WDR7 up-regulation upon knocking down of neighboring non-coding RNA using siRNAs encapsulated in polyamidoamine dendrimers.
Breast cancer is the second leading cause of cancer death in females. Understanding molecular mechanisms in cancer cells compared with normal cells is crucial for diagnostic and therapeutic strategies. Long intergenic non-protein coding RNA, a regulator of reprogramming (lincRNA-RoR) is a noncoding RNA which initially was detected in induced pluripotent stem cells, and it has an important role in cell reprogramming and highly expressed in breast cancer cells. A key point in successful gene silencing is the usage of siRNA delivery system that is safe and efficient. In this study, the fifth-generation of PAMAM dendrimer is used as a nanocarrier for entering siRNA molecules for gene silencing of lincRNA-RoR. WDR7 is the gene encoding adjacent of lincRNA-RoR, which has an important role in apoptosis and cell cycle. Gel retardation assay was used to find the best Negative/Positive (N/P) molar charge ratio of siRNA- PAMAM transfected into MDA-MB 231 cells. MTT assay was performed 24 hr after transfection revealed the IC50 value (half maximal inhibitory concentrations) about 100 nanomolar for lincRNA-ROR siRNA. The lincRNA-RoR and WDR7 gene expression changes were evaluated by real-time PCR after siRNA treatment and showed an increase in the gene expression of WDR7. This study showed that PAMAM dendrimer G5/ siRNA could be a useful system delivery for future gene therapy approaches.


Trophic interactions between rat nerves and blood vessels in denervated peripheral arteries and in anterior eye chamber transplants.
This investigation was undertaken to examine trophic interrelationships between nerves and arteries in male Wistar rats. Two approaches were used. (1) Surgical denervation of two peripheral muscular arteries in the thigh (the superficial epigastric and saphenous) was carried out on young animals (5-20 days old). (2) Arteries from young adults, either with a high density of innervation in situ (the tail artery), or virtually uninnervated (the femoral artery), were transplanted into intact or sympathectomized anterior eye chambers of adult rat hosts. In the denervation experiments, the maximum length of time before reinnervation occurred was 15 days postoperatively. The only evidence of morphological change in the vessel wall was in the external elastic lamina that became irregular and laminated. Reinnervation followed the typical developmental sequence, and was accelerated in the younger animals and by a double lesion. Translocating the proximal part of the nerve carrying the vasomotor innervation indicated that sprouting was directional toward the muscular arteries, bypassing an artery with very sparse innervation. The transplant experiments into the anterior eye chamber showed that only an artery densely innervated in situ (the tail artery) could induce reinnervation by iridean nerve sprouting. The tail artery, in the chamber lacking adrenergic innervation of the iris, became reinnervated by terminals with small agranular vesicles. These vesicles were part of Schwann cell complexes, at a similar relative density, occupying the same position in the vessel wall, as the ingrowing nerves in the fully innervated iris. The latter also had a proportion of terminals with the small clear vesicles. A small population of large granular vesicles could also be found in both types of terminals. Therefore, tissue normally having only sympathetic innervation cannot be assumed to be completely noninnervated when transplanted into a sympathectomized anterior eye chamber. The denervation and transplant experiments described here demonstrated the presence of trophic interactions between nerves and arteries, but also revealed a heterogeneity of response between vessels with very high and extremely low levels of innervation in situ.


Dissection of the antitumor mechanism of tetrandrine based on metabolite profiling and network pharmacology.
Tetrandrine, the Q-marker in Stephaniae Tetrandrae Radix, was proven to present an obvious antitumor effect. Until now, the metabolism and antitumor mechanism of tetrandrine have not been fully elucidated. The metabolites of tetrandrine in rats were profiled using ultra-high-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential antitumor mechanism of tetrandrine in vivo was predicted using network pharmacology. A total of 30 metabolites were characterized in rats after ingestion of tetrandrine (10 mg/kg), including 0 in plasma, 7 in urine, 11 in feces, 9 in liver, 8 in spleen, 4 in lung, 5 in kidney, 5 in heart, and 4 in brain. This study was the first to show the metabolic processes demethylation, hydroxylation, and carbonylation in tetrandrine. The pharmacology network results showed that tetrandrine and its metabolites could regulate AKT1, TNF, MMP9, MMP2, PAK1, and so on by involving in proteoglycan tumor pathway, PI3K-Akt signaling pathway, tumor pathway, MAPK signaling pathway, and Rap1 signaling pathway. The metabolism features of tetrandrine and its potential antitumor mechanism were summarized, providing data for further pharmacological validation.


Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women.
GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); or a double dummy placebo. Patients who received MK-677 alone or placebo through month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, with or without alendronate, increased insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo). MK-677 increased osteocalcin and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs. placebo). MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduced the effect of alendronate on resorption (NTx) as well (-52% vs. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, similar enhancement was not seen with MK-677 plus alendronate in BMD of the lumbar spine, total hip, or total body compared with alendronate alone. GH-mediated side effects were noted in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alendronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a concern when weighed against the potential side effects of enhanced GH secretion.


Assembly of Luminescent Chiral Gold(I)-Sulfido Clusters via Chiral Self-Sorting.
Due to the ubiquity of chirality in nature, chiral self-assembly involving self-sorting behaviors has remained as one of the most important research topics of interests. Herein, starting from a racemic mixture of SEG-based (SEG=SEGPHOS) chlorogold(I) precursors, a unique chiral butterfly-shape hexadecanuclear gold(I) cluster (Au16 ) with different ratios of RSEG and SSEG ligands is obtained via homoleptic and heterochiral self-sorting. More interestingly, by employing different chlorogold(I) precursors of opposite chirality (such as RSEG -Au2 and SBIN -Au2 (BIN=BINAP)), an unprecedented heteroleptic and heterochiral self-sorting strategy has been developed to give a series of heteroleptic chiral decanuclear gold(I) clusters (Au10 ) with propellor-shape structures. Heterochiral and heteroleptic self-sorting have also been observed between enantiomers of homoleptic chiral Au10 clusters to result in the heteroleptic chiral Au10 clusters via cluster-to-cluster transformation. Incorporation of heteroleptic ligands is found to decrease the symmetry from S4 of homoleptic meso Au10 to C2 of heteroleptic chiral Au10 clusters. The chirality has been transferred from the axial chiral ligands and stored in the heteroleptic gold(I) clusters.


PLK1 as one novel target for the poor prognosis of bladder cancer: An observational study.
Bladder cancer (BC) is one of the most common male malignant tumors and the most common urological tumor. However, the molecular mechanism and role of PLK1 on bladder cancer were unclear. Therefore, the study aims to explore the potential part of the overall survival of bladder cancer through bioinformatics analysis. GSE121711 and GSE130598, from the Gene Expression Omnibus database. The GEO2R screened differently expressed genes, and DAVID and Metascape were used for functional annotation. The cytoHubba made hub genes identification and expression. A total of 50 BC participants were recruited. After surgery, 50 BC tumor samples from BC patients and 50 adjacent standard bladder tissue samples were obtained. The RT-qPCR assay was performed to verify the expression of hub genes. The Kaplan-Meier Plotter analyzed the effect of hub gene expression for overall survival of BC. The compulsory module of Molecular Complex Detection tool analysis was shown, which included CDK1, TTK, AURKB, MELK, PLK1, and BUB1. And the six hub genes were up-regulated in the BC compared with the normal tissues. The relative expression levels of CDK1, TTK, AURKB, MELK, PLK1, and BUB1 were significantly higher in BC samples compared with the regular kidney tissue groups. The result demonstrated that CDK1, TTK, AURKB, MELK, PLK1, and BUB1 might be considered biomarkers for BC. Overall survival analysis showed that BC patients with high expression level of PLK1 had poorer overall survival times than those with low expression level (P < .05). The expression levels of CDK1, TTK, AURKB, MELK, and BUB1 was not related to the overall survival of BC patients (P > .05). The PLK1 gene might provide new ideas and evidence for bladder cancer research.


Effect of Shear on the Strength of Polymer-Induced Flocs
Micromechanics was used to show that the rupture strength of polymer-induced flocs varied with the hydrodynamic conditions at which the flocs were formed. A maximum floc strength at an intermediate shear rate was observed. The overall performance of the polymeric flocculants, as determined by two independent methods, showed that the conditions for optimal flocculation did not coincide with those for maximum floc strength. The amount of flocculation was explained in terms of the competing effects of the particle collision frequency and the destructive hydrodynamic forces. The contributing forces to the floc strength are, however, more likely to be densification of the floc by shear and the weakening of reattachment strengths. The evidence presented here may be useful for explaining flocculation data that depart from the constant yield stress theory. Thus, the notion of the floc strength varying with shear rate may offer an alternative to multilevel floc structure models in the description of flocculation kinetics. Copyright 1997 Academic Press. Copyright 1997Academic Press


[The irritable bowel syndrome in mental patients].
140 patients with the irritable bowel syndrome were examined. According to the results of clinical analysis of the manifestations, symptomatology and structure of comorbidity, two syndrome types were identified. These included those: with the phenomena of autonomic or conversive neurosis (89.3 and 10.7% respectively). The syndrome with signs autonomic neurosis were characterized by: 1) spontaneous or somatogenic manifestation; 2) homomorphism and stability of both abdominalgias and defecation disorders; 3) limitation of functional disorders in gastrointestinal organs; 4) syndromal and temporary (parallelism of formation and dynamics) comorbidity with endogenous diseases (66%) (cyclothymia, slowly progressive schizophrenia), hypochondriac development (16%) and anxious-phobic disorders (18%); 5) correlation with subclinic somatic pathology of gastrointestinal tract. Syndrome with the phenomena of conversive neurosis was characterized by: 1) psychogenically induced manifestation; 2) polymorphism and instability of abdomnalgias and stool disorders; 3) polymorphism of functional disorders of different organ systems; 4) syndromic and temporary (parallelism of formation and dynamics) comorbidity with subsyndromic psychic disorders: transitent hysterohypochondriac phobias (cardiophobia, tanatophobia)--60%, transitent (less than 2-3 months) hysteroaffective reactions caused by situations--40%; 5) none or minimal concomitant subclinical gastrointestinal pathology.


Minocycline and cefotaxime in the treatment of experimental murine Vibrio vulnificus infection.
We conducted an in vivo study with the mouse model of Vibrio vulnificus infection to evaluate the efficacies of therapy with minocycline or cefotaxime alone and in combination. V. vulnificus was introduced subcutaneously into the area over the right thigh. The inoculum size ranged from 1.0 x 10(3) to 1.2 x 10(8) CFU from experiment to experiment but was constant for all animals in the same experiment. Antibiotics were given intraperitoneally 2 h after the bacteria were inoculated. In experiments 1 to 4, the standard dose for humans was used to treat the infection, while in experiment 5, five times the standard dose for humans was used to treat the infection. In experiment 1, with a small inoculum of 5 x 10(3) CFU, all mice in the saline-treated control group and the cefotaxime-, minocycline-, and combined antibiotic-treated groups survived. In experiment 2, with a moderate inoculum of 1.2 x 10(5) CFU, all the mice in the three antibiotic-treated groups survived, while only two of nine mice in the control group survived. In experiment 3, with a large inoculum of 8.0 x 10(7) CFU, six of nine mice in the combined antibiotic-treated group survived, while only one of nine mice in the cefotaxime-treated group and none of the mice in the control and minocycline-treated groups survived. In experiment 4, with a large inoculum of 1.2 x 10(8) CFU, 8 of 20 mice in the combined antibiotic-treated group survived, while none of the 20 mice in the control group, the group treated with cefotaxime alone, and the group treated with minocycline alone survived. In experiment 5, in which mice were infected with a large inoculum of 6.6 x 10(7) CFU and treated with five times the standard human dose of antibiotics, 10 of 12 mice in the combined antibiotic-treated group survived, while only 4 of 12 mice in the minocycline-treated group, 1 of 12 mice in the cefotaxime-treated group, and none of the mice in the control group survived. In experiments 3 to 5, the difference in the survival rates between the combined antibiotic-treated and minocycline-treated groups was statistically significant (P < 0.05). These results indicate that combination therapy with cefotaxime and minocycline is distinctly more advantageous than therapy with the single antibiotic regimen for the treatment of severe experimental V. vulnificus infections.


Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4.
The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE epsilon4 is a genetic risk factor for FTD.


Development of 17 microsatellite markers for Ceratosolen constrictus, the pollinating fig wasp of Ficus fistulosa.
The obligate mutualism between figs (Ficus) and fig pollinating wasps (Agaonidae) is regarded as a classic example of mutualism. Seventeen polymorphic microsatellite loci were developed for Ceratosolen constrictus, the pollinating wasp of the dioecious fig Ficus fistulosa. The number of alleles per locus ranged from two to 15 and the observed and expected heterozygosities ranged from 0.040 to 0.846 and from 0.040 to 0.916, respectively. These microsatellite loci offer a powerful tool for evolutionary and population genetic studies in C. constrictus, and gene flow of F. fistulosa.


Observations on the relationship between the dietetic objective structured clinical examination and placement outcome.
Objective structured clinical examinations (OSCEs) are used extensively in medical education to prepare students for the clinical setting. Their use in dietetic education is still relatively new, and relationships to placement outcomes are unknown. The aim of this study was to explore 11 years of OSCE and placement data to answer the following questions: Does the OSCE predict dietetic placement outcome? and, What are the student perceptions of the benefits of OSCE in preparation for practice? Data were collected retrospectively from 328 students between 2006 and 2017 who had completed their final year OSCE and placement. Aggregate OSCE marks and mean marks obtained in active and passive OSCE stations were compared with placement outcome. Evaluation questionnaires completed by students at the end of the OSCE were collated. Aggregate marks achieved in OSCE stations were significantly different for students who passed (mean = 63.24, SD = 7.94), struggled (mean = 58.25, SD = 8.82) or failed (mean = 57.31, SD = 8.28) placement, P < 0.001. Majority of students perceived the OSCE as a meaningful and fair assessment (92%) that helped to prepare them for practice (82%). The OSCE provides a meaningful assessment of dietetic student skills in preparation for practice. Aggregate OSCE marks provide a consistent indicator of students who are likely to struggle in practice.


[Experience in the use of chemical compounds for the primary identification and differentiation of enteroviruses].
Data on the usage of chemical inhibitors nifan and belvtazid, which possess a selective and antienteroviral effect, in the primary identification of enteroviruses and their differentiation into polio- and non-poliomyelytic ones isolated from human clinical materials or the environment by using the cell culture are presented in the article. The method is recommended for the practical use by the virology service in the diagnostics of enteroviral infections and in the identification of cytopathic agents isolated from the enviroment.


Forward slide maneuver: a new method of advancing the Rotablator system.
In performing coronary rotational ablation, advancing the Rotablator (Heart Technology, Redmond, WA) out of the guiding catheter and through a tortuous, non-compliant vessel to reach the target lesion may be difficult and sometimes impossible without activation of the drive proximal to the target lesion. We report a technique not previously described for advancing the Rotablator to the target lesion before activating the drive by simultaneously advancing the burr control knob (slide) and the Teflon catheter sheath. Ten of 14 burrs (71%) ranging in size from 1.5 to 2.15 mm were successfully advanced in nine of ten (90%) cases in which the burr could not be advanced in the usual fashion (traction on the guidewire while advancing the sheath).


[Development of postgraduate education for doctors-internists].
Medical progress and to optimize the management of health is largely dependent upon the effectiveness of the modernization of education and science. The primary objective in this regard is the creation of a new management model clinics. International experience has confirmed the effectiveness of the cluster approach. Another important development is the transition to single-channel financing, improving the monitoring of the quality of medical care. To solve these problems it is necessary to develop a model management model clinic based on modern technologies of strategic management and information technology, optimizations of economic activity, social monitoring system of public satisfaction with the quality of medical care.


Evaluation of the American Heart Association Stroke Outcome Classification.
The purpose of this study was to evaluate the concurrent validity of the American Heart Association Stroke Outcome Classification (AHA.SOC) and compare performance of its function classification with that of the Modified Rankin Scale. The individuals in this study included the last 105 consecutive subjects who were part of a cohort of 459 stroke patients in the Kansas City Stroke Study. The patients were evaluated with a variety of standardized assessments at enrollment (within 14 days of stroke onset) and followed at 1, 3, and 6 months after stroke. Specifically, we examined validity of AHA.SOC by comparing its 3 domains (ie, Domain, Severe, and Function) with stroke severity. We correlated AHA.SOC-Function with scores of the Barthel Index, Lawton Instrumental Activities of Daily Living (IADL) Scale, and Medical Outcome Study 36-Item Short-Form Health Survey (SF-36) measures of physical function and mental health. Finally, we compared the discriminant ability of AHA.SOC-Function and the Modified Rankin Scale in assessing disability and handicap. These data were analyzed with the use of Spearman rank correlations and Kruskal-Wallis tests. All 3 domains of the AHA.SOC were significantly associated with stroke severity and scores of Barthel Index, Lawton IADL, and SF-36 physical function (all P<0.001). Both AHA.SOC-Function and the Modified Rankin Scale discriminated well the disabilities and handicap measured by Barthel Index, Lawton IADL, and SF-36 physical function (all P<0.001). The AHA.SOC was able to capture impairments, disabilities, and handicap after stroke. The AHA. SOC-Function performed equally as well as the Modified Rankin Scale in assessing disabilities related to basic activities of daily living but differentiated slightly better than the Modified Rankin Scale in assessing disabilities/handicap related to instrumental activities of daily living. Neither the AHA.SOC-Function nor the Modified Rankin Scale captured differences in mental health after stroke.


User satisfaction with the care of nurses.
To evaluate user satisfaction with the care of nurses. Cross-sectional study with a quantitative approach, performed in the medical clinic of the University Hospital of UFMA/HU/UFMA, with 150 users in the period from October 2013 to August 2014, through an identification form the and Patient Satisfaction Instrument. In the data analysis, Student t test, Kruskal Wallis and Spearman Linear Correlation were used. Users have reported high levels of satisfaction with all items and domains, with the highest average satisfaction related to technical and professional domain, followed by the domain trust, resulting in satisfactory internal consistency in all areas. Gender and level of education had a positive influence on patient satisfaction. The study showed that the satisfaction of users admitted to the medical clinic is correlated with technical skills, scientific knowledge and the individualization of care provided by nurses.


New insights into the contribution of arterial NCX to the regulation of myogenic tone and blood pressure.
Plasma membrane protein Na(+)/Ca(2+) exchanger (NCX) in vascular smooth muscle (VSM) cells plays an important role in intracellular Ca(2+) homeostasis, Ca(2+) signaling, and arterial contractility. Recent evidence in intact animals reveals that VSM NCX type 1 (NCX1) is importantly involved in the control of arterial blood pressure (BP) in the normal state and in hypertension. Increased expression of vascular NCX1 has been implicated in human primary pulmonary hypertension and several salt-dependent hypertensive animal models. Our aim is to determine the molecular and physiological mechanisms by which vascular NCX influences vasoconstriction and BP normally and in salt-dependent hypertension. Here, we describe the relative contribution of VSM NCX1 to Ca(2+) signaling and arterial contraction, including recent data from transgenic mice (NCX1(smTg/Tg), overexpressors; NCX1(sm-/-), knockouts) that has begun to elucidate the specific contributions of NCX to BP regulation. Arterial contraction and BP correlate with the level of NCX1 expression in smooth muscle: NCX1(sm-/-) mice have decreased arterial myogenic tone (MT), vasoconstriction, and low BP. NCX1(smTg/Tg) mice have high BP and are more sensitive to salt; their arteries exhibit upregulated transient receptor potential canonical channel 6 (TRPC6) protein, increased MT, and vasoconstriction. These observations suggest that NCX is a key component of certain distinct signaling pathways that activate VSM contraction in response to stretch (i.e., myogenic response) and to activation of certain G-protein-coupled receptors. Arterial NCX expression and mechanisms that control the local (sub-plasma membrane) Na(+) gradient, including cation-selective receptor-operated channels containing TRPC6, regulate arterial Ca(2+) and constriction, and thus BP.


[The interpreter: crossing communication barriers between healthcare providers and international patients].
As a result of the effects of globalization, cross-racial and cross-cultural marriages have become common phenomena in Taiwan society. The rapid increase in the number of immigrants coming to Taiwan has created a society that will need to confront the impact of the arrival of people from different cultures and the problems associated therewith. These challenges must also be faced by healthcare providers and patients. Since communication is a crucial aspect of healthcare situations, the cost of medical care can be very high and treatment may be of limited effect if communication between patients and healthcare providers is not sufficiently comprehensive. The use of an interpreter is therefore a popular solution to facilitate communication between healthcare providers and patients. The quality of interpretation, however, depends on the training of the interpreter, and will have a great influence on the outcome of health care. Without effective communication, the quality of health care cannot be improved. The question of how to provide continual monitoring of the quality of interpretation and establish a comprehensive training course for interpreters should therefore be further investigated in clinical research.


Optical phase modulation based on directly modulated reflection-mode OIL-VCSEL.
Optical phase modulation based on directly modulated reflection-mode optically injection-locked VCSEL is investigated based on standard OIL rate equations and reflection-mode OIL model. The phase information of both static and dynamic state is simulated. The difference of static state phase information between transmission- and reflection-mode OIL is numerically analyzed. With specific OIL parameters, the output power of directly modulated OIL-VCSEL remains constant and phase deviation of 0.934π rad is obtained. Results show that a directly modulated OIL-VCSEL can function as a key component in QPSK or 8PSK transmitters. Preliminary 2.5 Gb/s PSK modulation characteristic is demonstrated experimentally.


Order-disorder transition and weak ferromagnetism in the perovskite metal formate frameworks of [(CH3)2NH2][M(HCOO)3] and [(CH3)2ND2][M(HCOO)3] (M = Ni, Mn).
We report the synthesis, crystal structure, thermal, dielectric, Raman, infrared, and magnetic properties of hydrogen and deuterated divalent metal formates, [(CH3)2NH2][M(HCOO)3] and [(CH3)2ND2][M(HCOO)3], where M = Ni, Mn. On the basis of Raman and IR data, assignment of the observed modes to respective vibrations of atoms is proposed. The thermal studies show that for the Ni compounds deuteration leads to a decrease of the phase transition temperature Tc by 5.6 K, whereas it has a negligible effect on Tc in the Mn analogues. This behavior excludes the possibility of proton (deuteron) movement along the N-H···O (N-D···O) bonds as the microscopic origin of the first-order phase transition observed in these crystals below 190 K. According to single-crystal X-ray diffraction, the dimethylammonium (DMA) cations are dynamically disordered at room temperature, because the hydrogen bonds between the NH2 (ND2) groups and the metal-formate framework are disordered. The highly dynamic nature of hydrogen bonds in the high-temperature phases manifests in the Raman and IR spectra through very large bandwidth of modes involving vibrations of the NH2 (ND2) groups. The abrupt decrease in the bandwidth and shifts of modes near Tc signifies the ordering of hydrogen bonds and DMA(+) cations as well as significant distortion of the metal-formate framework across the phase transition. However, some amount of motion is retained by the DMA(+) cation in the ferroelectric phase and a complete freezing-in of this motion occurs below 100 K. The dielectric studies reveal pronounced dielectric dispersion that can be attributed to slow dynamics of large DMA(+) cations. The low-temperature studies also show that magnetic properties of the studied compounds can be explained assuming that they are ordered ferrimagnetically with nearly compensated magnetic moments of Ni and Mn. IR data reveal weak anomalies below 40 K that arise due to spin-phonon coupling. Our results also show that due to structural phase transition more significant distortion of the metal-formate framework occurs for the deuterated samples.


Thiol containing antioxidant drugs and the human immune system.
The over production of toxic oxygen species (TOS) by the phagocytic cells involved in inflammatory processes plays a crucial role in generating the immune defects which characterize both infections and neoplastic diseases. Since the thiol containing drugs, and N-acetylcysteine possess a high capacity for scavenging and inhibiting TOS, the question of whether these substances are able to protect, in vivo as well as in vitro, the function of lymphocytes isolated from the peripheral blood in patients suffering from chronic pulmonary diseases (CPD) was investigated. The lymphocytes isolated from healthy donors as well as those from CPD patients exposed in vitro to TOS showed a reduced viability and an impairment of functions in: (a) the ability to express HLA Class II and TAC antigens and (b) the capacity to stimulate and proliferate in allogenic (MLR) and autologous mixed lymphocyte reactions (AMLR). The presence of NAC or CAT blocked this toxicity. Cells isolated from healthy donors and patients following treatment with NAC were less sensitive to the in vitro toxicity of TOS.


HERMES: towards an integrated toolbox to characterize functional and effective brain connectivity.
The analysis of the interdependence between time series has become an important field of research in the last years, mainly as a result of advances in the characterization of dynamical systems from the signals they produce, the introduction of concepts such as generalized and phase synchronization and the application of information theory to time series analysis. In neurophysiology, different analytical tools stemming from these concepts have added to the 'traditional' set of linear methods, which includes the cross-correlation and the coherency function in the time and frequency domain, respectively, or more elaborated tools such as Granger Causality.This increase in the number of approaches to tackle the existence of functional (FC) or effective connectivity (EC) between two (or among many) neural networks, along with the mathematical complexity of the corresponding time series analysis tools, makes it desirable to arrange them into a unified-easy-to-use software package. The goal is to allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of these analysis methods from a single integrated toolbox.Here we present HERMES ( http://hermes.ctb.upm.es ), a toolbox for the Matlab® environment (The Mathworks, Inc), which is designed to study functional and effective brain connectivity from neurophysiological data such as multivariate EEG and/or MEG records. It includes also visualization tools and statistical methods to address the problem of multiple comparisons. We believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis.


Drosophila and Caenorhabditis elegans as Discovery Platforms for Genes Involved in Human Alcohol Use Disorder.
Despite the profound clinical significance and strong heritability of alcohol use disorder (AUD), we do not yet have a comprehensive understanding of the naturally occurring genetic variance within the human genome that drives its development. This lack of understanding is likely to be due in part to the large phenotypic and genetic heterogeneities that underlie human AUD. As a complement to genetic studies in humans, many laboratories are using the invertebrate model organisms (iMOs) Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode worm) to identify genetic mechanisms that influence the effects of alcohol (ethanol) on behavior. While these extremely powerful models have identified many genes that influence the behavioral responses to alcohol, in most cases it has remained unclear whether results from behavioral-genetic studies in iMOs are directly applicable to understanding the genetic basis of human AUD. In this review, we critically evaluate the utility of the fly and worm models for identifying genes that influence AUD in humans. Based on results published through early 2015, studies in flies and worms have identified 91 and 50 genes, respectively, that influence 1 or more aspects of behavioral responses to alcohol. Collectively, these fly and worm genes correspond to 293 orthologous genes in humans. Intriguingly, 51 of these 293 human genes have been implicated in AUD by at least 1 study in human populations. Our analyses strongly suggest that the Drosophila and C. elegans models have considerable utility for identifying orthologs of genes that influence human AUD.


A semi-parametric hybrid neural model for nonlinear blind signal separation.
Nonlinear blind signal separation is an important but rather difficult problem. Any general nonlinear independent component analysis algorithm for such a problem should specify which solution it tries to find. Several recent neural networks for separating the post nonlinear blind mixtures are limited to the diagonal nonlinearity, where there is no cross-channel nonlinearity. In this paper, a new semi-parametric hybrid neural network is proposed to separate the post nonlinearly mixed blind signals where cross-channel disturbance is included. This hybrid network consists of two cascading modules, which are a neural nonlinear module for approximating the post nonlinearity and a linear module for separating the predicted linear blind mixtures. The nonlinear module is a semi-parametric expansion made up of two sub-networks, one of which is a linear model and the other of which is a three-layer perceptron. These two sub-networks together produce a "weak" nonlinear operator and can approach relatively strong nonlinearity by tuning parameters. A batch learning algorithm based on the entropy maximization and the gradient descent method is deduced. This model is successfully applied to a blind signal separation problem with two sources. Our simulation results indicate that this hybrid model can effectively approach the cross-channel post nonlinearity and achieve a good visual quality as well as a high signal-to-noise ratio in some cases.


Identification of polyketide inhibitors targeting 3-dehydroquinate dehydratase in the shikimate pathway of Enterococcus faecalis.
Due to the emergence of resistance toward current antibiotics, there is a pressing need to develop the next generation of antibiotics as therapeutics against infectious and opportunistic diseases of microbial origins. The shikimate pathway is exclusive to microbes, plants and fungi, and hence is an attractive and logical target for development of antimicrobial therapeutics. The Gram-positive commensal microbe, Enterococcus faecalis, is a major human pathogen associated with nosocomial infections and resistance to vancomycin, the "drug of last resort". Here, we report the identification of several polyketide-based inhibitors against the E. faecalis shikimate pathway enzyme, 3-dehydroquinate dehydratase (DHQase). In particular, marein, a flavonoid polyketide, both inhibited DHQase and retarded the growth of Enterococcus faecalis. The purification, crystallization and structural resolution of recombinant DHQase from E. faecalis (at 2.2 Å resolution) are also reported. This study provides a route in the development of polyketide-based antimicrobial inhibitors targeting the shikimate pathway of the human pathogen E. faecalis.


Abatacept in the treatment of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory arthritis affecting 1% of the population. The immunologic dysfunction underlying this immune disorder is complex and intricate with the involvement of various immune cells as well as cytokines and surface molecules. While inhibition of TNF-alpha has changed the outlook of patients with this disorder, it regulates only one aspect of the inflammatory cascade associated with RA. This is corroborated by experience in the clinic, where a significant proportion of the patients do not have clinical benefit with such therapies. Furthermore, a number of patients experience blunting of the initial therapeutic benefits of TNF-alpha-targeted therapies. Thus, a different approach to regulate the immune dysfunction associated with RA is necessary. T cells are considered important in the pathogenesis of RA and abatacept, a fusion protein, was developed to abolish the activation of the T cell by blocking its interaction with the antigen-presenting cell. Abatacept has demonstrated promising clinical improvements in patients with RA. Although clinical experience with this new drug is limited and its mechanism of action remains to be understood, the data on the safety profile are reassuring.


The frequency of chimeric molecules as a consequence of PCR co-amplification of 16S rRNA genes from different bacterial species.
Our understanding of microbial diversity is greatly hampered by the inability to culture as much as 99% of the microbial community in the biosphere. Development of methods for identification and determining microbial phylogenies based on gene sequences, and for recovering genes directly from diverse environmental samples has made it possible to study microbes without the need for cultivation. PCR techniques have revolutionized retrieval of conserved gene sequences. However, it is well known that co-amplification of homologous genes may generate chimeric sequences leading to descriptions of non-existent species. To quantify the frequency of chimeric sequences in PCR amplification of 16S rRNA genes, we chose several 16S rDNAs with known sequences and mixed them for PCR amplifications under various conditions. Using this model system, we detected 30% occurrence of chimeric sequences after 30 cycles of co-amplification of two nearly identical 16S rRNA genes. The frequency of chimera formation decreased to 12.9% and 14.7% for templates with 82% and 86% similarity, respectively. We also examined effects of the number of amplification cycles, length of elongation periods and presence of damaged DNA on chimera formation. The results should provide useful information for microbiologists who use PCR-based strategies to retrieve conserved genes from mixed genomes.


Validation of health locus of control patterns in Swedish adolescents.
The purpose of the present study was to investigate the relationships between Health Locus of Control (HLOC) questionnaire subscales (Internal, Powerful Others, Chance) and self-esteem in Swedish adolescents (N = 506). Results from traditional correlational analyses were compared with findings using an alternative method of clustering individuals according to their pattern of scores on the three HLOC subscales. One-way analysis of variance, with eight possible groupings of high and/or low scores on the three subscales, indicated that those with a combination of strong belief in internal control of health, high degree of belief that health is determined by powerful others, and low degree of belief that health is a function of chance/luck had better self-esteem than those with a quite opposite pattern, involving high belief in chance and low belief in internal control. The potential benefit to researchers and clinicians of using this method of combining the HLOC subscales, instead of the traditional correlational method, is discussed.


Optical Coherence Tomography Angiography of Chorioretinal Diseases.
Fluorescein angiography (FA) and indocyanine green angiography (ICGA) have been the gold standard for the evaluation of retinal and choroidal vasculature in the last three decades and have revolutionized the diagnosis of retinal and choroidal vascular diseases. The advantage of these imaging modalities lies in their ability to document retinal and choroidal vasculature through the dynamic assessment of contrast transit over time in the intravascular and extravascular spaces. However, disadvantages include the absence of depth resolution, blurring of details by contrast leakage, and the inability to selectively evaluate different levels of the retinal and choroidal microvasculature. In addition, these angiographic methods require intravenous dye, which may cause adverse reactions such as nausea, vomiting, and rarely, anaphylaxis. Optical coherence tomography angiography (OCTA) is a noninvasive imaging technique that, in contrast to dye-based angiography, is faster and depth-resolved, allowing in some cases for more precise evaluation of the vascular plexuses of the retina and choroid. The method has been demonstrated in the assessment of various vascular diseases such as venous occlusions, diabetic retinopathy, macular neovascularization, and others. Limitations of this imaging modality include a small registered field of view and the inability to visualize leakage and dye transit over time. It is also subject to a variety of artifacts, including those generated by blinking and eye movement during image acquisition. However, more than an alternative for FA and ICGA, OCTA is bringing new insights to our understanding of retinal and choroidal vascular structure and is changing fundamental paradigms in the clinical management of pathologic conditions. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:848-861.].


The deployment of adenovirus-containing gene activated matrices onto severed axons after central nervous system injury leads to transgene expression in target neuronal cell bodies.
In previous studies, we showed that gene activated matrices (GAMs) containing nonviral vectors successfully deliver genes to neurons after optic nerve and spinal cord injury. In the present study, we evaluated whether adenoviral vectors delivered within a GAM increase the efficiency of local gene delivery to injured CNS neurons. Lyophilized GAMs containing collagen and adenoviral vectors were assessed in vitro and in vivo. We evaluated viral vector stability, release kinetics and efficiency of transduction for this GAM formulation in vitro using the quantitative polymerase chain reaction (qPCR), flow cytometry and fluorescence microscopy. Using PCR, reverse transcriptase-PCR and confocal microscopy, we assessed viral DNA retrograde axonal transport, green fluorescent protein (GFP) expression in retinal ganglion cells (RGCs) after GAM implantation into the wound of the rat transected optic nerve. qPCR analyses demonstrated that 100% of viral particles were retained within the collagen after lyophilization. In vitro studies demonstrated that 60% of the particles within the GAM were infective and not released from the collagen matrix when placed in water. By 24 h, GFP expression was detected within cells that have invaded the GAM. In vivo studies demonstrated that adenoviral particles were retrogradely transported in axons from the GAM implanted at the lesion site to the RGC in the retina where the corresponding mRNA was expressed. Analysis of the efficiency of cell transduction indicated that 69% of RGC express GFP. These studies demonstrate that lyophilized GAMs containing adenoviral particles within collagen are stable, retain a significant proportion of their infectivity and successfully and efficiently deliver genes to neurons after central nervous system injury.


Inclusion compounds of plant growth regulators in cyclodextrins. V. 4-Chlorophenoxyacetic acid encapsulated in beta-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin.
The crystal structures of 4-chlorophenoxyacetic acid (4CPA) included in beta-cyclodextrin (beta-CD) and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD) have been studied by X-ray diffraction. The 4CPA/beta-CD complex crystallizes as a head-to-head dimer in the space group C2 in the Tetrad packing mode. The packing modes of some beta-CD dimeric complexes, having unique stackings, are also discussed. The 4CPA/TMbetaCD inclusion complex crystallizes in the space group P2(1) and its asymmetric unit contains two crystallographically independent complexes, complex A and complex B, exhibiting different conformations. The host molecule of complex A is significantly distorted, as a glucosidic residue rotated about the O4'-C1 and C4-O4 bonds forms an aperture where the guest molecule is accommodated. The phenyl moiety of the guest molecule of complex B is nearly perpendicular to the mean plane of the O4n atoms. The conformations of the guest molecules of the two complexes are similar. The crystal packing consists of antiparallel columns as in the majority of the TMbetaCD complexes published so far.


Drug, Opioid-Involved, and Heroin-Involved Overdose Deaths Among American Indians and Alaska Natives - Washington, 1999-2015.
The opioid epidemic has resulted in a threefold increase in drug overdose deaths in the United States during 1999-2015 (1). Whereas American Indians/Alaska Natives (AI/AN) have experienced larger increases in drug overdose mortality than have other racial/ethnic groups in the United States (2), little is known about the regional impact of opioids in tribal and urban AI/AN communities. To address this data gap, death records from the Washington State Center for Health Statistics, corrected for misclassification of AI/AN race, were examined to identify trends and disparities in drug, opioid-involved, and heroin-involved overdose mortality rates for AI/AN and non-Hispanic whites (whites) in Washington. Although AI/AN and whites had similar overdose mortality rates during 1999-2001, subsequent overdose rates among AI/AN increased at a faster rate than did those among whites. During 2013-2015, mortality rates among AI/AN were 2.7 and 4.1 times higher than rates among whites for total drug and opioid-involved overdoses and heroin-involved overdoses, respectively. Washington death certificates that were not corrected for misclassification of AI/AN race underestimated drug overdose mortality rates among AI/AN by approximately 40%. National statistics on the opioid epidemic, which report that overdose mortality rates are significantly higher among whites than among AI/AN, are not reflective of regional prevalences, disparities, and trends. Comprehensive efforts to address the opioid epidemic in AI/AN communities rely on strong partnerships between tribal governments and local, state, and federal entities. Additional measures are needed for community-based surveillance, treatment, and prevention to effectively respond to the epidemic across diverse tribal and urban AI/AN communities.


Early Versus Late Culture Growth of Propionibacterium acnes in Revision Shoulder Arthroplasty.
Propionibacterium acnes is recognized as a pathogenic organism associated with periprosthetic joint infection following shoulder arthroplasty. The goal of our study was to determine the relationship between the time to P. acnes growth in culture and the likelihood of a culture result being a true positive versus a false positive based on the proportion of positive cultures and other perioperative findings in cases of revision shoulder arthroplasty. We retrospectively reviewed forty-six cases with P. acnes-positive cultures among patients who underwent revision shoulder arthroplasty between May 2010 and October 2014. Tissue and fluid was cultured anaerobically for a mean (and standard deviation) of 13.1 ± 3 days. Cases were categorized into one of two groups for analysis: probable true positive or probable contaminant (false-positive) on the basis of culture results and perioperative findings. The time to P. acnes culture growth was significantly shorter (p = 0.002) in the probable true-positive culture group compared with the probable contaminant group (median of five days [interquartile range, four to seven days]) compared with nine days [interquartile range, six to twelve days]). Among the thirty-seven cases in the probable true-positive group, no culture result turned positive after eleven days, whereas in the probable contaminant group, cultures turned positive after this time point in 44% (four of nine) of the cases. There were also significantly fewer days to P. acnes culture growth among cases with a higher number of positive cultures (p = 0.001) and a higher proportion of positive cultures (p < 0.001), regardless of group classification. P. acnes is the most commonly identified organism following revision shoulder arthroplasty. The proportion of positive cultures and the timing of culture growth may help to distinguish a true-positive from a false-positive culture result. Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Myotubularin-related proteins 3 and 4 interact with polo-like kinase 1 and centrosomal protein of 55 kDa to ensure proper abscission.
The myotubularins are a family of phosphatases that dephosphorylate the phosphatidylinositols phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-phosphate. Several family members are mutated in disease, yet the biological functions of the majority of myotubularins remain unknown. To gain insight into the roles of the individual enzymes, we have used affinity purification coupled to mass spectrometry to identify protein-protein interactions for the myotubularins. The myotubularin interactome comprises 66 high confidence (false discovery rate ≤1%) interactions, including 18 pairwise interactions between individual myotubularins. The results reveal a number of potential signaling contexts for this family of enzymes, including an intriguing, novel role for myotubularin-related protein 3 and myotubularin-related protein 4 in the regulation of abscission, the final step of mitosis in which the membrane bridge remaining between two daughter cells is cleaved. Both depletion and overexpression of either myotubularin-related protein 3 or myotubularin-related protein 4 result in abnormal midbody morphology and cytokinesis failure. Interestingly, myotubularin-related protein 3 and myotubularin-related protein 4 do not exert their effects through lipid regulation at the midbody, but regulate abscission during early mitosis, by interacting with the mitotic kinase polo-like kinase 1, and with centrosomal protein of 55 kDa (CEP55), an important regulator of abscission. Structure-function analysis reveals that, consistent with known intramyotubularin interactions, myotubularin-related protein 3 and myotubularin-related protein 4 interact through their respective coiled coil domains. The interaction between myotubularin-related protein 3 and polo-like kinase 1 relies on the divergent, nonlipid binding Fab1, YOTB, Vac1, and EEA1 domain of myotubularin-related protein 3, and myotubularin-related protein 4 interacts with CEP55 through a short GPPXXXY motif, analogous to endosomal sorting complex required for transport-I components. Disruption of any of these interactions results in abscission failure, by disrupting the proper recruitment of CEP55, and subsequently, of endosomal sorting complex required for transport-I, to the midbody. Our data suggest that myotubularin-related protein 3 and myotubularin-related protein 4 may act as a bridge between CEP55 and polo-like kinase 1, ensuring proper CEP55 phosphorylation and regulating CEP55 recruitment to the midbody. This work provides a novel role for myotubularin-related protein 3/4 heterodimers, and highlights the temporal and spatial complexity of the regulation of cytokinesis.


A selective placement strategy for surgical feeding tubes benefits trauma patients.
The indications for surgical feeding tube (SFT) placement in trauma patients are poorly defined. Patient selection is critical as complications from SFTs have been reported in up to 70% of patients. A previous analysis by our group determined that 25% of the SFTs we placed were unnecessary and that older patients, patients with head and spinal cord injuries, and patients who needed a tracheostomy were more likely to require long-term SFTs. Following this study, we modified our institutional guidelines for SFT placement. We hypothesized that a more selective placement strategy would result in fewer unnecessary SFTs. A retrospective review of all adult patients from 2012 to 2016 with an intensive care unit length of stay longer than 4 days and an SFT placed during admission was conducted. This group was compared to data collected prior to our change in practice (2007-2010). Data from 2011 were excluded as a washout period. "Necessary" SFT use was defined per established guidelines as either daily use of the SFT through discharge or for 28 days or longer and "unnecessary" SFT use as all others. Two hundred fifty-seven SFTs were placed from 2007 to 2010 and 244 from 2012 to 2016. Following implementation of our selective SFT placement strategy, unnecessary SFT placement decreased from 25% in 2007 to 2010 to 8% in 2012 to 2016 (p < 0.0001). Significant predictors of necessary SFT placement by univariate regression were as follows: increasing age (odds ratio [OR] 1.03/year; 95% confidence interval [CI], 1.01-1.04), head injury (OR, 2.80; 95% CI, 1.71-4.60), cervical spinal cord injury (OR, 4.42; 95% CI, 1.34-14.50), and need for tracheostomy (OR, 1.41; 95% CI, 2.21-7.67). The overall complication rate was 11% (9% in the selective group vs. 13% in the preselective group, p = 0.2574) and was highest following open SFT placement (22%). A selective placement strategy for SFTs in our trauma population resulted in fewer unnecessary SFTs and a trend toward fewer complications. Surgical feeding tubes should be placed through a percutaneous approach whenever possible. Therapeutic study, level IV.


Exploring inflammatory disease drug effects on neutrophil function.
Neutrophils are critical inflammatory cells; thus, it is important to characterize the effects of drugs on neutrophil function in the context of inflammatory diseases. Herein, chemically guided neutrophil migration, known as chemotaxis, is studied in the context of drug treatment at the single cell level using a microfluidic platform, complemented by cell viability assays and calcium imaging. Three representative drugs known to inhibit surface receptor expression, signaling enzyme activity, and the elevation of intracellular Ca(2+) levels, each playing a significant role in neutrophil chemotactic pathways, are used to examine the in vitro drug effects on cellular behaviors. The microfluidic device establishes a stable concentration gradient of chemokines across a cell culture chamber so that neutrophil migration can be monitored under various drug-exposure conditions. Different time- and concentration-dependent regulatory effects were observed by comparing the motility, polarization, and effectiveness of neutrophil chemotaxis in response to the three drugs. Viability assays revealed distinct drug capabilities in reducing neutrophil viability while calcium imaging clarified the role of Ca(2+) in the neutrophil chemotaxis. This study provides mechanistic insight into the drug effects on neutrophil function, facilitating comparison of current and potential pharmaceutical approaches.


Treatment outcomes for patients with multidrug-resistant tuberculosis in post-earthquake Port-au-Prince, Haiti.
We report outcomes and 12-month survival for the first cohort of patients to undergo multidrug-resistant tuberculosis (MDR-TB) treatment after the earthquake in Haiti. From March 3, 2010 to March 28, 2013, 110 patients initiated treatment of laboratory-confirmed MDR-TB at the Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Center in Port-au-Prince, Haiti. Twenty-seven patients (25%) were human immunodeficiency virus (HIV)-positive. As of October 31, 2013, 95 (86%) patients were either cured or alive on treatment, 4 (4%) patients defaulted, and 11 (10%) patients died. Culture conversion occurred by 30 days in 14 (13%) patients, 60 days in 49 (45%) patients, and 90 days in 81 (74%) patients. The probabilities of survival to 12 months were 96% (95% confidence interval [95% CI] = 89-99) and 85% (95% CI = 64-94) for HIV-negative and -positive patients, respectively. Despite adverse conditions, outcomes for patients with MDR-TB are highly encouraging. Major efforts are underway to scale up community directly observed therapy and expand care to other regions of Haiti.


Clinical application of Patlak plot CT-GFR in animals with upper urinary tract disease.
Glomerular filtration rate (GFR), an important parameter of renal function, is difficult to assess clinically. Serum creatinine and blood urea nitrogen measurements lack sensitivity, whereas radionuclide determination of GFR is not always available and requires postinjection patient isolation. GFR can be determined using computed tomography (CT), most commonly via Patlak plot analysis. Four adult cats, two adult dogs, and a foal underwent abdominal CT under general anesthesia for various diseases of the upper urinary tract. CT-GFR was measured with a single-slice dynamic acquisition and Patlak plot analysis. In five animals, the total CT-GFR appeared to be below normal, corresponding with mild (two animals) and moderate (two animals) increases of serum creatinine in four. In the two animals with normal or increased CT-GFR, serum creatinine was within the reference values. A significant negative logarithmic relationship was found between CT-GFR and serum creatinine values (P = 0.008; r2 = 0.75). No complications occurred during or following CT-GFR. CT examination provided clinically relevant information in 3/5 patients with possible ureteral obstruction and in 3/3 patients with suspected ureteral calculi. Single-slice dynamic CT-GFR was practical and provided clinically useful information in this small series of patients undergoing CT of the upper urinary tract. There was a significant relationship between CT-GFR and serum creatinine values, which supports the clinical potential of CT-GFR and justifies further investigation of this technique.


Optineurin insufficiency impairs IRF3 but not NF-κB activation in immune cells.
Optineurin is a widely expressed polyubiquitin-binding protein that has been implicated in regulating cell signaling via its NF-κB essential modulator-homologous C-terminal ubiquitin (Ub)-binding region. Its functions are controversial, with in vitro studies finding that optineurin suppressed TNF-mediated NF-κB activation and virus-induced activation of IFN regulatory factor 3 (IRF3), whereas bone marrow-derived macrophages (BMDMs) from mice carrying an optineurin Ub-binding point mutation had normal TLR-mediated NF-κB activation and diminished IRF3 activation. We have generated a mouse model in which the entire Ub-binding C-terminal region is deleted (Optn(470T)). Akin to C-terminal optineurin mutations found in patients with certain neurodegenerative diseases, Optn(470T) was expressed at substantially lower levels than the native protein, allowing assessment not only of the lack of Ub binding, but also of protein insufficiency. Embryonic lethality with incomplete penetrance was observed for 129 × C57BL/6 Optn(470T/470T) mice, but after further backcrossing to C57BL/6, offspring viability was restored. Moreover, the mice that survived were indistinguishable from wild type littermates and had normal immune cell distributions. Activation of NF-κB in Optn(470T) BMDM and BM-derived dendritic cells with TNF or via TLR4, T cells via the TCR, and B cells with LPS or anti-CD40 was normal. In contrast, optineurin and/or its Ub-binding function was necessary for optimal TANK binding kinase 1 and IRF3 activation, and both Optn(470T) BMDMs and bone marrow-derived dendritic cells had diminished IFN-β production upon LPS stimulation. Importantly, Optn(470T) mice produced less IFN-β upon LPS challenge. Therefore, endogenous optineurin is dispensable for NF-κB activation but necessary for optimal IRF3 activation in immune cells.


Site of upper airway obstruction in obstructive apnoea and influence of sleep stage.
Various sites along the upper airway (UA) are prone to narrow and collapse in patients affected by obstructive sleep apnoea. Sleep stages may eventually alter these sites. The present study was designed to determine the site(s) of UA obstruction and the influence of sleep stage on the pattern of obstruction. Twenty eight obstructive sleep apnoea patients underwent UA pressure measurements during polysomnography. Solid-state pressure sensors were located at the nasopharynx, oropharynx, tongue base, hypopharynx and oesophagus and the lower limit of UA obstruction was determined relying on the observed pressure pattern. The site of UA obstruction varied among consecutive apnoeas in all but two patients. The lower limit of UA obstruction was predominantly located at the nasoand oropharynx. Rapid eye movement (REM) sleep was associated with a tendency for obstruction to extend towards lower levels of the UA and nasopharyngeal occlusion was significantly less observed during REM compared to oropharyngeal obstruction. Upper airway obstruction involves more than one specific site of the upper airway in the majority of sleep apnoea patients. Obstruction at lower levels of the upper airway is more likely to be observed during rapid eye movement sleep.


High percentage of regulatory T cells before and after vitamin B12 treatment in patients with pernicious anemia.
In some previous studies, vitamin B12 treatment showed immunomodulatory effects and restored the immunological abnormalities in patients with pernicious anemia (PA). In the present study, peripheral blood T cell subsets, including regulatory T cells (T(reg)s), were examined before and after vitamin B12 treatment in PA patients. The percentages of CD4, CD8, Th1, Th2 and T(reg)s were examined in 23 PA patients before vitamin B12 treatment, in 23 other PA patients after vitamin B12 treatment and in 28 healthy controls. The mean percentage of CD8+ T cells was significantly higher in the control group (23.0%; 95% CI, 20.4-25.6%) than in the pre- (16.0%; 95% CI, 12.1-20.0%) and posttreatment groups (15.2%; 95% CI, 11.8-18.6%; p < 0.05). The CD4/CD8 ratio was significantly lower in the control group (2.01; 95% CI, 1.66-2.34) than in the pre- (3.45; 95% CI, 2.55-7.80) and posttreatment groups (2.97; 95% CI, 2.22-3.72; p < 0.05). There was no significant difference in the mean Th1/Th2 ratio among these groups. There were significant increases in the mean percentage of T(reg)s in the pre- (6.29%; 95% CI, 5.04-7.54%) and posttreatment groups (7.77%; 95% CI, 6.34-9.20%) compared with the control group (4.18%; 95% CI, 3.92-4.47%; p < 0.05). The percentage of T(reg)s was significantly higher in PA patients than in normal subjects, and this high T(reg) percentage was not different before and after vitamin B12 treatment. Other immunological alterations also did not recover after vitamin B12 treatment, so that these immunological changes appear to be the cause of PA and are not induced by vitamin B12 deficiency.


Endocrine regulation of neonatal hypoxia: role of glucose, oxygen, and epinephrine supplementation.
Responses of the endocrine system are vital in revealing the mechanisms of respiratory activities. The present study focused on changes in insulin and triiodothyronine concentration in serum, its receptors in the hearts of hypoxic neonatal rats and glucose, oxygen, and epinephrine resuscitated groups. The insulin concentration was significantly increased with a significant upregulation of receptors in hypoxic neonates. Triiodothyronine content and its receptors were significantly decreased in serum and the hearts of hypoxic neonates. The change in hormonal levels is an adaptive modification of the endocrine system to encounter the stress. The effectiveness of glucose resuscitation to hypoxic neonates was also reported.


Diabetic Foot Ulcers: Contemporary Assessment And Management.
Diabetic foot ulcer disease is the combination of vasculopathy, neuropathy and infection. It is important to identify the main aetiology and to treat it for optimal ulcer healing so that limb amputation may be prevented. A literature review spanning five years (2018-2021) was performed to assess the current understanding of these aetiologies and management options for their treatment. Peripheral artery disease is prevalent in patients with diabetes. Before performing any amputations, whether minor or major, vascular supply in these patients needs to be evaluated and, if needed, improved. Diabetic neuropathy is a long-term complication of uncontrolled diabetes. Patients' education is very important with respect to selfcare and prevention of foot complications arising out of minor trauma in diabetic population. Better foot care and regular use of off-loading shoe wear can prevent neuropathic diabetic foot ulcers. Infection in diabetic patients is mostly polymicrobial and it can present as superficial or deep infections. Early diagnosis, use of broad-spectrum antibiotics, and aggressive debridement, when needed, is advocated to prevent foot amputation. Contemporary treatment armamentarium provides many options for treating diabetic foot ulcers. Nevertheless, one must exhaust all preventive strategies to avoid ulcers in the first place. Once an ulcer has developed, it should be managed aggressively with appropriate soft tissue and, if required, with bony procedures. The current narrative review was planned to explore the current understanding about the main aetiologies of diabetic foot ulcers and about the available treatment options.


Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular-targeted therapy.
A multicenter cooperative study was conducted to clarify the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular-targeted therapy and the clinical usefulness of the Japanese metastatic renal cancer (JMRC) prognostic classification. Of 389 consecutive patients for whom treatment was started between 2008 and 2010 at 23 hospitals in Japan, 357 patients who received vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) or cytokine as initial systemic therapy were the subject of the present study. Patients were classified into three prognostic groups according to the JMRC prognostic classification. The endpoints were progression-free survival (PFS) and overall survival (OS) after the start of the initial treatment. The median PFS and OS for the entire cohort of 357 patients were 9.1 and 27.2 months, respectively. VEGFR-TKI were selected for patients with multiple organ metastases, those with liver metastasis, and those with bone metastasis. The median PFS and OS were 11.0 and 23.2 months and 5.4 and 38.2 months in the VEGFR-TKI group and the cytokines group, respectively. The JMRC prognostic classification was useful as a prognostic model for PFS and OS (c-indexes: 0.613 and 0.630 in patients who initially received VEGFR-TKI and 0.647 and 0.642 in patients who received cytokines, respectively). The present study showed for the first time the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular-targeted therapy. The JMRC prognostic classification may be clinically useful as a prognostic model.


The effect of substituting NaCl with KCl on Nabulsi cheese: chemical composition, total viable count, and texture profile.
The effect of substituting NaCl with KCl on Nabulsi cheese characteristics was investigated. Nabulsi cheese was made and stored in 4 different brine solutions at 18%, including NaCl only (A; control); 3NaCl:1KCl (wt/wt; B); 1NaCl:1KCl (wt/wt; C); and 1NaCl:3KCl (wt/wt; D). Chemical composition, proteolysis, total viable count, and texture profile analysis were assessed at monthly intervals for 5 mo. No significant effect was found among experimental cheeses in terms of chemical composition or texture profile. Proteolytic activities were higher in cheeses kept in brine solutions that contained higher KCl (B, C, and D) compared with the control. At the end of the storage period, water-soluble nitrogen in Nabulsi cheeses stored in B, C, and D was higher than that in the control cheese (A). In addition, total viable count increased significantly after 1 mo of storage for all salt treatments. Hardness and gumminess generally decreased significantly during storage within the same salt treatment.


Hydrogen Bonding Environment of the N3-H Group of Flavin Mononucleotide in the Light Oxygen Voltage Domains of Phototropins.
The light oxygen voltage (LOV) domain is a flavin-binding blue-light receptor domain, originally found in a plant photoreceptor phototropin (phot). Recently, LOV domains have been used in optogenetics as the photosensory domain of fusion proteins. Therefore, it is important to understand how LOV domains exhibit light-induced structural changes for the kinase domain regulation, which enables the design of LOV-containing optogenetics tools with higher photoactivation efficiency. In this study, the hydrogen bonding environment of the N3-H group of flavin mononucleotide (FMN) of the LOV2 domain from Adiantum neochrome (neo) 1 was investigated by low-temperature Fourier transform infrared spectroscopy. Using specifically 15N-labeled FMN, [1,3-15N2]FMN, the N3-H stretch was identified at 2831 cm-1 for the unphotolyzed state at 150 K, indicating that the N3-H group forms a fairly strong hydrogen bond. The N3-H stretch showed temperature dependence, with a shift to lower frequencies at ≤200 K and to higher frequencies at ≥250 K from the unphotolyzed to the intermediate states. Similar trends were observed in the LOV2 domains from Arabidopsis phot1 and phot2. By contrast, the N3-H stretch of the Q1029L mutant of neo1-LOV2 and neo1-LOV1 was not temperature dependent in the intermediate state. These results seemed correlated with our previous finding that the LOV2 domains show the structural changes in the β-sheet region and/or the adjacent Jα helix of LOV2 domain, but that such structural changes do not take place in the Q1029L mutant or neo1-LOV1 domain. The environment around the N3-H group was also investigated.


Recommending Unfunded Innovative Cancer Therapies: Ethical vs. Clinical Perspectives among Oncologists on a Public Healthcare System-A Mixed-Methods Study.
Over the past decade, there has been a growing development of innovative technologies to treat cancer. Many of these technologies are expensive and not funded by health funds. The present study examined physicians' perceptions of the ethical and clinical aspects of the recommendation and use of unfunded technologies for cancer treatment. This mixed-methods study surveyed 127 oncologists regarding their perceptions toward using unfunded innovative cancer treatment technologies, followed by in-depth interviews with 16 oncologists. Most respondents believed that patients should be offered all treatment alternatives, regardless of their financial situation. However, 59% indicated that they often face dilemmas regarding recommending new unfunded treatments to patients with financial difficulties and without private health insurance. Over a third (38%) stated that they felt uncomfortable discussing the cost of treatment with patients. A predictive model found that physicians facing patients whose medical condition worsened due to an inability to access new treatments, and who expressed the opinion that physicians can assist in locating funding for patients who cannot afford treatments, were more likely to recommend unfunded innovative therapies to patients (F = 5.22, R2 = 0.15, p < 0.001). Subsequent in-depth interviews revealed four key themes: economic considerations in choosing therapy, patient-physician communication, the public healthcare fund, and discussion of treatment costs. Physicians feel a professional commitment to offer patients the best medical care and a moral duty to discuss costs and minimize patients' financial difficulty. There is a need for careful and balanced use of innovative life-prolonging technologies while putting patients at the center of discourse on this complex and controversial issue. It is essential to develop a psychosocial support program for physicians and patients dealing with ethical and psychosocial dilemmas and to set guidelines for oncologists to conduct a comprehensive and collaborative physician-patient discourse regarding all aspects of treatment.


Fifteen-minute consultation: Breastfeeding in the first 2 weeks of life-a hospital perspective.
The beneficial health and economic impacts of breastfeeding are considerable. However the majority of babies in the UK are not exclusively breastfeeding by 6 weeks of age. The first few weeks of life are therefore a critical period to facilitate breastfeeding. Health professionals must have a thorough knowledge of normal breastfeeding patterns in order to minimise unnecessary interference, and an understanding of how to protect the breastfeeding relationship when medical problems occur.


ABCB1 C1236T, G2677T/A and C3435T polymorphisms in systemic lupus erythematosus patients.
P-glycoprotein (Pgp), the ABCB1 gene product, acts as an efflux pump that transports a large variety of substrates and is a mechanism of cell protection against xenobiotics. An increasing number of studies have shown that some ABCB1 polymorphisms may affect Pgp expression and activity, as well as affecting the development and susceptibility to diseases and pharmacological response. High activity of Pgp has been detected in systemic lupus erythematosus (SLE) patients. The C1236T, G2677T/A, and C3435T are the most commonly studied single nucleotide polymorphisms in the ABCB1 gene. Therefore, their frequencies were determined in Brazilian individuals with European ancestry (N = 143) and in SLE patients (N = 137). Genotyping was performed by PCR-RFLP analysis using specific primers followed by incubation with the appropriate restriction enzymes. The resulting DNA fragments were visualized on agarose or polyacrylamide gels. No statistically significant differences were observed in allelic and genotypic frequencies between SLE and healthy subjects (Fisher exact test). Nevertheless, the 2677A allelic frequency was lower in SLE patients with malar rash (0.007) compared with patients without this feature (0.04; P = 0.0054), while the frequency of this variant was higher in SLE patients with pleuritis (0.07) compared with patients without this feature (0.01; P = 0.0156). We suggest that although the ABCB1 polymorphisms do not directly interfere in SLE susceptibility, their evaluation, especially the 2677A allele, in other immunological processes may be interesting since they can interfere in clinical features of this disease.


A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization.
Microtubules are cylindrical protein polymers formed from αβ-tubulin heterodimers in the cytoplasm of eukaryotic cells. Microtubule disturbance may cause cell cycle arrest in the G2/M phase, and anomalous mitotic spindles will form. Microtubules are an important target for cancer drug action because of their critical role in mitosis. Several microtubule-targeting agents with vast therapeutic advantages have been developed, but they often lead to multidrug resistance and adverse side effects. Thus, single-target therapy has drawbacks in the effective control of tubulin polymerization. Molecular hybridization, based on the amalgamation of two or more pharmacophores of bioactive conjugates to engender a single molecular structure with enhanced pharmacokinetics and biological activity, compared to their parent molecules, has recently become a promising approach in drug development. The practical application of combined active scaffolds targeting tubulin polymerization inhibitors has been corroborated in the past few years. Meanwhile, different designs and syntheses of novel anti-tubulin hybrids have been broadly studied, illustrated, and detailed in the literature. This review describes various molecular hybrids with their reported structural-activity relationships (SARs) where it is possible in an effort to generate efficacious tubulin polymerization inhibitors. The aim is to create a platform on which new active scaffolds can be modeled for improved tubulin polymerization inhibitory potency and hence, the development of new therapeutic agents against cancer.


Immunomodulation by gut microbiota: role of Toll-like receptor expressed by T cells.
A close relationship exists between gut microbiota and immune responses. An imbalance of this relationship can determine local and systemic immune diseases. In fact the immune system plays an essential role in maintaining the homeostasis with the microbiota that normally resides in the gut, while, at the same time, the gut microbiota influences the immune system, modulating number and function of effector and regulatory T cells. To achieve this aim, mutual regulation between immune system and microbiota is achieved through several mechanisms, including the engagement of toll-like receptors (TLRs), pathogen-specific receptors expressed on numerous cell types. TLRs are able to recognize ligands from commensal or pathogen microbiota to maintain the tolerance or trigger the immune response. In this review, we summarize the latest evidences about the role of TLRs expressed in adaptive T cells, to understand how the immune system promotes intestinal homeostasis, fights invasion by pathogens, and is modulated by the intestinal microbiota.


Diagnosis of lysosomal storage disorders: evaluation of lysosome-associated membrane protein LAMP-1 as a diagnostic marker.
Early diagnosis of lysosomal storage disorders (LSDs), before the onset of irreversible pathologies, will be a key factor in the development of effective therapies for many of these disorders. Newborn screening offers a potential mechanism for the early detection of these disorders. From studies of both normal and LSD-affected human skin fibroblasts we identified the lysosome-associated membrane protein LAMP-1 as a potential diagnostic marker. We have developed a sensitive method for the quantification of this protein with a time-resolved fluorescence immunoassay. A soluble form of LAMP-1 was observed in plasma samples, and determination of 152 unaffected individuals gave a median value of 303 micrograms/L with the 5th and 95th percentile at 175 and 448 micrograms/L respectively. Plasma samples from 320 LSD-affected individuals representing 25 different disorders were assayed. We observed that 17 of the 25 disorder groups tested had > 88% of individuals above the 95th percentile of the control population, with 12 groups having 100% above the 95th percentile. Overall, 72% of patients had LAMP-1 concentrations above the 95th percentile of the unpartitioned control population. We suggest that LAMP-1 may be a useful marker in newborn screening for LSDs.


[The choice of the surgical procedure in treating a chronic disorder of the arterial blood supply to the brain].
Results of surgical treatment of 336 patients with chronic disorder of the brain arterial blood supply were summarized. Surgical tactics provided for maximum brain revascularization by means of simultaneous intervention on two-three arteries. Technical aspects of operative procedures elaborated in clinic are presented. Late follow-up results noted were good in 60.1% and fair--in 25.7%.


Fitness Measures Among Boy Scouts Completing the Personal Fitness Merit Badge.
Introduction A formative framework for positive lifestyle and health behaviors is established during adolescence. The Boy Scouts of America (BSA) is one organization that promotes healthy lifestyles among adolescent males and includes earning the Personal Fitness Merit Badge (PFMB). Despite the BSA Oath "to keep myself physically strong", there is a paucity of evidence describing fitness test (FT) outcomes or correlations between FT and variables including age or body mass index (BMI) among Boy Scouts. Therefore, the purpose of this study is to describe and correlate FT to age and BMI among adolescent Boy Scouts. Methods A prospective study design recruited Boy Scouts aged 11-17 years from Southeast Michigan using a sample of convenience. After securing physician clearance to participate, FT measures were performed utilizing previously established methodology. Third year doctor of physical therapy students trained in the measurement protocol performed the FT measures. Measures encompassed those required for the PFMB: BMI, pull-ups, push-ups, sit and reach flexibility test (SRF), sit-ups, and the one mile run (1MR). Data was analyzed using descriptive statistics, a Kruskal-Wallis test examined relationships between BMI and FT, and a nonparametric Spearman correlation examined correlations between FT performance and both age and BMI with statistical significance set at less than 0.05. Results Ninety-nine Boy Scouts, whose mean age was 12.6 years (SD 1.4), met the inclusion criteria. The mean BMI was 21.5 (kg/height (cm)) 2 (SD 5.4) with eight scouts meeting criteria of underweight, 56 normal weight, 14 overweight, and 21 obese. Fitness test results were as follows: pull-ups 1.75 (SD 2.7), push-ups 18.0 (SD 10.6), SRF 21.2 cm (SD 10.5), sit-ups 28.9 (SD 8.7), and the 1MR run 616.5 seconds (SD 156.8). When comparing normal weight scouts to overweight and obese scouts, a significantly higher frequency of pull-ups (p=0.002, p=.001), push-ups (p=0.02, p=0.03), sit-ups (p=0.01, p=0.003,), and decreased time for completion on the 1MR (p=0.001, p=0.001) was identified, respectively. Furthermore, while no correlations were identified by age, a negative correlation was identified between increased sit-up frequency (r=-0.36, p=0.001) and decreased 1MR time performance (r=0.39, p=0.001) and a higher BMI. Discussion While prior evidence suggests improved FT scores in adolescent males with advancing age, this was not observed. Less favorable PFMB required FT performance with an increased BMI among Boy Scouts is in congruence with prior reports for adolescent males. Conclusion Variations in FT performance levels were observed among Boy Scouts completing the initial FT requirements of the PFMB. However, correlations between higher BMI and less favorable FT performance were detected.


Genetic alteration in drug resistance markers of Plasmodium falciparum.
Plasmodium falciparum shows plasticity in its genome. For its survival it can delete certain genes (or portions) if not needed for its growth and has the capability to regulate its genes under various stages of its life cycle as well as under unfavourable environmental conditions. Parasite shows enormous amount of antigenic variation under immune pressure leading to the emergence of vaccine resistant strains. Similarly, under drug pressure it allows mutations to settle in the target genes. It is becoming more and more clear that with the continuous exposure to a drug, the parasite accumulates more and more number of mutations in these genes. By measuring the number of these point mutations among field isolates one can predict the efficacy of a particular drug. Therefore, these markers are useful tools at epidemiological level. This molecular surveillance can also help in slowing down the drug resistance if supported by a careful drug usage policy. Further studies are required to develop molecular markers for rest of the antimalarial drugs as well as the improvement on the existing molecular tools for accurate and rapid detection of drug resistant malaria.


Emergency department diversions: hospital and community strategies alleviate the crisis.
A nationwide surge in emergency department ambulance diversions in 2000-01 raised concerns about access and quality of care for critically ill patients, but the diversion problem has improved markedly over the past two years, according to findings from the Center for Studying Health System Change's (HSC) 2002-03 site visits to 12 nationally representative communities. Hospital efforts to improve bed management and patient flow, as well as community initiatives to monitor and control diversions, have played key roles in easing the problem. The success in bringing the diversion crisis under control offers an important lesson for policy makers--much can be done to better manage existing hospital capacity before potentially costly expansions are made.


Pseudomonas aeruginosa MutL protein functions in Escherichia coli.
Escherichia coli MutS, MutL and MutH proteins act sequentially in the MMRS (mismatch repair system). MutH directs the repair system to the newly synthesized strand due to its transient lack of Dam (DNA-adenine methylase) methylation. Although Pseudomonas aeruginosa does not have the corresponding E. coli MutH and Dam homologues, and consequently the MMRS seems to work differently, we show that the mutL gene from P. aeruginosa is capable of complementing a MutL-deficient strain of E. coli. MutL from P. aeruginosa has conserved 21 out of the 22 amino acids known to affect functioning of E. coli MutL. We showed, using protein affinity chromatography, that the C-terminal regions of P. aeruginosa and E. coli MutL are capable of specifically interacting with E. coli MutH and retaining the E. coli MutH. Although, the amino acid sequences of the C-terminal regions of these two proteins are only 18% identical, they are 88% identical in the predicted secondary structure. Finally, by analysing (E. coli-P. aeruginosa) chimaeric MutL proteins, we show that the N-terminal regions of E. coli and P. aeruginosa MutL proteins function similarly, in vivo and in vitro. These new findings support the hypothesis that a large surface, rather than a single amino acid, constitutes the MutL surface for interaction with MutH, and that the N- and C-terminal regions of MutL are involved in such interactions.


Male sex as a risk factor for the clinical course of skull base chordomas.
Chordomas of the skull base are rare and locally invasive and have a poor prognosis. The aim of this retrospective multicenter study was to evaluate the current pattern of care and clinical course and to identify prognostic factors. A total of 47 patients (26 men; mean age 48.5 years) treated in 5 centers were included. Histology was centrally reviewed; additionally, semiquantitative N- and E-cadherin expression analysis was performed. Prognostic factors were obtained from multivariate regression models. For survival analysis the Kaplan-Meier method was used. The median follow-up period was 5.2 years. Complete resection, incomplete resection, and extended biopsy were performed in 14.9%, 80.9%, and 4.3% of patients, respectively. Surgical morbidity was not associated with extent of resection. Adjuvant radiation therapy was performed in 30 (63.8%) of 47 patients. The median progression-free survival (PFS) was 7.3 years. Complete resection prolonged median overall survival (OS) (p = 0.04). Male patients presented with worse PFS (4.8 years vs 9.8 years; p = 0.04) and OS (8.3 years vs not reached; p = 0.03) even though complete resection was exclusively achieved in the male subpopulation. Multivariate analysis confirmed male sex as the most important risk factor for tumor progression (p = 0.04) and death (p = 0.02). Age, duration of symptoms, initial Karnofsky Performance Scale score, brainstem compression, involvement of the petrous bone, infiltration of the dura mater, modality and dose of radiation therapy, and the E- and N-cadherin expression patterns did not gain prognostic relevance. In skull base chordomas, male patients bear a higher risk of progressive disease and death. Male patients might benefit from more aggressive adjuvant therapy and/or from a closer follow-up schedule.


mTOR Pathway and mTOR Inhibitors in Head and Neck Cancer.
Head and neck cancer is the sixth most common type of Cancer worldwide. Since conventional treatment regimens are nonselective and are associated with systemic toxicities, intense investigations focus on molecular targeted therapy with high selectivity and low adverse effects. mTOR signaling pathway has been found to be activated in head and neck cancer, making it attractive for targeted therapy. In addition, expression levels of mTOR and downstream targets eIF4E, 4EBP1, S6K1, and S6 are potential diagnostic and prognostic biomarkers for head and neck cancer. mTOR inhibitors, such as rapamycin and its derivatives temsirolimus and everolimus, exhibit inhibitory effects on head and neck cancer in both in vitro cell line model and in vivo xenograft model. A large number of clinical trials have been initiated to evaluate the therapeutic effects of mTOR inhibitors on patients with head and neck cancer. mTOR inhibitor has potential as a single therapeutic agent or in combination with radiation, chemotherapeutic agents, or other targeted therapeutic agents to obtain synergistic repression on head and neck cancer.


[Complex evaluation of protein, purinic, carbohydrate and lipid metabolism in moderate and intense muscular activities].
The purpose of the current study was to investigate findings, peculiarities, parameters and indicators of protein, carbohydrate, lipid and purinic metabolism in the blood, erythrocytes and homogenate of femur muscles in case of moderate and maximal physical exertion. 24 male rats were studied. The above rats underwent muscular exertion in the form of loads during swimming. The load accounted for 10% of the body weight. Specific changes of metabolism due to the influence of moderate and maximal physical muscular exertion were revealed. Mechanisms of atherogenic effects in maximal muscular exertion are discussed.


Sol-gel transition of nanoparticles/polymer mixtures for sustained delivery of exenatide to treat type 2 diabetes mellitus.
The sol-gel transition of nanoparticles (NPs)/polymer mixture in aqueous medium was investigated for the sustained delivery of exenatide to treat type 2 diabetes mellitus. Exenatide-loaded multilayer NPs were prepared using a layer-by-layer approach which utilized the interaction between Pluronics and lipid bilayers as the main driving force for the construction of the multilayer. Pluronic F-127 was the polymer used, and it forms a gel at body temperature. Although the antidiabetic effects of exenatide-loaded multilayer NPs have been demonstrated previously in an animal model, in this work, the attempt was made to demonstrate the extended duration of antidiabetic effects, which was accomplished by localizing the exenatide-loaded NPs in muscular areas in the body through the gelation of Pluronic F-127. Transmittance electron microscopy and dynamic light scattering were used to examine the morphology of the multilayer NPs/polymer mixture. A change in the release pattern of exenatide was observed after gel formation at body temperature, and Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis was performed using native exenatide and a reference biomarker as control to observe whether exenatide extracted from the multilayer NPs and the multilayer NPs/Pluronic F-127 mixture degraded or not. We then observed the antidiabetic effect of exenatide-loaded multilayer NPs/Pluronic F-127 mixture by monitoring blood-glucose levels in db/db mice. In vitro and in vivo correlation was discussed regarding structural variation in the delivery vehicles.


Chromoblastomycosis murine model and in vitro test to evaluate the sensitivity of Fonsecaea pedrosoi to ketoconazole, itraconazole and saperconazole.
An experimental model of murine chromoblastomycosis and in vitro tests with Fonsecaea pedrosoi were used to test the sensitivity of this fungus to three different antimycotics. The experimental model was standardized in BALB/c mice inoculated intraperitoneally with a 10(6) CFU/ml suspension of a F. pedrosoi isolate. Clinical infection was evident after 5 days of inoculation. Three groups of 27 mice each were used in the experiment. One group was treated with ketoconazole (KTZ), another with itraconazole (ITZ) and the other with saperconazole (SPZ). Antimycotic therapy was continued for 21 days. The control group consisted of 40 mice which were inoculated, but not treated. Infection was documented by macroscopic and microscopic examination of affected tissue in addition to culture of tissue macerates. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) for the F. pedrosoi strain used were done. The in vitro results showed that SPZ was the most active with MIC 0.01 microgram/ml and MFC 0.1 microgram/ml, followed by ITZ. SPZ was also the most effective in vivo since 63% of the treated animals (p = 0.01) showed a curative effect after the observation period. We concluded that SPZ had the best in vitro and in vivo activity against F. pedrosoi.


On the genus Thalerommata Ausserer, 1875 (Araneae, Theraphosidae), with the description of six new species.
The poorly known mygalomorph genus Thalerommata Ausserer, 1875 is redescribed and rediagnosed. Thalerommata gracilis Ausserer, 1875 (type species) and T. macella (Simon, 1903) are rediagnosed. Thalerommata meridana (Chamberlin & Ivie, 1938) is considered a nomen dubium. Six new species are described: T. squamea n. sp., T. huila n. sp., T. splendens n. sp., T. pecki n. sp., T. maculata n. sp., and T. gertschi n. sp. Thalerommata is transferred from Barychelidae to Theraphosidae and considered closely related with Trichopelma Simon, 1888, with which it shares the biserially dentate superior tarsal claws in males in combination with non-incrassate PLS. The genus is distributed from northern South-America to the Caribbean.


Heroin incidence: a trend comparison between National Household Survey data and indicator data.
Because of the small proportion of the population reporting ever having used heroin, the year of first use data from NIDA's National Household Surveys on Drug Abuse conducted in 1977, 1979, and 1982 were pooled to show the number of new users in the household population by year of first use. In addition, the data were "smoothed" by using a 2-year moving average. The early 1970s and the mid-1970s epidemics were evident. These epidemic periods occurred at the same periods reported by high school seniors and by heroin users in treatment. The household self-report data trends based on age and frequency of use were also consistent with the trends in periods of initiation reported by heroin users in treatment as noted in drug abuse treatment admission data for year of first heroin use. Trends in indicators of heroin epidemics were compared with trends based on self-report data from the National Household Surveys. The trends in hepatitis B cases, heroin-related emergency room visits, heroin-related deaths, and the average retail heroin purity were consistent with the epidemic periods suggested by the household data. This consistency among the three sources of self-reported data on trends in year of first heroin use combined with the consistency of these self-reported data with the trends based on the indicators of heroin epidemics offers some validation to the use of retrospective direct questions concerning age of first use of heroin to monitor heroin incidence in the household population.


Special Section on Selected Topics in Biophotonics: Translating Novel Photonics Technology into Clinical Applications.
The editorial introduces the JBO Special Section on Selected Topics in Biophotonics: Translating Novel Photonics Technology into Clinical Applications.