Serum Magnesium Concentrations in the Canadian Population and Associations with Diabetes, Glycemic Regulation, and Insulin Resistance.
Total serum magnesium (Mg) concentration (SMC) is commonly used to assess Mg status. This study reports current SMCs of Canadians and their associations with demographic factors, diabetes, and measures of glycemic control and insulin resistance using results from the Canadian Health Measures Survey cycle 3 (2012-2013). Associations were examined in adults aged 20-79 years using linear mixed models. Mean SMCs and percentile distributions for 11 sex-age groups between 3 and 79 years (n = 5561) are reported. SMCs were normally distributed and differences (p < 0.05) among sex and age groups were small. Between 9.5% and 16.6% of adult sex-age groups had a SMC below the lower cut-off of a population-based reference interval (0.75-0.955 mmol·L-1) established in the United States population as part of the NHANES I conducted in 1971-1974. Having diabetes was associated with 0.04 to 0.07 mmol·L-1 lower SMC compared to not having diabetes in the various models. Body mass index, glycated hemoglobin, serum glucose and insulin concentrations, and homeostatic model assessment of insulin resistance were negatively associated with SMC. This is the first study to report SMCs in a nationally representative sample of the Canadian population. A substantial proportion of Canadians are hypomagnesaemic in relation to a population-based reference interval, and SMC was negatively associated with diabetes and indices of glycemic control and insulin resistance.


Role of the rttA gene in morphogenesis, stress response, and virulence in the human pathogenic fungus Penicillium marneffei.
Penicillium marneffei is a human pathogenic fungus and the only thermally dimorphic species of the genus. At 25°C, P. marneffei grows as a mycelium that produces conidia in chains. However, when incubated at 37°C or following infection of host tissue, the fungus develops as a fission yeast. Previously, a mutant (strain I133) defective in morphogenesis was generated via Agrobacterium-mediated transformation. Specifically, the rtt109 gene (subsequently designated rttA) in this mutant was interrupted by T-DNA insertion. We characterized strain I133 and the possible roles of the mutated rttA gene in altered P. marneffei phenotypes. At 25°C, the rttA mutant produces fewer conidia than the wild type and a complemented mutant strain, as well as slower rates of conidial germination; however, strain I133 continued to grow as a yeast in 37°C-incubated cultures. Furthermore, whereas the wild type exhibited increased expression of rttA at 37°C in response to the DNA-damaging agent methyl methane sulfonate, strain I133 was hypersensitive to this and other genotoxic agents. Under similar conditions, the rttA mutant exhibited decreased expression of genes associated with carbohydrate metabolism and oxidative stress. Importantly, when compared with the wild-type and the complemented strain, I133 was significantly less virulent in a Galleria infection model when the larvae were incubated at 37°C. Moreover, the mutant exhibited inappropriate phase transition in vivo. In conclusion, the rttA gene plays important roles in morphogenesis, carbohydrate metabolism, stress response, and pathogenesis in P. marneffei, suggesting that this gene may be a potential target for the development of antifungal compounds.


Brain HIV burden and length of survival after AIDS diagnosis.
Patients with AIDS in the late stages of disease can develop dementia. Previous studies have suggested HIV encephalitis is the pathological substrate of HIV-associated dementia. We hypothesized that patients who survive longer after the initial diagnosis of AIDS would have a higher brain HIV burden and consequently manifest dementia. We examined the relationship between length of survival after AIDS diagnosis and the presence of HIV encephalitis or HIV-associated dementia. We studied retrospectively the following parameters in 74 consecutive AIDS autopsies: length of survival after AIDS diagnosis, clinical diagnosis of dementia, and neuropathologic findings (including HIV burden assessment). Multinucleated giant cells (MNGC) were identified in 20% of the brains studied. HIV gp41 was detected by immunocytochemistry in 54%, approximately half of which had abundant HIV burden. Brains from all 4 patients who were clinically diagnosed with dementia and had no opportunistic neuropathologic changes contained MNGC and abundant HIV burden. Survival after AIDS diagnosis was significantly longer in patients with MNGC (p = 0.03) or abundant HIV burden (p = 0.02). A trend toward longer survival after AIDS diagnosis was apparent in patients with dementia, but did not reach statistical significance. These findings suggest that prolonged survival with immunosuppression may be a prerequisite for the development of HIV encephalitis.


Verification and feedback for medical students: an observational study during general practice rotations.
A general practice and family medicine rotation is mandatory as part of undergraduate medical education. However, little is known about the student-teacher interaction in this specific setting of ambulatory teaching. In this study we analysed how frequently preceptors verified students' history taking and clinical examination skills and how often they gave feedback. The type of feedback given was also categorised. From April to December 2012, 410 individual patient consultations were observed in 12 teaching practices associated with the Philipps University Marburg, Germany. Material was collected using structured field-note forms and videotaping. Descriptive data analysis was performed. Informed, written consent was provided by all participants. We analysed 410 consultations which lasted 14.8 min on average. In 130 (31.7%) consultations students took the patient's medical history; 124 (95.4%) of these were verified by the general practitioner (GP). Physical examination was performed by students in 202 (49.3%) of consultations; 169 (81.9%) of these were verified by the GP. Feedback occurred in 132 (32.2%) of the 410 patient consultations. Feedback was mostly non-specific and positive (68.9%), and occurred during consultation with the patient present. Specific, negative feedback also occurred relatively frequently (29.5%). Specific, positive and non-specific, negative responses were rarely given. GPs should give feedback more frequently and when doing so, focus on specific feedback. GPs should be further instructed in different feedback techniques.


Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy.
Acute generalized exanthematous pustulosis (AGEP) is a severe, usually drug-related reaction, characterized by an acute onset of mainly small non-follicular pustules on an erythematous base and spontaneous resolution usually within two weeks. Systemic involvement occurs in about 20% of cases. The course is mostly benign, and only in rare cases complications lead to life-threatening situations. Recent studies highlight the importance of genetic variations in interleukin-36 receptor antagonist gene (IL-36RN) in the pathogenesis of this disease. The physiopathology of AGEP remains unclear, but an involvement of innate and acquired immune cells together with resident cells (keratinocytes), which recruit and activate neutrophils via production of cytokines/chemokines such as IL-17, IL-36, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFα) and chemokine (C-X-C motif) ligand 8 (CXCL8)/IL-8, has been postulated. Treatment is based on the removal of the causative drug, supportive care, infection prevention and use of potent topical or systemic steroids.


Iridoid Glycosides Fraction Isolated from Veronica ciliata Fisch. Protects against Acetaminophen-Induced Liver Injury in Mice.
Veronica ciliata Fisch. has traditionally been used in Tibetan medicine for the treatment of hepatitis, cholecystitis, rheumatism, and urticaria. We analyzed the chemical composition of the iridoid glycosides fraction (IGF) isolated from V. ciliata and evaluated the antioxidant and hepatoprotective properties. The IGF was separated by high-speed countercurrent chromatography (HSCCC) and the main compounds were identified by ultra-performance liquid chromatography coupled to a photodiode array. We determined the in vitro antioxidant ability of the IGF through radical scavenging assays and assessed the in vivo hepatoprotective potential in an acetaminophen- (APAP-) induced acute liver injury murine model. The IGF was separated by HSCCC and three major iridoid glycosides (verproside, catalposide, and amphicoside) were identified as potent antioxidants and hepatoprotective compounds. Treatment with the IGF significantly suppressed the APAP-induced elevation in serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-alpha (TNF-α); improved serum total antioxidant capacity; decreased malondialdehyde formation; elevated superoxide dismutase and glutathione activity; and decreased expression of proinflammatory factors (TNF-α, nuclear factor kappa B) in the liver. Finally, we examined the histopathology of resected livers for evidence of hepatoprotection. The protection conferred by the IGF may be related to the reinforcement of antioxidant defense systems.


Slow growing Bacillus subtilis: deoxyribonucleic acid replication in turbidostat cultures.
Comparisons of slowly growing Bacillus subtilis cultures grown in batch culture, a chemostat, and a turbidostat were made. Cultures in a turbidostat were found to grow optimally and to be in balanced growth. The duration of deoxyribonucleic acid (DNA) replication, or C period, was estimated by means of an autoradiographic analysis, a genetic analysis, and determinations of DNA per cell. These measurements were performed on cells growing at different slow rates. The results showed that the C period increased with increasing generation times, but the increase in duration of the C period was not proportional to the increase in generation time.


Serum protein binding of valproic acid in fetus-mother pairs throughout pregnancy: correlation with oxytocin administration and albumin and free fatty acid concentrations.
The protein binding (expressed as percent free drug fraction) of the antiepileptic drug valproic acid (VPA) was studied in 65 fetus-mother pairs from weeks 13 to week 41 of gestation. The fetal free fractions (expressed as percent of total concentrations) of VPA were exceedingly high (greater than 50%) during weeks 13 to 16 of gestation; these values decreased to 20% by week 20 and further decreased gradually to 10% at term. There was a highly significant negative correlation between free VPA fractions and fetal albumin concentrations. Maternal free fractions of VPA gradually increased from 10% during early pregnancy to 20% at term. The free fractions of VPA were significantly higher in mothers who had received oxytocin. Thus, protein binding in the fetus exceeded that of the mother at term, whereas the converse was true during early gestation. These results agree with previous in vivo findings. It is likely that the free concentrations in the mother determine the drug effects and toxicity in both the mother and the fetus. Intermittent drug administration--particularly of large single doses--could result in a transient increase of the free concentrations of VPA, particularly because of the strong concentration dependence of VPA protein binding. Increased free fractions can also be expected from increased concentrations of displacing agents of endogenous or exogenous origin (other drugs).


[Influence of heredity, sex and season on the type of episode of bipolar disorder].
The aim of this work was to investigate if sex, age, family history, season and hypothyroidism have any influence on the type of episodes (manic, depressive, mixed) seen in bipolar patients. This retrospective study concerns a sample of 208 patients with a diagnosis of bipolar disorder (type I or II), who were admitted in one of two psychiatric centers between July 1996 and June 2000. The sex-ratio was 2.8 females for 1 male. Sex, family history and hypothyroidism were not associated with any type of episode. A higher percentage of depressive episodes was observed in the patients who were older than 50 and the average age of depressive patients was higher than that of other patients. There was no seasonal pattern in this study and the season did not influence the type of episode. The results indicate no influence of sex, season, family history and hypothyroidism on the type of episode presented. On the opposite, age seems to favour depression episode.


Biopolymer-Polysiloxane Double Network Aerogels.
A new series of transparent aerogels of biopolymer-polysiloxane double networks is reported. Biopolymer aerogels have attracted much attention from green and sustainable aspects but suffered from strong hydrophilicity and difficulty to make homogeneous structures in nanoscale; these drawbacks are overcome by compositing with a polysiloxane network. Alginate-polymethylsilsesquioxane aerogel has high optical transparency, water repellency, comparable superinsulation property and improved bending flexibility compared to pure polymethylsilsesquioxane aerogel. The nanoscale homogeneity is realized by separating the crosslinking steps for two networks in a sequential protocol: condensation of siloxane bonds and metal-crosslinking of biopolymer. The crosslinking order, biopolymer-first or siloxane-first, and universality/limitation of biopolymer-crosslinker pairs are discussed to construct fundamental chemistry of double network systems for their further application potentials.


Major depression and heart failure: Interest of monoamine oxidase inhibitors.
Several physiopathological hypotheses have been studied to explain the link between heart failure (HF) and major depression (MD). An increase of monoamine oxidase (MAO) has recently been found as a factor involved in the development of HF. The aim of this review is to provide a complete overview of the involvement of MAOs in HF comorbidity of MD and to discuss the pharmacological options. Our work highlights the scientific evidence of MAO involvement in the development of HF. Studies focusing on MAO-A seem to have reproducible results on HF, establishing the effect of this enzyme as well as the protective effect of its inhibition. Fewer studies addressed MAO-B; results are nonetheless encouraging. Based on this knowledge, the hypothesis of a rise of MAO activity in HF seems to be well established. The large prevalence of comorbid MD in HF could be due to the deamination of monoamines linked with MAOs activity. In addition, MAOIs are effective in MD and well tolerated among the elderly according to the literature. This original hypothesis provides a new perspective in the use of MAOIs in HF patients with MD.


Ultrastructural abnormalities in cultured exostosis chondrocytes.
Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by inappropriate chondrocyte proliferation and bone growth arising at the juxtaepiphyseal region of the long bones. HME is caused by mutations in the EXT 1 and EXT 2 genes, which have glycosyltransferase activity. These genes are responsible for synthesis of heparan sulfate (HS) chains, which are important signaling molecules in chondrocyte differentiation. HME chondrocytes in monolayer culture have been shown by transmission electron and deconvolution microscopy to contain enormous bundles of actin, cross-linked with muscle specific alpha-actinin. Here additional ultrastructural anomalies in HME chondrocytes are reported, including lobulated nuclei, shortened channels of rER, large numbers of cell processes and podosomes, nontypical junctions, elongated, bulbous-ended mitochondria, and reduced extracellular matrix. Microfilaments are present throughout the cytoplasm, compartmentalizing it, and isolating organelles. The excess microfilaments, attributed to increased cell adhesiveness, are likely to interfere with secretion and cytokinesis, and sterically hinder intracellular organelle differentiation. The observed surface modifications and cytoskeletal abnormalities are proposed to play a role in development of the mutant phenotype, via changes in cell adhesiveness and/or binding of signals to receptors, which results in loss of the unidirectionality of growth in the epiphyseal plate.


Carbon roadmap from syngas to polyhydroxyalkanoates in Rhodospirillum rubrum.
The gasification of organic waste materials to synthesis gas (syngas), followed by microbial fermentation, provides a significant resource for generating bioproducts such as polyhydroxyalkanoates (PHA). The anaerobic photosynthetic bacterium, Rhodospirillum rubrum, is an organism particularly attractive for the bioconversion of syngas into PHAs. In this study, a quantitative physiological analysis of R. rubrum was carried out by implementing GC-MS and HPLC techniques to unravel the metabolic pathway operating during syngas fermentation that leads to PHA production. Further, detailed investigations of the central carbon metabolites using (13) C-labelled substrate showed significant CO2 assimilation (of 40%) into cell material and PHA from syngas carbon fraction. By a combination of quantitative gene expression and enzyme activity analyses, the main role of carboxylases from the central carbon metabolism in CO2 assimilation was shown, where the Calvin-Benson-Bassham cycle (CBB) played a minor role. This knowledge sheds light about the biochemical pathways that contribute to synthesis of PHA during syngas fermentation being valuable information to further optimize the fermentation process.


The inborn errors of metabolism information system: A project of the Region 4 Genetics Collaborative Priority 2 Workgroup.
The Region 4 Genetics Collaborative has brought together metabolic clinicians and follow-up specialists from state departments of health in the region (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin) in a workgroup to create a dynamic registry, the Inborn Errors of Metabolism Information System, to facilitate gathering information about long-term follow-up for individuals identified by newborn blood spot screening. With the concept that by developing a core series of agreed-on data elements and general treatment strategies, differences in treatment plans could yield evidence about optimal treatment choices, data elements for initial intake, and interval follow-up were selected based on a paradigm condition, medium-chain acyl-CoA dehydrogenase deficiency. Demographic elements that will be used as a common data set for all conditions were identified along with condition-specific elements and general information to be obtained at intervals. Subjects were enrolled after obtaining prospective informed consent; data entry began in January 2007. Additional conditions have had data sets defined and data entry initiated; 21 disorders as of July 2009. Web-based data entry has been employed using DocSite® as the platform for data entry. With continued collaboration among members of the workgroup, we hope to extend the intellectual questions that can be explored using this data, expand the spectrum of the registry and number of patients engaged, and integrate the registry into additional domains.


Cognitive ability in early adulthood and risk of 5 specific psychiatric disorders in middle age: the Vietnam experience study.
Lower cognitive ability is a risk factor for some forms of psychopathology, but much of the evidence for risk is based on individuals who required specialist care. It is unclear whether lower ability influences the risk of particular patterns of comorbidity. To examine the relation between premorbid cognitive ability in early adulthood and the risk of major depression, generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), alcohol and other drug abuse or dependence, and comorbid forms of these conditions in midlife. Prospective cohort study in which cognitive ability was measured on enlistment into military service at a mean age of 20.4 years and psychiatric disorder was assessed by structured diagnostic interview at a mean age of 38.3 years. The United States. A total of 3258 male veterans, participants in the Vietnam Experience Study. Major depression, GAD, PTSD, and alcohol or other drug abuse or dependence since enlistment and currently, diagnosed according to the DSM-III. Lower cognitive ability was associated with an increased risk of depression, GAD, alcohol abuse or dependence, and PTSD and with some patterns of comorbidity. For a 1-SD decrease in cognitive ability, unadjusted odds ratios (95% confidence interval) for having these disorders currently were 1.32 (1.12-1.56) for depression, 1.43 (1.27-1.64) for GAD, 1.20 (1.08-1.35) for alcohol abuse or dependence, 1.39 (1.18-1.67) for PTSD, 2.50 (1.41-4.55) for PTSD plus GAD, 2.17 (1.47-3.22) for PTSD plus GAD plus depression, and 2.77 (1.12-6.66) for all 4 disorders. Most associations remained statistically significant after adjustment for confounders. Lower cognitive ability is a risk factor for several specific psychiatric disorders, including some forms of comorbidity. Understanding the mechanisms whereby ability is linked to individual patterns of psychopathology may inform intervention.


Memory skills mediating superior memory in a world-class memorist.
Laboratory studies have investigated how individuals with normal memory spans attained digit spans over 80 digits after hundreds of hours of practice. Experimental analyses of their memory skills suggested that their attained memory spans were constrained by the encoding time, for the time needed will increase if the length of digit sequences to be memorised becomes longer. These constraints seemed to be violated by a world-class memorist, Feng Wang (FW), who won the World Memory Championship by recalling 300 digits presented at 1 digit/s. In several studies we examined FW's memory skills underlying his exceptional performance. First FW reproduced his superior memory span of 200 digits under laboratory condition, and we obtained his retrospective reports describing his encoding/retrieval processes (Experiment 1). Further experiments used self-paced memorisation to identify temporal characteristics of encoding of digits in 4-digit clusters (Experiment 2), and explored memory encoding at presentation speeds much faster than 1 digit/s (Experiment 3). FW's superiority over previous digit span experts is explained by his acquisition of well-known mnemonic techniques and his training that focused on rapid memorisation. His memory performance supports the feasibility of acquiring memory skills for improved working memory based on storage in long-term memory.


Impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and adverse events of special interest in patients with rheumatoid arthritis or spondyloarthritis: a systematic analysis of the literature and meta-analysis.
To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state. A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies. Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (- 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups. We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.


Where do we find the best evidence?
As pressure on resources increases, decision makers in health care are increasingly seeking high-quality, scientific evidence to support clinical and health policy choices. Ultimately, legislators will look to develop performance measures based on evidence, rather than on consensus or commonality of practice. As plastic surgeons, we can take an increased role in producing impartial evidence on the efficacy of our surgical interventions. We can move away from the retrospective reporting of cases and nonrandomized studies and instead rely on prospective, randomized trials addressing important clinical issues. In doing so, we will challenge the common practice of basing clinical decisions solely on what we are taught, procedures we are most comfortable doing, or procedures that are most financially rewarding. These efforts will not only afford us the best opportunity to provide optimal care to patients but also allow us to demonstrate the inherent quality of our surgical specialty.


[Brazilian physician Nina Rodrigues: analysis of a scientific career].
One of the most productive ways of investigating the history of Brazilian medical practice at the turn of this century is to focus on the fruitful and ambiguous careers of those physicians that played an important role in the changes affecting the medical field at that time. This paper aims at analyzing the scientific career of physician-anthropologist Raimundo Nina Rodrigues, taking as its conceptual basis Pierrre Bourdieu's notion of "scientific field ". The paper's point of departure is the notion that the medical field is a space of confrontation that is structurally determined by previous conflicts in which physicians try to monopolize claims to scientific authority and competence. Nina Rodrigues' medical profile appears in this context as a precise indicator of the process of specialization and competition that took place during that period.


Development and characterization of nuclear microsatellite markers in the endophytic fungus Epichloë festucae (Clavicipitaceae).
Microsatellite primers were developed for the endophytic fungus Epichloë festucae, which is symbiotic with Festuca rubra, to study the population genetics of the species and to compare population structures between E. festucae and its host F. rubra. • We developed 14 polymorphic markers using the unplaced genomic scaffold sequences of E. festucae from GenBank. The number of alleles per locus (A) varied from four to 16, and unbiased haploid diversity (h) was 0.717 in eight populations located in the Faroe Islands, Finland, and Spain. The Spanish populations possessed a higher number of alleles and haploid diversity (on average A = 5.1 and h = 0.591, respectively) compared to northern populations (on average A = 1.5 and h = 0.199, respectively). • These polymorphic markers will be used by grass breeders for uses including the improvement of commercial turfgrass cultivars, and by population geneticists to study different species of the Epichloë genus.


Laparoscopic intragastric resection of gastric stromal tumor located at the esophago-cardiac junction.
We performed laparoscopic intragastric surgery (LIGS) for gastric stromal tumors located at the esophago-cardiac junction (ECJ) in 7 patients. The tumors measured 27 to 75 mm in diameters. Histologically, there were 4 cases of gastrointestinal stromal tumors, 2 leiomyomas, and 1 schwannoma. LIGS was performed with 1 camera port (10 mm) inserted by the open method and two 5-mm working ports inserted by puncturing the stomach. Tumors were enucleated or resected with appropriate margins confirming the muscle layer of the stomach wall and retrieved orally by gastrofiberscope. The mean surgical duration was 141.4 minutes. Recent patients took their first meal on day 3 postoperatively and were discharged within a week. There were no complications including stenosis or gastroesophageal reflux in any patient to date. LIGS is a feasible surgical option for gastric stromal tumors located at ECJ.


Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function.
Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease. To tackle this challenge, we develop and apply a systems biology approach to identify important transcription factors (TFs) in individual RA fibroblast-like synoviocyte (FLS) cell lines by integrating transcriptomic and epigenomic information. Based on the relative importance of the identified TFs, we stratify the RA FLS cell lines into two subtypes with distinct phenotypes and predicted active pathways. We biologically validate these predictions for the top subtype-specific TF RARα and demonstrate differential regulation of TGFβ signaling in the two subtypes. This study characterizes clusters of RA cell lines with distinctive TF biology by integrating transcriptomic and epigenomic data, which could pave the way towards a greater understanding of disease heterogeneity.


Dermatofibrosarcoma protuberans of the head and neck.
To elucidate the natural history of dermatofibrosarcoma protuberans of the head and neck, 17 cases were reviewed and compared with 92 others contained within the English literature. The prototypic case is seen as a firm, solitary, slowly enlarging, asymptomatic, cutaneous nodule between 2 and 5 cm in size and of two years' duration. It is more common in men and in persons aged between 30 and 40 years. The scalp and neck-supraclavicular fossa are the most common sites, accounting for half of the cases. Approximately 50% to 75% of the patients experience local recurrence after initial surgery and, of these, half to three fourths manifest within three years of treatment. Metastases, seen in no more than 6% of all cases, are almost invariably preceded by two or more local recurrences and occur primarily through the bloodstream to the lungs and bones and less often to regional lymph nodes. Prognostic factors, differential diagnosis, and histogenesis are included.


Simultaneous Arthroscopic Rotator Cuff Repair and Glenoid Microfracture in Active-Duty Military Patients Younger Than 50 Years: Outcomes at Midterm Follow-up.
While concomitant full-thickness rotator cuff tears and glenoid osteochondral defects are relatively uncommon in younger patients, military patients represent a unique opportunity to study this challenging injury pattern. To compare the outcomes of young, active-duty military patients who underwent isolated arthroscopic rotator cuff repair (ARCR) with those who underwent ARCR plus concurrent glenoid microfracture (ARCR+Mfx). It was hypothesized that ARCR+Mfx would produce significant improvements in patient-reported outcome measures. Cohort study; Level of evidence, 3. This was a retrospective analysis of consecutive active-duty military patients from a single base who underwent ARCR for full-thickness rotator cuff tears between January 2012 and December 2020. All patients were <50 years and had minimum 2-year follow-up data. Patients who underwent ARCR+Mfx were compared with those who underwent isolated ARCR based on the visual analog scale (VAS) for pain, Single Assessment Numeric Evaluation (SANE), American Shoulder and Elbow Surgeons (ASES) shoulder score, and range of motion. A total of 88 patients met the inclusion criteria for this study: 28 underwent ARCR+Mfx and 60 underwent isolated ARCR. The mean final follow-up was 74.11 ± 33.57 months for the ARCR+Mfx group and 72.87 ± 11.46 months for the ARCR group (P = .80). There were no differences in baseline patient characteristics or preoperative outcome scores between groups. Postoperatively, both groups experienced statistically significant improvements in all outcome scores (P < .0001 for all). However, the ARCR+Mfx group had significantly worse VAS pain (1.89 ± 2.22 vs 1.03 ± 1.70; P = .05), SANE (85.46 ± 12.99 vs 91.93 ± 12.26; P = .03), and ASES (86.25 ± 14.14 vs 92.85 ± 12.57; P = .03) scores. At the final follow-up, 20 (71.43%) patients in the ARCR+Mfx group and 53 (88.33%) patients in the ARCR group were able to remain on unrestricted active-duty military service (P = .05). Concomitant ARCR+Mfx led to statistically and clinically significant improvements in patient-reported outcome measures at the midterm follow-up. However, patients who underwent ARCR+Mfx had significantly worse outcomes and were less likely to return to active-duty military service than those who underwent isolated ARCR. The study findings suggest that ARCR+Mfx may be a reasonable option for young, active patients who are not candidates for arthroplasty.


Novel Chiral Bifunctional L-Thiazoline-Thiourea Derivatives: Design and Application in Enantioselective Michael Reactions.
Several novel chiral bifunctional L-thiazoline-thiourea derivatives were easily synthesized from commercially available L-cysteine in high yield. These catalysts were subsequently applied to the enantioselective Michael addition of acetylacetone to β-nitrostyrenes. The products with S configuration were obtained in 98% enantiomeric excess (ee) when the L-thiazoline-thiourea derivatives were used. A plausible transition state model is proposed to explain the observed enantioselectivities.


Microscopic derivation of Hubbard parameters for cold atomic gases.
We study the exact solution for two atomic particles in an optical lattice interacting via a Feshbach resonance. The analysis includes the influence of all higher bands, as well as the proper renormalization of molecular energy in the closed channel. This exact solution allows for the precise determination of the parameters in the Hubbard model and the two-particle bound state energy. We identify the regime, where a single band Hubbard model fails to describe the scattering properties of the atoms as well as the bound states energies.


[Medical treatment in laser (PRK) photoretractive keratotomy].
The need of medical treatment after photorefractive surgery has been studied by reviewing the literature on the subject and comparing their conclusions with our clinical experience. Considering the pre-operative and immediate post-operative medical treatment, there is a large consensus since the aim is treatment of pain and prevention of superinfection. The post-operative considerations for medical treatment are more controversial and can be considered as to be useful or possibly useful.


Distinct responses of Purkinje neurons and roles of simple spikes during associative motor learning in larval zebrafish.
To study cerebellar activity during learning, we made whole-cell recordings from larval zebrafish Purkinje cells while monitoring fictive swimming during associative conditioning. Fish learned to swim in response to visual stimulation preceding tactile stimulation of the tail. Learning was abolished by cerebellar ablation. All Purkinje cells showed task-related activity. Based on how many complex spikes emerged during learned swimming, they were classified as multiple, single, or zero complex spike (MCS, SCS, ZCS) cells. With learning, MCS and ZCS cells developed increased climbing fiber (MCS) or parallel fiber (ZCS) input during visual stimulation; SCS cells fired complex spikes associated with learned swimming episodes. The categories correlated with location. Optogenetically suppressing simple spikes only during visual stimulation demonstrated that simple spikes are required for acquisition and early stages of expression of learned responses, but not their maintenance, consistent with a transient, instructive role for simple spikes during cerebellar learning in larval zebrafish.


The ethics of biodefense.
This essay reviews major areas of ethical debate with regard to biodefense, focusing on cases in which biodefense presents ethical problems that diverge from those presented by naturally-occurring outbreaks of infectious disease. It concludes with a call for ethicists to study not only the ethical issues raised in biodefense programs, but also the ethics of biodefense more generally.


Chronic dietary L-arginine prevents endothelial dysfunction secondary to environmental tobacco smoke in normocholesterolemic rabbits.
Our goal was to determine whether environmental tobacco smoke causes endothelial dysfunction in the absence of hypercholesterolemia and whether such an effect can be prevented by supplementation with L-arginine. Environmental tobacco smoke exposure is associated with an increase in coronary artery disease events and mortality. We have previously demonstrated that environmental tobacco smoke causes endothelial dysfunction and atherosclerosis in rabbits with diet-induced hypercholesterolemia and atherosclerosis and that chronic dietary L-arginine supplementation prevents this. The effects of L-arginine supplementation (2.25% solution ad libitum) and environmental tobacco smoke (smoking chambers for 10 weeks) were examined with a 2 x 2 design in 32 rabbits fed a normal diet. Acetylcholine, calcium ionophore A23187, and nitroglycerin-induced vasorelaxation were assessed in aortic rings precontracted with phenylephrine. Endothelial L-arginine levels were measured by chromatography. Chronic L-arginine supplementation increased serum (P < .001) and endothelial (P = .003) L-arginine levels. Environmental tobacco smoke reduced endothelium-dependent acetylcholine-induced relaxation, and L-arginine blocked this adverse effect (P = .04). Environmental tobacco smoke tended to increase phenylephrine-induced contraction (P = .06). Neither environmental tobacco smoke nor L-arginine influenced A23187-induced relaxation nor endothelium-independent nitroglycerin-induced relaxation. Endothelial dysfunction secondary to environmental tobacco smoke may occur in the absence of diet-induced hypercholesterolemia and atherosclerosis. Chronic dietary supplementation with a nitric oxide donor such as L-arginine offsets the endothelial dysfunction associated with environmental tobacco smoke in normocholesterolemic rabbits, possibly through substrate loading of the nitric oxide pathway.


THE EFFECT OF SERPENTINE ON THE POPULATION STRUCTURE OF SILENE DIOICA (CARYOPHYLLACEAE).
Serpentine soils are rich in heavy metals and have a distinctive flora. Silene dioica is a member of the Scandinavian serpentine plant community but is also widespread outside serpentine soils. To study the population genetic consequences of serpentine stress and the origin and evolution of serpentine populations we analyzed the isozyme genetic structure of S. dioica. Seventeen populations located in the mountains of Västerbotten and Jämtland, central Sweden, were investigated by starch gel enzyme electrophoresis. About one half of the populations grow in serpentine soils and the rest on adjacent non-serpentine sites. Analyses of allele frequencies show that both serpentine and non-serpentine populations in the northern part of the studied area (Västerbotten) are genetically similar. Evidently serpentine does not exert strong selection acting upon isozyme loci. In the south (Jämtland), however, the serpentine populations exhibit genetic differentiation. This allozyme divergence is probably not due to direct selection but rather represents the effects of isolation and genetic drift. The results suggest that S. dioica has colonized serpentine repeatedly and that the tolerant populations have a multiple origin.


Treatment for sternoclavicular joint infections: a multi-institutional study.
Sternoclavicular joint (SCJ) infections are rare and difficult to manage. Surgery is necessary for treatment. A retrospective chart review of the university hospital and Veterans Administration (VA) hospitals of all patients treated for SCJ infections since 2001 was conducted. Fifteen [15] patients were identified and evaluated for the types of infections, risk factors, treatments and survival. All 15 patients were symptomatic including: pain [13], erythema [9], purulent drainage [3], fever greater than 38.3 °C [2], and leukocytosis [9]. The associated medical problems included: diabetes mellitus (DM), hypertension (HTN) and renal failure. All patients underwent intraoperative joint resection. Sixty-seven percent (67%) of intraoperative wound cultures grew staphylococcus aureus. Fourteen patients were discharged on intravenous antibiotics. The follow-up ranged between 1 week-11 months. Thirteen patients are currently alive without infection. Two patients died: 1 of sepsis and 1 of unknown causes after discharge. Symptomatic SCJ infections require surgical intervention. The most common organism was staphylococcus aureus.


Constitutive models for constrained compression of unimpacted and impacted human morselized bone grafts.
Morselized corticocancellous bone (MCB) is widely used in revision surgery with and without impaction. In the current study material parameters for the nonlinear viscoelastic and plastic responses of impacted and unimpacted human MCBs were determined during constrained compression. These models may be useful in finite element analyses of surgical constructs involving impacted and unimpacted MCBs. MCB is impacted layer by layer in the femoral canal during revision surgery. The influence of different layers on the mechanical properties was therefore also examined by comparing the relaxation strength and elastic and plastic strains for bone pellets impacted in one and two layers during constrained compression of human MCB. The relaxation strength was found to increase significantly by 14% for two layer pellets compared to one layer pellets, and the plastic strains decreased significantly by 15%, while the elastic strains were similar.


Sarilumab: First Global Approval.
Sarilumab (Kevzara™) is a fully human IgG1 monoclonal antibody that binds specifically to both soluble and membrane-bound interleukin (IL)-6 receptors (sIL-6Rα and mIL-6Rα) and thereby inhibits IL-6-mediated signalling through these receptors. Subcutaneous sarilumab is approved in Canada for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biological or non-biological disease-modifying anti-rheumatic drugs. It is under regulatory review for use in rheumatoid arthritis in other countries, including in the EU, USA and Japan. Sarilumab is also under phase II investigation for the treatment of juvenile idiopathic arthritis. This article summarizes the milestones in the development of sarilumab leading to its first global approval for the treatment of rheumatoid arthritis.


The Effect of a 30-Min Water-Pipe Smoking Session on Cognitive Measures and Cardio-Pulmonary Parameters.
One session of water-pipe tobacco smoking (WPS) can increase carboxyhemoglobin (COHb) to levels comparable to those reported in carbon monoxide poisoning, which may cause memory impairment and confusion. A prospective study evaluating healthy volunteers pre- and post-30 min of WPS session. Primary outcome parameters were executive cognitive measures [digit span test and Paced Auditory Serial Addition Test (PASAT)]. The effect of repeated cognitive testing 30 min apart without WPS was evaluated in age- and sex-matched healthy volunteers. Secondary outcome parameters included cardio-pulmonary, COHb, serum nicotine, and cytokine changes. Thirty-five subjects aged 25.6 ± 4.5 years smoked water-pipe for a 30-min session. Control group included 20 subjects aged 25.2 ± 5.1 years. Digit span test median score decreased after WPS (16 and 15, respectively, p = .003), insignificant decrease in controls. Median PASAT score increased after WPS (49 and 52, respectively, p = .009); however, a much larger significant increase was observed in controls (p ≤ .001). One WPS session resulted in significant increases in heart and respiratory rates and significant decrease in FEF25-75%. Post WPS, median COHb levels increased (from 2.2% to 10.7%, p < .0001) as did median serum nicotine levels (from 1.2 to 26.8 ng/mL, p < .0001). Serum cytokines levels: IL-2 and IL-6 increased (p < .0001 for each), and IL-10 and IL-5 decreased (p < .0001 and p = .04, respectively). One session of WPS resulted in significant negative effects on cognitive executive measures, significant increases in COHb and serum nicotine levels, and significant changes in serum cytokines. Our findings call for increasing awareness towards the possible consequences of cognitive alterations following a 30-min session of WPS. One 30-min session of water-pipe smoking resulted in negative effects on executive cognitive measures, increased carboxyhemoglobin and serum nicotine, and significant changes in serum cytokine levels. This study adds to the accumulating evidence on the harmful effects of water-pipe smoking, a growing epidemic, and calls for awareness of its possible consequences of acute cognitive alterations.


The impact of different surgical treatments for intracerebral hemorrhage on functional outcomes during the convalescent stage.
Ikejiri M, Yamamoto N, Ihara N, Mitsuyasu M, Shirataki A, Irie N. The impact of different surgical treatments for intracerebral hemorrhage on functional outcomes during the convalescent stage. Jpn J Compr Rehabil Sci 2021; 12: 9-14. We examined whether different surgical methods for intracerebral hemorrhage have an impact on functional outcomes at discharge from the Kaifukuki Rehabilitation Ward (KRW). The participants included 100 patients with first-onset hypertensive ICH. Craniotomy was performed in 52 patients, endoscopic hematoma evacuation in 31 patients, and functional independence measure (FIM), length of hospitalization, and rate of discharge to the home of the two groups were examined retrospectively. The time between surgery and admission to the KRW was significantly shorter in the endoscopic hematoma evacuation group than in the craniotomy group. Although there was no significant difference in the functional prognosis at discharge, endoscopic hematoma evacuation may contribute to higher FIM gain, shorter length of hospitalization, and a higher rate of discharge to home because of the ability to transfer to KRW earlier than in the case of craniotomy, owing to less surgical invasion. Endoscopic hematoma evacuation had a shorter time to admission to KRW than craniotomy; however, differences in surgical methods did not result in a difference in functional outcomes.


Ankylosis due to heterotopic ossification following primary total knee arthroplasty.
We present a case of ankylosis of the knee after knee arthroplasty due to heterotopic ossification in the ligaments. Treatment with resection of the collateral ligaments, reconstruction with a hinged implant and radiotherapy was successful.


Can antiretroviral therapy be used to prevent sexual transmission of human immunodeficiency virus type 1?
Approximately 5 million people annually are newly infected with human immunodeficiency virus (HIV). Although education, behavior modification, and promotion of condom use are effective transmission-prevention measures, the severity of the pandemic demands that all possible prevention strategies be explored. Antiretroviral therapy has the potential to decrease sexual transmission of HIV type 1 by reducing levels of HIV RNA and thus decreasing the risk that infected persons will transmit the disease or by its use as preexposure or postexposure prophylaxis. In this article, we explore the rationale for using antiretroviral therapy to prevent sexual transmission of HIV, as well as the limitations of this approach.


Effects of an implemented care policy on patient and personnel experiences of care.
A care policy was implemented within health care in the county of Västerbotten, Sweden. A questionnaire was administered before and after the implementation of the care policy to assess its effects. Patients within hospital care and primary health care described their experiences in a base-line study (n=3950) in 1994 and a follow-up study (n=2941) in 1996. On the same occasions personnel (n=2362 and 2310, respectively) answered the same questionnaire assessing what they thought their patients experienced. No significant positive effects of the implementation were seen by the patients. Fewer patients felt that they were understood when they talked about their problems, dared to express criticism or denied they were treated nonchalantly in the follow-up study. The experiences of the personnel were in line with those of the patients concerning nonchalant treatment in the follow-up study. Furthermore, fewer staff members thought that their patients felt they had adequate help with hygiene whilst more thought that their patients felt they were responded to in a loving way. One interpretation of the negative outcome is that organizational changes, strained resources and cuts in staffing during the 90s may have reduced the possibility of integrating the care policy in spite of an ambitious and extensive intervention.


Moringa oleifera restored semen quality, hormonal profile, and testicular morphology against Highly Active Antiretroviral Therapy-induced toxicity in adult male Wistar rats.
Reproductive toxicity has been greatly linked with Highly Active Antiretroviral Therapy (HAART) use. This study investigated the effects of Moringa oleifera Leaf Extract (MOE) on HAART-induced testicular toxicity in adult male Wistar rats. Twenty adult male Wistar rats (150-200 g) were assigned into four groups (n=5). Group A received distilled water; Group B received (orally) 200 mg/kg BW HAART only; Group C received (orally) 200 mg/kg BW HAART and 100 mg/kg BW MOE (low dose group) and Group D received (orally) 200 mg/kg BW HAART and 300 mg/kg BW MOE. At the end of the 28-day experiment, body and testicular weights were measured; serum and testis obtained were subjected to hormone profiling, biochemical and histological studies. HAART caused a significant decrease in body and testicular weight, testicular distortion and spermatogenic cell disorganization, altered semen quality and function, hormonal profiles, and oxidative stress markers (SOD, CAT, GSH) were significantly decreased with the concurrent increase in MDA level. However, treatment with MOE improved sperm parameters, testis morphology, antioxidants markers, and hormones assessments. The exposure to HAART produced marked testicular toxicity, ameliorated using Moringa oleifera leaf extract, thereby preserving testicular physiological function and morphology.


Chronic Venous Disease and Its Intersections With Diabetes Mellitus.
Chronic venous disease (CVD) is a vascular disorder in which blood return is severely compromised and CVD is usually characterized by venous hypertension. Along with obesity and diabetes mellitus, CVD is one of the most common civilization diseases. In general, the estimated prevalence of CVD ranges from 60-80 %. Early diagnosis and adequate treatment are important for preventing progression to more severe stages of the disease like venous leg ulcers. Clinical manifestations of CVD in initial stages of the disease are often asymptomatic. However, as CVD progresses, symptoms begin to develop. Treatment of CVD could be divided into conservative and surgical. Conservative therapy consists of compression, pharmacological treatment and lifestyle change. In cases where conservative therapy is ineffective, surgical or endovascular treatment may be required. The intersections between diabetes mellitus (DM) and CVD are not to be underestimated. CVD and DM have often the same risk factors. Symptoms of CVD can be modified by late complications of DM, but the incidence of different CVD degrees seems to be the same as in diabetics as in non-diabetics population. We are particularly concerned in diabetics about worse compliance with treatment due to their often-poorer adherence to treatment of DM and lifestyle changes. Moreover, there exist a higher risk of CVD and peripheral arterial disease in diabetics patients. Patients with CVD should always be inspected for the presence of DM, considering its presence can have a bearing on CVD symptoms, diagnostic procedures, and therapeutic strategies.


Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment.
Olfactory neuroblastoma (ONB, Esthesioneuroblastoma) is an infrequent neoplasm of the head and neck area derived from olfactory neuroepithelium. Despite relatively good prognosis a subset of patients shows recurrence, progression and/or metastatic disease, which requires additional treatment. However, neither prognostic nor predictive factors are well specified. Thus, we performed a literature search for the currently available data on disturbances in molecular pathways, cytogenetic changes and results gained by next generation sequencing (NGS) approaches in ONB in order to gain an overview of genetic alterations which might be useful for treating patients with ONB. We present briefly ONB molecular pathogenesis and propose potential therapeutic targets and prognostic factors. Possible therapeutic targets in ONB include: receptor tyrosine kinases (c-kit, PDGFR-b, TrkB; EGFR); somatostatin receptor; FGF-FGFR1 signaling; Sonic hedgehog pathway; apoptosis-related pathways (Bcl-2, TRAIL) and neoangiogenesis (VEGF; KDR). Furthermore, we compare high- and low-grade ONB, and describe its frequent mimicker: sinonasal neuroendocrine carcinoma. ONB is often a therapeutic challenge, so our goal should be the implementation of acquired knowledge into clinical practice, especially at pretreated, recurrent and metastatic stages. Moreover, the multicenter molecular studies are needed to increase the amount of available data.


Critique on the Use of Early Short-Term Dual Antiplatelet Therapy Following Minor Acute Cerebral Ischemic Events.
Two recent cerebrovascular studies, Clopidogrel (Clo) in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT), have purportedly demonstrated the superiority of early dual antiplatelet therapy (DAPT), using aspirin (ASA) plus Clo, in comparison to ASA alone following the occurrence of acute minor cerebral infarction or transient ischemic attack. However, limitations to these trials exist that may not have been adequately explored and presented in the literature, and which may impact the overall efficacy and benefit of DAPT in these situations. Herein we provide a detailed and extensive critique of these 2 trials and of a combined analysis, with particular attention to study data and analyses pertaining to hemorrhagic complications. DAPT may be superior to ASA alone in preventing recurrent cerebral ischemic events, but exclusively during the first 7-10 days of treatment, and probably only in the presence of acute infarction on cerebral imaging. The impact of minor hemorrhages, which are often clinically consequential and which frequently lead to permanent DAPT discontinuation, has not been adequately considered in the available analyses. Based on data from the trials, DAPT use causes more major and minor hemorrhages than ASA use alone or Clo alone, and Clo use results in fewer hemorrhages than the use of ASA alone. Analyses that include hemorrhage data from the period of Clo alone use as part of the DAPT data may provide inaccurate and erroneous conclusions regarding the relative safety and overall net benefit of DAPT use over ASA alone.


Collaborative practice: a successful model.
Recognizing the need for better collaboration, nursing personnel from two nonrelated health care facilities, acute care and rehabilitation hospitals, came together to establish a methodology to improve outcomes for patients with spinal cord injury (SCI). Focus areas were to facilitate communication and transition between hospitals. A collaborative practice model evolved for the patient with tetraplegia who is ventilator-dependent. This model has been successfully instituted in both institutions. This article describes the processes used in developing this model. It also includes recommendations for the reader to create a workable process in his or her respective institution.


Simultaneous non-invasive measurement of liquid gastric emptying and small bowel transit by combined 13C-acetate and H2-lactulose breath test.
The 13C-acetate breath test (13C-ABT) allows noninasive measurement of liquid gastric emptying time (LGET), the H2-lactulose breath (H2-LBT) measures orocecal transit time (OCTT). Because of different test principles, both tests can generally be combined. This would not only spare time and resources but may also deliver additional information on the integrated regulation of gastrointestinal motor functions. Our aim was to define an adequate test protocol and to generate normal values for the combined 13C-ABT/H2-LBT. Twenty two healthy volunteers participated (HV, 12 females, age: 26.5 ± 4.7 years, BMI: 22 ± 2.1 kgm(-2). Fasting subjects received 200 ml of an aequous solution containing 150 mg 13C-acetate and 10 g lactulose. Breath samples for H2 measurements were collected before ingestion of the test solution and afterwards at 5 min intervals for 180 min, for 13C measurements sampling intervals were prolonged to 15 min after the first hour. LGET was defined as time of maximal 13C-exhalation, OCTT as increase in H2 of ⩾ 20 ppm above basal. Small bowel transit time (SBTT) was calculated as the difference between OCTT and LGET. Mean [95% CI] values for LGET, OCTT and SBTT were 26 [23-30] min, 85 [68-102] min and 60 [44-76] min, respectively. Normal values for LGET and OCTT corresponded with published data. SBTT was not correlated with LGET (R2 = 0.019; p = 0.546). By contrast, there was a very tight and highly significant correlation between SBTT and OCTT (R2 = 0.933; p < 0.001). Multivariate linear regression analyses confirmed that age, sex and BMI had no significant effects on OCTT or SBTT while LGET was weakly correlated with BMI (R2 = 0.240; p = 0.021). In conclusion, the combined 13C-ABT/H2-LBT allows simultaneous measurement of LGET and OCTT as well as calculation of SBTT.


MiR-93-5p Promotes Cell Proliferation through Down-Regulating PPARGC1A in Hepatocellular Carcinoma Cells by Bioinformatics Analysis and Experimental Verification.
Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A, formerly known as PGC-1a) is a transcriptional coactivator and metabolic regulator. Previous studies are mainly focused on the association between PPARGC1A and hepatoma. However, the regulatory mechanism remains unknown. A microRNA associated with cancer (oncomiR), miR-93-5p, has recently been found to play an essential role in tumorigenesis and progression of various carcinomas, including liver cancer. Therefore, this paper aims to explore the regulatory mechanism underlying these two proteins in hepatoma cells. Firstly, an integrative analysis was performed with miRNA-mRNA modules on microarray and The Cancer Genome Atlas (TCGA) data and obtained the core regulatory network and miR-93-5p/PPARGC1A pair. Then, a series of experiments were conducted in hepatoma cells with the results including miR-93-5p upregulated and promoted cell proliferation. Thirdly, the inverse correlation between miR-93-5p and PPARGC1A expression was validated. Finally, we inferred that miR-93-5p plays an essential role in inhibiting PPARGC1A expression by directly targeting the 3'-untranslated region (UTR) of its mRNA. In conclusion, these results suggested that miR-93-5p overexpression contributes to hepatoma development by inhibiting PPARGC1A. It is anticipated to be a promising therapeutic strategy for patients with liver cancer in the future.


Relation of AURKB over-expression to low survival rate in BCRA and reversine-modulated aurora B kinase in breast cancer cell lines.
New therapeutic drug for breast cancer (BRCA), especially triple negative BRCA (TNBC), is urgently needed. Even though 2-(4-morpholinoanilino)-6-cyclohexylaminopurine (reversine) is an aurora kinase inhibitor, it also inhibits some cancer cells and human BRCA cells. However, the potential roles of reversine as a novel therapeutic agent for the treatment of BRCA remains unknown and must be further investigation. Thus, the relationship of reversine to aurora kinase in BCRA has not been reported. The relationship between AURKB and survival rate in BRCA has never been reported. Herein, we tested the roles of reversine on different BRCA cell line subtypes. We also investigated the relationship between AURKB and survival rate in BRCA as well as reversine to Aurora kinase expression in BCRA cell lines, including TNBC subtype, 4T1, MDA-MB-231, and luminal subtype MCF-7. Cell viability and apoptosis were detected using Cell Counting Kit-8 and flow cytometry analysis, respectively. Apoptotic and tumor-related proteins were tested using Western blot analysis. Important microRNAs that regulate BRCA were analyzed using RT-PCR. UALCAN public databases were used to analyze the targeted gene profiles, and the PROGgeneV2 database was used to study the prognostic implications of genes. Reversine inhibits cell proliferation and induces cell apoptosis by modulating caspase-3 and bax/bcl-2 among the three cell lines. Data from the UALCAN public database show that BRCA tissues expressed high gene levels of AURKB, TIMP1, MMP9, and TGFB1 compared with the normal tissue. Among the over-expressed genes in BRCA, AURKB ranks 9th in TNBC, 49th in luminal subtype, and 48th in HER2 subtype. High AURKB level in BRCA is highly related to the low survival rate in patients displayed in 18 databases searched via PROGgeneV2. The protein levels of aurora B kinase (Aurora B), which is encoded by AURKB gene, are highly suppressed by reversine in the three cell lines. The tumor-related proteins TGF-β1, TIMP1, and MMP9 are partially suppressed by reversine but with different sensitivity in the three cell lines. The reversine-affected microRNAs, such as miR129-5p, miR-199a-3p, and miR-3960, in MDA-MB-231 cell line might be the research targets in TNBC regulation. In BRCA, the level of AURKB are over-expressed and is related to low survival rate. Reversine contributes to anti-growth effect in BRCA cell lines, especially for TNBC, by modulating the aurora B. However, the invasiveness, metastasis, and anti-tumor effects of reversine in vivo and in vitro must be further investigated.


Radiographic and magnetic resonance imaging predicts severity of cruciate ligament fiber damage and synovitis in dogs with cranial cruciate ligament rupture.
Cruciate ligament rupture (CR) and associated osteoarthritis (OA) is a common condition in dogs. Dogs frequently develop a second contralateral CR. This study tested the hypothesis that the degree of stifle synovitis and cranial cruciate ligament (CrCL) matrix damage in dogs with CR is correlated with non-invasive diagnostic tests, including magnetic resonance (MR) imaging. We conducted a prospective cohort study of 29 client-owned dogs with an unstable stifle due to complete CR and stable contralateral stifle with partial CR. We evaluated correlation of stifle synovitis and CrCL fiber damage with diagnostic tests including bilateral stifle radiographs, 3.0 Tesla MR imaging, and bilateral stifle arthroscopy. Histologic grading and immunohistochemical staining for CD3+ T lymphocytes, TRAP+ activated macrophages and Factor VIII+ blood vessels in bilateral stifle synovial biopsies were also performed. Serum and synovial fluid concentrations of C-reactive protein (CRP) and carboxy-terminal telopeptide of type I collagen (ICTP), and synovial total nucleated cell count were determined. Synovitis was increased in complete CR stifles relative to partial CR stifles (P<0.0001), although total nucleated cell count in synovial fluid was increased in partial CR stifles (P<0.01). In partial CR stifles, we found that 3D Fast Spin Echo Cube CrCL signal intensity was correlated with histologic synovitis (SR = 0.50, P<0.01) and that radiographic OA was correlated with CrCL fiber damage assessed arthroscopically (SR = 0.61, P<0.001). Taken together, results of this study show that clinical diagnostic tests predict severity of stifle synovitis and cruciate ligament matrix damage in stable partial CR stifles. These data support use of client-owned dogs with unilateral complete CR and contralateral partial CR as a clinical trial model for investigation of disease-modifying therapy for partial CR.


Rates of HIV, syphilis, and HCV infections among different demographic groups of female sex workers in Guangxi China: evidence from 2010 national sentinel surveillance data.
To examine the prevalence of HIV, syphilis, and hepatitis C virus (HCV) infections by demographic characteristics and identify the subgroups of female sex workers (FSW) who are at a higher risk of the infections. Secondary analysis of the 2010 National Sentinel Surveillance (NSS) data was conducted in the current study. A total of 12,622 FSW recruited from 35 NSS sites in Guangxi, China were included in the analysis. FSW were tested for HIV, syphilis, and HCV. The overall prevalence of HIV, syphilis, and HCV infections were 1.0, 6.1, and 1.0%, respectively. The prevalence of HIV and syphilis infections was significantly higher among women who were 40 years of age or older, worked in small commercial sex venues or on the street, were divorced or widowed, or had no formal schooling. A very high HIV infection prevalence (8.2%) was observed among a small number of cross-border foreign FSW (n=49). The prevalence of HCV infection did not differ by most of the demographic characteristics. Living in other provinces or being a Zhuang-ethnic served as protective factors for HCV. The multivariable analyses confirmed the bivariate results suggesting higher prevalence of HIV and syphilis infections among FSW who were older, divorced or widowed, or had no formal schooling. Future HIV intervention prevention efforts among FSW need to pay particular attention to these women in order to effectively curtail the infections among this most-at-risk population as well as to prevent the further spread of HIV and syphilis to other populations.


Preconditioning and postconditioning: new strategies for cardioprotection.
Despite optimal therapy, the morbidity and mortality of coronary heart disease (CHD) remains significant, particularly in patients with diabetes or the metabolic syndrome. New strategies for cardioprotection are therefore required to improve the clinical outcomes in patients with CHD. Ischaemic preconditioning (IPC) as a cardioprotective strategy has not fulfilled it clinical potential, primarily because of the need to intervene before the index ischaemic event, which is impossible to predict in patients presenting with an acute myocardial infarction (AMI). However, emerging studies suggest that IPC-induced protection is mediated in part by signalling transduction pathways recruited at time of myocardial reperfusion, creating the possibility of harnessing its cardioprotective potential by intervening at time of reperfusion. In this regard, the recently described phenomenon of ischaemic postconditioning (IPost) has attracted great interest, particularly as it represents an intervention, which can be applied at time of myocardial reperfusion for patients presenting with an AMI. Interestingly, the signal transduction pathways, which underlie its protection, are similar to those recruited by IPC, creating a potential common cardioprotective pathway, which can be recruited at time of myocardial reperfusion, through the use of appropriate pharmacological agents given as adjuvant therapy to current myocardial reperfusion strategies such as thrombolysis and primary percutaneous coronary intervention for patients presenting with an AMI. This article provides a brief overview of IPC and IPost and describes the common signal transduction pathway they both appear to recruit at time of myocardial reperfusion, the pharmacological manipulation of which has the potential to generate new strategies for cardioprotection.


Low-phytate barley cultivars improve the utilization of phosphorus, calcium, nitrogen, energy, and dry matter in diets fed to young swine.
A 28-d experiment was conducted using 45 crossbred barrows with an average initial BW of 9.5 kg and age of 35 d to evaluate low-phytate barley (LPB) mutants (M) M422, M635, and M955, which were hulled, near-isogenic progeny of the normal barley (NB) Harrington and had 47, 66, and 80% less phytic acid, respectively, than NB. A hull-less LPB, M422-H, which was not near-isogenic to the other cultivars, was also evaluated. Apparent nutrient balance, bone measurements, and growth performance were the response criteria evaluated. The barrows were fed the diets to appetite in meal form in individual metabolism crates. Barley and soybean meal were the only sources of phytic acid. Dietary protein supplementation and ME/kg were equalized in all diets. The treatments were diets containing NB, M422, M635, or M422-H without or with added inorganic P (iP), or M955 without added iP. Diets with added iP contained 0.30% available P (aP), the same concentration of aP provided by the diet containing M955 without added iP. There were linear increases (P < or = 0.02) in ADG, G:F, metacarpal and radius bone strength, and fat-free dry weight, and in the absorption and retention (g/d and % of intake) of P and Ca with increasing dietary concentration of aP from the near-isogenic cultivars NB, M422, M635, or M955 without added iP. There were linear decreases in the grams (P < or = 0.02) and percentages (P < 0.001) of P and Ca excreted per day with increasing dietary concentration of aP without added iP. There were no responses for N or energy balance. Growth performance and bone response criteria did not differ for barrows fed the diet containing M955 or the near-isogenic diets containing NB, M422, or M635 with added iP. However, barrows fed the diet containing M955 had greater (P < or = 0.02) percentages of P, N, and energy absorption and retention, Ca absorption, and DM digestibility and had less (P < or = 0.02, g/d and %) excretion of P, N, energy, and Ca (g) per day than barrows fed the diets containing the near-isogenic NB or LPB cultivars with added iP. When dietary aP was equalized with iP, the excretion of P in feces plus urine (g/d) was reduced by 20.2, 27.9, and 44.6%, respectively, in barrows fed the diets containing M422 + iP, M635 + iP, or M955 compared with barrows fed the diet containing NB + iP. Energy utilization did not differ for barrows fed the diets containing hulled or hull-less LPB when ME/kg was equalized with lard. In conclusion, the apparent utilization of P and Ca, the bone strength and fat-free dry weight, and growth performance increased with increasing dietary concentration of aP provided by LPB, in association with linear decreases in P and Ca excretion. Barrows fed the diet containing M955 also had greater utilization and less excretion of P, Ca, N, energy, and DM than barrows fed the diets containing the near-isogenic NB or LPB cultivars with added iP to equalize aP at 0.30%.


Impact of peripheral arterial disease and acute ischemic stroke.
Peripheral arterial disease (PAD) is associated with coronary artery disease (CAD) and stroke, but data on the relationship between PAD and acute ischemic stroke are lacking. Therefore, we investigated this relationship. A total of 101 patients were enrolled on admission to Harasanshin General Hospital (Fukuoka, Japan) with their first ischemic stroke. All 101 patients underwent cranial CT and/or brain magnetic resonance imaging, duplex ultrasonography of the extracranial carotid arteries, and transthoracic echocardiography. The subjects were aged 41 to 92 years. PAD was present in 81/101 patients (80.2%), including 57/73 (78.1%) with small artery occlusion, 11/13 (84.6%) with large artery occlusion, and 13/15 (86.7%) with cardiogenic embolism. In 42 of these 81 patients (51.9%), PAD was asymptomatic. Serum apoprotein A1 levels were significantly higher and the intima-media thickness was significantly greater in the patients with PAD than in those without PAD. The modified Rankin scale score was significantly higher on admission in patients with PAD than in those without PAD. Stepwise logistic regression analysis revealed that the apoprotein A1 level and the modified Rankin scale score on admission were strongly associated with the occurrence of stroke in patients with PAD. Our results suggest that PAD is frequently associated with acute ischemic stroke. It may be important to perform screening for PAD in patients who have suffered an ischemic stroke.


The Swedish family: transition to parenthood.
Family interaction during pregnancy and the transition to parenthood creates the social environment in which the fetus becomes part of the family, family relationships and roles are reorganized, and the infant's temperament appears. The purpose of this study was to examine the relationships among family dynamics, parental-fetal attachment, and infant temperament across the transition to parenthood. A sample of 91 families in Helsingborg, Sweden completed the Family Dynamics Measure and the Maternal/Paternal Fetal Attachment Scale during the third trimester of pregnancy. When the infant was 8-9 months old, mothers (n = 62) and fathers (n = 54) again completed the Family Dynamics Measure. The mother completed the Revised Infant Temperament Questionnaire as well. Overall, we found small changes in family dynamics, with an increase in perceived role conflict and mutuality reported by mothers. Fathers reported greater fetal attachment than their partners. Greater paternal- and maternal fetal attachment was related to more positive family dynamics, and maternal-fetal attachment was positively related to infant mood at 8 months. The stability of family dynamics across the transition to parenthood is a sign that most families negotiate this transition without difficulty.


Metastatic Clear Cell Renal Cell Carcinoma Presenting with a Gingival Metastasis.
Metastatic deposits to the oral cavity are exceptionally rare. The commonest tumor types metastasizing to the oral cavity include lung and breast carcinoma. Renal cell carcinoma is believed to be the third most common infra clavicular tumor to metastasize to the head and neck. We report a case where an oral cavity deposit was the initial presentation for an occult clear cell renal carcinoma. Additional therapeutic options, including immunotherapy, tyrosine kinase inhibitors, and participation in a clinical trial, should be discussed with the patient despite the poor overall prognosis.


Distribution of Cu fraction in sediments using Suaeda heteroptera - Nereis succinea combination: A greenhouse study.
A knowledge of the total amount of heavy metals is not enough to assess the environmental impact of polluted soils. Therefore, the determination of Cu fractions in sediment is important to evaluate its behavior in the environment and its mobilization capacity. The distribution of Cu (II) fractions in the sediment was studied in a laboratory simulation experiment. The results indicated that the distribution of Cu fractions was related to the concentration of Cu in sediments. In the Suaeda heteroptera group, the content of exchangeable and carbonate-bound were reducing, while the Fe-Mn oxide- and organic matter-bound were basically raising. In the Nereis succinea group, the content of Fe-Mn oxide- and organic matter-bound were from raising to reducing, and the residual was basically reducing with the increasing Cu concentrations. Generally speaking, the existence of N. succinea could enhance the uptake of Cu in the coastal sediment planted with S. heteroptera. When S. heteroptera and N. succinea in combination, effect of S. heteroptera and N. succinea on Cu fractions in sediments was significantly higher than the two working singly.


Fungicide methyl thiophanate binding at sub-domain IIA of human serum albumin triggers conformational change and protein damage.
Fluorescence quenching data on interaction of a fungicide methyl thiophanate (MT) with human serum albumin (HSA) elucidated a primary binding site at sub-domain IIA. Stern-Volmer algorithm and double log plot revealed the binding affinity (K(a)) and capacity (n) of HSA as 1.65 x 10(4)M(-1) and 1.0 (r(2)=0.99), respectively. Cyclic voltammetric and circular dichroism (CD) studies reaffirmed MT-HSA binding and demonstrated reduction in alpha-helical content of HSA. Substantial release of the carbonyl and acid-soluble amino groups from MT treated HSA suggested protein damage. The plausible mechanism of methyl ((+)CH(3)) group transfer from MT to side chain NH group of tryptophan and HSA degradation elucidates the toxicological and clinical implications of this fungicide.


New pathway of conversion of pyridoxal to 4-pyridoxic acid.
The only enzyme demonstrated so far to catalyze the formation of 4-pyridoxic acid, the final excretory product of vitamin B6, was aldehyde oxidase. In this paper we have presented an evidence that another enzyme, NAD+-dependent aldehyde dehydrogenase, is capable of catalyzing this reaction. Rat mutants with high, low and no aldehyde oxidase activity excrete the same amount of isotope after a single injection of 3H-pyridoxol in a 12-day experiment; 4-pyridoxic acid is also present in the urine of animals without aldehyde oxidase activity. There is no correlation between the proportion of the excreted acid and the amount of pyridoxal excreted, after the injection of a single dose of the aldehyde form. The Km values for pyridoxal and NAD+, at pH 9.6, have been found to be 75 and 260 mumol/l, respectively. NAD+-dependent pyridoxal dehydrogenase was partially purified from the rat tissues, and the following specific enzyme activities (nmol-min-1-mg-1 protein) were found: red blood cell 71.5 +/- 3.0, intestine 64.9 +/- 9.0, muscle 61.4 +/- 1.6, brain 39.5 +/- 6.0, liver 34.4 +/- 3.3, kidney 21.1 +/- 5.6, heart 18.8 +/- 0.9, and lung 6.5 +/- 2.0. This is believed to be the first report demonstrating pyridoxal oxidation, catalyzed by an NAD+-dependent aldehyde dehydrogenase.


Dental status and satisfaction with oral function in a sample of community-dwelling elderly people in Japan.
The purpose of this study was to determine the influence of dental status on oral function and satisfaction among a group of independently living elderly persons in an urban area of Japan. The study sample consisted of participants of the Senior Citizens' College from 1995 to 1999. Their dental status and oral satisfaction were measured by a questionnaire. The number of usable questionnaires was 3967, or 80.8% of the total sample. The mean age of the subjects was 66.5+/-4.3 years, and 52.2% were male. Twenty-nine percent of them had a natural dentition, and 7.0% were edentulous in both jaws. The prevalence of edentulism in the study sample was significantly lower (p < 0.01) than that for the national survey. Overall, 66.4% of the subjects were satisfied with their ability to chew, 56.2% with the appearance of their teeth, 63.1% with their ability to speak clearly, and 76.5% with their ability to taste food. For complete-denture wearers, the greatest dissatisfaction was with speech (28.5%); however, for the RPD wearers, it was with chewing ability (21.7%). Sixty-one percent of complete-denture wearers reported that they were satisfied with their chewing ability, but only 11% of them could eat all three of the evaluated foods without difficulty. The multiple stepwise logistic regression analyses showed that both dental status and self-assessed general health had a significant association with dissatisfaction with all four oral functions and self-assessed impairment of chewing ability. There were significant associations between the elderly subjects' dental status and oral function.


[Cost effectiveness of local regional anesthesia in a remote area].
Loco-regional anesthesia techniques are considered as a simple and economic solution to problems posed by anesthesia in developing countries. However the cost benefits of some techniques are reduced by cardiovascular effects that affect the quantity and nature of peroperative vascular filling usually necessary during general anesthesia. The purpose of the present study was to ascertain the relative costs of these methods by comparing the quantity of crystalloid solution and blood administered during loco-regional anesthesias and general anesthesias in a general hospital center in Africa. In a retrospective cohort of 1050 consecutive patients operated on in the Surgery and Gynecology/Obstetrics Departments of the A. Sice Hospital in Pointe Noire (Congo), 495 included in a study comparing perimedullary anesthesia and general anesthesia. The total volume of solution and blood administered to the patients during the procedure was studied in function of the type of anesthesia and surgery performed. Results showed that the amount of crystalloid solution administered during peridural and spinal anesthesia tended to be higher. This difference was significant only for prostate surgery. Use of epidural anesthesia did not increase the quantity of fluid modified gelatin and blood transfused in this series. It was also observed that 55% of patients who underwent peridural anesthesia required further intravenous anesthesia as opposed to 18.8% of patients who underwent spinal anesthesia. These findings indicate that loco-regional anesthesia performed under standardized conditions does not significantly change the quantity and nature of preoperative filling usually necessary during general anesthesia. Thus these techniques can be considered as cost-effective in developing countries even though the long period necessary for practitioners to learn them results in a transient increase in cost. A prospective study by surgical groups with experience using loco-regional anesthesia is needed to confirm this study.


Determination of nine bioactive phenolic components usually found in apple juice by simultaneous UPLC-MS/MS.
The functional food ingredients of apple juice can significantly change during processing, transportation, and storage, thus affecting the quality of the product. A simple and derivation-free analytical method based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and optimized for the simultaneous determination of functional food ingredients in apple juice bought in the market. Cleanup steps and chromatographic conditions were optimized to remove interference and decrease the matrix effect. The nine target analytes were separated on an Acquity UPLC system equipped with a BEH C18 column and detected by electrospray ionization source (ESI) operating in positive subsection acquisition mode under multiple reaction monitoring (MRM) conditions. The results showed that p-hydroxybenzoic acid, protocatechuate, caffeic acid, chlorogenic acid, epicatechin, phloridzin, hyperoside, procyanidin B2, and rutin could be sufficiently separated for content determination within 6 min. In the concentration range of 20 μg/L-50 mg/L, nine standard samples exhibited a good linear fit with correlation coefficients above .985.


N-Heterocyclic Carbenes Carrying Weakly Coordinating Anions.
In this Concept article we provide a brief overview of the design and preparation of N-heterocyclic carbenes carrying weakly coordinating anions (WCA-NHCs). The anionic charge in these ligand systems is located on an exocyclic group, for example, B(C6 F5 )3 , tethered to the backbone of the imidazole ring, thus resembling a weakly coordinating moiety. With the general guiding principle behind the application of WCA-NHCs being the conversion of otherwise cationic NHC complexes into their overall neutral congeners, numerous transition metal as well as main group element complexes were isolated during the last decade, which are summarized herein.


Visual attention and expertise for forensic signature analysis.
Eye tracking was used to measure visual attention of nine forensic document examiners (FDEs) and 12 control subjects on a blind signature comparison trial. Subjects evaluated 32 questioned signatures (16 genuine, eight disguised, and eight forged) which were compared, on screen, with four known signatures of the specimen provider while their eye movements, response times, and opinions were recorded. FDEs' opinions were significantly more accurate than controls, providing further evidence of FDE expertise. Both control and FDE subjects looked at signature features in a very similar way and the difference in the accuracy of their opinions can be accounted for by different cognitive processing of the visual information that they extract from the images. In a separate experiment the FDEs re-examined a reordered set of the same 32 questioned signatures. In this phase each signature was presented for only 100 msec to test if eye movements are relevant in forming opinions; performance significantly dropped, but not to chance levels indicating that the examination process comprises a combination of both global and local feature extraction strategies.


The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells.
Do different chemotherapy drugs exert the same magnitude of cytotoxicity on dormant primordial follicles and the growing follicle fraction in the ovary in vivo and on mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro? Cyclophosphamide (alkylating agent) and cisplatin (alkylating like) impacted both primordial and pre-antral/antral follicles and both mitotic and non-mitotic granulosa cells, whereas the anti-metabolite cancer drug gemcitabine was detrimental only to pre-antral/antral follicles and mitotic non-luteinized granulosa cells. It is already known that anti-metabolite cancer drugs are less detrimental to the ovary than alkylating and alkylating like agents, such as cyclophosphamide and cisplatin. This assumption is largely based on the results of clinical reports showing lower rates of amenorrhea in women receiving anti-metabolite agent-based regimens compared with those treated with the protocols containing an alkylating drug or a platinum compound. But a quantitative comparison of gonadotoxicity with a histomorphometric proof of evidence has not been available for many chemotherapy drugs. Therefore, we combined in this study in vivo and in vitro models of human and rat origin that allows a comparative analysis of the impact of different chemotherapy agents on the ovary and granulosa cells using real-time quantitative cell indices, histomorphometry, steroidogenesis assays, and DNA damage and cell death/viability markers. We also aimed to investigate if there is a difference between mitotic and non-mitotic granulosa cells in terms of their sensitivity to the cytotoxic actions of chemotherapy drugs with different mechanisms of action. This issue has not been addressed previously. This translational research study involved in vivo analyses of ovaries in rats and in vitro analyses of granulosa cells of human and rat origin. For the in vivo assays, 54 4- to 6-week old Sprague-Dawley young female rats were randomly allocated into four groups of 13 to receive a single IP injection of: saline (control), gemcitabine (200 mg/kg), cisplatin (50 mg/kg) or cyclophosphamide (200 mg/kg). The animals were euthanized 72 h later. Follicle counts and serum AMH levels were compared between the groups. In vitro cytotoxicity studies were performed using mitotic non-luteinized rat (SIGC) and human (COV434, HGrC1) granulosa cells, and non-mitotic luteinized human (HLGC) granulosa cells. The cells were plated at a density of 5000 cells/well using DMEM-F12 culture media supplemented with 10% FBS. Chemotherapy agents were used at their therapeutic blood concentrations. The growth of mitotic granulosa cells was monitored real-time using xCelligence system. Live/dead cell and apoptosis assays were also carried out using intravital Yo-Pro-1 staining and cleaved caspase-3 expression, respectively. Estradiol (E2), progesterone (P) and anti-Mullerian hormone (AMH) levels were assayed with ELISA. Cyclophosphamide and cisplatin caused massive atresia of both primordials and growing follicles in the rat ovary whereas gemcitabine impacted pre-antral/antral follicles only. Cyclophosphamide and cisplatin induced apoptosis of both mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro. By contrast, cytotoxicity of gemcitabine was confined to mitotic non-luteinized granulosa cells. This study tested only three chemotherapeutic agents. The experimental methodology described here could be applied to other drugs for detailed analysis of their ovarian cytotoxicity. These findings indicate that in vivo and in vitro cytotoxic actions of chemotherapy drugs on the ovarian follicles and granulosa cells vary depending upon the their mechanism of action and the nature of the granulosa cells.


Induction of progesterone receptor with 17 beta-estradiol in human ovarian cancer.
We utilized a xenograft model of human ovarian cancer to study the ability of estrogen to induce progesterone receptor. Tumor cytosol from 17 beta-estradiol treated oophorectomized animals, but not oophorectomized controls, contained a [3H]ORG 2058 binding moiety of sedimentation coefficient 6-9S. This component showed specificity for the progestagens: progesterone, ORG 2058, and R5020 and for the antiprogestagen cyproterone acetate. At 1000-fold molar excess, 5 alpha-dihydrotestosterone competed partially for these sites while diethylstilbestrol, dexamethasone, and the antiandrogen, SCH 16423, were ineffective competitors. The dissociation constant for this progestagen binding entity was 0.14 nM using [3H]ORG 2058 as labeled ligand and R5020 as competitor. In addition, saturation analysis demonstrated that approximately 400 fmol of progestagen specific binding capacity was available per mg of cytosol protein. These data suggest that estrogen can induce progesterone receptor in human ovarian carcinoma.


Guidelines for pharmacoeconomic and outcomes research fellowship training programs: joint guidelines from the american college of clinical pharmacy and the international society of pharmacoeconomics and outcomes research.
Abstract Pharmacoeconomics and outcomes research (PEOR) demonstrates the added value of health services and treatments and is used by a variety of individuals in numerous settings to optimize patient care. Currently, 51 PEOR fellowship programs are publicized on Web sites from organizations such as the American College of Clinical Pharmacy (ACCP), the International Society of Pharmacoeconomics and Outcomes Research (ISPOR), and the Academy of Managed Care Pharmacy. These programs demonstrate the diversity of PEOR fellowships, as they are offered by sponsors in a variety of environments (e.g., academia, industry, consulting services, United States managed care, and government). Although the program sponsors vary, all fellowships should have the common goal of providing directed, highly individualized postgraduate training designed to prepare participants to become independent PEOR researchers. Like any health discipline, advancements in knowledge and technology along with changes in health care systems require refinement of existing training programs, including PEOR fellowships. Members of ACCP and ISPOR developed a survey instrument to assess structure, educational objectives, and outcome measures of PEOR fellowship programs. The survey objectives were to determine PEOR researchers' beliefs regarding qualifications of the training site, program, and preceptors(s) as well as fellowship applicant requirements, research commitment, didactic coursework and evaluation of fellows' research skills; and to develop PEOR fellowship guidelines based on data obtained from the survey. Pharmacoeconomics and outcomes research fellowship guidelines were originally published in 1999; this document outlines the revised PEOR fellowship guidelines based on recent literature and results of the ACCP-ISPOR survey described above. These guidelines are intended to assist PEOR researchers design, refine, and self-assess their fellowship program and to serve as a tool for prospective PEOR fellowship candidates to evaluate programs.


Lipid metabolism of commercial layers fed diets containing aflatoxin, fumonisin, and a binder.
Aflatoxins (AF) and fumonisins (FU) are a major problem faced by poultry farmers, leading to huge economic losses. This experiment was conducted to determine the effects of AF (1 mg/kg of feed) and FU (25 mg/kg of feed), singly or in combination, on the lipid metabolism in commercial layers and investigate the efficacy of a commercial binder (2 kg/t of feed) on reducing the toxic effects of these mycotoxins. A total of 168 Hisex Brown layer hens, 37 wk of age, were randomized into a 3 × 2 + 1 factorial arrangement (3 diets with no binder containing AF, FU, and AF+FU; 3 diets with binder containing AF, FU, and AF+FU; and a control diet with no mycotoxins and binders), totaling 7 treatments. The hens contaminated with AF showed the characteristic effects of aflatoxicosis, such as a yellow liver, resulting from the accumulation of liver fat, lower values of plasma very low-density lipoprotein and triglycerides, and higher relative weight of the kidneys and liver. Hepatotoxic and nephrotoxic effects of FU were not observed in this study. On the other hand, the FU caused a reduction in small intestine length and an increase in abdominal fat deposition. The glucan-based binder prevented some of the deleterious effects of these mycotoxins, particularly the effects of AF on hepatic lipid metabolism, kidney relative weight, and FU in the small intestine.


A colorectal cancer patient focus group develops an information package.
In order to deliver high quality care and empower cancer patients in decision-making, good quality information and communication are essential. We describe the development of an information booklet. A total of 22 colorectal cancer patients (12 male; median age, 72 years, range, 40-86 years) met on 3 occasions. Patients were asked to define their information needs and score them (1-4) according to importance. The information document was written. The second meeting involved feedback on the booklet. The modified booklet was reviewed/approved by the group before submission for local ethics committee approval prior to its distribution to other patients. All participants felt the project a good idea. Essential information included the surgeon's individual morbidity, mortality, survival, recurrence data and details of adjuvant therapies (score = 4). Also important were type of surgery, complications and postoperative recovery (score = 3). Simple anatomical drawings were also considered important. The booklet is now used to personalise information for all our patients and serves, in part, as a record of the key issues discussed during the consultation. The booklet has been evaluated in a randomised trial.


l-Ornithine and l-lysine stimulate gastrointestinal motility via transient receptor potential vanilloid 1.
The gastrointestinal (GI) tract senses and responds to intraluminal nutrients and these interactions often affect GI functions. We found that, among basic amino acids, l-ornithine (Orn) and l-lysine (Lys) stimulated but l-arginine (Arg) suppressed GI motility after oral administration (24 mmol/kg) in mice (Orn and Lys, 14.3 and 26.4% promotion; Arg, 7.7% suppression). We investigated the mechanism of the action of Orn and Lys on GI motility. Orn-induced promotion of small intestinal transit was significantly inhibited (p<0.05) by oral administration of capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. Moreover, the stimulatory effect of Orn and Lys was abolished in TRPV1-knockout mice. In TRPV1-transfected HEK293 cells, Orn and Lys (10 mM) evoked Ca2+ influx, which was blocked by ruthenium red, a TRP channel antagonist. These results suggest that Orn and Lys promote GI motility via activation of TRPV1. The GI motility stimulation by Orn and Lys was also blocked by atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, or NG -nitro-l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. Orally administered Orn and Lys stimulate GI motility via TRPV1, mAChR and NO synthase in mice.


Study of the reaction mechanism of the D-glutamic acid-adding enzyme from Escherichia coli.
The D-glutamic acid-adding enzyme of Escherichia coli, or MurD, was purified from an overproducing strain and a few aspects of its reaction mechanism were studied. The existence of a reactive cysteinyl residue was shown by the following experiments: (1) two thiol-modifying reagents, (5,5'-dithiobis)2-nitrobenzoic acid and 2-nitro-5-thiocyanobenzoic acid, inactivated the enzyme; (2) incubation with tetranitromethane led to inactivation and to the appearance of cysteic acid (not to 3-nitrotyrosine); (3) in each case, ATP or UDP-MurNAc-L-Ala (but not D-glutamic acid) protected the enzyme from inactivation. The existence of a reactive lysyl residue was shown by the action of 2,4,6-trinitrobenzenesulfonic acid, a reagent specific for lysyl residues present in phosphate-binding sites. The formation of an acyl phosphate intermediate was consistent with three types of results: (1) the molecular isotope exchange reaction, which took place only in the presence of phosphate, but which was not strictly dependent on the presence of ADP; (2) a release of phosphate, measured by the molybdate assay, observed when the enzyme was incubated with ATP and UDP-MurNAc-L-Ala (without D-glutamic acid); (3) the appearance of a new radioactive compound (besides ATP and Pi) after incubation for a few minutes with UDP-MurNAc-L-Ala and [gamma-32P]ATP. Finally, the fact that phosphinate 1 was a good inhibitor of the enzyme (IC50 = 0.7 microM) strongly suggested that a tetrahedral transition state follows the acyl phosphate in the reaction pathway.