrolled essential hypertension (office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg) previously treated with a renin-angiotensin-aldosterone system (RAAS) inhibitor plus hydrochlorothiazide were switched to once-daily FDTC therapy with perindopril/indapamide/amlodipine (5-10/1.25-2.5/5-10 mg). Patients were age- and sex-matched with a control group of hypertensive patients receiving free-combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-h ambulatory BP monitoring (ABPM) were evaluated at baseline and after 1 and 4 months. Significant reductions in ambulatory 24-h, daytime, and nighttime systolic BP, and pulse pressure (PP) were found in the FDTC group relative to reductions seen with free-combination therapy, after the first month only of follow-up. Target BP values (mean 24-h ambulatory systolic/diastolic BP < 130/80 mmHg) were reached by more recipients of FDTC than free-combination therapy (64.8% vs. 46.9%, p < 0.05) at month 4 of follow-up, despite reductions in 24-h ABPM values from baseline being similar in both groups at this time point. FDTC of perindopril/indapamide/amlodipine was effective at reducing SBP and PP in previously treated patients with uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the free-combination of a RAAS inhibitor, a diuretic, and a calcium antagonist.


Assessing the Antiproliferative Potential of a Novel Combretastatin A4 Derivative via Modulating Apoptosis, MAPK/ERK and PI3K/AKT Pathways in Human Breast Cancer Cells.
Breast cancer is the most predominant tumor in women. Even though current medications for distinct breast cancer subtypes are available, the non-specificity of chemotherapeutics and chemoresistance imposes major obstacles in breast cancer treatment. Although combretastatin A-4 (CA-4) has been well-reported to have potential anticancer activity, in vivo studies of CA-4 reveal a decrease in its activity. In this respect, a series of CA-4 analogues have been designed, from which one analog [(1-(3-chloro-4-fluorophenyl)-N-(2methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide, C25H22ClFN4O5] showed drastic cytotoxicity against breast cancer cells. Therefore, this research focused on investigating the in vitro molecular mechanism underlying the cytotoxicity of the CA-4 analogue, particularly the MAPK/ERK as well as PI3K/AKT pathways as attractive therapeutic targets in breast cancer. The cell viability of MCF-7, MDA-MB231, and MDA-MB453 was assessed after treatment with the CA-4 analogue, and apoptosis was analyzed via Annexin V-FITC/PI dual staining. MAPK/ERK and PI3K/AKT were thoroughly assessed using western blotting. Real-time PCR was used to estimate apoptosis-related markers, including the P53, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl2) genes. The CA-4 analogue reduced the survival of all cancerous cells in a concentration-dependent manner and induced apoptosis through the mitochondrial pathway (39.89 ± 1.5%, 32.82 ± 0.6%, and 23.77 ± 1.1% in MCF-7, MDA-MB231, and MDA-MB453 cells), respectively. The analogue also attenuated the expression of pMEK1/2/t-MEK1/2, p-ERK1/2/t-ERK1/2, p-PI3K/t-PI3K, and p-AKT/t-AKT proteins in all three cancer cell lines in a time-dependent manner. Furthermore, the CA-4 analogue upregulated the expression of the P53 gene and dramatically increased the ratio of Bax/Bcl2 genes. The enhanced cytotoxicity can be attributed to substituting the hydroxyl group in CA-4 with chlorine in the meta-position of ring B, substituting the para-methoxy group in CA-4 with fluorine in the analogue, and lastly, introducing an extension to the compound's structure (ring C). Therefore, CA-4 analogue can attenuate the proliferation of human breast cancer cells by inducing apoptosis and simultaneously suppressing the MAPK/ERK and PI3K/AKT pathways.


Recognizing and managing clinical problems in atopic dermatitis.
Atopic dermatitis is a pruritic, inflammatory cutaneous disorder found most frequently among patients with a personal or family history of atopic disease. A primary defect is found in bone marrow cells. The most consistent abnormality relates to the overproduction of IgE. Pharmacophysiologic abnormalities include abnormal vascular responses, abnormal sweating responses, and a reduced threshold for itch. In addition, seven of 12 patients with pure atopic dermatitis with no respiratory disease have an abnormal methacholine inhalation test. There is an abnormal response of leukocyte cyclic AMP to a variety of adenylate cyclase stimulants. Characteristic histological findings are interepidermal edema, called spongiosis, which is consistent with a composite of late-phase and delayed hypersensitivity. The brittle stratum corneum can be treated with hydration, a commonly neglected aspect of management. An overlooked complication is herpes simplex infection of the eye. Overall management includes stress control, treating allergenic trigger factors, topical steroids, systemic antibiotics, antihistamines, ultraviolet light, and hospitalization in severe cases.


Defective homocysteine metabolism: potential implications for skeletal muscle malfunction.
Hyperhomocysteinemia (HHcy) is a systemic medical condition and has been attributed to multi-organ pathologies. Genetic, nutritional, hormonal, age and gender differences are involved in abnormal homocysteine (Hcy) metabolism that produces HHcy. Homocysteine is an intermediate for many key processes such as cellular methylation and cellular antioxidant potential and imbalances in Hcy production and/or catabolism impacts gene expression and cell signaling including GPCR signaling. Furthermore, HHcy might damage the vagus nerve and superior cervical ganglion and affects various GPCR functions; therefore it can impair both the parasympathetic and sympathetic regulation in the blood vessels of skeletal muscle and affect long-term muscle function. Understanding cellular targets of Hcy during HHcy in different contexts and its role either as a primary risk factor or as an aggravator of certain disease conditions would provide better interventions. In this review we have provided recent Hcy mediated mechanistic insights into different diseases and presented potential implications in the context of reduced muscle function and integrity. Overall, the impact of HHcy in various skeletal muscle malfunctions is underappreciated; future studies in this area will provide deeper insights and improve our understanding of the association between HHcy and diminished physical function.


A WASp-binding type II phosphatidylinositol 4-kinase required for actin polymerization-driven endosome motility.
Endosomes in yeast have been hypothesized to move through the cytoplasm by the momentum gained after actin polymerization has driven endosome abscision from the plasma membrane. Alternatively, after abscission, ongoing actin polymerization on endosomes could power transport. Here, we tested these hypotheses by showing that the Arp2/3 complex activation domain (WCA) of Las17 (Wiskott-Aldrich syndrome protein [WASp] homologue) fused to an endocytic cargo protein (Ste2) rescued endosome motility in las17DeltaWCA mutants, and that capping actin filament barbed ends inhibited endosome motility but not endocytic internalization. Motility therefore requires continual actin polymerization on endosomes. We also explored how Las17 is regulated. Endosome motility required the Las17-binding protein Lsb6, a type II phosphatidylinositol 4-kinase. Catalytically inactive Lsb6 interacted with Las17 and promoted endosome motility. Lsb6 therefore is a novel regulator of Las17 that mediates endosome motility independent of phosphatidylinositol 4-phosphate synthesis. Mammalian type II phosphatidylinositol 4-kinases may regulate WASp proteins and endosome motility.


Inhibition of JNK aggravates the recovery of rat hearts after global ischemia: the role of mitochondrial JNK.
c-Jun N-terminal kinase (JNK), a stress-activated MAPK, is activated during cardiac ischemia-reperfusion (IR). The role of JNK inhibitors in cardioprotection against IR still remains controversial, in part, due to spill-over effects of non-specific inhibitors. In the present study, we sought to examine whether inhibition of JNK by SU3327, a specific JNK inhibitor that inhibits upstream JNK signaling rather than the kinase activity of JNK, improves cardiac function and reduces heart damage during IR. Hearts of male Sprague-Dawley rats perfused by Langendorff were subjected to 25 min of global ischemia followed by 30 min reperfusion in the presence or absence of SU3327. Cardiac function was monitored throughout the perfusion period. Myocardial damage was extrapolated from LDH activity in the coronary effluent. At the end of reperfusion, mitochondria were isolated and used to measure respiration rates and mitochondrial permeability transition pore opening. Protein analysis of mitochondria predictably revealed that SU3327 inhibited JNK phosphorylation. Although SU3327 significantly reduced cell damage during the first minutes of reperfusion, it did not improve cardiac function and, furthermore, reduced the mitochondrial respiratory control index. Interestingly, SU3327 activated the other stress-related MAPK, p38, and greatly increased its translocation to mitochondria. Mitochondrial P-JNK and P-p38 were co-immunoprecipitated with complex III of the electron transfer chain. Thus, JNK plays an essential role in cardiac signaling under both physiological and pathological conditions. Its inhibition by SU3327 during IR aggravates cardiac function. The detrimental effects of JNK inhibition are associated with reciprocal p38 activation and mitochondrial dysfunction.


Role of the cerebellum in implicit motor skill learning: a PET study.
To depict neural substrates of implicit motor learning, regional cerebral blood flow was measured using positron emission tomography (PET) in 13 volunteers in the rest condition and during performance of a unimanual two-ball rotation task. Subjects rotated two balls in a single hand; a slow rotation (0.5 Hz) was followed by two sessions requiring as rapid rotation as possible. The process was repeated four times by a single hand (Block 1) and then by the opposite hand (Block 2). One group of volunteers began with the right hand (n = 7), and the other with the left (n = 6). Performance was assessed by both quickness and efficiency of movements. The former was assessed with the maximum number of rotation per unit time, and the latter with the electromyographic activity under constant speed of the movement. Both showed learning transfer from the right hand to the left hand. Activation of cerebrum and cerebellum varied according to hand. Activation common to both hands occurred in the bilateral dorsal premotor cortex and parasagittal cerebellum, right inferior frontal gyms, left lateral cerebellum and thalamus, supplementary motor area, and cerebellar vermis. The left lateral cerebellum showed the most prominent activation on the first trial of the novel task, and hence may be related the early phase of learning, or "what to do" learning. Left parasagittal cerebellum activity diminished with training both in first and second blocks, correlating inversely with task performance. This region may therefore be involved in later learning or "how to do" learning. The activity of these regions was less prominent with prior training than without it. Thus the left cerebellar hemisphere may be related to learning transfer across hands.


Improving communication of medication changes using a pharmacist-prepared discharge medication management summary.
Background Discontinuity of care between hospital and primary care is often due to poor information transfer. Medication information in medical discharge summaries (DS) is often incomplete or incorrect. The effectiveness and feasibility of hospital pharmacists communicating medication information, including changes made in the hospital, is not clearly defined. Objective To explore the impact of a pharmacist-prepared Discharge Medication Management Summary (DMMS) on the accuracy of information about medication changes provided to patients' general practitioners (GPs). Setting Two medical wards at a major metropolitan hospital in Australia. Method An intervention was developed in which ward pharmacists communicated medication change information to GPs using the DMMS. Retrospective audits were conducted at baseline and after implementation of the DMMS to compare the accuracy of information provided by doctors and pharmacists. GPs' satisfaction with the DMMS was assessed through a faxed survey. Main outcome measure Accuracy of medication change information communicated to GPs; GP satisfaction and feasibility of a pharmacist-prepared DMMS. Results At baseline, 263/573 (45.9%) medication changes were documented by doctors in the DS. In the post-intervention audit, more medication changes were documented in the pharmacist-prepared DMMS compared to the doctor-prepared DS (72.8% vs. 31.5%; p < 0.001). Most GPs (73.3%) were satisfied with the information provided and wanted to receive the DMMS in the future. Completing the DMMS took pharmacists an average of 11.7 minutes. Conclusion The accuracy of medication information transferred upon discharge can be improved by expanding the role of hospital pharmacists to include documenting medication changes.