We, the developing rete testis, efferent ducts, and Wolffian duct, all hereby agree that we need to connect.
The mechanisms by which the rete testis joins the efferent ducts, which joins the Wolffian duct during development, are not known. Mouse and chick models have been helpful in identifying genes that are important for the development of each part, but genes have not been identified as to those that play a role in the joining of each part. Clinical implications of the failure of the male reproductive tract to form a fully functional conduit for spermatozoa are not trivial. Epididymal disjunction, the failure of the efferent ducts to join the testis, is one of several epididymal anomalies that have been observed in some boys who were cryptorchid at birth. A systematic review of studies focusing on the morphogenesis of the mesonephric duct and mesonephric tubules in different species, and identification of clinical issues should there be failure of these tissues to develop. PubMed and GUDMAP databases, and review of books on kidney development were searched for studies reporting on the mechanisms of morphogenesis of the kidney and epididymis. Gaps in our knowledge were identified, and hypotheses coupled with suggestions for future experiments were presented. A total of 64 papers were identified as relevant, of which 53 were original research articles and 11 were book chapters and reviews covering morphogenesis and clinical issues. Investigators utilized multiple species including, human, mouse, chick, Xenopus, bovine, and sheep. Fundamental understanding of the morphogenesis of the male reproductive tract is limited, especially the morphogenesis of the rete testis and efferent ducts. Therefore, it is not surprising that we do not understand how each part unites to form a whole. Only one mechanism of joining of one part of the tract to another was identified: the joining of the Wolffian duct to the cloaca via controlled apoptosis.


Set7 facilitates hepatitis C virus replication via enzymatic activity-dependent attenuation of the IFN-related pathway.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, usually resulting in persistent infection involving hepatic steatosis, cirrhosis, and hepatocellular carcinoma via escape of the host's immune response. Set7 is a lysine-specific methyltransferase that is involved in gene regulation and virus replication. However, the mechanism underlying the immune evasion between HCV and Set7 is not well understood. In this study, we observed that the expression of Set7 in Huh7.5.1 cells was upregulated by HCV infection, and high levels of Set7 expression were also found in the sera, PBMCs, and liver tissue of HCV patients relative to healthy individuals. Further investigation showed that Set7 enhanced HCV replication in an enzymatic activity-dependent manner. Moreover, our data showed that Set7 decreased the expression of virus-induced IFN and IFN-related effectors, such as dsRNA-activated protein kinase and 2',5'-oligoadenylate synthetase. Further investigation suggested that Set7 suppressed the endogenous IFN expression by reducing the nuclear translocation of IFN regulatory factor 3/7 and the p65 subunit of NF-κB and reduced IFN-induced dsRNA-activated protein kinase and 2',5'-oligoadenylate synthetase via attenuation of the phosphorylation of STAT1 and STAT2. Additionally, IFN receptors, including IFNAR1 and IFNAR2, which are located upstream of the JAK/STAT pathway, were reduced by Set7. Taken together, our results reveal that Set7 facilitates HCV replication through the attenuation of IFN signaling pathways and IFN-related effectors.


Violence.
Violence affects children and adolescents widely. Pediatricians see many of these effects and need to be prepared to address them. A key role for providers in addressing violence, however, lies in working to prevent it. In this endeavor, the provider must be knowledgeable about the risk factors and vigilant for discerning these risks during office visits. Family factors, peer group issues, other risky behaviors, and weapons availability and use all are within the range of topics that a provider might choose to address. At the same time, pediatricians have a key role to play as advocates for children in working with community partners to increase supports for children and families, to institute new programs to prevent violence, and to help remove firearms from the hands of children and youth.


Dynamic primitives in the control of locomotion.
Humans achieve locomotor dexterity that far exceeds the capability of modern robots, yet this is achieved despite slower actuators, imprecise sensors, and vastly slower communication. We propose that this spectacular performance arises from encoding motor commands in terms of dynamic primitives. We propose three primitives as a foundation for a comprehensive theoretical framework that can embrace a wide range of upper- and lower-limb behaviors. Building on previous work that suggested discrete and rhythmic movements as elementary dynamic behaviors, we define submovements and oscillations: as discrete movements cannot be combined with sufficient flexibility, we argue that suitably-defined submovements are primitives. As the term "rhythmic" may be ambiguous, we define oscillations as the corresponding class of primitives. We further propose mechanical impedances as a third class of dynamic primitives, necessary for interaction with the physical environment. Combination of these three classes of primitive requires care. One approach is through a generalized equivalent network: a virtual trajectory composed of simultaneous and/or sequential submovements and/or oscillations that interacts with mechanical impedances to produce observable forces and motions. Reliable experimental identification of these dynamic primitives presents challenges: identification of mechanical impedances is exquisitely sensitive to assumptions about their dynamic structure; identification of submovements and oscillations is sensitive to their assumed form and to details of the algorithm used to extract them. Some methods to address these challenges are presented. Some implications of this theoretical framework for locomotor rehabilitation are considered.


Seasonal variation in the incidence of acute renal colic.
Urolithiasis is a prevalent medical disease affecting the general population. Many epidemiological studies reported an association between a geographic area with a high mean daily temperature and urolithiasis disease. However, it is unclear if the seasonal variation in a high temperature geographical area will affect the acute presentation of renal colic to the emergency department. The aim of this study was to identify the effect of the seasonal variation on the presentation with acute urolithiasis disease. The design was a retrospective chart review, using the database in King Abdulaziz Medical City that was retrieved by the data management office in King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia. The study period was from January 26, 2016, to the end of December 2019. All patients who presented with renal colic, and diagnosed with urolithiasis using a noncontrast-enhanced computed tomography scan, have been included. A total of 1057 patients were included in this study. The majority (71.24%, n = 753) were male, and the mean age was 42.33 ± 16.12 years. The highest proportion presented in summer (31.22%), followed by spring (26.87%), fall (24.12%), and winter (17.79%). The majority of the sample (84.77%) presented with ureteral stones, and 15.23%with kidney stones. Most of the sample (78.33%) had no history of previous stone formation, with 21.67% being current stone former. The acute presentation with urolithiasis is higher during summer, followed by spring, fall, and winter. A public educational program is highly recommended to increase awareness about stone formation and the appropriate avoidance methods. To this end, additional research is required to understand the stone composition and appropriate methods to avoid developing urolithiasis.


Caregiver Psychological Burden in Pediatric Chronic Pain: A Systematic Review and Meta-Analysis of Associations with Caregiver Sociodemographic and Biopsychosocial Variables.
To investigate, via systematic review and meta-analysis, caregiver sociodemographic and biopsychosocial factors associated with anxiety, depression, posttraumatic stress symptoms, and stress of caregivers in the pediatric chronic pain context. EMBASE, Medline, and PsycINFO databases were searched from their inception to the search date (April 4, 2022). Studies were included if they examined caregivers of youth with chronic pain, were published in a peer-reviewed journal and assessed at least one quantitative association between relevant variables. Qualitative and intervention studies were excluded. A total of 3,052 articles were screened. Risk of bias was assessed using the JBI Checklist for analytical cross-sectional studies. Meta-analyses were conducted using robust variance estimation for associations reported in at least three studies, as well as a narrative synthesis of the evidence. Fourteen studies assessing 1,908 caregivers were included in this review. Meta-analytic results showed a positive pooled correlation coefficient between caregiver catastrophizing about their child's pain and caregiver anxiety (r = 0.51; 95% CI: 0.35-0.65; p<.01) and depression (r = 0.45; 95% CI: 0.29-0.58; p < .01). Self-blame and helplessness were related to increased caregiver anxiety (r = 0.55; 95% CI: 0.40-0.67; p<.01), but not depression. No significant relationship was found for pain-promoting behavior and anxiety or depression. The qualitative synthesis of all other eligible studies showed associations between relevant psychological burden variables and various caregiver factors, which were mainly psychosocial. Results should be interpreted with caution due to the small number of studies. Further research is needed to get a better understanding of these relationships and to examine the causal direction of effects.


Purification and functional characterization of human mitochondrial DNA polymerase gamma harboring disease mutations.
More than 150 different point mutations in POLG, the gene encoding the human mitochondrial DNA polymerase gamma (pol gamma), cause a broad spectrum of childhood and adult onset diseases like Alpers syndrome, ataxia-neuropathy syndrome and progressive external ophthalmoplegia. These disease mutations can affect the pol gamma enzyme's properties in numerous ways, thus potentially influencing the severity of the disease. Hence, a detailed characterization of disease mutants will greatly assist researchers and clinicians to develop a clear understanding of the functional defects caused by these mutant enzymes. Experimental approaches for characterizing the wild-type (WT) and mutant pol gamma enzymes are extensively described in this manuscript. The methods start with construction and purification of the recombinant wild-type and mutant forms of pol gamma protein, followed by assays to determine its structural integrity and thermal stability. Next, the biochemical characterization of these enzymes is described in detail, which includes measuring the purified enzyme's catalytic activity, its steady-state kinetic parameters and DNA binding activity, and determining the physical and functional interaction of these pol gamma proteins with the p55 accessory subunit.


Comparison of a preQ1 riboswitch aptamer in metabolite-bound and free states with implications for gene regulation.
Riboswitches are RNA regulatory elements that govern gene expression by recognition of small molecule ligands via a high affinity aptamer domain. Molecular recognition can lead to active or attenuated gene expression states by controlling accessibility to mRNA signals necessary for transcription or translation. Key areas of inquiry focus on how an aptamer attains specificity for its effector, the extent to which the aptamer folds prior to encountering its ligand, and how ligand binding alters expression signal accessibility. Here we present crystal structures of the preQ(1) riboswitch from Thermoanaerobacter tengcongensis in the preQ(1)-bound and free states. Although the mode of preQ(1) recognition is similar to that observed for preQ(0), surface plasmon resonance revealed an apparent K(D) of 2.1 ± 0.3 nm for preQ(1) but a value of 35.1 ± 6.1 nm for preQ(0). This difference can be accounted for by interactions between the preQ(1) methylamine and base G5 of the aptamer. To explore conformational states in the absence of metabolite, the free-state aptamer structure was determined. A14 from the ceiling of the ligand pocket shifts into the preQ(1)-binding site, resulting in "closed" access to the metabolite while simultaneously increasing exposure of the ribosome-binding site. Solution scattering data suggest that the free-state aptamer is compact, but the "closed" free-state crystal structure is inadequate to describe the solution scattering data. These observations are distinct from transcriptional preQ(1) riboswitches of the same class that exhibit strictly ligand-dependent folding. Implications for gene regulation are discussed.


The effect of neurohormonal factors, epigenetic factors, and gut microbiota on risk of obesity.
Molecular, cellular, and epidemiologic findings suggest that neurohormonal, epigenetic, and microbiologic mechanisms may influence risk for obesity by interacting with socioenvironmental factors. Homeostatic and nonhomeostatic neural controls of energy predispose people to obesity, and this predisposition may be exaggerated by the influence of media, marketing, and sleep patterns. Epigenetic gene regulation may account for the influence of modifiable early life or maternal exposures on obesity risk. Alterations in gut flora caused by infant feeding practices or later diet may influence the absorption and storage of energy. Further exploration of how these molecular-cellular mechanisms might increase obesity risk in response to modifiable socioeconomic factors requires the partnership of laboratory and public health researchers.


Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity.
The autophagy-lysosomal pathway is impaired in many neurodegenerative diseases characterized by protein aggregation, but the link between aggregation and lysosomal dysfunction remains poorly understood. Here, we combine cryo-electron tomography, proteomics, and cell biology studies to investigate the effects of protein aggregates in primary neurons. We use artificial amyloid-like β-sheet proteins (β proteins) to focus on the gain-of-function aspect of aggregation. These proteins form fibrillar aggregates and cause neurotoxicity. We show that late stages of autophagy are impaired by the aggregates, resulting in lysosomal alterations reminiscent of lysosomal storage disorders. Mechanistically, β proteins interact with and sequester AP-3 μ1, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. This leads to destabilization of the AP-3 complex, missorting of AP-3 cargo, and lysosomal defects. Restoring AP-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.


CYP1A1 3801T>C polymorphism implicated in altered xenobiotic metabolism is not associated with variations in sperm production and function as measured by total motile sperm and fertilization rates with intracytoplasmic sperm injection.
To evaluate the cytochrome P450 3801T>C polymorphism's frequency in relation to semen production, as determined by semen analysis parameters, and sperm function, as determined by fertilization rates with intracytoplasmic sperm injection (ICSI). Case-control study. Academic-affiliated private practice. This study included patients undergoing IVF from 2004 to 2014 grouped into categories based on semen analysis parameters performed at a single andrology laboratory. Cases were patients with total motile sperm (TMS) counts of ≤20 × 10(6). Frequency-matched controls were selected with TMS of >20 × 10(6). The 3801T>C polymorphism was identified using DNA from serum samples with real-time quantitative polymerase chain reaction. CYP1A1 3801T>C polymorphism frequency in TMS groups and distribution in fertilization rate outcomes with ICSI. A total of 460 cases were identified with ≤20 × 10(6) TMS, and 489 age-matched controls with >20 × 10(6) TMS were selected across the study time frame. For those with <5 × 10(6) vs. >20 × 10(6) TMS there was no difference when comparing heterozygous (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.66-1.40) or homozygous mutant (OR 1.33; 95% CI 0.52-3.20) with the wild-type patients. Additionally, no difference was seen when analyzing subgroups <5 × 10(6), 5-20 × 10(6), and >20 × 10(6) TMS in a similar fashion. Receiver operating characteristic (ROC) curve analysis did not find a significant TMS count based on presence of the polymorphism (area under the ROC curve = 0.51). There were 460 patients who underwent IVF/ICSI, and fertilization rates did not differ with presence of the polymorphism (area under the ROC curve = 0.50). Allele frequency of the 3801T>C polymorphism does not correlate with semen production as determined by TMS counts or sperm function as determined by fertilization rates with ICSI. The use of neither semen analysis parameters nor fertilization rates with ICSI helps identify CYP1A1 polymorphism carriers.


Sentinel lymph node biopsy in melanoma of the head and neck.
The sentinel lymph node is the first node or nodes to drain a cutaneous melanoma. Sentinel lymph node biopsy is performed to determine whether regional metastases are present. The authors' experience with the new technique of sentinel lymph node biopsy for melanoma of the head and neck is reported. During the period of January of 1992 to December of 1995, 58 consecutive patients were identified from the melanoma database who had localization of the sentinel lymph node for primary cutaneous melanoma of the head and neck. Techniques for identification of the sentinel node(s) include preoperative lymphoscintigraphy and intraoperative Lymphazurin dye (vital blue dye) and technetium-99m-labeled sulfur colloid injection around the primary tumor site with Neoprobe mapping. Fifty-eight patients (13 female, 45 male), mean age 61 years, with melanoma of the head and neck with a mean Breslow thickness of 2.21 mm. (range, 0.82-6.87 mm.) and no regional lymphadenopathy underwent sentinel node mapping. The sentinel node was successfully identified in 55 patients (95 percent). Blue dye was visualized in 85 of 126 sentinel nodes excised (67 percent), whereas the remainder of the sentinel nodes were localized with the Neoprobe. Forty-nine patients who had successful mapping and sentinel node biopsy had no evidence of metastatic disease in the sentinel node or other nodes in the basin. Six of the fifty-five patients (11 percent) had evidence of micrometastatic disease, and all six had the sentinel node as the only site of metastasis. Five of six patients with micrometastases had a subsequent neck dissection and/or superficial parotidectomy. None of these patients had evidence of "skip metastases" with a negative sentinel node and higher level nodes positive for metastases. In total, 6 of the 18 sentinel nodes (33 percent) identified in these six patients contained micrometastatic disease, whereas none of the 139 other nodes sampled had any evidence of metastases. The exact probability that all six unpaired observations would consist of involvement of only the sentinel nodes is p = 0.0312. By combining the two mapping techniques in patients with melanoma of the head and neck, the sentinel node(s) can be mapped and identified individually, similar to melanoma in other locations. The sentinel nodes have been shown to contain the first evidence of regional metastatic melanoma. This staging information can be used to plan therapeutic node dissections and adjuvant therapy that may have a survival benefit in patients with stage III melanoma of the head and neck. Lymphatic mapping can be used to make the surgical care of the melanoma patient more conservative, so that only those patients with solid evidence of regional node metastases are subjected to the morbidity and expense of a complete node dissection and the toxicities of adjuvant therapy.


Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor).
CTGF/CCN2, a hypertrophic chondrocyte-specific gene product, possessed the ability to repair damaged articular cartilage in two animal models, which were experimental osteoarthritis and full-thickness defects of articular cartilage. These findings suggest that CTGF/CCN2 may be useful in regeneration of articular cartilage. Connective tissue growth factor (CTGF)/CCN2 is a unique growth factor that stimulates the proliferation and differentiation, but not hypertrophy, of articular chondrocytes in vitro. The objective of this study was to investigate the therapeutic use of CTGF/CCN2. The effects of recombinant CTGF/CCN2 (rCTGF/CCN2) on repair of damaged cartilage were evaluated by using both the monoiodoacetic acid (MIA)-induced experimental rat osteoarthritis (OA) model and full-thickness defects of rat articular cartilage in vivo. In the MIA-induced OA model, quantitative real-time RT-PCR assays showed a significant increase in the level of CTGF/CCN2 mRNA, and immunohistochemical analysis and in situ hybridization revealed that the clustered chondrocytes, in which clustering indicates an attempt to repair the damaged cartilage, produced CTGF/CCN2. Therefore, CTGF/CCN2 was suspected to play critical roles in cartilage repair. In fact, a single injection of rCTGF/CCN2 incorporated in gelatin hydrogel (rCTGF/CCN2-hydrogel) into the joint cavity of MIA-induced OA model rats repaired their articular cartilage to the extent that it became histologically similar to normal articular cartilage. Next, to examine the effect of rCTGF/CCN2 on the repair of articular cartilage, we created defects (2 mm in diameter) on the surface of articular cartilage in situ and implanted rCTGF/CCN2-hydrogel or PBS-hydrogel therein with collagen sponge. In the group implanted with rCTGF/CCN2-hydrogel collagen, new cartilage filled the defect 4 weeks postoperatively. In contrast, only soft tissue repair occurred when the PBS-hydrogel collagen was implanted. Consistent with these in vivo effects, rCTGF/CCN2 enhanced type II collagen and aggrecan mRNA expression in mouse bone marrow-derived stromal cells and induced chondrogenesis in vitro. These findings suggest the utility of CTGF/CCN2 in the regeneration of articular cartilage.


Bridging the Divide between Neuroprosthetic Design, Tissue Engineering and Neurobiology.
Neuroprosthetic devices have made a major impact in the treatment of a variety of disorders such as paralysis and stroke. However, a major impediment in the advancement of this technology is the challenge of maintaining device performance during chronic implantation (months to years) due to complex intrinsic host responses such as gliosis or glial scarring. The objective of this review is to bring together research communities in neurobiology, tissue engineering, and neuroprosthetics to address the major obstacles encountered in the translation of neuroprosthetics technology into long-term clinical use. This article draws connections between specific challenges faced by current neuroprosthetics technology and recent advances in the areas of nerve tissue engineering and neurobiology. Within the context of the device-nervous system interface and central nervous system implants, areas of synergistic opportunity are discussed, including platforms to present cells with multiple cues, controlled delivery of bioactive factors, three-dimensional constructs and in vitro models of gliosis and brain injury, nerve regeneration strategies, and neural stem/progenitor cell biology. Finally, recent insights gained from the fields of developmental neurobiology and cancer biology are discussed as examples of exciting new biological knowledge that may provide fresh inspiration toward novel technologies to address the complexities associated with long-term neuroprosthetic device performance.


Clinical and demographic profile of cancer patients in a consultation-liaison psychiatric service.
An almost 50% prevalence of psychiatric disorders among cancer patients has prompted a series of studies on consultation-liaison psychiatry. Nonetheless, there are few reports on the epidemiological factors involving comorbidity between cancer and psychiatric disorders. To evaluate the epidemiological profile of cancer inpatients referred to the consultation-liaison psychiatric service in an oncology hospital during its first year of activity. Descriptive study. Tertiary-care teaching hospital. 319 patients referred 412 times to the consultation-liaison psychiatry service. From August 97 to July 98, an appraisal was made of data on all admissions registered at the Hospital do C ncer, and also all referrals registered at the consultation-liaison psychiatry service. The demographics and patients' clinical data, the type and flow of the request, and the evaluation conducted by the service were analyzed and comparisons with the hospital data were made. The distribution of the number of referrals was used to construct a profile of patients who had repeatedly used the service. Psychiatric diagnoses were found in 59% of the cases. Forty-three percent of these required medication, 18.3% needed psychotherapy, 22.1% family intervention and 20.5% guidance from the staff. Over 22.8% of the consultations were reevaluations, mainly involving younger male patients with worst prognoses. These patients required lengthier and more elaborate intervention, and had higher prevalence of depressive and behavioral disorders. A younger and mainly male population of non-surgical oncological cases was referred to the consultation-liaison psychiatric service during its first year of activity. The psychiatric disorder prevalence was higher than expected, and consisted predominantly of mood disorders. We detected a priority group, namely the reevaluated patients, who deserved special attention throughout the psychiatric interventions.


The effects of topical sodium cromoglicate on itch and flare in human skin induced by intradermal histamine: a randomised double-blind vehicle controlled intra-subject design trial.
Itch is a prominent feature of many skin diseases, particularly atopic dermatitis and cutaneous mastocytosis. Sodium cromoglicate (SCG), a chromone developed for the treatment of allergic disease has been shown to reduce the severity of itch when applied topically to subjects with atopic dermatitis. The aim of this study was to investigate whether topical sodium cromoglicate can reduce the severity of itch induced by intradermal histamine. SCG was introduced into the skin of healthy volunteers both by iontophoresis and by topical application using a new 4% cutaneous emulsion (Altoderm™). The skin was then challenged with intradermal histamine. Measurements were made of severity of itch, size of wheal and flare and change in blood flux SCG significantly reduced the severity of itch (P = 0.0045) and flare (P = 0.0143) when delivered by iontophoresis. SCG 4% cutaneous emulsion significantly reduced severity of itch (P = 0.024) and flare (P = 0.015) in atopic subjects. Trend analysis showed increasing effect on itch with increased concentrations of SCG, which was significant (P = 0.046). There were no effects on wheal or blood flux. Topically applied SCG, administered in a new cutaneous emulsion base, significantly reduced the itch and flare caused by intradermal histamine. The effect was greatest in atopic subjects and increased with the concentration of SCG in the emulsion. ISRCTN35671014.


Proteasomal inhibition reduces parkin mRNA in PC12 and SH-SY5Y cells.
Mutations in the gene encoding the E3 ubiquitin-protein ligase parkin have been shown to be a common genetic cause of familial early-onset Parkinson's disease (PD). In addition to its function in the ubiquitin-proteasome system (UPS), parkin has been ascribed general neuroprotective properties. Stress and mutation induced decreases in parkin solubility leading to compromised cytoprotection have recently been reported. We systematically investigated whether PD-related stresses including MG132 and epoxomicin (proteasomal impairment), tunicamycin (unfolded protein stress), and rotenone (mitochondrial dysfunction) resulted in expressional changes of parkin and other E3 ubiquitin ligases (dorfin, SIAH-1). Rotenone and tunicamycin did not change parkin mRNA levels, whereas proteasomal inhibition resulted in a reduction of parkin mRNA in PC12 cells as well as in SH-SY5Y cells. Therefore, surprisingly, cells did not react with a compensatory parkin upregulation under proteasomal inhibition, although, in parallel, parkin protein shifted to the insoluble fraction, reducing soluble parkin levels in the cytosol. Since the mRNA of the parkin-coregulated gene PACRG paralleled the parkin mRNA at least partly, we suspect a promoter-driven mechanism. Our study, therefore, shows a link between proteasomal impairment and parkin expression levels in cell culture, which is intriguing in the context of the described and debated proteasomal dysfunction in the substantia nigra of PD patients.


Increased high-risk coronary plaque burden is associated with arterial stiffness in patients with type 2 diabetes without clinical signs of coronary artery disease: a computed tomography angiography study.
Arterial stiffness and subclinical coronary atherosclerosis may yield valuable information on cardiovascular risk. We aimed to characterize coronary atherosclerosis in asymptomatic patients with type 2 diabetes and healthy controls and to investigate the association between baseline arterial stiffness and coronary plaque volumes after 5-year follow-up. Data from 45 patients and 61 matched controls were available for coronary plaque assessment. For analysis including carotid-femoral pulse wave velocity (PWV), 43 patients and 55 controls were available. At follow-up, mean (SD) age of participants was 63 ± 10 years, and mean diabetes duration (SD) in the patient group was 7.8 ± 1.4 years. Arterial stiffness (PWV) was assessed by tonometry at both visits. Total, calcified, noncalcified, low-density noncalcified coronary plaques volumes and other plaque characteristics were assessed by coronary computed tomography angiography at follow-up. Despite of similar or better blood pressure and plasma lipid control, patients had, compared with controls, a higher number of plaques with spotty calcifications (P < 0.01) and remodeling index more than 1.1 (P < 0.05), larger calcified plaque volumes [patients vs. 11 (0-65) vs. 3 (0-30) μl (P = 0.03)] and higher PWV [patients vs. controls at baseline: 9.1 ± 2.2 vs. 7.9 ± 1.4 m/s (P < 0.01), at follow-up: 9.3 ± 2.3 vs. 8.4 ± 1.8 m/s (P = 0.02)]. Baseline PWV was associated with volumes of all plaque types in crude analysis (P < 0.01) and with low-density noncalcified plaque volume in analysis adjusted for age, sex, diabetes and blood pressure (P = 0.01). Coronary plaques with unfavorable characteristics are more prevalent in well controlled asymptomatic patients with type 2 diabetes compared with healthy controls and independently associated with arterial stiffness.Clinical trials registration number: NCT02001532.


The influence of cyclizine and perphenazine on the emetic effect of meptazinol.
The effectiveness of 50 mg cyclizine and 2.5 mg perphenazine against the emetic sequelae of 100 mg meptazinol were studied in a randomized double-blind placebo-controlled trial. Three groups of 40 women received the opioid, together with an anti-emetic by i.m. injection, as premedication prior to minor gynaecological surgery. Beneficial or noxious effects were noted at standard time intervals and anaesthesia standardized as incremental methohexitone with nitrous oxide/oxygen. In the placebo group, 33 out of 40 subjects experienced either nausea or vomiting at some time after the opioid. Cyclizine, 50 mg, provided significant reduction of emetic tendency in both pre-operative and post-operative phases of the study with 22 out of 40 subjects experiencing nausea or vomiting overall. Perphenazine, 2.5 mg, showed no useful anti-emetic effect. Both anti-emetics increased the soporific effect of premedication at the 90-min interval. Subjects receiving perphenazine experienced significantly more dizziness than those of other groups.


Prevalence of the C282Y mutation of the hemochromatosis gene in liver transplant recipients and donors.
Hemochromatosis heterozygotes may be predisposed to end-stage liver disease from other causes. The aims of this study were to determine the prevalence of the hemochromatosis mutation, C282Y, in end-stage liver disease and to determine if transplantation of C282Y heterozygous livers adversely affected survival. The C282Y status of patients who underwent hepatic transplantation and, whenever possible, their donors, was determined and correlated with hepatic iron status. Survival was compared in patients who received livers from heterozygotes and normals. Prevalence of C282Y in recipients was compared with 5,211 voluntary blood donors. Twenty-six C282Y heterozygotes were detected among 304 transplant recipients (8.6%) compared with a prevalence of 8.4% in blood donors. Six of 26 heterozygous recipients (23%) had >/=2+ iron staining in their explanted livers compared with 40 of 277 wild-type livers (14%) (P = ns). There was no significant difference in mean hepatic iron concentration between C282Y heterozygotes and wild-type explanted livers with >/=2+ iron staining. Seven of 31 patients (23%) with alcoholic liver disease were C282Y heterozygotes. Twenty-four heterozygotes were detected in 141 donors (17.0%). Survival did not differ between recipients who received heterozygous or normal livers. The prevalence of C282Y heterozygotes in patients requiring liver transplantation does not differ significantly from the general population. Heterozygotes are not at increased risk of developing end-stage liver disease. Transplantation of C282Y heterozygous livers is a safe, effective practice.


Measurement of glycine in the human brain in vivo by 1H-MRS at 3 T: application in brain tumors.
Glycine is a key metabolic intermediate required for the synthesis of proteins, nucleic acids, and other molecules, and its detection in cancer could, therefore, provide biologically relevant information about the growth of the tumor. Here, we report measurement of glycine in human brain and gliomas by an optimized point-resolved spectroscopy sequence at 3 T. Echo time dependence of the major obstacle, myo-inositol (mI) multiplet, was investigated with numerical simulations, incorporating the 3D volume localization. The simulations indicated that a subecho pair (TE(1) , TE(2) ) = (60, 100) ms permits detection of both glycine and mI with optimum selectivity. In vivo validation of the optimized point-resolved spectroscopy was conducted on the right parietal cortex of five healthy volunteers. Metabolite signals estimated from LC Model were normalized with respect to the brain water signal, and the concentrations were evaluated assuming the total creatine concentration at 8 mM. The glycine concentration was estimated as 0.6 ± 0.1 mM (mean ± SD, n = 5), with a mean Cramér-Rao lower bound of 9 ± 1%. The point-resolved spectroscopy sequence was applied to measure the glycine levels in patients with glioblastoma multiforme. Metabolite concentrations were obtained using the water signal from the tumor mass. The study revealed that a subset of human gliomas contains glycine levels elevated 1.5-8 fold relative to normal.


Hair analysis as a biomonitor for toxicology, disease and health status.
Hair analysis receives a large amount of academic and commercial interest for wide-ranging applications. However, in many instances, especially for elemental or 'mineral' analysis, the degree of success of analytical interpretation has been quite minimal with respect to the extent of such endeavors. In this critical review we address the questions surrounding hair analysis with specific intent of discovering what hair concentrations can actually relate to in a biogenic sense. This is done from a chemistry perspective to explain why and how elements are incorporated into hair and their meaning. This includes an overview of variables attributed to altering hair concentrations, such as age, gender, melanin content, and other less reported factors. Hair elemental concentrations are reviewed with regard to morbidity, with specific examples of disease related effects summarized. The application of hair analysis for epidemiology and etiology studies is enforced. A section is dedicated specifically to the area of population studies with regards to mercury, which highlights how endogenous and exogenous incorporation relies on species dependant metabolism and metabolic products. Many of the considerations are relevant to other areas of interest in hair analysis, such as for drug and isotopic analysis. Inclusion of a table of elemental concentrations in hair should act as a valuable reference (298 references).


Expression and functional characterization of bluetongue virus VP2 protein: role in cell entry.
Segment 2 of bluetongue virus (BTV) serotype 10, which encodes the outer capsid protein VP2, was tagged with the S-peptide fragment of RNase A and expressed by a recombinant baculovirus. The recombinant protein was subsequently purified to homogeneity by virtue of the S tag, and the oligomeric nature of the purified protein was determined. The data obtained indicated that the majority of the protein forms a dimer and, to a lesser extent, some trimer. The recombinant protein was used to determine various biological functions of VP2. The purified VP2 was shown to have virus hemagglutinin activity and was antigenically indistinguishable from the VP2 of the virion. Whether VP2 is responsible for BTV entry into permissive cells was subsequently assessed by cell surface attachment and internalization studies with an immunofluorescence assay system. The results demonstrated that VP2 alone is responsible for virus entry into mammalian cells. By competition assay, it appeared that both VP2 and the BTV virion attached to the same cell surface molecule(s). The purified VP2 also had a strong affinity for binding to glycophorin A, a sialoglycoprotein component of erythrocytes, indicating that VP2 may be responsible for BTV transmission by the Culicoides vector to vertebrate hosts during blood feeding. Further, by various enzymatic treatments of BTV-permissive L929 cells, preliminary data have been obtained which indicated that the BTV receptor molecule(s) is likely to be a glycoprotein and that either the protein moiety of the glycoprotein or a second protein molecule could also serve as a coreceptor for BTV infection.


Incorporating peak grouping information for alignment of multiple liquid chromatography-mass spectrometry datasets.
The combination of liquid chromatography and mass spectrometry (LC/MS) has been widely used for large-scale comparative studies in systems biology, including proteomics, glycomics and metabolomics. In almost all experimental design, it is necessary to compare chromatograms across biological or technical replicates and across sample groups. Central to this is the peak alignment step, which is one of the most important but challenging preprocessing steps. Existing alignment tools do not take into account the structural dependencies between related peaks that coelute and are derived from the same metabolite or peptide. We propose a direct matching peak alignment method for LC/MS data that incorporates related peaks information (within each LC/MS run) and investigate its effect on alignment performance (across runs). The groupings of related peaks necessary for our method can be obtained from any peak clustering method and are built into a pair-wise peak similarity score function. The similarity score matrix produced is used by an approximation algorithm for the weighted matching problem to produce the actual alignment result. We demonstrate that related peak information can improve alignment performance. The performance is evaluated on a set of benchmark datasets, where our method performs competitively compared to other popular alignment tools. The proposed alignment method has been implemented as a stand-alone application in Python, available for download at http://github.com/joewandy/peak-grouping-alignment.


Reconstruction of the laryngopharynx after hemicricoid/hemithyroid cartilage resection. Preliminary functional results.
To evaluate the use of a sensate radial forearm free flap and free cartilage graft for reconstruction of the laryngopharyngeal defect that results from resection of pyriform sinus carcinoma that extends to the apex of the pyriform sinus and includes the hemithyroid and hemicricoid cartilages. Case series review of 6 patients treated during a 2 1/2-year period with an average follow-up of 23 months. Factors evaluated included oncologic outcome, as well as functional outcome with regard to the onset and quality of the airway, speech, and deglutition. Mount Sinai School of Medicine, New York, NY, an academic, tertiary referral center. Six men ranging in age from 51 to 73 years underwent a partial laryngopharyngectomy that included the hemicricoid and hemithyroid cartilages as well as the ipsilateral thyroid lobe and either unilateral or bilateral lymph node dissections for squamous cell cancer that involved the apex of the pyriform sinus. These extensive laryngopharyngeal defects were reconstructed with a sensate radial forearm flap that resurfaced the endolarynx, restored the depth of the pyriform sinus, and reconstructed the remainder of the hypopharynx. In the final 4 patients, a free costal cartilage graft was used to restore the infrastructure of the larynx. The status of the margins, the incidence and site of recurrent cancer, the quality of speech, and the times to decannulation and removal of the gastrostomy tube. Three recurrences developed, with 1 each at the primary site, in the neck, and systemically. All but 1 patient who had completed radiotherapy by the last follow-up had been decannulated, and all but 1 patient regained the ability to maintain nutrition by mouth. Complications were limited to pharyngocutaneous fistulae requiring surgical closure in 3 patients early in the series. Functional reconstruction of extensive laryngopharyngeal defects can be achieved with a sensate radial forearm flap and a cartilage graft, with favorable functional results and acceptable morbidity, thus expanding the limits of conservation laryngopharyngeal surgery.


Plasma levels of inflammatory mediators in vestibular migraine.
Objectives: Vestibular migraine (VM) is an under-recognized entity with substantial burden for the individual and society. The underlying mechanism of VM and its distinction from other migraine mechanisms still remain unclear. Inflammatory pathways have been suggested to contribute to vestibular migraine. Our aim was to further investigate the possible role of inflammation in the pathophysiology of VM.Methods: We recruited 30 patients with VM diagnosed according to ICHD-3 criteria and 50 gender- and age-matched controls. Blood samples were obtained from 11 VM patients during an attack and from 13 VM patients under prophylactic treatment. Plasma levels of calcitonin gene related peptide (CGRP), neurokinin A (NKA), substance P (SP), NLRP1, NLRP3, caspase-1, IL-1β, IL-6, TNF-α and NFκB were measured by ELISA.Results: IL-6 levels were significantly reduced in VM patients, whereas levels of other inflammation parameters were comparable to those of healthy controls. Levels of inflammatory mediators were not correlated with clinical parameters. Likewise, there were no significant differences among VM patients with and without headache attack and prophylactic treatment.Conclusion: Our results argue against involvement of systemic inflammation in the pathophysiology of VM.


Imitation as behaviour parsing.
Non-human great apes appear to be able to acquire elaborate skills partly by imitation, raising the possibility of the transfer of skill by imitation in animals that have only rudimentary mentalizing capacities: in contrast to the frequent assumption that imitation depends on prior understanding of others' intentions. Attempts to understand the apes' behaviour have led to the development of a purely mechanistic model of imitation, the 'behaviour parsing' model, in which the statistical regularities that are inevitable in planned behaviour are used to decipher the organization of another agent's behaviour, and thence to imitate parts of it. Behaviour can thereby be understood statistically in terms of its correlations (circumstances of use, effects on the environment) without understanding of intentions or the everyday physics of cause-and-effect. Thus, imitation of complex, novel behaviour may not require mentalizing, but conversely behaviour parsing may be a necessary preliminary to attributing intention and cause.


Safety and efficacy of pulmonary vein antral isolation in patients with obstructive sleep apnea: the impact of continuous positive airway pressure.
Obstructive sleep apnea (OSA) may be associated with pulmonary vein antrum isolation (PVAI) failure. The aim of the present study was to investigate if treatment with continuous positive airway pressure (CPAP) improved PVAI success rates. From January 2004 to December 2007, 3000 consecutive patients underwent PVAI. Patients were screened for OSA and CPAP use. Six hundred forty (21.3%) patients had OSA. Patients with OSA had more procedural failures (P=0.024) and hematomas (P<0.001). Eight percent of the non-OSA paroxysmal atrial fibrillation patients had nonpulmonary vein antrum triggers (non-PV triggers) and posterior wall firing versus 20% of the OSA group (P<0.001). Nineteen percent of the non-OSA nonparoxysmal atrial fibrillation population had non-PV triggers versus 31% in the OSA group (P=0.001). At the end of the follow-up period (32±14 months), 79% of the non-CPAP and 68% of the CPAP group were free of atrial fibrillation (P=0.003). Not using CPAP in addition to having non-PV triggers strongly predicted procedural failure (hazard ratio, 8.81; P<0.001). OSA was an independent predictor for PVAI failure. Treatment with CPAP improved PVAI success rates. Patients not treated with CPAP in addition to having higher prevalence of non-PV triggers were 8 times more likely to fail the procedure.


The Female Sex Work Industry in a District of India in the Context of HIV Prevention.
HIV prevalence in India remains high among female sex workers. This paper presents the main findings of a qualitative study of the modes of operation of female sex work in Belgaum district, Karnataka, India, incorporating fifty interviews with sex workers. Thirteen sex work settings (distinguished by sex workers' main places of solicitation and sex) are identified. In addition to previously documented brothel, lodge, street, dhaba (highway restaurant), and highway-based sex workers, under-researched or newly emerging sex worker categories are identified, including phone-based sex workers, parlour girls, and agricultural workers. Women working in brothels, lodges, dhabas, and on highways describe factors that put them at high HIV risk. Of these, dhaba and highway-based sex workers are poorly covered by existing interventions. The paper examines the HIV-related vulnerability factors specific to each sex work setting. The modes of operation and HIV-vulnerabilities of sex work settings identified in this paper have important implications for the local programme.


GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer.
The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated GATA4/5 promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer. Promoter methylation of GATA4/5 was analyzed in colorectal tissue and fecal DNA from colorectal cancer patients and healthy controls using methylation-specific PCR. The potential function of GATA4/5 as tumor suppressors was studied by inducing GATA4/5 overexpression in human colorectal cancer cell lines. GATA4/5 methylation was observed in 70% (63/90) and 79% (61/77) of colorectal carcinomas, respectively, and was independent of clinicopathologic features. Methylation frequencies in normal colon tissues from noncancerous controls were 6% (5 of 88, GATA4; P < 0.001) and 13% (13 of 100, GATA5; P < 0.001). GATA4/5 overexpression suppressed colony formation (P < 0.005), proliferation (P < 0.001), migration (P < 0.05), invasion (P < 0.05), and anchorage-independent growth (P < 0.0001) of colorectal cancer cells. Examination of GATA4 methylation in fecal DNA from two independent series of colorectal cancer patients and controls yielded a sensitivity of 71% [95% confidence interval (95% CI), 55-88%] and specificity of 84% (95% CI, 74-95%) for colorectal cancer detection in the training set, and a sensitivity of 51% (95% CI, 37-65%) and specificity of 93% (95% CI, 84-100%) in the validation set. Methylation of GATA4/5 is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells in vitro. GATA4 methylation in fecal DNA may be of interest for colorectal cancer detection.


Epidermal culture and grafting. A brief review.
In summary, technological advances in culturing epidermis for the purpose of grafting allow this approach in the treatment of cutaneous wounds. Certainly, full- and split-thickness autografts offer immediate availability and permanent wound coverage, but they also involve a large, painful donor site. Cultured epidermal autografts can provide permanent wound coverage, but the delay required for cultivation of confluent sheets of keratinocytes makes them somewhat less desirable. Both allografts and cultured allografts, on the other hand, are available for immediate use, but the possibility of infectious disease transmission may be a concern. In any case, all types of skin grafts function as biological dressings that promote the proliferation of the host's epidermis and, thus, facilitate the ability of the patient's skin to repair itself.


Ubiquitin-like prokaryotic MoaD as a fusion tag for expression of heterologous proteins in Escherichia coli.
Eukaryotic ubiquitin and SUMO are frequently used as tags to enhance the fusion protein expression in microbial host. They increase the solubility and stability, and protect the peptides from proteolytic degradation due to their stable and highly conserved structures. Few of prokaryotic ubiquitin-like proteins was used as fusion tags except ThiS, which enhances the fusion expression, however, reduces the solubility and stability of the expressed peptides in E. coli. Hence, we investigated if MoaD, a conserved small sulfur carrier in prokaryotes with the similar structure of ubiquitin, could also be used as fusion tag in heterologous expression in E. coli. Fusion of MoaD to either end of EGFP enhanced the expression yield of EGFP with a similar efficacy of ThiS. However, the major parts of the fusion proteins were expressed in the aggregated form, which was associated with the retarded folding of EGFP, similar to ThiS fusions. Fusion of MoaD to insulin chain A or B did not boost their expression as efficiently as ThiS tag did, probably due to a less efficient aggregation of products. Interestingly, fusion of MoaD to the murine ribonuclease inhibitor enhanced protein expression by completely protecting the protein from intracellular degradation in contrast to ThiS fusion, which enhanced degradation of this unstable protein when expressed in E. coli. Prokaryotic ubiquitin-like protein MoaD can act as a fusion tag to promote the fusion expression with varying mechanisms, which enriches the arsenal of fusion tags in the category of insoluble expression.


[The use of laser radiation and sinusoidal modulated currents in the therapy of patients with chronic calculous pyelonephritis].
The authors present a technique of treating chronic calculous pyelonephritis with laser radiation and sinusoidal modulated currents which promotes a complete elimination of the calculus fragments in 100, 70 and 50% of the patients in the stone size 0.2-0.5 cm, 0.5-0.7 cm and > 7 cm, respectively. This combined therapy had also antiinflammatory, and immunity-stimulating effects.


Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer.
We determined whether concurrent blockage of vascular endothelial growth factor (VEGF) receptor and epidermal growth factor (EGF) receptor signaling by two novel tyrosine kinase inhibitors, PTK 787 and PKI 166, respectively, can inhibit angiogenesis and, hence, the growth and metastasis of human pancreatic carcinoma in nude mice. Highly metastatic human pancreatic carcinoma L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice began receiving oral doses of PTK 787 and PKI 166 three times weekly. Some groups of mice also received i.p. injections of gemcitabine twice a week. The mice were necropsied when the control mice became moribund. Treatment with PTK 787 and PKI 166, with gemcitabine alone, or with the combination of PTK 787, PKI 166, and gemcitabine produced 69, 50, and 97% reduction in the volume of pancreatic tumors, respectively. Administration of protein tyrosine kinase inhibitors and gemcitabine also significantly decreased the incidence of lymph node and liver metastasis. The therapeutic efficacy directly correlated with a decrease in circulating proangiogenic molecules (VEGF, interleukin-8), a decrease in microvessel density, a decrease in proliferating cell nuclear antigen staining, and an increase in apoptosis of tumor cells and endothelial cells. Therapies produced by combining gemcitabine with either PKI 166 or PTK 787 were similar to those produced by combining gemcitabine with both PKI 166 and PTK 787. These results suggest that blockade of either epidermal growth factor receptor or VEGF receptor signaling combined with chemotherapy provides an effective approach to the therapy of pancreatic cancer.


Effect of UV radiation on thermotolerance, ethanol tolerance and osmotolerance of Saccharomyces cerevisiae VS1 and VS3 strains.
After a previous mass screening and enrichment programme for the isolation of thermotolerant yeasts, VS1, VS2, VS3 and VS4 strains isolated from soil samples, collected within the hot regions of Kothagudem Thermal Power Plant, AP, India, had a better thermotolerance, osmotolerance and ethanol tolerance than the other isolates. Among these isolates VS1 and VS3 were best performers. Efforts were made to further improve their osmotolerance, thermotolerance and ethanol tolerance by treating them with UV radiation. Mutants of VS1 and VS3 produced more biomass and ethanol than the parent strains at high temperature and glucose concentrations. The amount of biomass produced by VS1 and VS3 mutants was 0.25 and 0.20 g l(-1) more than the parent strains at 42 degrees C using 2% glucose. At high glucose concentrations VS1 and VS3 mutants produced biomass which was 0.70 and 0.30 g l(-1) at 30 degrees C and 0.10 and 0.20 g l(-1) at 40 degrees C more than the parent strains. The amount of ethanol produced by the mutants (VS1 and VS3) was 8.20 and 1.20 g l(-1) more than the parent strains at 42 degrees C using 150 g l(-1) glucose. More ethanol was produced by mutants (VS1 and VS3) than the parents at high glucose concentrations of 5.0 and 6.0 g l(-1) at 30 degrees C and 13.0 and 3.0 g l(-1) at 42 degrees C, respectively. These results indicated that UV mutagenesis can be used for improving thermotolerance, ethanol tolerance and osmotolerance in VS1 and VS3 yeast strains.


Self-report pain and symptom measures for primary dysmenorrhoea: a critical review.
Primary dysmenorrhoea (PD) is highly prevalent among women of reproductive age and it can have significant short- and long-term consequences for both women and society as a whole. Validated symptom measures are fundamental for researchers to understand women's symptom experience of PD and to test symptom interventions. The objective of this paper was to critically review the content and psychometric properties of self-report tools to measure symptoms of PD. Databases including PubMed, PsychoINFO, Cumulative Index of Nursing and Allied Health Literature, and Health and Psychosocial Instruments were searched for self-report symptom measures that had been used among women with either PD or perimenstrual symptoms. A total of 15 measures met inclusion criteria and were included in the final analysis. The measures were categorized into generic pain measures, dysmenorrhoea-specific measures, and tools designed to measure perimenstrual symptoms. These measures had varying degrees of comprehensiveness of symptoms being measured, relevance to PD, multidimensionality and psychometric soundness. No single measure was found to be optimal for use, but some dysmenorrhoea-specific measures could be recommended if revised and further tested. Key issues in symptom measurement for PD are discussed. Future research needs to strengthen dysmenorrhoea-specific symptom measures by including a comprehensive list of symptoms based on the pathogenesis of PD, exploring relevant symptom dimensions beyond symptom severity (e.g., frequency, duration, symptom distress), and testing psychometric properties of the adapted tools using sound methodology and diverse samples.


Sex Offenders in the Digital Age.
With most youths now using the Internet and social networking sites (SNSs), the public has become increasingly concerned about risks posed by online predators. In response, lawmakers have begun to pass laws that ban or limit sex offenders' use of the Internet and SNSs. At the time of this article, 12 states and the federal government have passed legislation attempting to restrict or ban the use of SNSs by registered sex offenders. These laws have been successfully challenged in 4 states. In this article, we discuss examples of case law that illustrate evolving trends regarding Internet and social networking site restrictions on sex offenders on supervised release, as well as those who have already completed their sentences. We also review constitutional questions and empirical evidence concerning Internet and social networking use by sex offenders. To our knowledge, this is the first paper in the psychiatric literature that addresses the evolving legal landscape in reference to sex offenders and their use of the Internet and SNSs. This article is intended to help inform forensic mental health professionals who work with sex offenders on current concerns in this rapidly evolving legal landscape.


oca2 Regulation of chromatophore differentiation and number is cell type specific in zebrafish.
We characterized a zebrafish mutant that displays defects in melanin synthesis and in the differentiation of melanophores and iridophores of the skin and retinal pigment epithelium. Positional cloning and candidate gene sequencing link this mutation to a 410-kb region on chromosome 6, containing the oculocutaneous albinism 2 (oca2) gene. Quantification of oca2 mutant melanophores shows a reduction in the number of differentiated melanophores compared with wildtype siblings. Consistent with the analysis of mouse Oca2-deficient melanocytes, zebrafish mutant melanophores have immature melanosomes which are partially rescued following treatment with vacuolar-type ATPase inhibitor/cytoplasmic pH modifier, bafilomycin A1. Melanophore-specific gene expression is detected at the correct time and in anticipated locations. While oca2 zebrafish display unpigmented gaps on the head region of mutants 3 days post-fertilization, melanoblast quantification indicates that oca2 mutants have the correct number of melanoblasts, suggesting a differentiation defect explains the reduced melanophore number. Unlike melanophores, which are reduced in number in oca2 mutants, differentiated iridophores are present at significantly higher numbers. These data suggest distinct mechanisms for oca2 in establishing differentiated chromatophore number in developing zebrafish.


Low-cost catalysts for the control of indoor CO and PM emissions from solid fuel combustion.
Cu-Mn based mixed oxide type low-cost catalysts have been prepared in supported form using mesoporous Al(2)O(3), TiO(2) and ZrO(2) supports. These supports have been prepared by templating method using a natural biopolymer, chitosan. The synthesized catalysts have been characterized by XRD, BET-SA, SEM, O(2)-TPD and TG investigations. The catalytic activity for CO as well as PM oxidation was studied, in a view of their possible applications in the control of emissions from solid fuel combustion of rural cook-stoves. The trend observed for the catalytic activity of the synthesized catalysts for CO oxidation was ZrO(2)>TiO(2)>Al(2)O(3) while for PM oxidation it was observed to be TiO(2)>ZrO(2)>Al(2)O(3). The effect of CO(2), SO(2) and H(2)O on CO oxidation activity was also investigated, and despite partial deactivation, the catalysts show good CO oxidation activity. An effective regeneration treatment was attempted by heating the partially deactivated catalysts in presence of oxygen. Redox properties of TiO(2) and ZrO(2) and their structure appeared to be responsible for their promotional activity for CO and PM oxidation reactions. These unordered mesoporous materials could be useful for such reactions where mass transfer is more important than shape and size selectivity.


[Reliability and validity in measuring physical and mental health construct of the Portuguese version of MOS SF-36].
To identify and evaluate the Psychometric validity of the two general dimensions of the Short Form (SF)-36 Portuguese version. A representative sample of 1446 adults (60,4% women) resident in Porto, Portugal completed a structured questionnaire and a Portuguese version of SF-36, final data allowed the estimation of all 8 sub-dimensions for 1326 (91,7%) participants. The internal consistency was evaluated using the Cronbach's alpha. Principal components analysis (PCA) was used to test the dimensionality. To evaluate the construct validity of the two general dimensions the sample was divided into 4 groups, according to the presence of chronic diseases and depression (evaluated by Beck Depression Inventory). Logistic regression was use to measure how the new dimensions capture the theoretical differences between groups and bootstrapping to check the principal components loadings reliability. To evaluate loss of discrimination power when using only the 2 general dimensions, for the different groups, we compared the area under the ROC curve of the logistic regression with the original dimensions and the logistic regression with the 2 dimensions. The Cronbach s alpha was 0.82 for the physical and 0.87 for the mental dimension. The total variance explained by the extraction of 2 components was 70.4%. The 4 sub-dimensions from physical domain correlated more strongly with the first component (r=[0.69-0.83]), and the 4 sub-dimensions from the mental domain correlated more highly with the second component (r=[0.65-0.88]). The largest standard deviation obtained for principal components loadings of the bootstrapping was 0.05. The general dimensions capture the theoretical differences between groups. There were no significant differences between the areas under the ROC curve of the logistic regression for the original sub-dimensions and the general dimensions. The use of the two SF-36 summary measures, physical and mental health, allows us to analyse the results more efficiently without loss of information and capture different manifestations of health status.


Direct evidence for the role of inhibition in resolving interference in memory.
Interference from competing material at retrieval is a major cause of memory failure. We tested the hypothesis that such interference can be overcome by suppressing competing responses. In a three-phase task, participants in the critical interference condition first performed a vowel-counting task (Phase 1) that included pairs of orthographically similar words (e.g., allergy and analogy). After a delay, participants were asked to solve word fragments (e.g., a _ l _ _ gy) that resembled both words in a pair they had seen, but could be completed only by one of these words (Phase 2). We then measured the consequence of having successfully resolved interference in Phase 2 by asking participants to read a list of words, including rejected competitor words (i.e., the word in each pair that could not be used to solve the word fragments), as quickly as possible (Phase 3). Participants in the interference condition were slower to name the competitor words than participants in conditions that did not require interference resolution. These results constitute direct evidence for the role of active suppression in resolving interference during memory retrieval.


Preconcentration of Cu(II), Cd(II) and Pb(II) on Amberlite XAD-4 resin functionalized with N,N'-bis(o-vanillinidene)-ethylenediamine and their determination by FAAS in water samples.
A new polystyrene divinylbenzene-based chelating resin was synthesized by functionalizing Amberlite XAD-4 with N,N'-bis(o-vanillinidene)ethylenediamine. This resin was capable of preconcentrating Cu(II), Cd(II) and Pb(II) in water samples prior to FAAS determination. Various parameters, such as the pH, eluent type and concentration, volume of the eluent and the sample, and diverse ion effects have been studied. The recoveries for the analytes under the optimum working conditions were higher than 95%. The accuracy of the method was tested with standard reference materials (MBH-C31XB20, GBW-02703 and CRM BCR-32) and Cd(II), Cu(II) and Pb(II) standard solutions. The method was successfully applied to water samples.


Variation in skeletal microstructure of the coral Galaxea fascicularis: effects of an aquarium environment and preparatory techniques.
To compare the crystalline microstructure of exsert septa, polyps of the scleractinian coral Galaxea fascicularis were sampled from shallow reef flat colonies, from colonies living at a depth of 9 m, and from colonies kept in a closed-circuit aquarium. Septal crystal structure and orientation was markedly different between corals in the field and in aquaria. In samples collected from deep water, acicular crystals were composed of conglomerates of finer crystals, and skeletal filling was considerably reduced when compared with samples collected from shallow water. Comparisons were also made between septa prepared in sodium hypochlorite (commercial bleach), sodium hydroxide (NaOH), hydrogen peroxide (H(2)O(2)), and distilled water (dH(2)O). Commercial bleach was the most effective solvent for tissue dissolution in investigations of skeletal structure. Samples prepared in NaOH commonly displayed crystalline artefacts, while the use of dH(2)O and H(2)O(2) was labor intensive and often resulted in unclean preparations. Fusiform crystals were seen only on G. fascicularis septa prepared in bleach and on Acropora formosa axial corallites prepared in either bleach or dH(2)O. We suggest that the mechanical agitation and additional washing necessary for samples prepared in dH(2)O, NaOH, or H(2)O(2) resulted in the loss of fusiform crystals from these preparations.


Using cDNA microarray to assess Parkinson's disease models and the effects of neuroprotective drugs.
The remarkable progress made by molecular biology and molecular genetics during the past decade, and the advent of the novel tools of genomics and proteomics, are expected to reveal differential expression profiles of thousands of genes and proteins involved in the degeneration of dopamine-containing cells in Parkinson's disease and allow more focused treatments according to individual genotypes. Of particular interest is the application of microarrays in drug discovery and design to identify 'fingerprints' as potential candidate targets for drug intervention. The major microarray findings relevant to Parkinson's disease and its neurotoxin-induced animal and cell models will be discussed, with particular reference to the neuroprotective therapeutic potential that could arise from the development of drugs 'a la carte'.


Trends in Imaging Workup of the Male Breast: Experience from a Single Center.
Male breast cancer (MBC) is a rare disease representing less than 1% of breast cancers. In the absence of a screening program, such as for females, the diagnostic workup is critical for early detection of MBC. To summarize our institutional experience in the workup of male patients referred for breast imaging, emphasizing the clinical, imaging, and histopathological characteristics of the MBC cohort. All male patients who underwent breast imaging between 2011 and 2016 in our institution were retrospectively reviewed. Clinical, radiological, and histopathological data were collected and statistically evaluated. All images were reviewed using the American College of Radiology Breast Imaging Reporting and Data System. 178 male patients (average age 61 years, median age 64), underwent breast imaging in our institution. The most common indication for referral was palpable mass (49%) followed by gynecomastia (16%). Imaging included mostly mammography or ultrasound. Biopsies were performed on 56 patients, 38 (68%) were benign and 18 (32%) were malignant. In all, 13 patients had primary breast cancer and 5 had metastatic disease to the breast. Palpable mass at presentation was strongly associated with malignancy (P = 0.007). Mammography and ultrasound remain the leading modalities in breast imaging among males for diagnostic workup of palpable mass, with gynecomastia being the predominant diagnosis. However, presentation with palpable mass was also associated with malignancy. Despite a notable MBC rate in our cohort, the likelihood of cancer is low in young patients and in cases of gynecomastia.


Non-pulmonary vein epicardial foci of atrial fibrillation identified in the left atrium after pulmonary vein isolation.
Pulmonary vein (PV) isolation (PVI) has been demonstrated to be an effective technique for curing atrial fibrillation (AF). AF foci that cannot be isolated by PVI (non-PV foci) can become the cause of AF recurrence. The purpose of this study was to investigate the characteristics of non-PV AF foci. Two hundred consecutive patients with symptomatic AF underwent electrophysiologic studies. In all patients, successful ostial or antral PVI was achieved with a multielectrode basket catheter (MBC). In 45 patients, spontaneous AF was induced even after PVI. In 23 of those patients, 30 AF foci were found in the left atrium (LA) (12 in the PV antrum, and 18 in the LA wall). Twenty-six of those foci were eliminated by focal ablation guided by an MBC. Five of those foci (four in the PV antrum and one in the LA posterior wall) were speculated to be located epicardially because a small potential preceding the LA potential was recorded from the MBC electrodes during AF initiation at the successful ablation site where single large potentials were recorded during sinus rhythm and a longer duration of radiofrequency energy delivery was needed to eliminate them. MBC mapping with induction of spontaneous AF may be useful for identifying non-PV AF foci in the LA after PVI. In some of those non-PV foci, mainly around the PVI lesions, a few electrophysiologic findings suggesting an epicardial location were observed. This may be a rationale for the efficacy of extensive PV ablation.


Post-natal ultrasound morpho-dynamic evaluation of mild fetal hydronephrosis: a new management.
Fetal hydronephrosis is the most common anomaly detected on antenatal ultrasound examination, affecting 1-5% pregnancies. A new management in mild antenatal renal pelvis dilatation (ARPD), using a technique based on both morphological and dynamical evaluation. Prospective study conducted during a 36-months period in 180 consecutive newborns referred as having mild ARPD. Examinations consisted in a morphological ultra-sound (US) scan evaluating antero-posterior diameter, renal parenchyma, ureteral evidence and pelvis morphology and, subsequently, a dynamic evaluation to analyze any change of the urinary tract during bladder voiding. All children were evaluated both at 3rd day and 1 month after birth. They were divided among those with negative examinations and those with at least one positive scan, trying to discriminate within the latter, children suspected for transient pyelectasis from those suspected for organic pathology. 108 patients had normal US findings both at birth and at 1 month. The remaining 72 babies had at least one abnormal US examination: 54 were suspected for transient pyelectasis, while 18 suspected for organic pathology. At the end of the study, 61 babies (33.9%) had final diagnosis of transient pyelectasis and 11 cases (6.1%) of organic pathology. At one month the dynamic pattern of US findings had the highest negative predictive value, while renal parenchyma evaluation has the highest accuracy. a dynamic US approach allowed to better select among infants suspected for transient pyelectasis from those suspected for organic pathology, avoiding unnecessary and invasive examinations in healthy babies.


The effects of industry funding and positive outcomes in the interpretation of clinical trial results: a randomized trial among Dutch psychiatrists.
Most studies are inclined to report positive rather than negative or inconclusive results. It is currently unknown how clinicians appraise the results of a randomized clinical trial. For example, how does the study funding source influence the appraisal of an RCT, and do positive findings influence perceived credibility and clinical relevance? This study investigates whether psychiatrists' appraisal of a scientific abstract is influenced by industry funding disclosures and a positive outcome. Dutch psychiatrists were randomized to evaluate a scientific abstract describing a fictitious RCT for a novel antipsychotic drug. Four different abstracts were created reporting either absence or presence of industry funding disclosure as well as a positive or a negative outcome. Primary outcomes were the perceived credibility and clinical relevance of the study results (10-point Likert scale). Secondary outcomes were the assessment of methodological quality and interest in reading the full article. Three hundred ninety-five psychiatrists completed the survey (completion rate 45%). Industry funding disclosure was found not to influence perceived credibility (Mean Difference MD 0.12; 95% CI - 0.28 to 0.47, p?) nor interpretation of its clinical relevance (MD 0.14; 95% CI - 0.54 to 0.27, p?). A negative outcome was perceived as more credible than a positive outcome (MD 0.81 points; 95% Confidence Interval (CI) 0.43 to 1.18, p?), but did not affect clinical relevance scores (MD -0.14; 95% CI - 0.54 to 0.27). In this study, industry funding disclosure was not associated with the perceived credibility nor judgement of clinical relevance of a fictional RCT by psychiatrists. Positive study outcomes were found to be less credible compared to negative outcomes, but industry funding had no significant effects. Psychiatrists may underestimate the influence of funding sources on research results. The fact that physicians indicated negative outcomes to be more credible may point to more awareness of existing publication bias in the scientific literature.


Surgical Emergencies in Intestinal Venous Malformations.
Venous malformations (VMs) can occur in any part of the body; however, the gastrointestinal tract is a frequent location. These are usually asymptomatic, thus, representing a challenge to diagnosis. Intestinal location of VMs can be associated with severe complications that ultimately require an emergency surgery. Our aim was to analyze all patients with an intestinal VM with special focus on those who required emergency surgery. A retrospective study of patients presenting complication caused by intestinal VM was performed. Clinical records, associated anomalies, physical findings, and treatment were assessed. Twenty-one patients had a diagnosis of intestinal VM, 16 (76%) were associated to blue rubber bleb nevus syndrome (BRBNS) and 5 (24%) were isolated. Only four (19%) of the total cases presented an episode of acute abdomen with hemodynamic instability that required an emergency surgery. Findings included two gastrointestinal bleedings, one volvulus, and one intussusception of small bowel. All patients underwent an uneventful recovery and are presently doing well. Intestinal VM can be challenging to diagnose in emergency situations, such as gastrointestinal situation or acute abdomen. The complications associated with it must be kept in mind, regardless of its low incidence.


Spillover transmission is mediated by the excitatory GABA receptor LGC-35 in C. elegans.
Under most circumstances, GABA activates chloride-selective channels and thereby inhibits neuronal activity. Here, we identify a GABA receptor in the nematode Caenorhabditis elegans that conducts cations and is therefore excitatory. Expression in Xenopus oocytes demonstrates that LGC-35 is a homopentameric cation-selective receptor of the cys-loop family exclusively activated by GABA. Phylogenetic analysis suggests that LGC-35 evolved from GABA-A receptors, but the pore-forming domain contains novel molecular determinants that confer cation selectivity. LGC-35 is expressed in muscles and directly mediates sphincter muscle contraction in the defecation cycle in hermaphrodites, and spicule eversion during mating in the male. In the locomotory circuit, GABA release directly activates chloride channels on the muscle to cause muscle relaxation. However, GABA spillover at these synapses activates LGC-35 on acetylcholine motor neurons, which in turn cause muscles to contract, presumably to drive wave propagation along the body. These studies demonstrate that both direct and indirect excitatory GABA signaling plays important roles in regulating neuronal circuit function and behavior in C. elegans.


Release of atrial natriuretic factor from heart-lung preparations of inbred Dahl rats.
Isolated heart-lung preparations from hypertensive inbred Dahl salt-hypertension sensitive (S) and normotensive inbred Dahl salt-hypertension resistant (R) rats were perfused using 15% washed rat red blood cells in Krebs-Ringer bicarbonate buffer. Atrial pressures were increased by increasing venous return (preload) or by increasing the arterial resistance (afterload). Increases in preload at a constant afterload produced increases in the right and left atrial pressures equivalent between S and R strains. Atrial natriuretic factor (ANF) release was linearly related to right atrial pressure (RAP) or left atrial pressure (LAP) in either strain, but S released more ANF at each level of preload, and the slope of the line relating ANF release to RAP was significantly greater in S than R. When the heart-lung preparations were subjected to changes in afterload at a constant preload, LAP was significantly increased in R but not in S rats, and concomitantly ANF increased in R but not in S. In the afterload experiments, as in the preload studies, S released more ANF than R for comparable LAP. It is concluded that 1) at any atrial pressure, hearts of hypertensive S rats release more ANF than hearts of normotensive R rats, 2) this strain difference is probably a consequence of hypertension, and 3) the observed relationships between ANF release and atrial pressures support the contention that atrial distention stimulates the release of ANF.


Severe sequelae in bilateral acute iris transillumination syndrome secondary to the use of oral moxifloxacin: a case report.
Moxifloxacin is a fourth-generation fluoroquinolone used as a second-line treatment for multiple bacterial infections. Uveitis has been described as an adverse effect related to this medication. Although several case reports have been published describing uveitis and bilateral acute iris transillumination syndrome related to moxifloxacin, we present a unique case of a patient with severe sequelae associated with bilateral acute iris transillumination syndrome secondary to the use of oral moxifloxacin. A 45-year-old Colombian hispanic female presented bilateral conjunctival hyperemia, decreased visual acuity, blurred vision, photophobia, and ocular pain after 15 days of treatment with systemic moxifloxacin for an upper tract respiratory infection. The patient presented unilateral anterior chamber pigment dispersion, mydriatic and nonreactive pupils, extensive iris transillumination defects, and secondary glaucoma. Blood and aqueous humor tests were negative for infectious and autoimmune diseases. Moxifloxacin-induced bilateral acute iris transillumination syndrome was diagnosed. Permanent sequelae such as ocular pain, photophobia, and focus difficulty secondary to severe bilateral iridian atrophy and inability of synkinetic reflex were left. Additionally, glaucoma was diagnosed, and Ahmed valve implantation was required. We should be aware of the possible association between moxifloxacin and bilateral acute iris transillumination syndrome. A detailed anamnesis, adequate examination, and laboratory tests are necessary to reach an early diagnosis and treatment to avoid unnecessary therapies. Larger studies should be carried out to understand the pathophysiology, diagnosis, management, and sequelae of the disease.


Role of bacteria in the pathogenesis of recurrent uveitis in horses from the southeastern United States.
To determine the role of intraocular bacteria in the pathogenesis of equine recurrent uveitis (ERU) in horses from the southeastern United States by evaluating affected eyes of horses with ERU for bacterial DNA and intraocular production of antibodies against Leptospira spp. Aqueous humor, vitreous humor, and serum samples of 24 clinically normal horses, 52 horses with ERU, and 17 horses with ocular inflammation not associated with ERU (ie, non-ERU inflammation). Ribosomal RNA quantitative PCR (real-time PCR) assay was used to detect bacterial DNA in aqueous humor and vitreous humor from clinically normal horses (n = 12) and horses with chronic (> 3-month) ERU (28). Aqueous humor and serum were also evaluated for anti-Leptospira antibody titers from clinically normal horses (n = 12), horses with non-ERU inflammation (17), and horses with confirmed chronic ERU (24). Bacterial DNA was not detected in aqueous humor or vitreous humor of horses with ERU or clinically normal horses. No significant difference was found in titers of anti-Leptospira antibodies in serum or aqueous humor among these 3 groups. Only 2 horses, 1 horse with ERU and 1 horse with non-ERU inflammation, had definitive intraocular production of antibodies against Leptospira organisms. In horses from the southeastern United States, Leptospira organisms may have helped initiate ERU in some, but the continued presence of the organisms did not play a direct role in the pathogenesis of this recurrent disease.


[Importance of internal fixation for talar neck fractures].
Fracture of the talus, which articulates with 4 other bones in the ankle and foot, must be properly diagnosed, classified and treated to avoid the common complications of post-traumatic osteoarthritis and avascular necrosis. Knowledge of blood supply and anatomy is imperative, since the surgical approach must not damage the few vascular structures that remain intact after the trauma. We present 5 cases of fractures at the neck of the talus. All underwent internal fixation, 1 after closed reduction and 4 after open reduction. In all the results were satisfactory, although 1 patient developed avascular necrosis of the talar body.


The pathogen of ventilator-associated pneumonia does not influence the mortality rate of surgical intensive care unit patients treated with a rotational antibiotic system.
Ventilator-associated pneumonia (VAP) is one of the leading causes of morbidity in critically ill surgical patients. Certain pathogens (e.g., methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa) have been associated with an excess mortality rate from sepsis in several studies, but not in the surgical setting specifically or when protocol-driven antibiotic therapy is administered. We sought to determine which factors and, in particular, whether the individual pathogen affected the mortality rate in our surgical intensive care unit (ICU), where a rotational antibiotic system has been employed continuously since 1997. We hypothesized that the type of pathogen and illness severity were the primary influences on the mortality rate of patients with VAP. A total of 198 consecutive patients from a university surgical ICU, with clinical signs of VAP confirmed by quantified isolation of significant numbers of a pathogen (> or =10(4) colony-forming units [cfu]/mL) from bronchoalveolar (BAL) fluid obtained by fiberoptic bronchoscopy, were identified prospectively from January 2001 to November 2004. The data collected were age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) III score, multiple organ dysfunction score, unit day of diagnosis, time (h) to antibiotic administration (TTA), appropriateness of initial therapy (AIT), unit and hospital length of stay, and mortality rate. Pathogens were classified as non-lactose-fermenting gram-negative bacilli (NGNB), lactose-fermenting gram-negative bacilli (LGNB), methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, yeast, community-acquired pneumonia (e.g., Streptococcus pneumoniae), or other pathogens. Patients with a polymicrobial isolate were placed in the "other" category. The overall mortality rate was 32.3% vs. 55% as predicted by APACHE III normative data. The overall AIT was 92%. The mortality rate for NGNB infections was 35.6% vs. 29.4% for LGNB infections (p = NS). By logistic regression, neither TTA, AIT, nor pathogen influenced the mortality rate. The type of pathogen does not influence death in surgical ICU patients with VAP diagnosed rigorously and treated by a rotational antibiotic system. The high proportion of AIT as a result of the rotational antibiotic administration system optimizes bacterial killing and negates the impact of bacterial resistance, contributing to better outcomes.


Control of gene expression of adrenal steroid hydroxylases and related enzymes.
Utilization of cDNA probes specific for various components of the bovine adrenocortical steroidogenic pathway have led to the conclusion that there are three levels of regulation of steroid hydroxylase gene expression. In each case it is postulated that specific classes of proteins bind to regulatory regions of these genes and modulate their transcription. Throughout adult life, cAMP-dependent regulation via SHIP protein(s) is the predominant mechanism by which optimal steroidogenic capacity is maintained. A second type of regulation is tissue-specific. One subclass of tissue-specific expression is the "all-or-none" type whereby steroid 21-hydroxylase and 11 beta-hydroxylase gene expression occur only in adrenal cortex and not in other steroidogenic tissues. A second subclass of tissue-specific expression is the "variable" type whereby 17 alpha-hydroxylase and cholesterol side chain cleavage (SCC) activity are both expressed in ovarian thecal cells but only SCC activity is expressed in corpus luteum. The third type of regulation is cAMP-independent and leads to fetal-imprinting (initial expression of steroid hydroxylase genes during fetal life).


Exercise behavior and patient-reported outcomes in women with early breast cancer receiving locoregional radiation therapy.
Radiation therapy is associated with acute treatment-related complications that can lead to decreased quality of life (QOL). Exercise has been shown in other cancer treatment settings to improve negative outcomes. We conducted a prospective pilot study to explore the association between exercise, patient-reported outcomes, and acute radiation therapy toxicities. Women receiving curative breast radiation therapy were enrolled. Each patient completed an exercise behavior/QOL survey before or during the first week of treatment and again during the last week of treatment. Exercise behavior was quantified with the Godin Leisure Time Exercise Questionnaire (metabolic equivalent [MET] hours per week). Measurements to evaluate upper extremity lymphedema and shoulder range of motion were completed. Skin toxicity was assessed weekly. Patient-reported outcomes were measured using standardized questionnaires. Forty-five patients were enrolled. Mean patient age was 54 (range, 28-73) years. Mean METs in the exercise cohort (≥9 METs/wk) was 21 per week (range, 11-38, n = 14); 3 per week (range, 0-8, n = 25) in the nonexercise cohort (<9 METs/wk). Women in the exercise cohort showed improvements in treatment-induced quality of life and fatigue (not significant) despite more extensive surgical, medical, and radiation treatment. No differences in treatment-related toxicities, pain, or sleep scores were noted. Lymphedema was mild (<3 cm) in the entire patient cohort. The vast majority of current exercise oncology literature implicates physical activity as an independent predictor of QOL in cancer patients. Our study noted similar trends, but they were not statistically significant. This may be due to our finding that patient-reported outcomes with radiation therapy are relatively high compared with other treatment modalities and remain stable throughout treatment. Thus, it may be that radiation therapy has a limited impact on QOL in breast cancer patients. Exercise may be best used as a targeted therapy in patients at high risk for poor QOL or radiation-related toxicities at baseline.


Changes in pharmacokinetics and in effect of furosemide in the elderly.
In this paper the general changes in the pharmacokinetics of drugs in the elderly are summarized. The suggestion is proposed, that in the case of diuretics--which act after renal excretion--the results of these changes are totally different: contrary to other drugs the standard dose of a diuretic must have less saliuretic effect instead of more effect. This thesis is supported by the results of experiments with furosemide in old patients: the kinetics are changed as expected, leading to higher plasma levels and increased Area Under the (plasma level versus time) Curve (AUC), but the effects are--dependent on renal function--decreased. To a certain degree kinetics and dynamics of furosemide can be explained and predicted on the basis of simple patient parameters. If diuretics are used in old people to treat congestive heart failure, the normal adult dose has to be used, and occasionally a larger dose has to be given.


Random-scanning mutagenesis.
Oligonucleotide-mediated mutagenesis is a useful tool for engineering nucleotide changes at defined positions in a DNA sequence. Oligonucleotide-based approaches are commonly used to introduce missense mutations at individual codons in a gene or gene segment, thereby revealing the functional importance of specific amino acid residues in a protein. For mutagenesis studies involving tracts of polypeptide sequence, investigators typically change each successive residue to alanine or to a limited number of alternative amino acids. Although these strategies can provide useful information, it is sometimes desirable to test a broader spectrum of amino acid changes at the targeted positions. This article describes a facile, oligonucleotide-based method for generating all 19 possible replacements at individual amino acid sites within a protein. This technique is known as "random-scanning mutagenesis" and is illustrated herein using examples from our studies of a conserved polymerase motif in HIV-1 reverse transcriptase.


Knocking down the transcript of protein kinase C-lambda modulates hypothalamic glutathione peroxidase, melanocortin receptor and neuropeptide Y gene expression in amphetamine-treated rats.
It has been reported that neuropeptide Y (NPY) contributes to the behavioral response of amphetamine (AMPH), a psychostimulant. The present study examined whether protein kinase C (PKC)-λ signaling was involved in this action. Moreover, possible roles of glutathione peroxidase (GP) and melanocortin receptor 4 (MC4R) were also examined. Rats were given AMPH daily for 4 days. Hypothalamic NPY, PKCλ, GP and MC4R were determined and compared. Pretreatment with α-methyl-para-tyrosine could block AMPH-induced anorexia, revealing that endogenous catecholamine was involved in regulating AMPH anorexia. PKCλ, GP and MC4R were increased with maximal response on Day 2 during AMPH treatment, which were concomitant with the decreases in NPY. cAMP response element binding protein (CREB) DNA binding activity was increased during AMPH treatment, revealing the involvement of CREB-dependent gene transcription. An interruption of cerebral PKCλ transcript could partly block AMPH-induced anorexia and partly reverse NPY, MC4R and GP mRNA levels to normal. These results suggest that PKCλ participates in regulating AMPH-induced anorexia via a modulation of hypothalamic NPY gene expression and that increases of GP and MC4R may contribute to this modulation. Our results provided molecular evidence for the regulation of AMPH-induced behavioral response.


Characterization of a canine CD44 specific monoclonal antibody.
Monoclonal antibodies (mAbs) were generated against a CD44 mRNA expressing (RT-PCR) macrophage/monocyte cell line (DH82) from a dog with malignant histiocytosis. The mAbs, that reacted with DH82 cells by FACS analysis were tested on formalin-fixed, paraffin-embedded tissues. Exclusively the incubation of DH82 cell pellets with mAbs from clone 2D10 resulted in a cell membrane associated immunoreaction. Immunoelectron microscopy specified, that the antibody bound exclusively to the cell membrane and processes of DH82 cells. The mAb was tested on a variety of normal canine tissues, including lymphoid, urinary, alimentary, respiratory, and endocrine organs, nervous tissues, liver, pancreas, skin, and muscles. Furthermore, tumour and inflamed tissues were tested for immunoreaction with the mAb. Immunohistologically, the 2D10 mAb reacted with macrophages/monocytes, subsets of lymphocytes, epithelial cells, and central nervous system white matter. FACS analysis of canine peripheral blood leukocytes showed, that a high proportion of lymphocytes and granulocytes were positive with this mAb. Western blot analysis revealed, that the 2D10 mAb bound to a protein with a molecular weight of about 85 kDa. The results of FACS and Western blot analyses, RT-PCR, immunohistology and immunoelectron microscopy strongly suggest that the antigen detected by the 2D10 mAb is most likely the canine equivalent of human CD44, a cell bound hyaluronan binding proteoglycan.


Does living in remote Australia lessen the impact of hardship on psychological distress?
Rural and remote regions tend to be characterised by poorer socioeconomic conditions than urban areas, yet findings regarding differences in mental health between rural and urban areas have been inconsistent. This suggests that other features of these areas may reduce the impact of hardship on mental health. Little research has explored the relationship of financial hardship or deprivation with mental health across geographical areas. Data were analysed from a large longitudinal Australian study of the mental health of individuals living in regional and remote communities. Financial hardship was measured using items from previous Australian national population research, along with measures of psychological distress (Kessler-10), social networks/support and community characteristics/locality, including rurality/remoteness (inner regional; outer regional; remote/very remote). Multilevel logistic regression modelling was used to examine the relationship between hardship, locality and distress. Supplementary analysis was undertaken using Australian Household, Income and Labour Dynamics in Australia (HILDA) Survey data. 2161 respondents from the Australian Rural Mental Health Study (1879 households) completed a baseline survey with 26% from remote or very remote regions. A significant association was detected between the number of hardship items and psychological distress in regional areas. Living in a remote location was associated with a lower number of hardships, lower risk of any hardship and lower risk of reporting three of the seven individual hardship items. Increasing hardship was associated with no change in distress for those living in remote areas. Respondents from remote areas were more likely to report seeking help from welfare organisations than regional residents. Findings were confirmed with sensitivity tests, including replication with HILDA data, the use of alternative measures of socioeconomic circumstances and the application of different analytic methods. Using a conventional and nationally used measure of financial hardship, people residing in the most remote regions reported fewer hardships than other rural residents. In contrast to other rural residents, and national population data, there was no association between such hardship and mental health among residents in remote areas. The findings suggest the need to reconsider the experience of financial hardship across localities and possible protective factors within remote regions that may mitigate the psychological impact of such hardship.


[Various indicators of iron metabolism during lactation].
Milk levels of iron, the iron-binding protein lactoferrin, percentage of iron in this protein have been estimated in 288 milk samples of normal lactating women. Milk iron concentrations varied within the first day and declined with time of lactation. Similar patterns of change were characteristic for lactoferrin which was highest in milk during the 1st month of lactation but steadily fell by the end of lactation. Iron percentage in lactoferrin remained low during one year of lactation, suggesting a bacteriostatic function of milk lactoferrin.


[Virological control of laboratory mice].
Virological control of laboratory mice can be obtained by serology or virus isolation from the animals. Advantages and inconveniencies of these two techniques are discussed. Special techniques i.e. preparation of immune sera or cultures of infected tissues, are also described.