EAU Guidelines on the Assessment of Non-neurogenic Male Lower Urinary Tract Symptoms including Benign Prostatic Obstruction.
Lower urinary tract symptoms (LUTS) represent one of the most common clinical complaints in adult men and have multifactorial aetiology. To develop European Association of Urology (EAU) guidelines on the assessment of men with non-neurogenic LUTS. A structured literature search on the assessment of non-neurogenic male LUTS was conducted. Articles with the highest available level of evidence were selected. The Delphi technique consensus approach was used to develop the recommendations. As a routine part of the initial assessment of male LUTS, a medical history must be taken, a validated symptom score questionnaire with quality-of-life question(s) should be completed, a physical examination including digital rectal examination should be performed, urinalysis must be ordered, post-void residual urine (PVR) should be measured, and uroflowmetry may be performed. Micturition frequency-volume charts or bladder diaries should be used to assess male LUTS with a prominent storage component or nocturia. Prostate-specific antigen (PSA) should be measured only if a diagnosis of prostate cancer will change the management or if PSA can assist in decision-making for patients at risk of symptom progression and complications. Renal function must be assessed if renal impairment is suspected from the history and clinical examination, if the patient has hydronephrosis, or when considering surgical treatment for male LUTS. Uroflowmetry should be performed before any treatment. Imaging of the upper urinary tract in men with LUTS should be performed in patients with large PVR, haematuria, or a history of urolithiasis. Imaging of the prostate should be performed if this assists in choosing the appropriate drug and when considering surgical treatment. Urethrocystoscopy should only be performed in men with LUTS to exclude suspected bladder or urethral pathology and/or before minimally invasive/surgical therapies if the findings may change treatment. Pressure-flow studies should be performed only in individual patients for specific indications before surgery or when evaluation of the pathophysiology underlying LUTS is warranted. These guidelines provide evidence-based practical guidance for assessment of non-neurogenic male LUTS. An extended version is available online (www.uroweb.org/guidelines). This article presents a short version of European Association of Urology guidelines for non-neurogenic male lower urinary tract symptoms (LUTS). The recommended tests should be able to distinguish between uncomplicated male LUTS and possible differential diagnoses and to evaluate baseline parameters for treatment. The guidelines also define the clinical profile of patients to provide the best evidence-based care. An algorithm was developed to guide physicians in using appropriate diagnostic tests.


Body Muscle-to-Fat Ratio, Rather Than Fat-to-Muscle Ratio, Significantly Correlates With Measured Insulin Resistance in Patients With Type 2 Diabetes Mellitus.
Insulin resistance (IR) assessment is important in treating type 2 diabetes mellitus (T2DM). We thus compared body muscle-to-fat ratio (BMFR) and fat-to-muscle ratio (FMR) values against M/I values as clinical index of IR. Subject included 118 untreated T2DM patients. Hyperinsulinemic-euglycemic clamp examination was performed to calculate the M/I as index of IR. Body composition was measured by impedance analysis using InBody770. Simple linear regression analyses confirmed correlations between M/I and BMFR (B: 0.756 (P < 0.01), coefficients of determination (R2): 0.572, mean absolute error (MAE): 3.19, and root mean squared error (RMSE): 4.14), and between M/I and FMR (B: -0.601 (P < 0.01), R2: 0.362, MAE: 3.97, and RMSE: 5.05). Against the M/I values, BMFR also showed better goodness-of-fit than did FMR. In comparing correlation coefficients, the BMFR absolute B value was significantly larger than that of FMR (P = 0.027). BMFR is more useful than FMR in quantifying IR in patients with T2DM because the correlation between BMFR and the insulin sensitivity index M/I is significantly greater than that between FMR and M/I.


Exploring the evolution of novel enzyme functions within structurally defined protein superfamilies.
In order to understand the evolution of enzyme reactions and to gain an overview of biological catalysis we have combined sequence and structural data to generate phylogenetic trees in an analysis of 276 structurally defined enzyme superfamilies, and used these to study how enzyme functions have evolved. We describe in detail the analysis of two superfamilies to illustrate different paradigms of enzyme evolution. Gathering together data from all the superfamilies supports and develops the observation that they have all evolved to act on a diverse set of substrates, whilst the evolution of new chemistry is much less common. Despite that, by bringing together so much data, we can provide a comprehensive overview of the most common and rare types of changes in function. Our analysis demonstrates on a larger scale than previously studied, that modifications in overall chemistry still occur, with all possible changes at the primary level of the Enzyme Commission (E.C.) classification observed to a greater or lesser extent. The phylogenetic trees map out the evolutionary route taken within a superfamily, as well as all the possible changes within a superfamily. This has been used to generate a matrix of observed exchanges from one enzyme function to another, revealing the scale and nature of enzyme evolution and that some types of exchanges between and within E.C. classes are more prevalent than others. Surprisingly a large proportion (71%) of all known enzyme functions are performed by this relatively small set of 276 superfamilies. This reinforces the hypothesis that relatively few ancient enzymatic domain superfamilies were progenitors for most of the chemistry required for life.


Enhanced Succinate Oxidation with Mitochondrial Complex II Reactive Oxygen Species Generation in Human Prostate Cancer.
The transformation of prostatic epithelial cells to prostate cancer (PCa) has been characterized as a transition from citrate secretion to citrate oxidation, from which one would anticipate enhanced mitochondrial complex I (CI) respiratory flux. Molecular mechanisms for this transformation are attributed to declining mitochondrial zinc concentrations. The unique metabolic properties of PCa cells have become a hot research area. Several publications have provided indirect evidence based on investigations using pre-clinical models, established cell lines, and fixed or frozen tissue bank samples. However, confirmatory respiratory analysis on fresh human tissue has been hampered by multiple difficulties. Thus, few mitochondrial respiratory assessments of freshly procured human PCa tissue have been published on this question. Our objective is to document relative mitochondrial CI and complex II (CII) convergent electron flow to the Q-junction and to identify electron transport system (ETS) alterations in fresh PCa tissue. The results document a CII succinate: quinone oxidoreductase (SQR) dominant succinate oxidative flux model in the fresh non-malignant prostate tissue, which is enhanced in malignant tissue. CI NADH: ubiquinone oxidoreductase activity is impaired rather than predominant in high-grade malignant fresh prostate tissue. Given these novel findings, succinate and CII are promising targets for treating and preventing PCa.


The profile of high-risk pregnancy in El-Mansoura city.
Proper screening techniques should be used for all pregnant women attending antenatal clinics to pick up the factors that qualify the pregnant women for a risky pregnancy. High-risk pregnancy identification is a challenging work. This study aimed to describe the profile of high-risk pregnancy in El-Mansoura city. The study was conducted on 750 pregnant women attending antenatal clinics in three hospitals in El-Mansoura city, where 250 women were chosen from each setting. A modified version of Morrison and Olsen (1979) high risk scoring inventory tool was used to collect the socioeconomic, biological, medical, reproductive and current pregnancy risk factors in the study sample. It also assessed the risk level whether low, moderate or high. The results revealed that among all women, 63.8% of the sample were at a high-risk, while 25.0 % of them were at a moderate-risk and only 11.2% were at low-risk. About 70.0% of the high-risk pregnant women were in their third trimester followed by 23.0% in the second trimester and only 7.1% were in the first trimester. About 5.9% of the women were at a high-risk because of polluted housing condition, 1.9% because of heart diseases Class capital I, Ukrainian or II, 5.2% because of diabetes mellitus, 4.2% because of hypertension and 14.9% because of previous cesarean section. On the other hand 14.8% women were at moderate risk because of their illiteracy, 29.2% of them for being short, 14.7%, 10.6% of them because of being teenagers or over 35 years of age, respectively, 12.6% of because they had a history of gestational diabetes and 32.8%of them because of anemia, 23.2% because urinary tract infection, 16.9% because of albuminuria, and 12.0% because of glucoseuria. Finally identifying the profile of high -risk pregnancy women is mandatory.


Ultrasound-Guided Percutaneous Radiofrequency Ablation of Liver Metastasis From Ovarian Cancer: A Single-Center Initial Experience.
The aim of this study was to evaluate the feasibility, effectiveness, and safety of ultrasound-guided percutaneous radiofrequency ablation (RFA) for the treatment of liver metastasis from ovarian cancer (OC). A retrospective review was performed on 11 patients (mean age, 53.0 ± 10.1 years) with 22 liver metastases (mean diameter, 2.0 ± 0.8 cm) from OC undergone RFA. Radiofrequency ablation was carried out with Starburst XL electrodes (RITA Medical System, Mountain View, CA) or Cool-tip electrodes (Cool-tip Systems; Valleylab, Boulder, CO). The tumor response, time to progression, and survival after RFA were assessed. Complete ablation was achieved for all lesions. The technique effectiveness was 100%. During the follow-up period, local tumor progression was observed in 1 (4.5%) of 22 lesions. The median time to progression was 8.0 months after RFA. Three patients died because of disease progression after 13, 18, and 24 months, respectively. The mean overall survival time after RFA was 53.1 ± 10.0 months, with the 1-, 3-, and 5-year overall survival rates of 100%, 61%, and 61%, respectively. No major complications were encountered. Radiofrequency ablation as an alternative treatment strategy is feasible and effective for selected patients with liver metastasis from OC, providing a high rate of local tumor control.


In-Plane Propagation of Light in Transition Metal Dichalcogenide Monolayers: Optical Selection Rules.
The optical selection rules for interband transitions in WSe_{2}, WS_{2}, and MoSe_{2} transition metal dichalcogenide monolayers are investigated by polarization-resolved photoluminescence experiments with a signal collection from the sample edge. These measurements reveal a strong polarization dependence of the emission lines. We see clear signatures of the emitted light with the electric field oriented perpendicular to the monolayer plane, corresponding to an interband optical transition forbidden at normal incidence used in standard optical spectroscopy measurements. The experimental results are in agreement with the optical selection rules deduced from group theory analysis, highlighting the key role played by the different symmetries of the conduction and valence bands split by the spin-orbit interaction. These studies yield a direct determination of the bright-dark exciton splitting, for which we measure 40±1 meV and 55±2 meV in WSe_{2} and WS_{2} monolayer, respectively.


Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis.
The genus Flavivirus contains many important pathogens, including dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). AR-12 is a celecoxib-derived anticancer agent that possesses antiviral activity against a broad range of viruses. We pharmacologically exploited this unique activity to develop additional antiviral agents, resulting in the production of the AR-12 derivatives P12-23 and P12-34. At nanomolar concentrations, these compounds were effective in suppressing DENV, ZIKV and JEV replication, exhibiting 10-fold improvements in the efficacy and selectivity indices as compared to AR-12. Regarding the mode of antiviral action, P12-23 and P12-34 inhibited viral RNA replication but had no effect on viral binding, entry or translation. Moreover, these AR-12 derivatives co-localized with mitochondrial markers, and their antiviral activity was lost in mitochondria-depleted cells. Interestingly, exogenous uridine or orotate, the latter being a metabolite of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), abolished the antiviral activity of AR-12 and its derivatives. As DHODH is a key enzyme in the de novo pyrimidine biosynthesis pathway, these AR-12 derivatives may act by targeting pyrimidine biosynthesis in host cells to inhibit viral replication. Importantly, treatment with P12-34 significantly improved the survival of mice that were subcutaneously challenged with DENV. Thus, P12-34 may warrant further evaluation as a therapeutic to control flaviviral outbreaks.


Do untreated intraspinal anomalies in congenital scoliosis impact the safety and efficacy of spinal correction surgery? A retrospective case-control study.
Intraspinal anomalies associated with congenital scoliosis (CS) complicate the decision-making process for spinal correction surgery in CS patients. Recently, deformity correction surgery without prior prophylactic neurological intervention has been recognized to be safe in CS patients with intact or stable neurological status. However, no case-control study has identified the surgical outcomes and risks of spinal correction surgery in this patient population. The authors sought to investigate the safety and efficacy of spinal correction surgery for CS associated with untreated intraspinal anomalies (split cord malformation [SCM], tethered cord, and/or syringomyelia) with intact or stable neurological status. A group of CS patients with intraspinal anomalies (CS+IA) and another group of CS patients without intraspinal anomalies (CS-IA) undergoing 1-stage posterior correction surgery were retrospectively reviewed. The radiographic and clinical outcomes and postoperative complications were compared between the 2 groups. There were 57 patients in the CS+IA group and 184 patients in the CS-IA group. No significant difference was observed in age, sex, spinal curve pattern, main Cobb angle, and flexibility of the main curve between the 2 groups (p > 0.05 for all). The postoperative correction rates of the major curve were comparable between the 2 groups (53.5% vs 55.7% for the CS+IA and CS-IA groups, respectively, p > 0.05). No significant difference was observed in the incidence of either implant-related or neurological complications between 2 groups. No patients in the CS+IA group developed neurological complications, whereas 1 patient in the CS-IA group experienced transient weakness of the left lower extremity after surgery. Coexisting intraspinal anomalies (SCM, tethered cord, and/or syringomyelia) in CS patients with normal or stable neurological status do not significantly increase the risk of neurological complications of correction surgery. Prophylactic neurosurgical intervention for intraspinal anomalies before correction surgery might be unnecessary for these patients.


Outbreaks of short-incubation ocular and respiratory illness following exposure to indoor swimming pools.
Chlorination destroys pathogens in swimming pool water, but by-products of chlorination can cause human illness. We investigated outbreaks of ocular and respiratory symptoms associated with chlorinated indoor swimming pools at two hotels. We interviewed registered guests and companions who stayed at hotels X and Y within 2 days of outbreak onset. We performed bivariate and stratified analyses, calculated relative risks (RR), and conducted environmental investigations of indoor pool areas. Of 77 guests at hotel X, 47 (61%) completed questionnaires. Among persons exposed to the indoor pool area, 22 (71%) of 31 developed ocular symptoms [RR = 24; 95% confidence interval (CI), 1.5-370], and 14 (45%) developed respiratory symptoms (RR = 6.8; 95% CI, 1.0-47) with a median duration of 10 hr (0.25-24 hr). We interviewed 30 (39%) of 77 registered persons and 59 unregistered companions at hotel Y. Among persons exposed to the indoor pool area, 41 (59%) of 69 developed ocular symptoms (RR = 24; 95% CI, 1.5-370), and 28 (41%) developed respiratory symptoms (RR = 17; 95% CI, 1.1-260) with a median duration of 2.5 hr (2 min-14 days). Four persons sought medical care. During the outbreak, the hotel X's ventilation system malfunctioned. Appropriate water and air samples were not available for laboratory analysis. CONCLUSIONS AND RELEVANCE TO PROFESSIONAL PRACTICE: Indoor pool areas were associated with illness in these outbreaks. A large proportion of bathers were affected; symptoms were consistent with chloramine exposure and were sometimes severe. Improved staff training, pool maintenance, and pool area ventilation could prevent future outbreaks.


CD20-negative T-cell-rich B-cell lymphoma as a progression of a nodular lymphocyte-predominant Hodgkin's lymphoma treated with rituximab: a molecular analysis using laser capture microdissection.
Rituximab is a chimeric anti-CD20 monoclonal antibody. It has shown efficacy in patients with B-cell non-Hodgkin lymphoma and also in CD20-positive Hodgkin lymphoma. Recently, CD20-negative tumors have been described after Rituximab therapy. We report a 34-year-old man with a history of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), treated with different chemotherapy regimens, including anthracyclines and Rituximab. After 4 years in complete remission, he developed a CD20-negative T-cell-rich B-cell lymphoma (TCRBCL) presenting as multiple lung lesions. This case shows the difficulties in the diagnosis of CD20-negative lymphomas when the number of tumor cells is low and when they are found in a predominant T-cell context. Using anti-CD79a as a B-cell marker is mandatory to overcome the difficulties in identifying these tumors. Moreover, this case illustrates the usefulness of laser capture microdissection to obtain purified cell populations for molecular studies in lymphomas with relative paucity of tumor cells, as well as the need to analyze different IgH gene regions to decrease the rate of false-negative results in PCR clonality studies.


Clinical manifestations, complications, and treatment of brucellosis: evaluation of 72 cases.
Brucellosis is an important disease in developing countries. We aimed to determine the epidemiologic, clinical, and laboratory characteristics of brucellosis, which still has a high morbidity in Turkey. Seventy-two patients with brucellosis, monitored at our clinic from January 2004 to July 2010, were reviewed retrospectively. The average age was determined to be 44.8 ± 18 years, and 40 of the patients were female (55.6%). The most frequent transmission route was the use of raw milk and dairy products, in 45 of the patients (62.5%). The most frequent complaints were joint pain, high fever, weakness, low back pain, and gastrointestinal symptoms, whereas the most frequent physical examination findings were fever, osteoarticular involvement, splenomegaly, hepatomegaly, and lymphadenopathy. All of the patients were positive for Rose Bengal testing. The standard tube agglutination titer was 1/160 or higher in 64 (88.9%) patients. Brucella melitensis was isolated from blood cultures of 13 (18.1%) patients and bone marrow cultures of 7 (9.7%) patients. Complications of sacroiliitis in 6 (8.3%), spondylodiscitis in 4 (5.6%), endocarditis in 2 (2.8%), neurobrucellosis in 1 (1.4%), and epididymo-orchitis in 1 (1.4%) of the patients were observed. Brucellosis has various clinical presentations. It should be included in the differential diagnosis of high fever and joint pains in endemic countries.


Laryngotracheal consequences of pediatric cardiac surgery.
To determine the incidence and character of clinically significant laryngotracheal anomalies in pediatric patients undergoing surgical repair of congenital cardiac defects at a tertiary care center. Single-center retrospective review. The charts of pediatric patients who required surgical treatment for congenital heart disease over a 4-year period were reviewed. Forty-eight of 1957 patients were seen in inpatient consultation by the otolaryngology service. The parameters studied included cardiac diagnosis, reason for consultation, findings on examination, and follow-up. There were 16 (33%) cases of subglottic stenosis, which were graded according to the Cotton-Myer classification system as follows: grade 1 (n=8); grade 2 (n=3); and grade 3 (n=5). Three of the 16 patients with subglottic stenosis required tracheotomy and 4 required laryngotracheal reconstruction. Nine (19%) of the 48 patients were diagnosed as having unilateral true vocal cord paralysis and 3 (6%) as having bilateral paralysis. With the exception of 1 patient, all patients with true vocal cord paralysis on the left side had undergone repair of the aortic arch. Pediatric patients with congenital cardiac disease are predisposed to laryngeal anomalies owing to (1) frequent intubation, (2) prolonged ventilatory support, and (3) recurrent laryngeal nerve injury. In our patients, subglottic stenosis was the most common laryngeal abnormality. When recognized early, in the eschar phase, most of these cases can be managed with sequential endoscopic debridement, which is conceptually similar to debridement that is performed after functional endoscopic sinus surgery. Established stenosis requires more vigorous intervention, the invasive degree of which depends on the length and circumference of the narrowing. Unilateral vocal paralysis tends to be a self-limited problem, while an elegant solution to bilateral paralysis remains elusive.


Catalysis by the JmjC histone demethylase KDM4A integrates substrate dynamics, correlated motions and molecular orbital control.
The N ε-methyl lysine status of histones is important in the regulation of eukaryotic transcription. The Fe(ii) and 2-oxoglutarate (2OG) -dependent JmjC domain enzymes are the largest family of histone N ε-methyl lysine demethylases (KDMs). The human KDM4 subfamily of JmjC KDMs is linked with multiple cancers and some of its members are medicinal chemistry targets. We describe the use of combined molecular dynamics (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) methods to study the mechanism of KDM4A, which catalyzes demethylation of both tri- and di-methylated forms of histone H3 at K9 and K36. The results show that the oxygen activation at the active site of KDM4A is optimized towards the generation of the reactive Fe(iv)-oxo intermediate. Factors including the substrate binding mode, correlated motions of the protein and histone substrates, and molecular orbital control synergistically contribute to the reactivity of the Fe(iv)-oxo intermediate. In silico substitutions were performed to investigate the roles of residues (Lys241, Tyr177, and Asn290) in substrate orientation. The Lys241Ala substitution abolishes activity due to altered substrate orientation consistent with reported experimental studies. Calculations with a macrocyclic peptide substrate analogue reveal that induced conformational changes/correlated motions in KDM4A are sequence-specific in a manner that influences substrate binding affinity. Second sphere residues, such as Ser288 and Thr289, may contribute to KDM4A catalysis by correlated motions with active site residues. Residues that stabilize key intermediates, and which are predicted to be involved in correlated motions with other residues in the second sphere and beyond, are shown to be different in KDM4A compared to those in another JmjC KDM (PHF8), which acts on H3K9 di- and mono-methylated forms, suggesting that allosteric type inhibition is of interest from the perspective of developing selective JmjC KDM inhibitors.


Sonographic study of repair, gapping and tendon bowstringing after primary flexor digitorum profundus repair in zone 2.
We report sonographic findings with clinical outcomes after zone 2 flexor digitorum profundus tendon repairs in ten fingers. The tendons underwent a six-strand M-Tang core repair, no circumferential suture, and partial or complete division of the pulleys. Over 12 months after surgery and using ultrasound, we found no gapping at the repair site during finger motion. When the pulleys were divided, there was sonographic evidence of tendon bowstringing, but the bowstringing was minimal. Clinically, we did not find any fingers that displayed tendon bowstringing or had functional loss. With ultrasound examination, the repaired tendons remained enlarged over 12 months. Two patients developed heterotopic ossifications at the repair site without tendon gliding, and these required tenolysis. We conclude that the tendon repair site does not gap when a strong core suture is used in the repair without adding peripheral sutures. There is no notable tendon bowstringing clinically, though the repaired tendons have sonographic evidence of minor bowstringing. III.


Observed communication skills: how do they relate to the consultation content? A nation-wide study of graduate medical students seeing a standardized patient for a first-time consultation in a general practice setting.
In this study, we wanted to investigate the relationship between background variables, communication skills, and the bio-psychosocial content of a medical consultation in a general practice setting with a standardized patient. Final-year medical school students (N = 111) carried out a consultation with an actor playing the role of a patient with a specific somatic complaint, psychosocial stressors, and concerns about cancer. Based on videotapes, communication skills and consultation content were scored separately. The mean level of overall communication skills had a significant impact upon the counts of psychosocial issues, the patient's concerns about cancer, and the information and planning parts of the consultation content being addressed. Gender and age had no influence upon the relationship between communication skills and consultation content. Communication skills seem to be important for final-year students' competence in addressing sensitive psychosocial issues and patients' concerns as well as informing and planning with patients being representative for a fairly complex case in general practice. This result should be considered in the design and incorporation of communication skills training as part of the curriculum of medical schools.


TT8 controls its own expression in a feedback regulation involving TTG1 and homologous MYB and bHLH factors, allowing a strong and cell-specific accumulation of flavonoids in Arabidopsis thaliana.
The control of TT8 expression was investigated in this study, and it was demonstrated that it constitutes a major regulatory step in the specific activation of the expression of flavonoid structural genes. First, the GUS activity generated in planta from a TT8::uidA construct revealed cell-specific activation of the TT8 promoter consistent with the known involvement of the TT8 bHLH factor in proanthocyanidin, anthocyanin and mucilage biosynthesis. Moreover, the activity of this reporter construct was strongly affected in ttg1, TT2 overexpressers (OE), and PAP1-OE, suggesting interplay between TT2, PAP1, TTG1 and the activation of the TT8 promoter in planta. To further investigate the mechanisms involved, we used 35S::TT2-GR and 35S::TTG1-GR transgenic plants (expressing fusion proteins with the glucocorticoid receptor), as well as one-hybrid experiments, to determine the direct effect of these factors on TT8 expression. Interestingly, in vivo binding of TT2 and PAP1 to the TT8 promoter was dependent on the simultaneous expression of TT8 or the homologous bHLH factors GL3 and EGL3. Consistent with these results, the activity of the TT8::uidA reporter was strongly affected in the seed endothelium of a tt8 mutant. Similarly, a strong decrease in the level of TT8 mRNA was detected in the siliques of a gl3 x egl3 mutant and in plants that express a dominant negative form of the PAP1 protein, suggesting that TT8 expression is controlled by different combinations of MYB and bHLH factors in planta. The importance of this positive feedback mechanism in the strong and specific induction of proanthocyanidin biosynthesis in the seed coat of Arabidopsis thaliana is discussed.


Effect of media heights on the performance of biological aerated filter.
The optimum media height of carbon oxidation and nitrification in a down-flow biological aerated filter was determined, and the distribution of the heterotrophic and nitrifying populations through studying the changes of organic carbon contents and ammonia concentration at different media height was got. The results showed that as a down flow BAF with granular media, the active layer of nitrifiers was deeper than heterotrophs in BAF. And the optimum media height for the removal of SS, COD(Cr) and NH4+ -N was 40 cm, 60 cm and 80 cm respectively. The removal efficiency of SS, COD(Cr), and NH4+ -N was 79.1%, 63.9% and 96.4% respectively under the influent COD(Cr), and NH4+ -N of 122.1 mgCOD(Cr)/L and 14.84 mgNH4+ -N/L, the influent flux of 15.8 L/h, air to liquid ratio of 3:1.


Perception of Graphical Virtual Environments by Blind Users via Sensory Substitution.
Graphical virtual environments are currently far from accessible to blind users as their content is mostly visual. This is especially unfortunate as these environments hold great potential for this population for purposes such as safe orientation, education, and entertainment. Previous tools have increased accessibility but there is still a long way to go. Visual-to-audio Sensory-Substitution-Devices (SSDs) can increase accessibility generically by sonifying on-screen content regardless of the specific environment and offer increased accessibility without the use of expensive dedicated peripherals like electrode/vibrator arrays. Using SSDs virtually utilizes similar skills as when using them in the real world, enabling both training on the device and training on environments virtually before real-world visits. This could enable more complex, standardized and autonomous SSD training and new insights into multisensory interaction and the visually-deprived brain. However, whether congenitally blind users, who have never experienced virtual environments, will be able to use this information for successful perception and interaction within them is currently unclear.We tested this using the EyeMusic SSD, which conveys whole-scene visual information, to perform virtual tasks otherwise impossible without vision. Congenitally blind users had to navigate virtual environments and find doors, differentiate between them based on their features (Experiment1:task1) and surroundings (Experiment1:task2) and walk through them; these tasks were accomplished with a 95% and 97% success rate, respectively. We further explored the reactions of congenitally blind users during their first interaction with a more complex virtual environment than in the previous tasks-walking down a virtual street, recognizing different features of houses and trees, navigating to cross-walks, etc. Users reacted enthusiastically and reported feeling immersed within the environment. They highlighted the potential usefulness of such environments for understanding what visual scenes are supposed to look like and their potential for complex training and suggested many future environments they wished to experience.


[Percutaneous transvenous balloon dilatation of mitral valve stenosis].
In this study, 42 consecutive symptomatic patients (median age 60 (30-78) years, 86% females) with mitral valve stenosis (57% had severely deformed and/or calcified mitral valves) were treated with (Inoue) balloon dilatation during the period August 1989-June 1994. Mitral valve area and cardiac output increased by 67 and 25%, whereas the transmital gradient as well as pulmonary artery pressure fell by 45% and 21%, respectively, after the dilatation. Follow-up at a mean of 16 (1-46) months revealed a total mortality of 12% (cardiac mortality of 7%). Five patients developed significant' mitral regurgitation after the treatment and four of these had subacute mitral valve replacement. A further four patients received an artificial valve during the follow-up period. During the follow-up period the increase in valve area remained unchanged, and accordingly 97% of the patients were in New York Heart Association functional class I-II. Balloon dilatation was an acceptable treatment in the described elderly population with significant mitral stenosis and deformed valves.


Reduced susceptibility of DNA methyltransferase 1 hypomorphic (Dnmt1N/+) mice to hepatic steatosis upon feeding liquid alcohol diet.
Methylation at C-5 (5-mdC) of CpG base pairs, the most abundant epigenetic modification of DNA, is catalyzed by 3 essential DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b). Aberrations in DNA methylation and Dnmts are linked to different diseases including cancer. However, their role in alcoholic liver disease (ALD) has not been elucidated. Dnmt1 wild type (Dnmt1(+/+)) and hypomorphic (Dnmt1(N/+)) male mice that express reduced level of Dnmt1 were fed Lieber-DeCarli liquid diet containing ethanol for 6 weeks. Control mice were pair-fed calorie-matched alcohol-free liquid diet, and Dnmtase activity, 5-mdC content, gene expression profile and liver histopathology were evaluated. Ethanol feeding caused pronounced decrease in hepatic Dnmtase activity in Dnmt1(+/+) mice due to decrease in Dnmt1 and Dnmt3b protein levels and upregulation of miR-148 and miR-152 that target both Dnmt1 and Dnmt3b. Microarray and qPCR analysis showed that the genes involved in lipid, xenobiotic and glutathione metabolism, mitochondrial function and cell proliferation were dysregulated in the wild type mice fed alcohol. Surprisingly, Dnmt1(N/+) mice were less susceptible to alcoholic steatosis compared to Dnmt1(+/+) mice. Expression of several key genes involved in alcohol (Aldh3b1), lipid (Ppara, Lepr, Vldlr, Agpat9) and xenobiotic (Cyp39a1) metabolism, and oxidative stress (Mt-1, Fmo3) were significantly (P<0.05) altered in Dnmt1(N/+) mice relative to the wild type mice fed alcohol diet. However, CpG islands encompassing the promoter regions of Agpat9, Lepr, Mt1 and Ppara were methylation-free in both genotypes irrespective of the diet, suggesting that promoter methylation does not regulate their expression. Similarly, 5-mdC content of the liver genome, as measured by LC-MS/MS analysis, was not affected by alcohol diet in the wild type or hypomorphic mice. Although feeding alcohol diet reduced Dnmtase activity, the loss of one copy of Dnmt1 protected mice from alcoholic hepatosteatosis by dysregulating genes involved in lipid metabolism and oxidative stress.


Perturbed reward processing in pediatric bipolar disorder: an antisaccade study.
Pediatric bipolar disorder is a severe and impairing illness. Characterizing the impact of pediatric bipolar disorder on cognitive function might aid in understanding the phenomenology of the disorder. While previous studies of pediatric bipolar disorder have reported deficits in cognitive control and reward behavior, little is understood about how affective processes influence behavioral control. Relative to prior studies using manual-response paradigms, eye movement tasks provide a more precise assessment of reward sensitivity and cognitive and motor control. The current study compares 20 youths with bipolar disorder (mean age = 13.9 years ± 2.22) and 23 healthy subjects (mean age = 13.8 years ± 2.49) on a mixed pro-antisaccade task with monetary incentives. On both types of saccades, participants were presented with three types of incentives: those where subjects can win money, lose money, or neither win nor lose money. Impaired reward processing was found in youths with bipolar disorder relative to controls, particularly on antisaccades. This difference was reflected in lower error rates during incentive trials in the control but not in the bipolar disorder group. By comparison, no group differences were found on prosaccade trials. The results provide further evidence for deficits in cognitive and reward processing in bipolar disorder.


Human salivary Raman fingerprint as biomarker for the diagnosis of Amyotrophic Lateral Sclerosis.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease leading to progressive and irreversible muscle atrophy. The diagnosis of ALS is time-consuming and complex, with the clinical and neurophysiological evaluation accompanied by monitoring of progression and a long procedure for the discrimination of similar neurodegenerative diseases. The delayed diagnosis strongly slows the potential development of adequate therapies and the time frame for a prompt intervention. The discovery of new biomarkers could improve the disease diagnosis, as well as the therapeutic and rehabilitative effectiveness and monitoring of the pathological progression. In this work saliva collected from 19 patients with ALS, 10 affected by Parkinson's disease, 10 affected by Alzheimer's disease and 10 healthy subjects, was analysed using Raman spectroscopy, optimizing the parameters for detailed and reproducible spectra. The statistical multivariate analysis of the data revealed a significant difference between the groups, allowing the discrimination of the disease onset. Correlation of Raman data revealed a direct relationship with paraclinical scores, identifying multifactorial biochemical modifications related to the pathology. The proposed approach showed a promising accuracy in ALS onset discrimination, using a fast and sensitive procedure that can make more efficient the diagnostic procedure and the monitoring of therapeutic and rehabilitative processes in ALS.


Effect of Tight Glycemic Control Protocol on Hypoglycemia and Mortality in the Burn Unit: A Case-Control Study.
Burn injury pathophysiology is characterized by severe catabolic state and poor glycemic control. A tight glycemic control protocol using insulin for burn victims has yielded inconsistent mortality and morbidity outcomes. To compare the effect of standard and tight glycemic control protocols on mortality and hypoglycemia events in critical care burn patients. We conducted a case-control study of burn victims admitted to the burn intensive care unit between 2005 and 2011. Patients were assigned to either a standard or a tight glycemic control protocol. Of the 38 burn patients in the study, 28 were under a tight glycemic control protocol. No differences in glucose area-under-the-curve per day levels were observed between the groups (148.3 ± 16 vs. 157.8 ± 16 mg/dl in the standard and tight glycemic control protocol groups respectively, P < 0.12). The hypoglycemic event rate was higher in the tight glycemic control protocol group (46.4% vs. 0%, P < 0.008). No difference in mortality rate was noted (67.9% vs. 50%, P < 0.31). Mortality-independent risk factors found on multivariate analysis included total body surface area (adjusted hazard ratio [AHR] 1.039, 95% confidence interval [95%CI] 1.02-1.06, P < 0.001), white blood cell count on admission (AHR 1.048, 95%CI 1.01-1.09, P < 0.02) and surgery during hospitalization (AHR 0.348, 95%CI 0.13-0.09, P < 0.03). The tight glycemic control protocol in burn patients was associated with higher rates of hypoglycemic events, and no association was found with improved survival in the acute setting of burn trauma care.


Langerhans' cells in patients with psoriasis: effect of treatment with PUVA, PUVA bath, etretinate and anthralin.
Suction blisters were raised in lesions and normal appearing skin of patients with psoriasis. The blister roof which contains the epidermis separated at the dermal-epidermal junction was stained with ATPase, OKT-6 and anti-HLA-DR monoclonal antibodies. The technique permits the counting of the Langerhans' cells per mm2. Their mean number varied between 888-987 cells per mm2 in control subjects with the three staining procedures. In patients with psoriasis, the number of cells before treatment was between 1110-1179 in uninvolved skin and 521-1001 per mm2 in the lesions as measured using both monoclonal antibodies and ATPase. However, the latter technique seemed to be inappropriate for lesional skin. After treatment with PUVA bath or oral PUVA with or without etretinate, fewer Langerhans' cells were seen in both lesions and normal appearing skin with the appearance of giant Langerhans' cells with long dendrites. In patients healed with anthralin + UV-B the Langerhans' cells appeared normal in number and size.


[Quality assessment of antibiotic prescriptions dispensed at public health units in Belo Horizonte, Minas Gerais, Brazil, 2002].
Overuse of antibiotics is a public health problem and has raised discussions concerning their rational use. This cross-sectional study focuses on the use of systemic antibiotics under the Belo Horizonte Municipal Health Department, Minas Gerais, Brazil, evaluating prescriptions dispensed in March 2002, based on WHO indicators for antibiotic use. On average, 20% of prescriptions dispensed involved at least one systemic antibiotic, among which approximately 46% originated from health care facilities not belonging to the municipal system itself. Amoxicillin was the most frequently prescribed antibiotic, followed by benzathine penicillin. Recording of technical data (dose, intervals between doses, administration, and treatment period) varied from 23.6 to 99.6%. Some 10% of prescriptions failed to specify the treatment period. The study showed the need for rules to allow quality improvement of antibiotic prescriptions, assuring the rational use of such medication by municipal health services.


CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis.
Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. We hypothesize that CSF1R plays a critical role in myeloid cell responses that restrict viral replication and locally restimulate recruited antiviral T cells within the CNS. The impact of CSF1R signaling during West Nile virus infection was assessed in vivo using a mouse model of neurotropic infection. Pharmacological inactivation of CSF1R was achieved using PLX5622 prior to infection with virulent or attenuated strains of West Nile virus (WNV), an emerging neuropathogen. The subsequent effect of CSF1R antagonism on virologic control was assessed by measuring mortality and viral titers in the CNS and peripheral organs. Immune responses were assessed by flow cytometric-based phenotypic analyses of both peripheral and CNS immune cells. Mice treated with CSF1R antagonist prior to infection exhibited higher susceptibility to lethal WNV infection and lack of virologic control in both the CNS and periphery. CSFR1 antagonism reduced B7 co-stimulatory signals on peripheral and CNS antigen-presenting cells (APCs) by depleting CNS cellular sources, which limited local reactivation of CNS-infiltrating virus-specific T cells and reduced viral clearance. Our results demonstrate the impact of CSF1R antagonism on APC activation in the CNS and periphery and the importance of microglia in orchestrating the CNS immune response following neurotropic viral infection. These data will be an important consideration when assessing the benefit of CSF1R antagonism, which has been investigated as a therapeutic for neurodegenerative conditions, in which neuroinflammation is a contributing factor.


Cholinergic and non-cholinergic functions of two acetylcholinesterase genes revealed by gene-silencing in Tribolium castaneum.
We compared biological functions of two acetylcholinesterase genes (TcAce1 and TcAce2) in Tribolium castaneum, a globally distributed major pest of stored grain products and an emerging model organism, by using RNA interference. Although both genes expressed at all developmental stages and mainly in the brain, the transcript level of TcAce1 was 1.2- to 8.7-fold higher than that of TcAce2, depending on developmental stages. Silencing TcAce1 in 20-day larvae led to 100% mortality within two weeks after eclosion and increased larval susceptibilities to anticholinesterase insecticides. In contrast, silencing TcAce2 did not show insect mortality and significantly affect insecticide susceptibility, but delayed insect development and reduced female egg-laying and egg hatching. These results demonstrate for the first time that TcAce1 plays a major role in cholinergic functions and is the target of anticholinesterase insecticides, whereas TcAce2 plays an important, non-cholinergic role in female reproduction, embryo development, and growth of offspring.


Pesticide exposure and lung cancer mortality in Leningrad province in Russia.
This study was carried out to examine the association between pesticide exposure and lung cancer mortality. We conducted an autopsy based case-control study in Leningrad Province in Russia. A total of 540 lung cancer cases and 582 controls were identified among subjects who had died in the hospitals of the Leningrad province between 1993 and 1998. Using work history records, we assessed exposure to pesticide at the level of industry and job title. Unconditional logistic regression was used to calculate adjusted odds ratio for pesticide exposure and lung cancer mortality. There was no association between ever exposure to pesticide and lung cancer mortality overall (odds ratio=1.06, 95% confidence interval=0.82-1.36) and in both men (odds ratio=1.11, 95% confidence interval=0.84-1.46) and women (odds ratio=0.74, 95% confidence interval=0.37-1.46). We observed no statistically significant odds ratio by duration of pesticide exposure, intensity of pesticide exposure, and cumulative pesticide exposures with lung cancer mortality in both smokers and nonsmokers. Odds ratio also did not differ when the analysis was restricted to individuals who had exposure data with high confidence scores. Our findings suggest no associations between pesticide exposures and mortality of lung cancer in the population of the Leningrad province in Russia that deserves further evaluation.


Serial measurements of circulating plasma cells before and after induction therapy have an independent prognostic impact in patients with multiple myeloma undergoing upfront autologous transplantation.
Circulating plasma cells at diagnosis, prior to auto-transplant and at relapse have a negative impact on survival in multiple myeloma. However, the impact of kinetics of circulating plasma cells along the course of illness has not been defined. We have analyzed 247 newly diagnosed multiple myeloma patients undergoing early auto-transplant who had paired evaluation of circulating plasma cells at diagnosis and pre-transplant by 6-color flow cytometry. A total of 117 patients had no detectable circulating plasma cells at both time points (CPC-/-), 82 had circulating plasma cells at diagnosis followed by complete eradication after induction (CPC+/-) and 48 had circulating plasma cells at transplant, including persistence of cells (CPC+/+; n=45) or emergence of new cells (CPC-/+; n=3) after induction. The rate of post-transplant stringent complete response was 32% in the CPC-/-, 30% in CPC+/- and 12% in CPC+/+ or -/+ groups (P=0.018). At a median follow up of 58 months from transplantation, the median progression-free survival in the 3 respective groups were 30, 24 and 14 months, and the 5-year overall survival rates were 83%, 70% and 43% (P<0.001 for both comparisons). On a multivariate analysis for overall survival, the risk of mortality was higher in CPC +/- (hazard ratio 2.7, 95%CI: 1.3-5.8; P=0.009) and CPC+/+ or -/+ (hazard ratio 5.7, 95%CI: 2.5-13.1; P<0.001) groups compared to the CPC-/- group. Monitoring for circulating plasma cells before induction therapy and before transplant by 6-color flow cytometry is predictive of survival in newly diagnosed myeloma and should be incorporated into clinical trials.


The cost-effective, but forgotten, medical endometriosis therapy: a prospective, quasi-randomized study on progestin therapy.
Endometriosis represents nowadays a real burden for the patients as well as for the physicians, as it requires surgical and/or medical treatment, often long - termed and repeated. Moreover, the high costs necessary to diagnose and treat endometriosis represent a real economic burden, being comparable to other chronic diseases like diabetes or rheumatoid arthritis. Therefore, the physicians dealing with this disease should take into account not only the efficacy of the treatment, but also the economic aspects and patients compliance. The present paper analyses the efficiency of progestins (lynestrenol and medrogestone) in endometriosis as a cost - effective, but forgotten medical therapy of the disease. Our study underlines the good tolerability of progestins, as they have limited side effects, the compliance of patients being high. They are also low-cost medications, which could represent an effective alternative method in the endometriosis treatment, especially in less - developed countries that cannot afford the higher therapeutic costs.


[Acute pancreatitis: clinical and therapeutic study with somatostatin].
A clinical and therapeutical study of 47 patients with the diagnosis of acute pancreatitis is reported. According to Ranson's criteria patients were initially classified as suffering from mild (28) and severe (18) acute pancreatitis. Twenty-eight, 11, 7 and 1 patients had biliary, alcoholic, idiopathic and neoplastic causes, respectively, of their conditions. The classification of episodes was made on the basis of clinical manifestations, biologic investigations, and imaging diagnosis, and is shown in the corresponding tables. The therapeutic profile was a randomized double-blind study: perfused somatostatin (SS) versus placebo (P) (physiologic saline 0.9%). The administration of somatostatin in perfusion (250 mcg/h/48 hours) did not improve significantly the parameters used to score the severity, although the mortality rate decreased significantly (p < 0.05) in the group of patients with the severe form of the disease.


New insights into the regulation of synaptic plasticity from an unexpected place: hippocampal area CA2.
The search for molecules that restrict synaptic plasticity in the brain has focused primarily on sensory systems during early postnatal development, as critical periods for inducing plasticity in sensory regions are easily defined. The recent discovery that Schaffer collateral inputs to hippocampal area CA2 do not readily support canonical activity-dependent long-term potentiation (LTP) serves as a reminder that the capacity for synaptic modification is also regulated anatomically across different brain regions. Hippocampal CA2 shares features with other similarly "LTP-resistant" brain areas in that many of the genes linked to synaptic function and the associated proteins known to restrict synaptic plasticity are expressed there. Add to this a rich complement of receptors and signaling molecules permissive for induction of atypical forms of synaptic potentiation, and area CA2 becomes an ideal model system for studying specific modulators of brain plasticity. Additionally, recent evidence suggests that hippocampal CA2 is instrumental for certain forms of learning, memory, and social behavior, but the links between CA2-enriched molecules and putative CA2-dependent behaviors are only just beginning to be made. In this review, we offer a detailed look at what is currently known about the synaptic plasticity in this important, yet largely overlooked component of the hippocampus and consider how the study of CA2 may provide clues to understanding the molecular signals critical to the modulation of synaptic function in different brain regions and across different stages of development.


Hyperfibrinogenemia alone does not affect the patency of microvascular anastomosis: clinical experience and animal study.
Preventing vascular thrombosis in microsurgery is a prerequisite for a successful outcome. High plasma fibrinogen levels have been associated with thromboembolic risk in patients with cancer or cardiovascular disease. Patients with these comorbidities and associated hyperfibrinogenemia oftentimes require microsurgical reconstruction. This situation causes us to hesitate. Previously in our experience, 8 of 10 patients with hyperfibrinogenemia (> 500 mg/dL) underwent successful free-tissue transfer after oral cancer ablation. Based on this clinical observation, we investigated whether hyperfibrinogenemia contributes to the patency of a microvascular anastomosis. Optimal dosage of fibrinogen (300 mg/kg, intravenously) significantly increased the fibrinogen level in the plasma of the rodent hyperfibrinogenemia model. Forty male Lewis rats (weight = 300-350 g) were injected intravenously by normal saline and fibrinogen (300 mg/kg), respectively (n = 20 in each subgroup). Femoral artery and femoral vein division and reanastomosis were performed after 2 hours in rats with or without fibrinogen injection. The platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), and the platelet aggregation test induced with adenosine diphosphate (ADP) were also measured preoperatively. The ratios of circulating activated platelets as demonstrated by p-selectin (CD62P) was analyzed by flow cytometry preoperatively and 2 hours postoperatively. Laser Doppler flowmetry was used to assess the patency of the anastomosis preoperatively and 2 hours postoperatively. Vascular patency was assessed 7 days postoperatively. The results showed that the platelet count, PT and APTT levels had no significant difference among the control and the experimental group. There were no significant differences found in the ratios of CD62P expression (P = 0.65) and ADP aggregation test (P = 0.17) in comparing both groups. There were no statistical differences in the patency rates (P > 0.05) or perfusion units of femoral arteries (P = 0.84) and femoral veins (P = 0.51) after vessels division and reanastomosis, respectively. In summary, there was no correlation between experimentally induced hyperfibrinogenemia and the enhancement of thrombosis risk after microvascular surgery. This experimental data can lend support to the idea that microvascular anastomosis could be safely performed in patients with hyperfibrinogenemia alone without untoward thrombotic complications.


Evidence for nonsynaptic neuronal interaction.
1. Evidence is presented that synaptic interactions within and between the statocyst and visual pathways of Hermissenda are eliminated after 0.5-4 min exposure to 20-40 mM Co2+. 2. Synaptic blockade was also produced by perfusion with low Ca2+ (5mM) plus 10-20 mM Co2+. 3. Depolarization of hair cells by impulses of type A photoreceptors remains after the same exposure to Co2+, or low Ca2+ plus Co2+. 4. The increased resistance previously observed during this depolarization of hair cells cannot be observed after exposure to Co2+. 5. The depolarization which remains after exposure to Co2+ did not change with different levels of membrane potential from -20 mV below to +10 mV above the resting level. 6. The time course of potassium accumulation, monitored by the amplitude of the type A impulse afterpotential, closely followed the time course of hair cell depolarization and also of changes in the amplitude of the hair cell afterpotential. 7. The depolarization of hair cells by type A impulses decreased with increased extracellular potassium, but was only slightly reduced by lowered extracellular potassium. 8. The amount of potassium accumulation following a type A impulse train could be estimated from the effects of changes in extracellular potassium in the perfusate on the type A impulse afterpotential. From this extimated increase of extracellular potassium it was possible to predict with some accuracy, the observed hair cell depolarization. 9. Although type A cells are not electrically coupled to ipsilateral hair cells, firing of these hair cells slightly depolarized the type A photoreceptor which excites them. 10. Strophanthidin (10-4 M) did not block the depolarization of hair cells by type A impulses. 11. The data are evidence for nonsynaptic excitation of hair cells by type A photoreceptor impulses. The data are also consistent with the interpretation that the excitation arises from potassium accumulation around the type A and hair cell axonal membranes.


The influence of carbon dioxide on brain activity and metabolism in conscious humans.
A better understanding of carbon dioxide (CO(2)) effect on brain activity may have a profound impact on clinical studies using CO(2) manipulation to assess cerebrovascular reserve and on the use of hypercapnia as a means to calibrate functional magnetic resonance imaging (fMRI) signal. This study investigates how an increase in blood CO(2), via inhalation of 5% CO(2), may alter brain activity in humans. Dynamic measurement of brain metabolism revealed that mild hypercapnia resulted in a suppression of cerebral metabolic rate of oxygen (CMRO(2)) by 13.4% ± 2.3% (N=14) and, furthermore, the CMRO(2) change was proportional to the subject's end-tidal CO(2) (Et-CO(2)) change. When using functional connectivity MRI (fcMRI) to assess the changes in resting-state neural activity, it was found that hypercapnia resulted in a reduction in all fcMRI indices assessed including cluster volume, cross-correlation coefficient, and amplitude of the fcMRI signal in the default-mode network (DMN). The extent of the reduction was more pronounced than similar indices obtained in visual-evoked fMRI, suggesting a selective suppression effect on resting-state neural activity. Scalp electroencephalogram (EEG) studies comparing hypercapnia with normocapnia conditions showed a relative increase in low frequency power in the EEG spectra, suggesting that the brain is entering a low arousal state on CO(2) inhalation.


Plasma BDNF Levels Following Transcranial Direct Current Stimulation Allow Prediction of Synaptic Plasticity and Memory Deficits in 3×Tg-AD Mice.
Early diagnosis of Alzheimer's disease (AD) supposedly increases the effectiveness of therapeutic interventions. However, presently available diagnostic procedures are either invasive or require complex and expensive technologies, which cannot be applied at a larger scale to screen populations at risk of AD. We were looking for a biomarker allowing to unveil a dysfunction of molecular mechanisms, which underly synaptic plasticity and memory, before the AD phenotype is manifested and investigated the effects of transcranial direct current stimulation (tDCS) in 3×Tg-AD mice, an experimental model of AD which does not exhibit any long-term potentiation (LTP) and memory deficits at the age of 3 months (3×Tg-AD-3M). Our results demonstrated that tDCS differentially affected 3×Tg-AD-3M and age-matched wild-type (WT) mice. While tDCS increased LTP at CA3-CA1 synapses and memory in WT mice, it failed to elicit these effects in 3×Tg-AD-3M mice. Remarkably, 3×Tg-AD-3M mice did not show the tDCS-dependent increases in pCREB Ser133 and pCaMKII Thr286 , which were found in WT mice. Of relevance, tDCS induced a significant increase of plasma BDNF levels in WT mice, which was not found in 3×Tg-AD-3M mice. Collectively, our results showed that plasticity mechanisms are resistant to tDCS effects in the pre-AD stage. In particular, the lack of BDNF responsiveness to tDCS in 3×Tg-AD-3M mice suggests that combining tDCS with dosages of plasma BDNF levels may provide an easy-to-detect and low-cost biomarker of covert impairment of synaptic plasticity mechanisms underlying memory, which could be clinically applicable. Testing proposed here might be useful to identify AD in its preclinical stage, allowing timely and, hopefully, more effective disease-modifying interventions.


Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort.
The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy. Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer. In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10(-9)) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10(-5)), with Gleason score (P=5 × 10(-4)) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions. For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.


Sarcomeric Gene Variants and Their Role with Left Ventricular Dysfunction in Background of Coronary Artery Disease.
: Cardiovascular diseases are one of the leading causes of death in developing countries, generally originating as coronary artery disease (CAD) or hypertension. In later stages, many CAD patients develop left ventricle dysfunction (LVD). Left ventricular ejection fraction (LVEF) is the most prevalent prognostic factor in CAD patients. LVD is a complex multifactorial condition in which the left ventricle of the heart becomes functionally impaired. Various genetic studies have correlated LVD with dilated cardiomyopathy (DCM). In recent years, enormous progress has been made in identifying the genetic causes of cardiac diseases, which has further led to a greater understanding of molecular mechanisms underlying each disease. This progress has increased the probability of establishing a specific genetic diagnosis, and thus providing new opportunities for practitioners, patients, and families to utilize this genetic information. A large number of mutations in sarcomeric genes have been discovered in cardiomyopathies. In this review, we will explore the role of the sarcomeric genes in LVD in CAD patients, which is a major cause of cardiac failure and results in heart failure.


Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21.
Primary congenital glaucoma (Buphthalmos) is an autosomal recessive eye disorder, postulated to result from developmental defects in the anterior eye segment. Previously, we reported two chromosomal locations for this condition on 2p21 (GLC3A) and 1p36 (GLC3B) respectively. In this study, heritable mutations of human cytochrome P4501B1 gene (CYP1B1) in affected individuals of five well-characterized families linked to the GLC3A locus are described. CYP1B1 gene has previously been mapped within the GLC3A candidate region and its expression in the trabecular meshwork cells has been demonstrated in this study. Three different homozygous mutations were identified and characterized: a 13 bp deletion in exon III; an insertion of a single cytosine base in exon II; and a larger deletion affecting the 5' end of exon III and the adjacent intronic region. All of these are frameshift mutations that are predicted to remove domains essential for the function of the CYP1B1 protein. Therefore, it is expected that all these mutations result in functional null alleles. The mutations detected in the affected members of these families were not present in 470 chromosomes from randomly selected normal individuals, thus strongly suggesting that CYP1B1 is the gene for the GLC3A locus on 2p21. The results are discussed in the context of the earlier hypothesis that 'drug-metabolizing' enzymes might modulate the processes of growth and differentiation by controlling the steady-state-levels of oxygenated growth-effector molecules.


Anaesthesia for bilateral mastectomy in a Jehovah's Witness patient with epilepsy and review of alternatives to homologous blood transfusion.
The anaesthetic management of a Jehovah's Witness patient for bilateral mastectomy for carcinoma of the breast is described. The patient is also a known epileptic patient who developed fits the night before surgery. Surgery was re-scheduled for one week later to allow control of the epilepsy. Surgery was carried out under general anaesthesia. The patient refused blood transfusion. Modified normovolaemic haemodilution was the alternative to homologous blood transfusion used in the patient. This was safe except for the post-operative morbidity due to severe anaemia in the patient. The surgical outcome was good. The safety of not transfusing blood in Jehovah's Witness patient for surgical procedures for which blood transfusion is needed is well illustrated by this case. A review of alternatives to homologous blood transfusion is done.


Childhood maltreatment and its effect on neurocognitive functioning: Timing and chronicity matter.
Childhood maltreatment represents a complex stressor, with the developmental timing, duration, frequency, and type of maltreatment varying with each child (Barnett, Manly, & Cicchetti, 1993; Cicchetti & Manly, 2001). Multiple brain regions and neural circuits are disrupted by the experience of child maltreatment (Cicchetti & Toth, in press; DeBellis et al., 2002; McCrory & Viding, 2010; Teicher, Anderson, & Polcari, 2012). These neurobiological compromises indicate the impairment of a number of important cognitive functions, including working memory and inhibitory control. The present study extends prior research by examining the effect of childhood maltreatment on neurocognitive functioning based on developmental timing of maltreatment, including onset, chronicity, and recency, in a sample of 3- to 9-year-old nonmaltreated (n = 136) and maltreated children (n = 223). Maltreated children performed more poorly on inhibitory control and working-memory tasks than did nonmaltreated children. Group differences between maltreated children based on the timing of maltreatment and the chronicity of maltreatment also were evident. Specifically, children who were maltreated during infancy, and children with a chronic history of maltreatment, exhibited significantly poorer inhibitory control and working-memory performance than did children without a history of maltreatment. The results suggest that maltreatment occurring during infancy, a period of major brain organization, disrupts normative structure and function, and these deficits are further instantiated by the prolonged stress of chronic maltreatment during the early years of life.


Catalyst-free growth of InAs nanowires on Si (111) by CBE.
We investigate a growth mechanism which allows for the fabrication of catalyst-free InAs nanowires on Si (111) substrates by chemical beam epitaxy. Our growth protocol consists of successive low-temperature (LT) nucleation and high-temperature growth steps. This method produces non-tapered InAs nanowires with controllable length and diameter. We show that InAs nanowires evolve from the islands formed during the LT nucleation step and grow truly catalyst-free, without any indium droplets at the tip. The impact of different growth parameters on the nanowire morphology is presented. In particular, good control over nanowire aspect ratio is demonstrated. A better understanding of the growth process is obtained through the development of a theoretical model combining the diffusion-induced growth scenario with some specific features of the catalyst-free growth mechanism, along with the analysis of the V/III flow ratio influencing material incorporation. As a result, we perform a full mapping of the nanowire morphology versus growth parameters which provides useful general guidelines on the self-induced formation of III-V nanowires on silicon.


A survey of bullous diseases in a Turkish university hospital: clinicoepidemiological characteristics and follow-up
Autoimmune bullous diseases, if left untreated, are life-threatening conditions affecting primarily skin and mucous membranes. These blistering disorders are characterized by epidermal or subepidermal detachment. Autoimmunity plays a key role in pathogenesis; therefore, immunosuppressive agents are the treatment of choice. The aim of this study is to document relative frequencies of different autoimmune bullous diseases, patient characteristics, treatment options, and side effects in patients presenting to our bullous skin disease center at İstanbul University, Cerrahpaşa, Cerrahpaşa Medical Faculty. Medical files were examined retrospectively for all patients with autoimmune bullous diseases who were followed up between 2003 and 2019 at the Bullous Skin Disease Center at İstanbul University, Cerrahpaşa. A total of 346 patient files were examined. Pemphigus vulgaris was the most frequent autoimmune bullous disease, followed by bullous pemphigoid and pemphigus foliaceus, according to our study. There is a general female predominancy for all autoimmune bullous diseases. The most commonly preferred treatment options were high-dose daily corticosteroids. This retrospective study summarizes the patient characteristics, comorbidities, treatment choices, and side effects during 16 years of clinical practice.


Differential effects of nerve transection on the ACh and GABA receptors of chick ciliary ganglion neurons.
Chick ciliary ganglion neurons have nicotinic acetylcholine receptors (AChRs) that mediate chemical transmission through the ganglion, and GABAA receptors of unknown significance. Previous experiments examining the role of cell-cell interactions in regulating neuronal AChRs have shown that postganglionic axotomy of ciliary ganglia in newly hatched chicks causes a 10-fold decline in total AChRs within 5 d compared with unoperated contralateral ganglia and that preganglionic denervation causes a 3-fold decline within 10 d. Many of the AChRs are known to be intracellular; of those present on the cell surface, only a small fraction appears to be functionally available normally. In the present experiments, the effects of the operations on functional AChRs and GABAA receptors in the plasma membrane of the neurons were examined by removing the ganglia 5 d after axotomy or 10 d after denervation, dissociating them into single cells, and immediately measuring their ACh and GABA sensitivities with intracellular recording techniques. The ACh sensitivity of axotomized ciliary ganglion neurons was reduced 10-fold compared with neurons from unoperated contralateral ganglia of the same chicks. The reduction could be largely accounted for by a decrease in the maximum response and did not arise from a change either in the dose-response curve or the acetylcholinesterase activity of the neurons. Autoradiographic studies using a radiolabeled anti-AChR monoclonal antibody also demonstrated a substantial decrease in the total number of surface AChRs associated with axotomized neurons. In contrast, axotomy had no unilateral effect on the GABA response.(ABSTRACT TRUNCATED AT 250 WORDS)


A primer on quantitative bias analysis with positive predictive values in research using electronic health data.
In health informatics, there have been concerns with reuse of electronic health data for research, including potential bias from incorrect or incomplete outcome ascertainment. In this tutorial, we provide a concise review of predictive value-based quantitative bias analysis (QBA), which comprises epidemiologic methods that use estimates of data quality accuracy to quantify the bias caused by outcome misclassification. Health informaticians and investigators reusing large, electronic health data sources for research. When electronic health data are reused for research, validation of outcome case definitions is recommended, and positive predictive values (PPVs) are the most commonly reported measure. Typically, case definitions with high PPVs are considered to be appropriate for use in research. However, in some studies, even small amounts of misclassification can cause bias. In this tutorial, we introduce methods for quantifying this bias that use predictive values as inputs. Using epidemiologic principles and examples, we first describe how multiple factors influence misclassification bias, including outcome misclassification levels, outcome prevalence, and whether outcome misclassification levels are the same or different by exposure. We then review 2 predictive value-based QBA methods and why outcome PPVs should be stratified by exposure for bias assessment. Using simulations, we apply and evaluate the methods in hypothetical electronic health record-based immunization schedule safety studies. By providing an overview of predictive value-based QBA, we hope to bridge the disciplines of health informatics and epidemiology to inform how the impact of data quality issues can be quantified in research using electronic health data sources.


Pharmacotherapy and ROP: Going Back to the Basics.
Retinopathy of prematurity (ROP) is a leading cause of blindness in preterm infants around the world. Through the development of animal models and clinical trials our understanding of the pathophysiology of this disease and approach to therapy has evolved significantly since ROP was first described in the 1940s in the United States. The mainstay of treatment in ROP remains ablative laser therapy to the avascular retina but pharmacologic agents are being more and more commonly used with new targets for pharmacotherapy emerging. This paper summarizes our current understanding of the pathophysiology of ROP based on the data gleaned from animal models and discusses current approaches to pharmacotherapy.


Abnormal mitral valve anatomy in d-transposition of the great arteries: anatomic characterization and surgical outcomes.
Mitral valve anomalies can occur with S,D,D-transposition of the great arteries (d-TGA). Their influence on surgical technique and outcome after an arterial switch operation (ASO) has not been well described. Patients with d-TGA who underwent ASO from February 1990 to January 2011 were identified. Echocardiograms, operative reports, hospital course, and latest follow-up evaluation were reviewed. A total of 218 infants underwent ASO at a median age of 15.8 days. Survival was 95 % during a mean follow-up period of 60 months. Nine patients (4 %) were found to have similar mitral valve anomalies including anterior malalignment conoventricular septal defect, anterior displacement of the mitral valve toward the left ventricular outflow tract (LVOT), malpositioning of the posteromedial papillary muscle, unusual rotation of the mitral valve leaflets orienting the commissure toward the anterior ventricular septum, and redundant mitral valve tissue extending into the LVOT. Coarctation was more frequent in this subgroup (33 vs. 10 %; p = 0.05). Preoperative echocardiography consistently indicated suspicion of a cleft mitral valve with chordal attachments to the ventricular septum causing potential LVOT obstruction. Operative inspection did not identify a cleft or anomalous attachments in any patient, and no valvuloplasty or chordal manipulation was performed. The average hospital length of stay were similar (30.7 vs. 25.3 days; p = 0.54). One patient died late due to progressive LVOT obstruction, and one required heart transplantation. No patient had significant mitral valve regurgitation. We conclude that mitral valve anomalies associated with d-TGA are rare but present with consistent anatomic features and higher risk of coarctation. Unusual mitral valve apparatus positioning and chordal redundancy can suggest the need for valvuloplasty and chordal resection preoperatively, but this is rarely needed.


A return-on-investment analysis of impacts on James Cook University medical students and rural workforce resulting from participation in extended rural placements.
Although all James Cook University (JCU) medical students complete multiple rural placements, some undertake extended 5-10 month rural placements in their final year. This study uses return-on-investment (ROI) methodology to quantify student and rural medical workforce benefits of these 'extended placements' from 2012 to 2018. Forty-six medical graduates were sent a survey exploring the benefits to students and to the rural workforce from participation in extended placements, as well as estimated costs to students, deadweight (how much change would have occurred without participating), and attribution (how much change was due to other experiences). The key student and rural workforce benefits were each assigned a 'financial proxy' to allow calculation of ROI as a dollar value that could be compared with the costs to students and to the medical school. Of the graduates, 25/46 responded (54%), reporting the major benefit was 'greater depth and breadth of clinical skills'. The overall cost of undertaking extended placements for students was $60,264 (AUD), while the medical school costs were $32,560 (total costs: $92,824). Given the total value of benefits ($705,827) calculated for the key student benefit of increased clinical skills and confidence in the internship year ($32,197) and for the key rural workforce benefit of willingness to work rurally ($673,630), the ROI from the extended rural programs is $7.60 for every dollar spent. This study confirms significant positive impacts of extended placements on final-year medical students with longer-term benefits for rural workforce. This positive ROI is important evidence for shifting the conversation around supporting extended placements from one of cost to one of value.


Tumor immunity against a simian virus 40 oncoprotein requires CD8+ T lymphocytes in the effector immune phase.
The required activities of CD4(+) T cells and antibody against the virally encoded oncoprotein simian virus 40 (SV40) Tag have previously been demonstrated by our laboratory to be mediators in achieving antitumor responses and tumor protection through antibody-dependent cell-mediated cytotoxicity (ADCC). In this study, we further characterize the necessary immune cell components that lead to systemic tumor immunity within an experimental pulmonary metastatic model as the result of SV40 Tag immunization and antibody production. Immunized animals depleted of CD8(+) T cells at the onset of experimental tumor cell challenge developed lung tumor foci and had an overall decreased survival due to lung tumor burden, suggesting a role for CD8(+) T cells in the effector phase of the immune response. Lymphocytes and splenocytes harvested from SV40 Tag-immunized mice experimentally inoculated with tumor cells synthesized increased in vitro levels of the Th1 cytokine gamma interferon (IFN-gamma), as assessed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry assays. CD8(+) T-cell activity was also heightened in SV40 Tag-immunized and tumor cell-challenged mice, based upon intracellular production of perforin, confirming the cytolytic properties of CD8(+) T cells against tumor cell challenge. Altogether, these data point to the role of recombinant SV40 Tag protein immunization in initiating a cytotoxic T-lymphocyte (CTL) response during tumor cell dissemination and growth. The downstream activity of CD8(+) T cells within this model is likely initiated from SV40 Tag-specific antibody mediating ADCC tumor cell destruction.


Adverse histology, homozygous loss of CDKN2A/B, and complex genomic alterations in locally advanced/metastatic renal mucinous tubular and spindle cell carcinoma.
Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare subtype of renal cell carcinoma with characteristic histologic features and chromosomal alterations. Although typically indolent, a small subset of cases has been reported to exhibit aggressive clinical behavior. We retrospectively identified 33 patients with MTSCC, consisting of 10 cases of locally advanced/metastatic MTSCC (pT3 or N1 or M1) and 23 kidney-confined MTSCC (pT1/T2) without disease recurrence or progression. Utilizing a single-nucleotide polymorphism array and a targeted next-generation sequencing platform, we examined genome-wide molecular alterations in 24 cases, including 11 available samples from 8 patients with locally advanced/metastatic MTSCC. Ten patients with locally advanced/metastatic MTSCC were 8 females (80%) and 2 males (20%). At nephrectomy, 7 of these 10 cases (70%) were pT3 or pN1 while the remaining 3 (30%) were pT1/T2. Eight patients (80%) developed metastases and common sites included lymph node (4, 40%), bone (4, 40%), and retroperitoneum (3, 30%). Four patients died of disease (40%) during follow-up. Locally advanced/metastatic MTSCCs shared typical MTSCC genomic profiles with loss of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22, while some exhibited additional complex genomic alterations, most frequently a relative gain of 1q (7/8). Homozygous loss of CDKN2A/B was observed in 3 (38%) locally advanced/metastatic MTSCCs. Tumor necrosis, solid nested/sheet pattern, irregular trabecular/single-file infiltration in a desmoplastic stroma, lymphovascular space invasion, and increased mitotic activity were associated with locally advanced/metastatic MTSCCs (all p < 0.05). Our findings reveal that MTSCCs with aggressive clinical behavior have progressed through clonal evolution; CDKN2A/B deletion and additional complex genomic abnormalities may contribute to this process. Recognizing the morphologic presentation of high-grade MTSCC and evaluating adverse histologic features seen in these tumors can help establish a definitive diagnosis and stratify patients for treatment and prognostication.


Maternal exposure to dioxin reduces hypothalamic but not pituitary metabolome in fetal rats: a possible mechanism for a fetus-specific reduction in steroidogenesis.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) reduces the synthesis of pituitary gonadotropins in a fetal age-specific manner. The pituitary synthesis of gonadotropins is regulated by the hypothalamus and, thus, needs the differentiation and development of the hypothalamus requiring a number of factors including energy supply and neurotransmitters. To investigate the mechanism whereby TCDD reduces fetal gonadotropins, we carried out a comparative study on the metabolomes of the hypothalamus and pituitary using fetal and mature Wistar rats. Male fetuses at gestational day (GD)20 were removed from dams treated orally with TCDD (1 microg/kg) at GD15, and the metabolome profiles were analyzed by gas chromatography-mass spectrometry (GC-MS). The principal component analysis of GC-MS data revealed that TCDD caused a change in the profile of fetal metabolome more markedly in the hypothalamus than in the pituitary. In sharp contrast, TCDD did not cause any marked alteration in hypothalamic as well as pituitary metabolomes in male rats born of untreated dams and treated with TCDD at postnatal day 49. It was also demonstrated that a number of fetal hypothalamic components, including glutamine and gamma-aminobutyric acid, are reduced by TCDD. These results demonstrate a possibility that TCDD may reduce the metabolic activity of the hypothalamus in a fetus-specific fashion, resulting in the reduced synthesis of gonadotropins.


Utilization of screening mammography in New Hampshire: a population-based assessment.
The objective of screening mammography is to identify breast carcinoma early, which requires routine screening. Although self-report data indicate that screening utilization is high, the results of this population-based assessment indicated that utilization is lower than reported previously. The authors compared New Hampshire population data from the 2000 Census with clinical encounter data for the corresponding time obtained from the New Hampshire Mammography Network, a mammography registry that captures approximately 90% of the mammograms performed in participating New Hampshire facilities. The results showed that approximately 36% of New Hampshire women either never had a mammogram or had not had a mammogram in > 27 months (irregular screenees), and older women (80 yrs and older) were less likely to be screened (79% unscreened/underscreened) compared with younger women (ages 40-69 yrs; 28-32% unscreened/underscreened). Of the screened women, 44% were adhering to an interval of 14 months, and 21% were adhering within 15 months and 26 months. The remaining 35% of the women had 1 or 2 mammograms and did not return within 27 months. Routine mammography screening may be occurring less often than believed when survey data alone are used. An important, compelling concern is the reason women had one or two mammograms only and then did not return for additional screening. This area deserves additional research.


Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues.
Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --> Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and m-cresol. In these crystals, insulin exists as R6 zinc hexamers containing a number of phenol or m-cresol molecules associated with aromatic side chains at the dimer-dimer interfaces. At the monomer-monomer interfaces, the B28 Pro --> Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and A1 Gly, has also determined. This forms an R6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two m-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions.


La desesperación in Latino migrant day laborers and its role in alcohol and substance-related sexual risk.
The purpose of this study was to better understand the relation between psychological distress and alcohol and substance related sexual risk in Latino migrant day laborers (LMDLs). In addition to examining the roles of depression and anxiety, it was also necessary to examine the role of desesperación, a popular Latino idiom of distress frequently expressed by LMDLs in response to the thwarting of major migration related life goals such as traveling to the U.S. in search of work to support families, projects and purchases in country of origin. Given the structural vulnerability of LMDLs to under-employment and frequent unemployment, LMDLs also refer to desesperación as a prelude to problem drinking, substance use, and sexual risk taking. Hence we developed and validated a scale of desesperación for LMDLs to explore this culturally relevant construct of psychological distress in this unique population of Latinos. Based on a cross sectional survey of 344 LMDLs, this study found that the dissatisfaction subscale of desesperación predicted alcohol-related sexual risk taking, while depression predicted substance-related sexual risk taking. These findings are discussed including implications of preventing alcohol and substance related sexual risk taking in LMDLs.


Effect of serotype 5 adenoviral and serotype 2 adeno- associated viral vector-mediated gene transfer to salivary glands on the composition of saliva.
Key to the development of a useful clinical therapy is the minimization of side effects. Routine safety testing, however, does not provide information about the physiological status of many potentially useful gene transfer target sites. In this study, we evaluated the longitudinal effects of intrasalivary duct delivery of recombinant serotype 5 adenoviral (rAd5; 10(9)-10(10) particles/gland in rats) and recombinant serotype 2 adeno-associated viral (rAAV2; 10(8)-10(9) particles/gland in mice) vectors on salivary composition. Both vectors led to modest, transient alterations in several salivary components that thereafter returned to normal. The changes suggested two initial specific consequences of rAd5 and rAAV2 vector administration: (1) a modest breach of the mucosal barrier in the targeted glands, indicated by elevations in salivary albumin, total protein, and Na+ levels, and (2) an innate host response, indicated by transient elevations in either salivary lactoferrin and IgA levels (rAd5) or mucin (rAAV2). These studies are consistent with the notion that administration of modest doses of rAd5 and rAAV2 vectors to salivary glands for a therapeutic purpose can be accomplished without severe or permanent injury to the target tissue, or compromise to its essential exocrine physiological function.


Drug monomers from Salvia miltiorrhiza Bge. promoting tight junction protein expression for therapeutic effects on lung cancer.
Salvia miltiorrhiza Bge. is a traditional Chinese medicine (TCM) that has been used for treatment of various diseases, including cancer by activating blood circulation and removing blood stasis. Tanshinone (TanIIA) and cryptotanshinone (CPT) are major lipophilic compounds extracted from the root of Salvia miltiorrhiza Bge., which are considered to be the effective compounds affecting the efficacy of the anti-tumor therapy of Salvia miltiorrhiza Bge. We have explored the mechanism of CPT and TanIIA exerting inhibition in non-small cell lung cancer (NSCLC) to provide experimental data support for guiding the translational development and clinical application of anti-tumor components of TCM. The subcutaneous tumor model and in vitro culture model of A549 cells was constructed to evaluate CPT and TanIIA's tumour-inhibitory effect respectively. RNA sequencing (RNA-seq) and bioinformatics analysis were conducted to identify differentially expressed genes (DEGs) and signalling pathways related to CPT and TanIIA treatment. qRT-PCR and Western blot were used to explore the mechanism of CPT and TanIIA intervention on NSCLC. Both CPT and TanIIA significantly inhibited the proliferation of A549 tumor cells and tumor growth in animal models. After intervention, the migration ability decreased and the level of apoptosis increased. RNA-seq results showed that both CPT and TanIIA could cause gene differential expression, miR-21-5p as one of the most significant gene expression differences between the two groups, and could act on cell connectivity. CPT and TanIIA play a regulatory role in regulating tight junction proteins (Occludin and ZO1), and Occludin mRNA and protein levels were reduced in an in vitro miR-21-5p overexpression A549 cell model. The mechanisms may be related to the reduction of miR-21-5p expression to increase the level of promoted tight junction protein expression for the purpose of inhibiting proliferation and invasion of NSCLC.


District health information system assessment: a case study in iran.
Health care managers and personnel should be aware and literate of health information system in order to increase the efficiency and effectiveness in their organization. Since accurate, appropriate, precise, timely, valid information and interpretation of information is required and is the basis for policy planning and decision making in various levels of the organization. This study was conducted to assess the district health information system evolution in Iran according to WHO framework. This research is an applied, descriptive cross sectional study, in which a total of twelve urban and eight rural facilities, and the district health center at Falavarjan region were surveyed by using a questionnaire with 334 items. Content and constructive validity and reliability of the questionnaire were confirmed with correlation coefficient of 0.99. Obtained data were analyzed with SPSS 16 software and descriptive statistics were used to examine measures of WHO compliance. The analysis of data revealed that the mean score of compliance of district health information system framework was 35.75 percent. The maximum score of compliance with district health information system belonged to the data collection process (70 percent). The minimum score of compliance with district health information system belonged to information based decision making process with a score of 10 percent. District Health Information System Criteria in Isfahan province do not completely comply with WHO framework. Consequently, it seems that health system managers engaged with underlying policy and decision making processes at district health level should try to restructure and decentralize district health information system and develop training management programs for their managers.


Abdominal ultrasound in the evaluation of fibrosis and portal hypertension in an area of schistosomiasis low endemicity.
This study was undertaken in the municipality of Bananal, São Paulo, an endemic area for schistosomiasis with a prevalence under 10% and low parasite load among infected individuals. Our objective was to identify the clinical forms of schistosomiasis among 109 patients in whom the disease had been diagnosed through direct fecal analysis and who had been medicated with oxamniquine at the time of the Plan for the Intensification of Schistosomiasis Control Actions (1998-2000). These patients were submitted to an abdominal ultrasonography and fecal analysis by Kato-Katz method, four years, on average, after the end of the Plan. Five patients, whose abdominal ultrasound images were compatible with either peripheral or central periportal fibrosis and portal hypertension, were identified. None of the 109 patients presented Schistosoma mansoni eggs at fecal analysis. Ultrasonography is a sensitive, noninvasive diagnostic method that allows a better identification of the extent of liver involvement in schistosomiasis cases.


SOD3 Suppresses the Expression of MMP-1 and Increases the Integrity of Extracellular Matrix in Fibroblasts.
The superoxide dismutase (SOD) family functions as a reactive oxygen species (ROS)-scavenging system by converting superoxide anions into hydrogen peroxide in the cytosol (SOD1), mitochondria (SOD2), and extracellular matrix (SOD3). In this study, we examined the potential roles of SOD family members in skin aging. We found that SOD3 expression levels were significantly more reduced in the skin tissues of old mice and humans than in young counterparts, but SOD1 and SOD2 expression levels remained unchanged with aging. Accordingly, we analyzed the effects of SOD3 on intracellular ROS levels and the integrity of the extracellular matrix in fibroblasts. The treatment of foreskin fibroblasts with recombinant SOD3 reduced the intracellular ROS levels and secretion of MMP-1 while increasing the secretion of type I collagen. The effects of SOD3 were greater in fibroblasts treated with the TNF-α. SOD3 treatment also decreased the mRNA levels and promoter activity of MMP-1 while increasing the mRNA levels and promoter activities of COL1A1 and COL1A2. SOD3 treatment reduced the phosphorylation of NF-κB, p38 MAPK, ERK, and JNK, which are essential for MMP-1 transactivation. In a three-dimensional culture of fibroblasts, SOD3 decreased the amount of type I collagen fragments produced by MMP-1 and increased the amount of nascent type I procollagen. These results demonstrate that SOD3 reduces intracellular ROS levels, suppresses MMP-1 expression, and induces type I collagen expression in fibroblasts. Therefore, SOD3 may play a role in delaying or preventing skin aging.