Impact of Alzheimer's Disease, Lewy Body and Vascular Co-Pathologies on Clinical Transition to Dementia in a National Autopsy Cohort.
We examined the effect of vascular or Lewy body co-pathologies in subjects with autopsy-confirmed Alzheimer's disease (AD) on the rate of cognitive and functional decline and transition to dementia. In an autopsy sample of prospectively characterized subjects from the National Alzheimer's Coordinating Center database, neuropathology diagnosis was used to define the groups of pure AD (pAD, n = 84), mixed vascular and AD (ADV, n = 54), and mixed Lewy body disease and AD (ADLBD, n = 31). Subjects had an initial Clinical Dementia Rating-Global (CDR-G) score <1, Mini-Mental State Examination ≥15, a final visit CDR-G >1, ≥3 evaluations, and Braak tangle stage ≥III. We compared the rate of cognitive and functional decline between the groups. The rate of functional and cognitive decline was lower for ADV, and ADV patients had less severe deficits on CDR-G and the CDR-Sum of Boxes scores at the last visit than pAD and ADLBD patients. No significant differences were noted between ADLBD and pAD patients. After controlling for age at death, the odds of reaching CDR ≥1 at the last visit were lower in the ADV subjects compared to the pAD subjects. The mean rate of functional and cognitive decline among ADV subjects was slower than among either pAD or ADLBD patients. Vascular pathology did not increase the odds of attaining CDR ≥1 when occurring with AD in this national cohort.


Anxiety levels, fear-avoidance beliefs, and disability levels at baseline and at 1 year among subjects with acute and chronic low back pain.
To compare anxiety levels, fear-avoidance beliefs, and disability levels over 1 year for patients with acute (< or =3 months) and chronic (>3 months) low back pain (LBP). Prospective study with questionnaire measurements. Tertiary care clinic. Patients with acute or chronic LBP who resided in a 3-county local area and presented to our clinic for initial evaluation. Administration of and results analysis from Fear-Avoidance Beliefs Questionnaire, Oswestry Disability Index, Pain and Impairment Relationship Scale, and Spielberger State-Trait Anxiety Inventory at baseline and 12 months. Trait anxiety was measured at baseline only. Scores from questionnaires assessing fear-avoidance beliefs and state and trait anxiety, as well as LBP disability levels. In total, 138 patients with acute LBP and 107 with chronic LBP were enrolled. Of these patients, 111 with acute and 86 with chronic LBP completed the study. The 2 groups were statistically indistinguishable at baseline on all measures except trait anxiety scores, which were significantly higher in the group with chronic LBP than in the acute group (P = .01). At 1 year, the acute group had a statistically significant improvement in all outcome measures except state anxiety. The group with chronic LBP had significant improvement in all measures except fear-avoidance beliefs and state anxiety. Overall, the group with acute LBP improved more in all measurement instruments than the chronic LBP group (a statistically significant difference) except state anxiety. The group with chronic LBP exhibited a higher level of trait anxiety at baseline than those with acute LBP and, unlike the acute LBP group, did not have improved fear-avoidance beliefs over 1 year. The relationship between anxiety and chronic LBP is novel. Because anxiety is potentially modifiable, future studies that evaluate the relationship between LBP and anxiety are warranted.


Proximal Periodontal Support Adjacent to Untreated Peri-implantitis Lesions: A Cross-Sectional Analysis.
To assess site-related features of peri-implantitis occurring adjacent to teeth and its association with the proximal periodontal bone level. Periapical radiographs were collected from partially edentulous patients exhibiting peri-implantitis adjacent to teeth. The following variables were quantified: intrabony defect width (DW), implant marginal bone loss (MBLi), tooth marginal bone loss (MBLt), implant-tooth distance (ITd), intrabony defect angulation (DA), adjacent periodontal bone peak height (ABPh), and implant-tooth angulation (ITa). A correlation matrix using the Spearman correlation coefficient was created to explore the dependence of these variables. Univariate linear regression analysis was carried out by means of generalized estimating equations (GEE), using MBLt as dependent variable. Overall, 61 patients and 84 implants were included in this study, consisting of a total of 105 implant sites facing adjacent teeth. This resulted in 515 linear and 194 angular measurements. A total of 11 different statistically significant associations were demonstrated between the different variables analyzed. Moreover, the univariate regression analysis revealed significant positive associations between MBLt and MBLi (P = .013) and between MBLt and periodontitis (PD) (P = .014). These associations were confirmed in the multivariate model. Teeth adjacent to untreated peri-implantitis lesions are associated with proximal loss of periodontal support. This finding is more remarkable in scenarios that display short implant-tooth distance.


Hierarchical classification of gene ontology terms using the GOstruct method.
Protein function prediction is an active area of research in bioinformatics. Yet, the transfer of annotation on the basis of sequence or structural similarity remains widely used as an annotation method. Most of today's machine learning approaches reduce the problem to a collection of binary classification problems: whether a protein performs a particular function, sometimes with a post-processing step to combine the binary outputs. We propose a method that directly predicts a full functional annotation of a protein by modeling the structure of the Gene Ontology hierarchy in the framework of kernel methods for structured-output spaces. Our empirical results show improved performance over a BLAST nearest-neighbor method, and over algorithms that employ a collection of binary classifiers as measured on the Mousefunc benchmark dataset.


Renal cold storage followed by transplantation impairs expression of key mitochondrial fission and fusion proteins.
The majority of transplanted kidneys are procured from deceased donors which all require exposure to cold storage (CS) for successful transplantation. Unfortunately, this CS leads to renal and mitochondrial damage but, specific mitochondrial targets affected by CS remain largely unknown. The goal of this study is to determine whether pathways involved with mitochondrial fusion or fission, are disrupted during renal CS. Male Lewis rat kidneys were exposed to cold storage (CS) alone or cold storage combined with transplantation (CS/Tx). To compare effects induced by CS, kidney transplantation without CS exposure (autotransplantation; ATx) was also used. Mitochondrial function was assessed using high resolution respirometry. Expression of mitochondrial fusion and fission proteins were monitored using Western blot analysis. CS alone (no Tx) reduced respiratory complex I and II activities along with reduced expression of the primary mitochondrial fission protein, dynamin related protein (DRP1), induced loss of the long form of Optic Atrophy Protein (OPA1), and altered the mitochondrial protease, OMA1, which regulates OPA1 processing. CS followed by Tx (CS/Tx) reduced complex I, II, and III activities, and induced a profound loss of the long and short forms of OPA1, mitofusin 1 (MFN1), and mitofusin 2 (MFN2) which all control mitochondrial fusion. In addition, expression of DRP1, along with its primary receptor protein, mitochondrial fission factor (MFF), were also reduced after CS/Tx. Interestingly, CS/Tx lead to aberrant higher molecular weight OMA1 aggregate expression. Our results suggest that CS appears to involve activation of the OMA1, which could be a key player in proteolysis of the fusion and fission protein machinery following transplantation. These findings raise the possibility that impaired mitochondrial fission and fusion may be unrecognized contributors to CS induced mitochondrial injury and compromised renal graft function after transplantation.


Cost-Effectiveness of HIV Retention and Re-engagement Interventions in High-Income Countries: A Systematic Literature Review.
Engagement in lifelong HIV care is critical for both patient and public health, yet there are limited resources to invest in improving HIV outcomes. We systematically reviewed evidence on the cost-effectiveness of retention and re-engagement interventions. We searched five databases for peer-reviewed studies published between 2010 and 2020. We assessed reporting and methods quality, extracted data on target populations, interventions, and cost-effectiveness, and evaluated overall strength of evidence. Eleven studies met inclusion criteria, and eight had moderate-high quality. Cost-effectiveness estimates ranged from cost-saving to over $1,000,000/quality-adjusted life year (QALY) gained. Of the 73 cost-effectiveness ratios reported, 64% were < $100,000/QALY gained. Interventions were more likely to be cost-effective when targeted to high-risk groups, implemented in locations where baseline retention levels were low, and when used in combination with other high-impact HIV interventions (such as prevention). Overall, existing evidence is moderately strong that retention and/or re-engagement interventions can be cost-effective in high-income countries.


Health related quality of life among the Thai people with unilateral lower limb amputation.
To study the health related quality of life (HRQOL) among Thai unilateral lower limb amputees and determine the factors associated with a good HRQOL. A postal survey with the WHOQOL-BREF-Thai questionnaire (26 items) to 1300 people with LLA who received a lower limb prostheses from Siriraj Hospital, Prapokklao Hospital, and Ratchaburi Hospital between 2001 and 2005 was conducted. Descriptive statistics were used to report the level of HRQOL. Chi-Square, independent Sample t-test and multivariate analysis by stepwise logistic regression were used to determine the factors associated with a good QOL. Three hundred and nine questionnaires were completed from the 321 returned questionnaires (response rate 24.7%). Among these, 278 people were with unilateral LLA. They were 221 males and 57 females with mean age 46.9 +/- 13.9 years old. The number of people with LLA who had poor, fair and good QOL were 14 (5%), 241 (86.7%), and 23 (8.3%), respectively. Demographically, the people with LLA who had long duration of amputation (p = 0.001), higher education (p = 0.005), and had been employed after amputation (p < 0.001) had significantly better HRQOL. The amputees who had good wearing comfort (p = 0.04) after wearing the prostheses, had no phantom pain (p = 0.02), used no gait aids (p = 0.01), and had no body image anxiety (p = 0.01) had significantly better HRQOL. The factors associated with the good HRQOL were higher education (OR 3.2), having been employed after amputation (OR 2.1), and having good prosthetic wearing comfort (OR 1.3). Thai people with unilateral LLA reported primarily fair HRQOL. Having higher education, having been employed after amputation, and having good prosthetic wearing comfort were associated with the good HRQL.


[Mammographic findings after breast-preserving procedure].
Clinical evaluation of the breast after breast-conserving surgery and postoperative irradiation for carcinoma is made difficult by the changes induced by the treatment. Therefore mammographic evaluation, comprises an important part of the follow-up of these patients. The interpretation of the mammograms requires knowledge of the changes expected to occur after treatment. In this paper we describe such changes as experienced in our department.


Stereospecific total synthesis of somocystinamide A.
The first total synthesis of somocystinamide A, a disulfide dimer with extremely labile enamide functional groups, was accomplished in a concise and stereospecific manner. Somocystinamide A is reported to possess exceptionally potent antiangiogenic and tumoricidal activities. The current work should enable further pharmacological investigation of this important natural product.


A highly sensitive and reusable electrochemical mercury biosensor based on tunable vertical single-walled carbon nanotubes and a target recycling strategy.
In this work, a novel electrochemical Hg2+ biosensor with high sensitivity and excellent reusability was presented. The sensor was based on tunable vertical single-walled carbon nanotubes (v-SWCNTs) and a target recycling strategy. A facile and scalable approach involving the conformational regulation of self-assembled monolayers was established for the fabrication of v-SWCNTs with tailored orientation and homogeneity. The obtained v-SWCNTs exhibited superior properties including a large specific area, high electrical conductivity, and excellent substrate binding strength, opening up a wide horizon for advanced electrochemical applications. Meanwhile, an efficient Hg2+ recycling strategy was designed using exonuclease III. In this strategy, a trace amount of Hg2+ triggered consecutive nicking reactions, and numerous report probes were released to bind with v-SWCNTs through π-π interactions. Based on the innovative design, an ultralow detection limit of 3 fM (S/N = 3), a wide linear range from 10 fM to 1 μM, high selectivity, and good reliability were achieved for a Hg2+ assay in water and serum samples using the prepared biosensor. Besides, due to the reversibility of π-π interactions, the stable v-SWCNT interface was regenerated for 50 consecutive measurements without obvious signal loss, making it a promising candidate for routine and efficient Hg2+ monitoring.


Thirty-nine-year survival with the Starr-edwards mitral valve prosthesis.
We report a case of a 57 year-old woman with Starr-Edwards model 6120 mitral valve replacement and Kay-Shiley bioprosthetic tricuspid valve replacement in 1968 at Niguarda Hospital in Milan. The mitral caged-ball has proved its excellent durability and its good hemodynamic performance in many patients, even if subject to high tendency to thrombosis. In literature there is no evidence of durability of this prosthesis longer than 35 years. Our patient after 39 years from mitral valve replacement lives a happy and fulfilling life (NYHA II), with no evidence of hemolysis, ball variance, symptomatic embolization or major bleeding.


Cost-effectiveness of drug abuse treatment for primary prevention of acquired immunodeficiency syndrome: epidemiologic considerations.
The prevention of AIDS has justified recent increases in drug abuse treatment expenditures. Three of the epidemiologic considerations involved in assessing the cost-effectiveness of drug treatment for primary prevention of AIDS among IV drug users were discussed. First, the considerable geographic variation in the prevalence of the virus that causes AIDS suggests that areas with relatively low infection levels may be more cost-effective targets when allocating limited drug abuse treatment resources. Expansions and modifications in the current national HIV-1 serologic surveillance system will be needed to make informed resource allocation decisions. Second, when comparing the cost-effectiveness of two alternative treatment modalities or programs, the number of new HIV-1 infections does not appear to be an appropriate outcome measure. Serologic testing should be supplemented with self-reported drug use behaviors, with or without drug testing. Finally, significant opportunity costs may be associated with employing drug abuse treatment as the principal approach to primary prevention of HIV-1 infection among IVDUs, when alternative and complementary approaches are also effective. Specifically, treatment expansion is unlikely to be cost-effective when the demand for publicly funded treatment slots exceeds the number available and in communities where only a small minority of IVDUs are enrolled in treatment.


Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women.
Menopause is associated with decreased lean body mass and increased fat due to aging and declining hormone secretion. Estrogens or estrogen-progestins have been used to alleviate vasomotor symptoms. However, estrogen-androgen (E/A) therapy is also used for vasomotor symptom relief and has been shown to increase lean body mass while decreasing fat mass. The objective of this 16-wk, double-blind, randomized, parallel group clinical trial was to compare esterified estrogen plus methyltestosterone (1.25 mg estrogen + 2.5 mg methyltestosterone/d; E/A group) vs. esterified estrogen alone (1.25 mg/d; E group) on body composition. Forty postmenopausal women (mean age, 57 yr) participated. Compared with estrogen treatment alone, women in the E/A group increased their total lean body mass and reduced their percentage fat for all body parts (P < 0.05). After E/A treatment, there were statistically significant increases in lean body mass by 1.232 kg [0.181 +/- 0.004, 0.81 +/- 0.057, and 0.24 +/- 0.009 kg in the upper body (P = 0.021), trunk (P = 0.001), and lower body (P = 0.047), respectively]. In the E group, the increase was 0.31 +/- 0.004, 0.021 +/- 0.03, and 0.056 +/- 0.05 kg in the upper body, trunk, and lower body, respectively. In the E/A group, body fat was reduced by 0.90 kg (P = 0.18 for the trunk only), and percentage body fat declined by 7.4% (P < or = 0.05 for all body parts). Lower body strength increased by 23.1 kg (51 lb) in the E/A group vs. only 11 kg (24.25 lb) in the E group (P = 0.002 between groups). A statistically significant increase in weight (2.7 +/- 5.1 vs. 0.1 +/- 4.6 lb; P < 0.05) was observed in the E/A group compared with the E group. When subjects were given self-reporting questionnaires, more improvement was noted in sexual functioning and quality of life in the E/A group when compared with patients receiving E alone. There were no noteworthy side effects. In conclusion, E/A replacement therapy can improve body composition, lower-body muscle strength, quality of life, and sexual functioning in postmenopausal women.


In-Hospital Formula Supplementation of Healthy Newborns: Practices, Reasons, and Their Medical Justification.
In-hospital formula supplementation is a common practice and has been shown to be a strong determinant of shorter exclusive and any breastfeeding. To investigate the reasons for and circumstances in which in-hospital formula supplementation occurs and whether the stated reasons are medically acceptable. This prospective cohort study was conducted among 342 mother-infant pairs from April to July 2011 at the Department of Obstetrics and Gynecology, University Hospital of Split, Croatia. Data were collected based on "every feed" charts and WHO/UNICEF "Questionnaire for Monitoring Baby-Friendly Hospitals". We used WHO/UNICEF Baby-Friendly Hospital Initiative and Academy of Breastfeeding Medicine documents on indications for supplemental feeding. During the first 48 hours and entire hospital stay, 49.5% and 62.8% of infants, respectively, received supplements, given on average 16.68 ± 18.6 hours after delivery. In 94.1% of supplemented infants, healthy newborns were given artificial milk, of which 5.9% of mothers had not been notified. The most common maternal reasons for supplementing were "lack of milk" (49.8%), a "crying baby" (35.5%), "cesarean section" (11.5%), newborn weight loss (10.6%), and sore nipples (10.1%). Of all the given reasons, 24.6% were categorized as being medically acceptable. Primiparas were 1.3 times more likely to supplement in hospital, whereas multiparas were 1.3 times more likely to exclusively breastfeed. In our study, most reasons for formula supplementation of healthy term newborns were not standard acceptable medical reasons, indicating a need for improved maternal support, revision of hospital policies, and training of hospital staff.


Leptin cut-off values for determination of metabolic syndrome: third national surveillance of risk factors of non-communicable diseases in Iran (SuRFNCD-2007).
Leptin is strongly contributed to the clustering of metabolic syndrome (MetS) components and potentially can be regarded as a single predictor of MetS. This population-based study, for the first time, reports the diagnostic accuracy of different leptin cut-points for determining MetS. Further, the current study compares the predictive ability of the appropriate threshold of leptin with insulin resistance. Data of the individuals without history of known diabetes mellitus, aged 25-64 years, from the third national surveillance of risk factors of non-communicable diseases (SuRFNCD-2007) were analyzed. MetS was defined due to either adult treatment panel III (ATPIII) or the modified international diabetes federation (IDF) criteria. Receiver-operating characteristic (ROC) curves were depicted to define cut-off of serum leptin, using the maximum Youden index and the shortest distance methods. Further, the values of leptin cut-offs in prediction of MetS were compared with those of insulin resistance (defined as homeostasis model assessment of insulin resistance >1.775). In men, the optimal cut-offs of leptin for IDF- and ATPIII-defined MetS were 3.6 ng/ml (positive predictive value, PPV: 56.5%; negative predictive value, NPV: 72.7%) and 4.1 ng/ml (PPV: 49.6%; NPV: 78.1%), respectively. In women, the optimal threshold was equal to 11.0 ng/ml (PPV: 53.8%; NPV: 73.0% for IDF criteria and PPV: 60.1%; NPV: 64.9% for ATPIII criteria). The diagnostic accuracy of these values in identifying MetS was similar to that of insulin resistance. Therefore, leptin is comparable to insulin resistance in identifying MetS and can be used as single predictor of MetS.


Structural requirements of tetracycline-Tet repressor interaction: determination of equilibrium binding constants for tetracycline analogs with the Tet repressor.
We used the Tn10-encoded Tet repressor, which has a highly specific binding capacity for tetracycline, to probe contacts between the drug and protein by chemical interference studies of the antibiotic. For that purpose, the equilibrium association constants of modified tetracyclines with the Tet repressor and Mg2+ cations were determined quantitatively. The results confirm the previous notion that Mg2+ probably binds with the oxygens at positions 11 and 12 and is absolutely required for protein-drug recognition. Modifications were introduced at positions seven, six, five, and four of the drug, and anhydrotetracycline was also studied. Substitutions or eliminations of functions at these positions influenced binding to the Tet repressor up to 35-fold. The introduction of an azido function at position seven in 7-azidotetracycline and epimerization of the substituents at position four in 4-epitetracycline lead to a 2- or 25-fold reduction, respectively, of Tet repressor affinity in those compounds. Anhydrotetracycline bound about 35-fold more strongly than tetracycline did, indicating that the oxygen at position 11 may be involved in Tet repressor recognition. This increased binding is in contrast to the lower antibiotic activity of anhydrotetracycline and indicates that the Tet repressor and ribosomes recognize the drug differently.


REV1 mediated mutagenesis in base excision repair deficient mouse fibroblast.
The DNA polymerase beta (Pol beta) null background renders mouse embryonic fibroblast (MEF) cells base excision repair deficient and hyper-mutagenic upon treatment with the monofunctional alkylating agent, methyl methanesulfonate (MMS). This effect involves an increase in all types of base substitutions, with a modest predominance of G to A transitions. In the present study, we examined the hypothesis that the MMS-induced mutagenesis in the Pol beta null MEF system is due to a lesion bypass mechanism. We studied the effect of RNAi mediated down-regulation of the lesion bypass factor REV1. The steady-state level of REV1 protein was reduced by more than 95% using stable expression of a siRNA construct in a Pol beta null cell line. We found that REV1 expression is required for the MMS-induced mutagenesis phenotype of Pol beta null MEF cells. In contrast, cell survival after MMS treatment is not reduced in the absence of REV1.


Structural deformation upon protein-protein interaction: a structural alphabet approach.
In a number of protein-protein complexes, the 3D structures of bound and unbound partners significantly differ, supporting the induced fit hypothesis for protein-protein binding. In this study, we explore the induced fit modifications on a set of 124 proteins available in both bound and unbound forms, in terms of local structure. The local structure is described thanks to a structural alphabet of 27 structural letters that allows a detailed description of the backbone. Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%). This proportion is even greater in the interface regions (41%). Interface regions preferentially involve coils. Our analysis further reveals that some structural letters in coil are not favored in the interface. We show that certain structural letters in coil are particularly subject to modifications at the interface, and that the severity of structural change also varies. These information are used to derive a structural letter substitution matrix that summarizes the local structural changes observed in our data set. We also illustrate the usefulness of our approach to identify common binding motifs in unrelated proteins. Our study provides qualitative information about induced fit. These results could be of help for flexible docking.


Development of a National TMJ Implant Registry and Repository-- NIDCR's TIRR.
To provide a national systematic program to collect removed TMJ implants and biological tissues, make them available to researchers, and study them in conjunction with long-term clinical follow-up, with the ultimate goal of stimulating research toward understanding the safety and outcomes of TMJ implants. Two synchronized divisions: The Registry, recruiting clinicians and/or surgeons and patients, and collecting comprehensive clinical patient data over time; the Repository, procuring and archiving high quality, well characterized biological specimens and retrieved implants for dissemination. Clinicians, surgeons, patients, researchers, pilot studies. October 2002-present: Recruited 34 TMJ surgeons, 34 TMJ clinicians; registered 723 surgical/non-surgical TMJD patients and control subjects; collected 542 specimens, blood, saliva; initiated 19 projects using TIRR resources; produced 60 publications and presentations nationally and internationally; sent ten grants into review, with more being developed. Continuing collection of long-term data for the development of new and improved implant designs and materials and investigation into understanding pathological mechanisms of TMJD.


Accurate regeneration of an electrical synapse between two leech neurones after destruction of the ensheathing glial cell.
An interneurone, the S cell in the central nervous system of the leech, regenerates its severed axon and forms an electrical synapse with its target, another S cell, entirely within the ensheathment of two glial cells. After the two glial cells were killed selectively by intracellular injection of protease, axonal regeneration and synapse formation occurred in a normal fashion during the month following nerve injury. Soon after reconnexion of S cells, the conduction of impulses across the non-rectifying electrical junction between the cells was more reliable from the target than into it from the thinner regenerating axon. The distal segments of severed S-cell axons survived for weeks or months after destruction of their glial cells, indicating that the ensheathing glia is not required for long-term survival of axon segments. The distal axon segment of the S cell remained connected to the target axon at the normal region of synapse midway between ganglia within the nerve cord. In about half the cases in which reconnexion between injured S cell and target S cell occurred between 10 and 25 days following nerve crush, the regenerating neurone had formed an electrical synapse with its severed distal axon and had thereby become reconnected, indirectly, with its target. In the other cases, reconnexion was by direct contact. By 4 weeks, the proportion of injured S cells that were coupled and making direct contact with their targets rose to more than 80% of the total population, indicating that regeneration continued until the two S cells contacted one another directly. This is similar to the course of S-cell regeneration in the presence of the ensheathing glia. Microscopy of the regenerating neurone and both its distal axon segment and its target showed that the site of synapse formation in the absence of the usual glial sheath was normal. Fluorescence microscopy following intracellular injection of Lucifer Yellow dye, which crosses between S cells at the electrical synapse, showed that the regenerated synapse formed specifically between S cells. Moreover, the target did not form alternative synapses when regeneration failed.


The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
We have identified a human homolog of the bacterial MutS and S. cerevisiae MSH proteins, called hMSH2. Expression of hMSH2 in E. coli causes a dominant mutator phenotype, suggesting that hMSH2, like other divergent MutS homologs, interferes with the normal bacterial mismatch repair pathway. hMSH2 maps to human chromosome 2p22-21 near a locus implicated in hereditary nonpolyposis colon cancer (HNPCC). A T to C transition mutation has been detected in the -6 position of a splice acceptor site in sporadic colon tumors and in affected individuals of two small HNPCC kindreds. These data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with HNPCC suggest that hMSH2 is the HNPCC gene.


Motivational profiles of medical students: association with study effort, academic performance and exhaustion.
Students enter the medical study with internally generated motives like genuine interest (intrinsic motivation) and/or externally generated motives like parental pressure or desire for status or prestige (controlled motivation). According to Self-determination theory (SDT), students could differ in their study effort, academic performance and adjustment to the study depending on the endorsement of intrinsic motivation versus controlled motivation. The objectives of this study were to generate motivational profiles of medical students using combinations of high or low intrinsic and controlled motivation and test whether different motivational profiles are associated with different study outcomes. Participating students (N = 844) from University Medical Center Utrecht, the Netherlands, were classified to different subgroups through K-means cluster analysis using intrinsic and controlled motivation scores. Cluster membership was used as an independent variable to assess differences in study strategies, self-study hours, academic performance and exhaustion from study. Four clusters were obtained: High Intrinsic High Controlled (HIHC), Low Intrinsic High Controlled (LIHC), High Intrinsic Low Controlled (HILC), and Low Intrinsic Low Controlled (LILC). HIHC profile, including the students who are interest + status motivated, constituted 25.2% of the population (N = 213). HILC profile, including interest-motivated students, constituted 26.1% of the population (N = 220). LIHC profile, including status-motivated students, constituted 31.8% of the population (N = 268). LILC profile, including students who have a low-motivation and are neither interest nor status motivated, constituted 16.9% of the population (N = 143). Interest-motivated students (HILC) had significantly more deep study strategy (p < 0.001) and self-study hours (p < 0.05), higher GPAs (p < 0.001) and lower exhaustion (p < 0.001) than status-motivated (LIHC) and low-motivation (LILC) students. The interest-motivated profile of medical students (HILC) is associated with good study hours, deep study strategy, good academic performance and low exhaustion from study. The interest + status motivated profile (HIHC) was also found to be associated with a good learning profile, except that students with this profile showed higher surface strategy. Low-motivation (LILC) and status-motivated profiles (LIHC) were associated with the least desirable learning behaviours.


Reticular infiltrations alone without mass in the mesentery and omentum identified at contrast-enhanced CT: efficacy of US-guided percutaneous core biopsy.
To evaluate the diagnostic efficacy of ultrasonographically (US) guided percutaneous core biopsy of reticular infiltrations alone without mass in the mesentery and omentum at contrast material-enhanced abdominal computed tomography (CT). This study was approved by the institutional review board, and the need for obtaining signed informed consent was waived for this retrospective analysis. From March 2004 to May 2009, 45 patients (mean age, 52.3 years; age range, 21-89 years) with reticular infiltrations alone without mass in the mesentery and omentum at contrast-enhanced abdominal CT underwent US-guided percutaneous core biopsy. Twenty-one men and 24 women were included. The area with the severest infiltrations at CT was targeted during real-time US-guided percutaneous biopsy. Biopsy results were compared with the final results of surgery or follow-up. The diagnostic accuracy of US-guided percutaneous biopsy was then calculated. One patient had an insufficient biopsy specimen. Among the 44 patients with sufficient biopsy specimens, 17 patients had malignancy, 12 had tuberculosis, and 15 had nonspecific inflammation. All 29 patients with malignancy and tuberculosis at biopsy had that confirmed with surgery or follow-up results. Two of 15 patients with nonspecific inflammation at percutaneous biopsy were confirmed as having malignancy at surgery and four as having tuberculosis after improvement with empirical antituberculosis therapy. The diagnostic accuracy of US-guided percutaneous biopsy of reticular infiltrations in the mesentery and omentum was 84%; the sensitivity and specificity was, respectively, 89% and 100% for malignancy, 75% and 100% for tuberculosis, and 90% and 83% for nonspecific inflammation. US-guided percutaneous core biopsy is a feasible diagnostic method with high specificity for confirmative diagnosis of reticular infiltrations alone in the mesentery and omentum at contrast-enhanced CT.


Factors Considered When Ranking Military Orthopedic Surgery Residency Candidates.
The intangible personal characteristic grit has become a popular topic of concentration within contemporary psychology studies. Grit is defined as persistent work on a focused topic for an extended period of time until a desired goal is achieved. Its application to physician selection and development is not well known. We sought to determine which factors were considered most important among leadership within the U.S. Army's orthopedic surgical training programs when selecting applications and ascertain if grit was one of the primary factors. A standardized, 18-question survey was sent to all program chairs, program directors, and assistant program directors at the six U.S. Army orthopedic surgery residency programs. Questions included demographic factors pertaining to both the individual and their respective training program. Participants were asked to rank, in order, the 10 most important variables when considering applicants. Each variable was ranked using a point system (1-10 with 10 as the best score), referred to as the factor score (FS). Further statistical analyses using descriptive statistics, paired t-test, and ANOVA were performed and reported. The response rate was 83% (15/18). The most important variable considered was the applicant's performance on their audition rotation (FS = 9.8), which was significantly more important than any other variable (P = 0.001). The second most important variable was the applicant's USMLE scores (FS = 7.13), followed by involvement in research (FS = 5.60) and conscientiousness (FS = 4.73), respectively. Grit was considered the fifth most important variable (FS = 4.27). There was no significant difference in the ranking of grit among the different programs (P = 0.282). In applicants with low United States Medical Licensing Examination scores according to leadership idiosyncrasy, their audition rotation was considered a redeeming portion of their application (P = 0.02) followed by their level of grit. The most important factor when considering an orthopedic surgery applicant was how well the applicant performed on an audition rotation, followed by their United States Medical Licensing Examination scores. Grit has become an important consideration in resident selection.


[Ultrasonic study of the large intestine in Hirschsprung's disease in children].
The authors have proposed a method of ultrasonic control of the dynamics of the colon size in children with Hirschsprung's disease with the filling of the colon with a 1% solution of sodium chloride. The method may be used as an independent examination.


Inhibitory role of dietary protein restriction on the development and expression of immune-mediated antitubular basement membrane-induced tubulointerstitial nephritis in rats.
The protective effect of dietary protein restriction on the development and expression of immune-mediated interstitial nephritis was evaluated in Brown Norway rats with anti-tubular basement membrane disease. In the first series of experiments, pair-fed rats received low protein (LP) (3% casein) or normal protein (NP) (27% casein), normocaloric diets. After 6 wk, each group was immunized with renal tubular antigen in adjuvant to produce anti-tubular basement membrane antibody (alpha TBM-Ab) and tubulointerstitial nephritis. The kidneys harvested from NP rats after four more weeks on the diet had histologically more severe interstitial disease than the LP rats (histologic severity; NP = 3.1 +/- 0.2 vs. LP = 1.1 +/- 0.3; P less than 0.001), and serum creatinine values were concordantly different (NP = 1.34 +/- 0.02 vs. LP = 0.82 +/- 0.03). Titers of alpha TBM-Ab were similar in both groups, while the T cell-mediated immune response, as measured by delayed-type hypersensitivity (DTH), was nonspecifically impaired in LP rats when compared with the NP group. Admixture cotransfers of LP plus NP cells failed to demonstrate active suppression as an explanation for the depressed DTH in LP rats. The therapeutic role of dietary protein restriction was also examined in rats with established alpha TBM disease. In these experiments, rats were first immunized and fed NP diets for 4 wk (histologic severity = 3.0 +/- 0.2; creatinine = 1.78 +/- 0.02), and then were divided into two groups and followed for six more weeks on either LP or NP diets. LP rats, under these conditions, developed less disease than those fed NP diet (histologic severity; NP = 3.2 +/- 0.3 vs. LP = 1.4 +/- 0.2; P less than 0.001), and serum creatinine values were concordantly different (NP = 1.92 +/- 0.05 vs. LP = 0.97 +/- 0.02). Again, the titers of alpha TBM-Ab in both LP and NP groups were similar. These data collectively suggest that LP diet has a protective effect both on the development and extent of tubulointerstitial nephritis that is perhaps, in part, related to the selective abrogation of effector T cell immunity.


Migration, Remittances and Nutrition Outcomes of Left-Behind Children: A National-Level Quantitative Assessment of Guatemala.
Historically, Guatemalans have suffered high rates of poverty and malnutrition while nearly ten percent of their population resides abroad. Many Guatemalan parents use economic migration, mainly international migration to the United States, as a means to improve the human capital prospects of their children. However, as this investigation shows, the timing of migration events in relation to left-behind children's ages has important, often negative and likely permanent, repercussions on the physical development of their children. To illustrate these dynamics, this investigation uses an instrumental variables framework to disentangle the countervailing effects of Guatemalan fathers' absences due to migration from concomitant remittances on left-behind children's growth outcomes. Based on national-level data collected in 2000, the investigation reveals that the international migration of a father in the previous year is correlated with a 22.1% lower length/height-for-age z-score for the average left-behind child aged ≤ 3. In contrast, the receipt of remittance income has no influence on the physical stature of a child, which may indicate that migrant fathers with young children are not able to achieve economic success soon enough during their ventures abroad to fully ameliorate the harmful effects caused by their absences.


Human Papillomavirus 16 E6 Antibodies in Individuals without Diagnosed Cancer: A Pooled Analysis.
The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted. A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and <1,000] or (ii) high seroreactivity (MFI ≥ 1,000). Associations of moderate and high HPV16 E6 seroreactivity with (i) demographic risk factors; and seropositivity for (ii) other HPV16 proteins (E1, E2, E4, E7, and L1), and (iii) E6 proteins from non-HPV16 types (HPV6, 11, 18, 31, 33, 45, and 52) were evaluated. Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2-51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3-15.4); E2 (OR, 7.7; 95% CI, 1.4-29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6-119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9-81.8). No associations were observed with moderate HPV16 E6 seroreactivity. High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors. Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection.


Combinations of variations in multiple genes are associated with hypertension.
The genetic analysis of hypertension has revealed complex and inconsistent results, making it difficult to draw clear conclusions regarding the impact of specific genes on blood pressure regulation in diverse human populations. Some of the confusion from previous studies is probably due to undetected gene-gene interactions. Instead of focusing on the effects of single genes on hypertension, we examined the effects of interactions of alleles at 4 candidate loci. Three of the loci are in the renin-angiotensin-system, angiotensinogen, ACE, and angiotensin II type 1 receptor, and they have been associated with hypertension in at least 1 previous study. The fourth locus studied is a previously undescribed locus, named FJ. In total, 7 polymorphic sites at these loci were analyzed for their association with hypertension in 51 normotensive and 126 hypertensive age-matched individuals. There were no significant differences between the 2 phenotypic classes with respect to either allele or genotype frequencies. However, when we tested for nonallelic associations (linkage disequilibrium), we found that of the 120 multilocus comparisons, 16 deviated significantly from random in the hypertensive class, but there were no significant deviations in the normotensive group. These findings suggest that genetic interactions between multiple loci rather than variants of a single gene underlie the genetic basis of hypertension in our study subjects. We hypothesize that such interactions may account for the inconsistent findings in previous studies because, unlike our study, prior studies almost always examined single-locus effects and did not consider the effects of variation at other potentially interacting loci.


Circulating rather than cardiac angiotensin-(1-7) stimulates cardioprotection after myocardial infarction.
Angiotensin (Ang)-(1-7) attenuates the development of heart failure. In addition to its local effects on cardiovascular tissue, Ang-(1-7) also stimulates bone marrow, which harbors cells that might complement the therapeutic effect of Ang-(1-7). We studied the effects of Ang-(1-7) either produced locally in the heart or subcutaneously injected during the development of heart failure induced by myocardial infarction (MI) and explored the role of cardiovascular progenitor cells in promoting the effects of this heptapeptide. Effects of Ang-(1-7) on bone marrow-derived mononuclear cells in rodents, particularly endothelial progenitor cells, were investigated in vitro and in vivo in rats, in mice deficient for the putative Ang-(1-7) receptor Mas, and in mice overexpressing Ang-(1-7) exclusively in the heart. Three weeks after MI induction through permanent coronary artery occlusion, effects of Ang-(1-7) either produced locally in the heart or injected into the subcutaneous space were investigated. Ang-(1-7) stimulated proliferation of endothelial progenitor cells isolated from sham or infarcted rodents. The stimulation was blunted by A779, a Mas receptor blocker, or by Mas deficiency. Infusion of Ang-(1-7) after MI increased the number of c-kit- and vascular endothelial growth factor-positive cells in infarcted hearts, inhibited cardiac hypertrophy, and improved cardiac function 3 weeks after MI, whereas cardiomyocyte-derived Ang-(1-7) had no effect. Our data suggest circulating rather than cardiac Ang-(1-7) to be beneficial after MI. This beneficial effect correlates with a stimulation of cardiac progenitor cells in vitro and in vivo. This characterizes the heptapeptide as a promising new tool in stimulating cardiovascular regeneration under pathophysiological conditions.


Tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group proteins.
To investigate tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group (PcG) proteins. Tissue microarrays containing matched primary and recurrent ovarian tumors from the same patients were constructed for detection of PcG protein expression. Survival analyses of clinicopathological parameters and expression of PcG proteins were performed on progression-free survival (PFS) and overall survival (OS) of patients. Genetic and epigenetic heterogeneity was explored in aspects of gene copy number and microRNA (miRNA) profiling. PcG proteins were heterogeneously expressed in primary versus recurrent tumors (P<0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of BMI1 and EZH2 in first-onset lymph node metastases with shortened PFS was demonstrated (P=0.010, P=0.019); and a significant association of intensive expression of BMI1 and EZH2 in recurrent tumors with shortened OS was demonstrated (P=0.042, P=0.047). Importantly, BMI1 and EZH2 expression provided significant independent prognostic parameters in multivariate analyses (P<0.05). Gene amplification did not always coincide with PcG protein expression. Eight miRNAs were found to be downregulated in recurrent tumors, among which miR-298 might indirectly regulate the expression of EZH2 through transcription factor ILF3. Tumor heterogeneity exists in the recurrence of epithelial ovarian cancer, manifested by PcG protein expression and underlying genetic and epigenetic alterations. Intensive expression of BMI1 and EZH2 are predictors of earlier relapse and shorter OS, independent of grade and chemotherapy sensitivity. EZH2 and miR-298 have great potential to be new targets for treatment of recurrent ovarian cancer.


Fluorescent TEM-1 β-lactamase with wild-type activity as a rapid drug sensor for in vitro drug screening.
We report the development of a novel fluorescent drug sensor from the bacterial drug target TEM-1 β-lactamase through the combined strategy of Val216→Cys216 mutation and fluorophore labelling for in vitro drug screening. The Val216 residue in TEM-1 is replaced with a cysteine residue, and the environment-sensitive fluorophore fluorescein-5-maleimide is specifically attached to the Cys216 residue in the V216C mutant for sensing drug binding at the active site. The labelled V216C mutant has wild-type catalytic activity and gives stronger fluorescence when β-lactam antibiotics bind to the active site. The labelled V216C mutant can differentiate between potent and impotent β-lactam antibiotics and can distinguish active-site binders from non-binders (including aggregates formed by small molecules in aqueous solution) by giving characteristic time-course fluorescence profiles. Mass spectrometric, molecular modelling and trypsin digestion results indicate that drug binding at the active site is likely to cause the fluorescein label to stay away from the active site and experience weaker fluorescence quenching by the residues around the active site, thus making the labelled V216C mutant to give stronger fluorescence in the drug-bound state. Given the ancestor's role of TEM-1 in the TEM family, the fluorescent TEM-1 drug sensor represents a good model to demonstrate the general combined strategy of Val216→Cys216 mutation and fluorophore labelling for fabricating tailor-made fluorescent drug sensors from other clinically significant TEM-type β-lactamase variants for in vitro drug screening.


Activation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of Aplysia.
The ability of sodium pyrithione (NaP), an agent that produces delayed neuropathy in some species, to alter neuronal physiology was accessed using ratiometric imaging of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in fura PE-filled cultured Aplysia bag cell neurons. Bath-application of NaP evoked a [Ca(2+)](i) elevation in both somata and neurites with an EC(50) of approximately 300 nM and a Hill coefficient of approximately 1. The response required the presence of external Ca(2+), had an onset of 3-5 min, and generally reached a maximum within 30 min. 2-Methyl-sulfonylpyridine, a metabolite and close structural analog of NaP, did not elevate [Ca(2+)](i). Under whole-cell current-clamp recording, NaP produced a approximately 14 mV depolarization of resting membrane potential that was dependent on external Ca(2+). These data suggested that NaP stimulates Ca(2+) entry across the plasma membrane. To minimize the possibility that a change in cytosolic pH was the basis for NaP-induced Ca(2+) entry, bag cell neuron intracellular pH was estimated with the dye 2',7'-bis(carboxyethyl-5(6)-carboxy-fluorescein acetoxy methylester. Exposure of the neurons to NaP did not alter intracellular pH. The slow onset and sustained nature of the NaP response suggested that a cation exchange mechanism coupled either directly or indirectly to Ca(2+) entry could underlie the phenomenon. However, neither ouabain, a Na(+)/K(+) ATPase inhibitor, nor removal of extracellular Na(+), which eliminates Na(+)/Ca(2+) exchanger activity, altered the NaP-induced [Ca(2+)](i) elevation. Finally, the possibility that NaP gates a Ca(2+)-permeable ion channel in the plasma membrane was examined. NaP did not appear to activate two major forms of bag cell neuron Ca(2+)-permeable ion channels, as Ca(2+) entry was unaffected by inhibition of voltage-gated Ca(2+) channels using nifedipine or by inhibition of a voltage-dependent, nonselective cation channel using a high concentration of tetrodotoxin. In contrast, two potential store-operated Ca(2+) entry current inhibitors, SKF-96365 and Ni(2+), attenuated NaP-induced Ca(2+) entry. We conclude that NaP activates a slow, persistent Ca(2+) influx in Aplysia bag cell neurons.


Cellular folate binding proteins; function and significance.
It appears that specific functions may be assigned to some of the cellular folate binding proteins with some degree of certainty. Those that are membrane bound or derived from membranes probably have a role in transport of folate molecules into the cell. This is in spite of the fact that the localization of this protein to the plasma membrane has been carried out in only a limited number of cases. The role of the folate binding protein of L. casei in transport is much clearer. Bacteria provide the opportunity to obtain mutants defective in both transport and binding, and such mutants are more difficult to obtain with mammalian cell lines. The intracellular folate binding proteins have been discovered so far only in liver. The fact that the folate binding proteins in rat liver mitochondria are two enzymes, dimethylglycine dehydrogenase and sarcosine dehydrogenase, suggests that enzyme activities may eventually be discovered for the other intracellular folate binding proteins. This may not possible, however, and a reasonably strong case has been made that the folate binding protein of cytosol, FBP-CII, serves in a storage role. Such a storage role is difficult to prove since it depends, in part, on the demonstration that the protein becomes progressively less saturated during deficiency--a situation true also for enzymes.


Evaluation of The Fetal Heart Rate Monitoring with The Non-Invasive Electrocardiography Signals.
Fetal heart rate monitoring is a crucial element in determining the health of the fetus during pregnancy. In this paper, we evaluate the fetal heart rate (FHR) and maternal heart rate (MHR) between our non-invasive fetal monitoring system, Femom, developed by a Biorithm and the Huntleigh computerized cardiotocography (cCTG) together with the Sonicaid FetalCare3 software by comparing the accuracy, sensitivity, and reliability through using Bland-Altman analysis, Positive Percent Agreement (PPA) and Intraclass Correlation Coefficient (ICC) respectively. Femom device is a part of the Femom system which collects abdominal electrocardiogram (aECG) signals. Femom sever then processes the collected signals to generate FHR and MHR using novel algorithms. We collected data from 285 pregnant participants who were at least of 28 weeks of gestational age. FHR accuracy consists of mean bias and limit-of-agreement (LoA). The FHR bias is 0.05 beat per minute (BPM) and LoA is [-8.7 8.8] with 95% confidence interval (95% CI) measured using Bland Altman analysis. The PPA of 90.9% reflects FHR sensitivity. Reliability is measured with absolute ICC and consistency ICC. The absolute ICC is of 88% and consistency ICC of 94%. For MHR evaluation, accuracy is measured using Bland Altman analysis which provided a bias of 0.35 BPM and LoA of [-7 6.2] with 95% CI. The MHR sensitivity calculated using PPA is 98% while the MHR reliability is with the absolute value of 99% and consistency ICC of 99%.


Enhanced clearing of Candida biofilms on a 3D urothelial cell in vitro model using lysozyme-functionalized fluconazole-loaded shellac nanoparticles.
Candida urinary tract biofilms are increasingly witnessed in nosocomial infections due to reduced immunity of patients and the hospital ecosystem. The indwelling devices utilized to support patients with urethral diseases that connect the unsterilized external environment with the internal environment of the patient are another significant source of urinary tract biofilm infections. Recently, nanoparticle (NP)-associated therapeutics have gained traction in a number of areas, including fighting antibiotic-resistant bacterial biofilm infection. However, most studies on nanotherapeutic delivery have only been carried out in laboratory settings rather than in clinical trials due to the lack of precise in vitro and in vivo models for testing their efficiency. Here we develop a novel biofilm-infected 3D human urothelial cell culture model to test the efficiency of nanoparticle (NP)-based antifungal therapeutics. The NPs were designed based on shellac cores, loaded with fluconazole and coated with the cationic enzyme lysozyme. Our formulation of 0.2 wt% lysozyme-coated 0.02 wt% fluconazole-loaded 0.2 wt% shellac NPs, sterically stabilised by 0.25 wt% poloxamer 407, showed an enhanced efficiency in removing Candida albicans biofilms formed on 3D layer of urothelial cell clusteroids. The NP formulation exhibited low toxicity to urothelial cells. This study provides a reliable in vitro model for Candida urinary tract biofilm infections, which could potentially replace animal models in the testing of such antifungal nanotechnologies. The reproducibility and availability of a well-defined biofilm-infected 3D urothelial cell culture model give valuable insights into the formation and clearing of fungal biofilms and could accelerate the clinical use of antifungal nanotherapeutics.


Direct regulation of shikimate, early phenylpropanoid, and stilbenoid pathways by Subgroup 2 R2R3-MYBs in grapevine.
The stilbenoid pathway is responsible for the production of resveratrol in grapevine (Vitis vinifera L.). A few transcription factors (TFs) have been identified as regulators of this pathway but the extent of this control has not been deeply studied. Here we show how DNA affinity purification sequencing (DAP-Seq) allows for the genome-wide TF-binding site interrogation in grape. We obtained 5190 and 4443 binding events assigned to 4041 and 3626 genes for MYB14 and MYB15, respectively (approximately 40% of peaks located within −10 kb of transcription start sites). DAP-Seq of MYB14/MYB15 was combined with aggregate gene co-expression networks (GCNs) built from more than 1400 transcriptomic datasets from leaves, fruits, and flowers to narrow down bound genes to a set of high confidence targets. The analysis of MYB14, MYB15, and MYB13, a third uncharacterized member of Subgroup 2 (S2), showed that in addition to the few previously known stilbene synthase (STS) targets, these regulators bind to 30 of 47 STS family genes. Moreover, all three MYBs bind to several PAL, C4H, and 4CL genes, in addition to shikimate pathway genes, the WRKY03 stilbenoid co-regulator and resveratrol-modifying gene candidates among which ROMT2-3 were validated enzymatically. A high proportion of DAP-Seq bound genes were induced in the activated transcriptomes of transient MYB15-overexpressing grapevine leaves, validating our methodological approach for delimiting TF targets. Overall, Subgroup 2 R2R3-MYBs appear to play a key role in binding and directly regulating several primary and secondary metabolic steps leading to an increased flux towards stilbenoid production. The integration of DAP-Seq and reciprocal GCNs offers a rapid framework for gene function characterization using genome-wide approaches in the context of non-model plant species and stands up as a valid first approach for identifying gene regulatory networks of specialized metabolism.


Analysis of the interaction of FtsZ with itself, GTP, and FtsA.
The interaction of FtsZ with itself, GTP, and FtsA was examined by analyzing the sensitivity of FtsZ to proteolysis and by using the yeast two-hybrid system. The N-terminal conserved domain consisting of 320 amino acids bound GTP, and a central region of FtsZ, encompassing slightly more than half of the protein, was cross-linked to GTP. Site-directed mutagenesis revealed that none of six highly conserved aspartic acid and asparagine residues were required for GTP binding. These results indicate that the specificity determinants for GTP binding are different than those for the GTPase superfamily. The N-terminal conserved domain of FtsZ contained a site for self-interaction that is conserved between FtsZ proteins from distantly related bacterial species. FtsZ320, which was truncated at the end of the conserved domain, was a potent inhibitor of division although it expressed normal GTPase activity and could polymerize. FtsZ was also found to interact directly with FtsA, and this interaction could also be observed between these proteins from distantly related bacterial species.


Sling plication for recurrent stress urinary incontinence.
: Management of recurrent stress urinary incontinence (SUI) after synthetic mid-urethral sling placement is a challenging clinical dilemma. This case series describes a safe, minimally invasive treatment option for recurrent SUI after failure of the primary mid-urethral sling procedure. : Twenty women with recurrent SUI after previous synthetic mid-urethral sling placement underwent plication of the sling with 2-0 polyester suture under intravenous sedation with an intra-operative cough stress test between December 2004 and December 2008. A retrospective chart review was performed to obtain pertinent preoperative and postoperative data. : Nine of the patients had prior retropubic synthetic mid-urethral slings. The other 11 women had transobturator mid-urethral slings, 10 of whom had slings via the outside-in approach and 1 had a single-incision mini-sling placed. The mean patient age was 59.8 years (range 38-83 years). Sling plication was performed at a median of 159.5 days after initial sling placement (range 26-2090 days). Overall 85% of patients had subjective improvement in SUI after sling plication with a median follow-up of 54.5 days (range 29-972 days). Those patients with prior retropubic slings had a 100% improvement rate compared to 72% improvement with prior obturator slings (P = 0.22). The subjective cure rate was 65%, 88% for the retropubic slings and 45% for the transobturator slings (P = 0.07). There were no complications. : Midline plication of previously placed synthetic mid-urethral slings is a safe and effective method of treating recurrent SUI.


Adaptation of the Aesop's Fable paradigm for use with raccoons (Procyon lotor): considerations for future application in non-avian and non-primate species.
To gain a better understanding of the evolution of animal cognition, it is necessary to test and compare the cognitive abilities of a broad array of taxa. Meaningful inter-species comparisons are best achieved by employing universal paradigms that standardize testing among species. Many cognitive paradigms, however, have been tested in only a few taxa, mostly birds and primates. One such example, known as the Aesop's Fable paradigm, is designed to assess causal understanding in animals using water displacement. To evaluate the universal effectiveness of the Aesop's Fable paradigm, we applied this paradigm to a previously untested taxon, the raccoon (Procyon lotor). We first trained captive raccoons to drop stones into a tube of water to retrieve a floating food reward. Next, we presented successful raccoons with objects that differed in the amount of water they displaced to determine whether raccoons could select the most functional option. Raccoons performed differently than corvids and human children did in previous studies of Aesop's Fable, and we found raccoons to be innovative in many aspects of this task. We suggest that raccoon performance in this paradigm reflected differences in tangential factors, such as behavior, morphology, and testing procedures, rather than cognitive deficiencies. We also present insight into previously undocumented challenges that should better inform future Aesop's Fable studies incorporating more diverse taxa.


European Code against Cancer 4th Edition: Physical activity and cancer.
Physical activity is a complex, multidimensional behavior, the precise measurement of which is challenging in free-living individuals. Nonetheless, representative survey data show that 35% of the European adult population is physically inactive. Inadequate levels of physical activity are disconcerting given substantial epidemiologic evidence showing that physical activity is associated with decreased risks of colon, endometrial, and breast cancers. For example, insufficient physical activity levels are thought to cause 9% of breast cancer cases and 10% of colon cancer cases in Europe. By comparison, the evidence for a beneficial effect of physical activity is less consistent for cancers of the lung, pancreas, ovary, prostate, kidney, and stomach. The biologic pathways underlying the association between physical activity and cancer risk are incompletely defined, but potential etiologic pathways include insulin resistance, growth factors, adipocytokines, steroid hormones, and immune function. In recent years, sedentary behavior has emerged as a potential independent determinant of cancer risk. In cancer survivors, physical activity has shown positive effects on body composition, physical fitness, quality of life, anxiety, and self-esteem. Physical activity may also carry benefits regarding cancer survival, but more evidence linking increased physical activity to prolonged cancer survival is needed. Future studies using new technologies - such as accelerometers and e-tools - will contribute to improved assessments of physical activity. Such advancements in physical activity measurement will help clarify the relationship between physical activity and cancer risk and survival. Taking the overall existing evidence into account, the fourth edition of the European Code against Cancer recommends that people be physically active in everyday life and limit the time spent sitting.


Inhibition of tristetraprolin deadenylation by poly(A) binding protein.
Tristetraprolin (TTP) is the prototype for a family of RNA binding proteins that bind the tumor necrosis factor (TNF) messenger RNA AU-rich element (ARE), causing deadenylation of the TNF poly(A) tail, RNA decay, and silencing of TNF protein production. Using mass spectrometry sequencing we identified poly(A) binding proteins-1 and -4 (PABP1 and PABP4) in high abundance and good protein coverage from TTP immunoprecipitates. PABP1 significantly enhanced TNF ARE binding by RNA EMSA and prevented TTP-initiated deadenylation in an in vitro macrophage assay of TNF poly(A) stability. Neomycin inhibited TTP-promoted deadenylation at concentrations shown to inhibit the deadenylases poly(A) ribonuclease and CCR4. Stably transfected RAW264.7 macrophages overexpressing PABP1 do not oversecrete TNF; instead they upregulate TTP protein without increasing TNF protein production. The PABP1 inhibition of deadenylation initiated by TTP does not require the poly(A) binding regions in RRM1 and RRM2, suggesting a more complicated interaction than simple masking of the poly(A) tail from a 3'-exonuclease. Like TTP, PABP1 is a substrate for p38 MAP kinase. Finally, PABP1 stabilizes cotransfected TTP in 293T cells and prevents the decrease in TTP levels seen with p38 MAP kinase inhibition. These findings suggest several levels of functional antagonism between TTP and PABP1 that have implications for regulation of unstable mRNAs like TNF.


Role of ultrasonography in diagnosis of scrotal disorders: a review of 110 cases.
To determine the role of ultrasonography in diagnosis of scrotal disorders. This study was carried out after institutional review board approval was granted, and informed consent was waived. Between January 2005 and January 2007, 144 patients aged 12 years and older with scrotal symptoms, who underwent scrotal ultrasonography (US), were retrospectively reviewed. The clinical presentation, outcome, and US results were analysed. The presentation symptoms were divided into three groups including scrotal pain, painless scrotal mass or swelling, and others. Surgery was performed in 32 patients. Of 144 patients, 110 had clinical follow-up and constituted the material of this study. The patients ranged in age from 13 to 82 years (mean 38.6 years). Of 110 patients, 84 (76.4%) presented with scrotal pain, 21 (19%) had painless scrotal mass or swelling and 5 (4.5%) had other symptoms. Of the 84 patients with scrotal pain, 52 had infection, 4 had testicular torsion, 7 had testicular trauma, 10 had varicocele, 4 had hydrocele, 1 had epididymal cyst, 1 had scrotal sac and groin metastases, and 5 had unremarkable results. Of the 21 patients who presented with painless scrotal mass or swelling, 18 had extratesticular lesions and 3 had intratesticular lesions. All the extratesticular lesions were benign. Of the 3 intratesticular lesions, one was due to tuberculous epididymo-orchitis, one was non-Hodgkin's lymphoma, and one was metastasis from liposarcoma. Of the 5 patients who presented with other symptoms, 4 had undescended testes, and 1 had gynaecomastia. US gave incorrect diagnosis in only one patient with scrotal pain. The most common cause of scrotal pain was infection. The most common cause of scrotal mass or swelling was extratesticular lesion. US plays an important role in the diagnosis of scrotal disorders and in planning for proper management.


Contribution of a thymic humoral factor to the development of an immunologically competent population from cells of mouse bone marrow.
The hypothesis that cells located in mouse bone marrow can acquire immunological competence by a process that involves interaction with a noncellular component of the thymus was tested using an in vitro assay of graft-versus-host reactivity as a criterion of cell competence. When suspensions of C57BL bone marrow cells were incubated in thymus extract and injected into mice incapable of inducing a response in the graft-versus-host assay as a result of neonatal thymectomy, or adult thymectomy plus irradiation, or because of genetic similarity with the (C3H x C57BL)F(1) tissue used for challenge in the assay, competent cells were recovered from the spleens of the injected mice. The reactive cells were shown to be of bone marrow origin since immune reactivity was related to the genetic makeup of the bone marrow cells rather than that of the intermediate recipients. A thymic factor was involved in the process leading to immune reactivity by these cells, as bone marrow cells incubated in xenogeneic or syngeneic thymic extracts induced a graft-versus-host response after passage through nonresponsive mice, whereas incubation of bone marrow cells in xenogeneic lymph node or spleen extracts or in culture medium only did not lead to subsequent reactivity. Participation of peripheral lymphoid tissue seemed essential in this process since bone marrow cells tested directly after exposure to thymic extract failed to induce a graft-versus-host response. C57BL bone marrow cells exposed to thymus extract and cultured together with fragments of (C3H x C57BL)F(1) spleen tissue in vitro were competent to induce a graft-versus-host response; thus, these components would seem to be sufficient as well as necessary for the immunodifferentiation process leading to graft-versus-host activity. It is concluded that one step in the process by which bone marrow cells acquire competence vis-a-vis the graft-versus-host response depends upon a thymic agent that is noncellular and extractable, and that another stage in this process is under the influence of components found within the peripheral lymphoid tissue environment. It is suggested that differentiation of precursor cells to competence could occur by progressive development of the cells in separate compartments of the lymphoid system.


Temporal change in microdosimetry to bone marrow and stromal progenitor cells from alpha-particle-emitting radionuclides incorporated in bone.
The microdistributions of the alpha-particle-emitting bone surface-seeking radionuclides (239)Pu, (241)Am and (233)U in the mouse femoral shaft have been studied using computer-based image analysis of neutron-induced and alpha-particle track autoradiographs, prepared from femora of CBA/H mice which had been injected with 40 kBq kg(-1) of radionuclide (as citrate solution) at times from 1 to 448 days previously. Employing dosimetric methods, radiation dose rates and cumulative radiation doses to regions of the bone marrow thought to contain hemopoietic and stromal progenitor cells susceptible to neoplastic transformation to leukemia and osteosarcomas have been calculated. It has been shown that the three radionuclides differ in their relative deposition on the bone surfaces, and that patterns of changing redistribution with time are also varied. For stromal progenitor cells, which are thought to be targets for induction of osteosarcoma and are found in proximity to the bone surfaces, cumulative doses showed the trend (239)Pu > (241)Am > (233)U, correlating well with incidences of osteosarcoma observed in mice. Cumulative doses to the primitive hemopoietic stem cells, concentrated in the central marrow and thought to be susceptible to neoplastic transformation to myeloid leukemia, were considerably lower and also showed the trend plutonium > americium > uranium.


Ghrelin enhances olfactory sensitivity and exploratory sniffing in rodents and humans.
Olfaction is an integral part of feeding providing predictive cues that anticipate ingestion. Although olfactory function is modulated by factors such as prolonged fasting, the underlying neural mechanisms remain poorly understood. We recently identified ghrelin receptors in olfactory circuits in the brain. We therefore investigated the role of the appetite-stimulating hormone ghrelin in olfactory processing in rodents and humans, testing the hypothesis that ghrelin lowers olfactory detection thresholds and enhances exploratory sniffing, both being related to food seeking. In rats, intracerebroventricular ghrelin decreased odor detection thresholds and increased sniffing frequency. In humans, systemic ghrelin infusions significantly enhanced sniff magnitudes in response to both food and nonfood odorants and air in comparison to control saline infusions but did not affect the pleasantness ratings of odors. This is consistent with a specific effect on odor detection and not the hedonic value of odors. Collectively, our findings indicate that ghrelin stimulates exploratory sniffing and increases olfactory sensitivity, presumably enhancing the ability to locate, identify, and select foods. This novel role is consistent with ghrelin's overall function as a signal amplifier at the molecular interface between environmental and nutritional cues and neuroendocrine circuits controlling energy homeostasis.


Long term follow-up of patients with chronic hepatitis C treated with interferon alpha.
Interferon alpha (IFN alpha) treatment for chronic hepatitis C induces a sustained biochemical and virological response at six months after completing 24 weeks of therapy in approximately 10% of patients. The long term durability of this 'sustained' response is still controversial. The aim of this multicentre study was to assess the long term virological response in patients considered to have achieved a sustained biochemical response six months after completing IFN treatment. The majority (36 of 41) of the sustained responders identified had been treated for six months with IFN therapy. Twenty-nine of the 41 patients (70%) had undetectable hepatitis C virus (HCV) RNA after a mean follow-up of 38 months after cessation of treatment (range six to 92 months). All but one of those 29 individuals had normal serum alanine aminotransferase (ALT) levels. Of the 16 patients (out of 41) who had been tested for HCV RNA six months after treatment, HCV RNA remained undetectable in 14 (88%) at final follow-up. Serum ALT values in the 11 of 12 patients whose HCV RNA was positive at final follow-up were lower than pretreatment values, and in six cases were within the normal range. The long term sustained virological response in those considered a 'sustained responder' six months after receiving only six months of IFN is high. Measurement of ALT is an unreliable marker of sustained response to therapy.


Studies of the drug resistance response of sensitive and drug-resistant strains in a microfluidic system.
Since the discovery of bacterial drug resistance, its dynamics have been the focus in biophysics studies. In this paper, we used a new microfluidic system to monitor the responses of sensitive and drug-resistant strains of E. coli in different β-lactam ceftriaxone concentrations at the single cell level and traced each individual cell's states such as cell length, GFP protein expression and growth rate. The β-lactamase production of the drug-resistant strain is quantified by fluorescence intensity, as the GFP gene co-transcribes with the enzyme expression gene. Our results show that the drug-resistant strain can endure a much higher concentration of antibiotics than the sensitive strain and has an antibiotic concentration ratio from the cell death state to the cell elongation state that is much larger than that of the sensitive strain. The single cell data and simulation suggest that bacteria with slower growth rates have higher drug resistance both in the sensitive and drug-resistant strains. The drug-resistant strain shows adaptation behavior, but no adaptation is found in the sensitive strain after changing to a high antibiotic concentration. A mathematical model of cell growth can qualitatively explain the observed behavior. The quantitative measurement of single-cell phenotype changes and dynamic analysis presented in this study should shed light on the antibiotic process of different bacteria.


Vitamins as hormones.
Vitamins A and D are the first group of substances that have been reported to exhibit properties of skin hormones, such as organized metabolism, activation, inactivation, and elimination in specialized cells of the tissue, exertion of biological activity, and release in the circulation. Vitamin A and its two important metabolites, retinaldehyde and retinoic acids, are fat-soluble unsaturated isoprenoids necessary for growth, differentiation and maintenance of epithelial tissues, and also for reproduction. In a reversible process, vitamin A is oxidized IN VIVO to give retinaldehyde, which is important for vision. The dramatic effects of vitamin A analogues on embryogenesis have been studied by animal experiments; the clinical malformation pattern in humans is known. Retinoic acids are major oxidative metabolites of vitamin A and can substitute for it in vitamin A-deficient animals in growth promotion and epithelial differentiation. Natural vitamin A metabolites are vitamins, because vitamin A is not synthesized in the body and must be derived from carotenoids in the diet. On the other hand, retinoids are also hormones - with intracrine activity - because retinol is transformed in the cells into molecules that bind to and activate specific nuclear receptors, exhibit their function, and are subsequently inactivated. The mechanisms of action of natural vitamin A metabolites on human skin are based on the time- and dose-dependent influence of morphogenesis, epithelial cell proliferation and differentiation, epithelial and mesenchymal synthetic performance, immune modulation, stimulation of angiogenesis and inhibition of carcinogenesis. As drugs, vitamin A and its natural metabolites have been approved for the topical and systemic treatment of mild to moderate and severe, recalcitrant acne, photoaging and biologic skin aging, acute promyelocytic leukaemia and Kaposi's sarcoma. On the other hand, the critical importance of the skin for the human body's vitamin D endocrine system is documented by the fact that the skin is both the site of vitamin D (3)- and 1,25-dihydroxyvitamin D (3) [1, 25(OH) (2)D (3)]-synthesis and a target organ for 1,25(OH) (2)D (3). 1,25(OH) (2)D (3) is not only essential for mineral homeostasis and bone integrity, but also for numerous further physiologic functions including regulation of growth and differentiation in a broad variety of normal and malignant tissues, including cells derived from prostate, breast and bone. In keratinocytes and other cell types, 1,25(OH) (2)D (3) regulates growth and differentiation. Consequently, vitamin D analogues have been introduced for the treatment of the hyperproliferative skin disease psoriasis. Other newly detected functions of vitamin D analogues include profound effects on the immune system as well as protection against cancer and other diseases, including autoimmune and infectious diseases, in various tissues. Current investigation of the biological effects of vitamin D analogues are likely to lead to new therapeutic applications that, besides cancer prevention, may include the prevention and treatment of infectious as well as of inflammatory skin diseases. This review summarizes existing knowledge on vitamins A and D, the major vitamin-hormones of the skin.


A low-temperature, photoinduced thiol-ene click reaction: a mild and efficient method for the synthesis of sugar-modified nucleosides.
Sugar-modified nucleosides are prime synthetic targets in anticancer and antiviral drug development. Radical mediated thiol-ene coupling was applied for the first time on nucleoside enofuranoside derivatives to produce a broad range of thio-substituted d-ribo, -arabino, -xylo and l-lyxo configured pyrimidine nucleosides. In contrast to the analogous reactions of simple sugar exomethylenes, surprisingly, hydrothiolation of nucleoside alkenes under the standard conditions of various initiation methods showed low to moderate yields and very low stereoselectivity. Optimizing the reaction conditions, we have found that cooling the reaction mixture has a significant beneficial effect on both the conversion and the stereoselectivity, and UV-light initiated hydrothiolation of C2'-, C3'- and C4'-exomethylene derivatives of nucleosides at -80 °C proceeded in good to high yields, and, in most cases, in excellent diastereoselectivity. Beyond the temperature, the solvent, the protecting groups on nucleosides and, in some cases, the configuration of the thiols also affected the stereochemical outcome of the additions. The anomalous l-lyxo diastereoselectivity observed upon the addition of 1-thio-β-d-gluco- and galactopyranose derivatives onto C4',5'-unsaturated uridines is attributed to steric mismatch between the d-ribo C4'-radical intermediates and the β-configured 1-thiosugars.


Evidence for intact memory-guided attention in school-aged children.
Visual scenes contain many statistical regularities such as the likely identity and location of objects that are present; with experience, such regularities can be encoded and can ultimately facilitate the deployment of spatial attention to important locations. Memory-guided attention has been extensively examined in adults with the 'contextual cueing' paradigm and has been linked to specific neural substrates - a medial temporal lobe (MTL)-frontoparietal network. However, it currently remains unknown when this ability comes 'online' during development. Thus, we examined the performance of school-aged children on an age-appropriate version of the contextual cueing paradigm. Children searched for a target fish among distractor fish in new displays and in 'old' displays on a touchscreen computer. Old displays repeated across blocks of trials and thus provided an opportunity for prior experience with the invariant configuration of the stimuli to guide attentional deployment. We found that over time children searched old displays significantly faster than new displays, thus revealing intact memory-guided attention and presumed function of an MTL-frontoparietal network in 5- to 9-year-olds. More generally, our findings suggest that children are remarkably sensitive to the inherent structure of their visual environment and this enables attentional deployment to become more efficient with experience.


Solid Dispersion of Resveratrol Supported on Magnesium DiHydroxide (Resv@MDH) Microparticles Improves Oral Bioavailability.
Resveratrol, because of its low solubility in water and its high membrane permeability, is collocated in the second class of the biopharmaceutical classification system, with limited bioavailability due to its dissolution rate. Solid dispersion of resveratrol supported on Magnesium DiHydroxide (Resv@MDH) was evaluated to improve solubility and increase bioavailability of resveratrol. Fluorimetric microscopy analysis displays three types of microparticles with similar size: Type 1 that emitted preferably fluorescence at 445 nm with bandwidth of 50 nm, type 2 that emitted preferably fluorescence at 605 nm with bandwidth of 70 nm and type 3 that is non-fluorescent. Micronized pure resveratrol displays only microparticles type 1 whereas type 3 are associated to pure magnesium dihydroxide. Dissolution test in simulated gastric environment resveratrol derived from Resv@MDH in comparison to resveratrol alone displayed better solubility. A 3-fold increase of resveratrol bioavailability was observed after oral administration of 50 mg/kg of resveratrol from Resv@MDH in rabbits. We hypothesize that type 2 microparticles represent magnesium dihydroxide microparticles with a resveratrol shell and that they are responsible for the improved resveratrol solubility and bioavailability of Resv@MDH.


Pneumocolon as an aid to small-bowel studies.
A prospective study was performed in 138 consecutive patients referred for small-bowel examination to evaluate the use of the pneumocolon when there was poor demonstration of the terminal ileum. One hundred and twenty-two patients were examined by enteroclysis (small-bowel enema) and 16 by small-bowel meal. Pneumocolon was used in 38 of the small-bowel enemas and in eight of the small-bowel meal examinations. In 29 cases (21 small-bowel enema; eight small-bowel meal) the use of the pneumocolon significantly improved demonstration of the terminal ileum. When the distal ileum is not adequately seen on a small-bowel study, pneumocolon serves as a useful additional technique.


The choice of anesthesia as a career by undergraduates in a Saudi university.
In order to find out the career preferences of Saudi medical undergraduates as they relate to anesthesiology, questionnaires were distributed and received from 40 pre-clinical students and 26 clinical students immediately after their two-week anesthesia posting. Almost half of the preclinical students made their final choice. None of the students in this group made anesthesiology a first choice, though about 67.5% had heard about anesthesia. Among the students in the clinical group, medicine, surgery and general practice were the most common choices. Only one indicated anesthesiology a first choice. Most of the clinical students indicated that their I.C.U. rotation was the most enjoyable part of their anesthesia posting. The student's suggestions for improvement in their posting included a longer period than the present 2 weeks and more opportunity to acquire the required clinical skills. The authors advise a positive drive to Saudi medical undergraduates to take up the specialty of anesthesiology as a career in order to correct the present shortage.


Oral contraceptives for pain associated with endometriosis.
Endometriosis is a common gynaecological condition which affects many women of reproductive age worldwide and is a major cause of pain and infertility. The modern oral contraceptive pill is widely used to treat pain occurring as a result of endometriosis, although the evidence for its efficacy is limited. To assess the effects of the oral contraceptive pill (OCP) in comparison to other treatments for painful symptoms of endometriosis in women of reproductive age. We searched the Menstrual Disorders and Subfertility Group Specialised Register of controlled trials; Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2006); MEDLINE (January 1966 to September 2006); EMBASE (1980 to September 2006); National Research Register; and reference lists of articles. All truly randomised controlled trials of the use of oral contraceptive pills in the treatment of women of reproductive age with symptoms ascribed to the diagnosis of endometriosis and made visually at surgical procedure were included. Study quality assessment and data extraction were carried out independently by two review authors. One of the assessors was an expert in the content matter. We contacted study authors for additional information. Only one study met the inclusion criteria, in which a total of 57 women were allocated to two groups to compare an OCP to a GnRH analogue. Methods of randomisation and allocation concealment were unclear and the study was acknowledged by its authors to be underpowered. Women in the GnRH analogue group became amenorrhoeic during the treatment period of six months, whilst women in the OCP group reported a decrease in dysmenorrhoea. No evidence of a significant difference between the two groups was observed in terms of dysmenorrhoea at six months follow up after stopping treatment (OR 0.48; 95% CI 0.08 to 2.90). Some evidence for a decrease in dyspareunia was found at the end of treatment in women in the GnRH analogue group, although no evidence of a significant difference in dyspareunia was observed at the end of the six months follow up (OR 4.87; 95% CI 0.96 to 24.65). The limited data we found available suggests that this is no evidence of a difference in outcomes between the the oral contraceptive pill (OCP) studied and GnRH analogue was as effective as a GnRH analogue in treating for endometriosis-associated painful symptoms of endometriosis. However, the lack of studies with larger sample sizes, or focusing on other comparable treatments is concerning and further research is needed to fully evaluate fully the role of OCPs oral contraceptive pills in managing symptoms associated with ement of endometriosis.


Early detection of Alzheimer's disease using the Cambridge Cognitive Examination (CAMCOG).
Dementia screening instruments, such as the Cambridge Cognitive Examination (CAMCOG), measure a variety of cognitive functions. However, memory impairment generally is the first sign of Alzheimer's disease (AD). It seems logical, therefore, to use only memory-related items for the early detection of AD. We divided the CAMCOG into a memory section and a non-memory section, and tested the hypothesis that the memory section predicts AD better than the non-memory section. We also provide normative data for both sections. Normal subjects (N = 169) and patients with incident AD (i.e. satisfying AD criteria between 1 and 3 years from baseline: N = 25) were participants in the Amsterdam Study of the Elderly (AMSTEL), a population-based longitudinal study on cognitive decline and dementia. Patients with prevalent AD (i.e. satisfying AD criteria at baseline: N = 155) were either recruited in a memory clinic or came from AMSTEL. Normal subjects were cognitively intact at baseline and remained so for at least 3 years. The CAMCOG was administered to all subjects. AD was diagnosed by DSM-III-R criteria. Logistic regression analysis showed that the memory section was related to prevalent AD, whereas in multivariate analysis the non-memory section was not (after correction for the memory score and demographic characteristics). A similar analysis showed that the memory section predicted incident AD, as did a higher score on the non-memory section. The MMSE did not predict incident AD better than age alone. For the early detection of AD it is best to use the memory and non-memory sections separately instead of the total CAMCOG score.


Mirizzi syndrome: choice of surgical procedure in the laparoscopic era.
Impaction of a calculus in gallbladder neck or cystic duct or even in its remnant may produce common hepatic duct stricture by direct mechanical impression or associated inflammation. This clinical entity is referred to as Mirizzi syndrome. Four patients were operated on for Mirizzi syndrome. This represents 0.9% of the 444 patients who underwent laparoscopic cholecystectomy in our clinic. Two cases with Mirizzi syndrome type I, one of which had a stone in a gallbladder remnant, were successfully treated by laparoscopic cholecystectomy without any complications. One patient developed a bile leakage; fistulography via a sump drain revealed bile leakage from the laceration site of the stone, and the patient was reoperated on to perform a Roux-en-Y hepaticojejunostomy. The patient was lost due to cardiopulmonary arrest originating from septic shock. In another case diagnosed as Mirizzi type II, the operation was converted to an open procedure due to intense inflammation and fibrosis around the area of the Calot's triangle. Subtotal cholecystectomy was done and the defect on the common hepatic duct repaired by means of a gallbladder flap over the T tube.


Fournier's gangrene and its emergency management.
Fournier's gangrene (FG) is a rare but life threatening disease. Although originally thought to be an idiopathic process, FG has been shown to have a predilection for patients with diabetes as well as long term alcohol misuse; however, it can also affect patients with non-obvious immune compromise. The nidus is usually located in the genitourinary tract, lower gastrointestinal tract, or skin. FG is a mixed infection caused by both aerobic and anaerobic bacterial flora. The development and progression of the gangrene is often fulminating and can rapidly cause multiple organ failure and death. Because of potential complications, it is important to diagnose the disease process as early as possible Although antibiotics and aggressive debridement have been broadly accepted as the standard treatment, the death rate remains high.


Plasma levels of leptin and visfatin in rheumatoid arthritis patients; is there any relationship with joint damage?
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder, primarily targeting the synovium and articular cartilage that leads to joint damage. Recent reports have suggested the role of adipocytokines in mediating joint damage; however it still is a matter of debate. The purpose of this study was to evaluate the association between serum values of adiopocytokines (leptin, visfatin) and radiographic joint damage in patients with RA. Fifty-four patients diagnosed with RA, based on Revised ACR Criteria 2010, with 1-5 year disease duration since diagnosis, were enrolled. Twenty-nine of patients had erosion in radiographic studies and 25patients had no erosion. Radiographic joint damages were defined according to Larsen Score. Additionally, serum levels of adipocytokines were measured and cross-sectional associations with radiographic damage were explored, adjusting for pertinent confounders. The serum level of visfatin were significantly higher in patients with radiographic joint damage compared with patients with no joint damage (P=0.013). This difference remained significant after adjustment for C-reactive protein levels (P=0.008), but not after adjustment for disease duration (P=0.247). The mean leptin serum levels were not different between these two groups (P=0.903). There was a positive correlation between leptin levels and BMI (r=0.494, P<0.001). However, after adjustment for BMI, leptin levels had no difference between two groups (P=0.508). This study revealed that visfatin levels were significantly higher in patients with radiographic joint damage dependently to disease duration. Therefore, it seems that adipocytokine may be a valuable factor in therapeutic targets in the future.


Viral-Cellular DNA Junctions as Molecular Markers for Assessing Intra-Tumor Heterogeneity in Cervical Cancer and for the Detection of Circulating Tumor DNA.
The development of cervical cancer is frequently accompanied by the integration of human papillomaviruses (HPV) DNA into the host genome. Viral-cellular junction sequences, which arise in consequence, are highly tumor specific. By using these fragments as markers for tumor cell origin, we examined cervical cancer clonality in the context of intra-tumor heterogeneity. Moreover, we assessed the potential of these fragments as molecular tumor markers and analyzed their suitability for the detection of circulating tumor DNA in sera of cervical cancer patients. For intra-tumor heterogeneity analyses tumors of 8 patients with up to 5 integration sites per tumor were included. Tumor islands were micro-dissected from cryosections of several tissue blocks representing different regions of the tumor. Each micro-dissected tumor area served as template for a single junction-specific PCR. For the detection of circulating tumor-DNA (ctDNA) junction-specific PCR-assays were applied to sera of 21 patients. Samples were collected preoperatively and during the course of disease. In 7 of 8 tumors the integration site(s) were shown to be homogenously distributed throughout different tumor regions. Only one tumor displayed intra-tumor heterogeneity. In 5 of 21 analyzed preoperative serum samples we specifically detected junction fragments. Junction-based detection of ctDNA was significantly associated with reduced recurrence-free survival. Our study provides evidence that HPV-DNA integration is as an early step in cervical carcinogenesis. Clonality with respect to HPV integration opens new perspectives for the application of viral-cellular junction sites as molecular biomarkers in a clinical setting such as disease monitoring.