Ethical and legal controversies in cloning for biomedical research--a South African perspective.
Therapeutic embryonic stem cell research raises a number of ethical and legal issues. The promised benefits are new and important knowledge of human embryological development, gene action, and the production of transplantable tissue and organs that could be effective in reversing or curing currently irreversible disease processes. However, this research involves the deliberate production, use, and ultimate destruction of cloned embryos, hence re-awakening the debate on the moral status of the embryo. Other moral anxieties include the possibility that women (as donors of ova) would be exploited, that this research would land on the slippery slope of reproductive cloning, and that promises made too early could lead to false hope among sick patients. It also raises the question of intellectual and actual property rights in human cell lines and the techniques by which they are produced. Review of legal systems internationally reveals that there is no global consensus on therapeutic embryonic stem cell research. Legal considerations are very much influenced by ethical deliberations on the moral status of the embryo. The South African parliament is promulgating legislation permitting therapeutic cloning, thereby demonstrating a commitment by the state to act in the best interests of patients and of regenerative medicine.


Favorable adsorption of capped amino acids on graphene substrate driven by desolvation effect.
The use of graphene-based nanomaterials is being explored in the context of various biomedical applications. Here, we performed a molecular dynamics simulation of individual amino acids on graphene utilizing an empirical force field potential (Amber03). The accuracy of our force field method was verified by modeling the adsorption of amino acids on graphene in vacuum. These results are in excellent agreement with those calculated using ab initio methods. Our study shows that graphene exhibits bioactive properties in spite of the fact that the interaction between graphene and amino acids in a water environment is significantly weaker as compared to that in vacuum. Furthermore, the adsorption characteristics of capped and uncapped amino acids are significantly different from each other due to the desolvation effect. Finally, we conclude that when assessing protein-surface interactions based on adsorption of single amino acids, the minimum requirement is to use capped amino acids as they mimic residues as part of a peptide chain.


Dietary heme-mediated PPARα activation does not affect the heme-induced epithelial hyperproliferation and hyperplasia in mouse colon.
Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is overcompensated by hyperproliferation and hyperplasia of crypt cells. Transcriptome analysis of mucosa of heme-fed mice showed, besides stress- and proliferation-related genes, many upregulated lipid metabolism-related PPARα target genes. The aim of this study was to investigate the role of PPARα in heme-induced hyperproliferation and hyperplasia. Male PPARα KO and WT mice received a purified diet with or without heme. As PPARα is proposed to protect against oxidative stress and lipid peroxidation, we hypothesized that the absence of PPARα leads to more surface injury and crypt hyperproliferation in the colon upon heme-feeding. Heme induced luminal cytotoxicity and lipid peroxidation and colonic hyperproliferation and hyperplasia to the same extent in WT and KO mice. Transcriptome analysis of colonic mucosa confirmed similar heme-induced hyperproliferation in WT and KO mice. Stainings for alkaline phosphatase activity and expression levels of Vanin-1 and Nrf2-targets indicated a compromised antioxidant defense in heme-fed KO mice. Our results suggest that the protective role of PPARα in antioxidant defense involves the Nrf2-inhibitor Fosl1, which is upregulated by heme in PPARα KO mice. We conclude that PPARα plays a protective role in colon against oxidative stress, but PPARα does not mediate heme-induced hyperproliferation. This implies that oxidative stress of surface cells is not the main determinant of heme-induced hyperproliferation and hyperplasia.


Reversed-phase high pressure liquid chromatography of globin chains: its application for the prenatal diagnosis of beta-thalassemia.
The separation of alpha, beta, G gamma and A gamma globin chains by reversed phase high pressure liquid chromatography has been studied using columns of octadecylsilyl-silica. All separations were performed in solvent mixtures of water and acetonitrile acidified with phosphoric acid or the hydrophobic ionpairing reagent trifluoroacetic acid. The addition of trifluoroacetic acid or the chaotropic agent NaClO4 to the mobile phase increased the resolution and the peak sharpness of the eluted globin chains. The use of decreasing gradients of TFA or NaClO4 and chromatography at 40 degree were useful steps for the separation of alpha and beta globin chains, a prerequisite for the successful application of this method for the prenatal diagnosis of beta-thalassemia. The beta/gamma synthetic ratio obtained from blood samples taken by fetoscopy from normal fetuses and fetuses with beta-thalassemia trait were measured simultaneously by CM-cellulose chromatography and high pressure liquid chromatography. The values obtained by HPLC were very similar but slightly lower than those obtained by CM-cellulose chromatography. The new method is fast and accurate and will prove to be useful for prenatal diagnosis involving globin chain separation.


Screening for cognitive impairment among patients with work-related stress complaints in Denmark: validation and evaluation of objective and self-report tools.
Many patients with work-related stress display cognitive impairment that may hamper recovery. We examined objective and subjective tools for screening of cognitive impairment in this patient group. Patients were assessed with Danish versions of the objective Screen for Cognitive Impairment in Psychiatry (SCIP-D), standardized neuropsychological tests that tapped into the same cognitive domains, the self-assessed Cognitive Failure Questionnaire (CFQ), and several additional scales of symptom severity and psychosocial status. Concurrent validity of the SCIP-D and CFQ was assessed by calculation of Pearson's correlation coefficients between the objective and subjective tools and the scores on more conventional standardized neuropsychological tests. Decision validity was assessed with logistic receiver-operating-characteristic analyses using a cut-score approach to the objective and the subjective test results to predict impairment detected by the standardized tests. Cognitive norms were established through the data of 79 healthy controls. SCIP-D scores were compared between patients and healthy controls with independent t-tests. We included 82 patients with work-related stress. The SCIP-D total scores were strongly associated with standardized neuropsychological tests (r=0.76, P<0.001). The self-assessed CFQ was not associated with either measure of objective cognitive functioning (r≤0.12, P≥0.30). The optimal SCIP-D total-score cut of ≤72 identified 43.2% of the patients with global objective cognitive impairment. The patients performed mildly-to.moderately lower than the healthy controls on the SCIP-D total score (Cohen's d=0.39) and the subtests for working memory (d=0.39) and processing speed (d=0.61). The SCIP-D is a valid screening tool sensitive to objective performance-based cognitive impairment among patients with work-related stress.


Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.
Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-kappaB activity predict the Blau syndrome/EOS clinical phenotype. Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-kappaB activity, which was defined as the ratio of NF-kappaB activity without a NOD2 ligand, muramyldipeptide, to NF-kappaB activity with muramyldipeptide. All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-kappaB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-kappaB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment. NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.


ClC-3 is a candidate of the channel proteins mediating acid-activated chloride currents in nasopharyngeal carcinoma cells.
Acid-activated chloride currents have been reported in several cell types and may play important roles in regulation of cell function. However, the molecular identities of the channels that mediate the currents are not defined. In this study, activation of the acid-induced chloride current and the possible candidates of the acid-activated chloride channel were investigated in human nasopharyngeal carcinoma cells (CNE-2Z). A chloride current was activated when extracellular pH was reduced to 6.6 from 7.4. However, a further decrease of extracellular pH to 5.8 inhibited the current. The current was weakly outward-rectified and was suppressed by hypertonicity-induced cell shrinkage and by the chloride channel blockers 5-nitro-2-3-phenylpropylamino benzoic acid (NPPB), tamoxifen, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS). The permeability sequence of the channel to anions was I(-) > Br(-) > Cl(-) > gluconate(-). Among the ClC chloride channels, ClC-3 and ClC-7 were strongly expressed in CNE-2Z cells. Knockdown of ClC-3 expression with ClC-3 small interfering (si)RNA prevented the activation of the acid-induced current, but silence of ClC-7 expression with ClC-7 siRNA did not significantly affect the current. The results suggest that the chloride channel mediating the acid-induced chloride current was volume sensitive. ClC-3 is a candidate of the channel proteins that mediate or regulate the acid-activated chloride current in nasopharyngeal carcinoma cells.


[Severe acute respiratory syndrome (SARS). Lesson and challenges].
After four months of silence before a new incursion of severe acute respiratory syndrome virus (SARS), world wide investigators specially from Asia had have to face a coronavirus capable of great spreading and inducing high morbidity. The source and the capacity of this virus to associate with other opportunist microorganisms to induce progression of the disease, remain unclear. The comparison of the genomic sequence of different strains has generated discrepancies as for if the SARS epidemic arose as an unique outbreak or it was produced for more than one genotype. However, this fact is secondary to the imminent threat that was controlled in August of 2003, after affecting 8.422 individuals, but before which we should be remain alert, since it is clear that the end of the SARS is not yet here; and that the appearance of a single case can mean the beginning of a new wave, joining the outbreak of other diseases such as the avian flu. In this regard, it is very important to know the epidemic bases of morbid-mortality of SARS and to keep a world wide surveillance in order to detect possible further cases.


Pseudoretraction of the eyelid in thyroid-associated orbitopathy.
Two patients with previously stable thyroid-associated orbitopathy presented with the fairly sudden onset of apparent upper eyelid retraction in their nondominant eye, accompanied by asymmetry of the eyebrows, with elevation on the side without the eyelid retraction. No other signs of worsening of the orbitopathy were present, and instillation of 2.5% phenylephrine hydrochloride in the contralateral, dominant eye relieved the eyelid retraction and normalized the eyebrow position. At surgery, both patients were found to have levator aponeurogenic ptosis in the eyelid that appeared to be "normal." This occurrence is explained by Hering's law and should be considered in planning surgery to reestablish palpebral fissure symmetry in such patients.


Surveillance strategies in the management of penile cancer.
Penile cancer is a rare disease and can be associated with a high risk of recurrence in regional lymph nodes and distant sites. Surveillance strategies geared towards early detection and treatment are recommended given the significant morbidity and mortality associated with recurrences. Although physical examination is the single most important surveillance strategy, imaging is an important adjunct in high-risk disease and certain clinical scenarios.


Will graduate entry free nursing from the shackles of class and gender oppression?
Debates in nursing focus on the provision of good nursing care and its relation to academic status. For example, are nurses "too posh to wash" if they believe entry to the profession should require a degree, or is this a case of them having pretensions "above their station"? This article discusses the nature of oppression and its relationship to hierarchy, and concludes that nurses are oppressed through gender and socioeconomic class. It also examines the profession's social position, arguing thatthe majority of nurses identify with the most oppressed social class.


Host cell selection of Murray Valley encephalitis virus variants altered at an RGD sequence in the envelope protein and in mouse virulence.
We have passaged the prototype strain of Murray Valley encephalitis virus in SW13 (human) cells, sequenced the E and M genes, and examined the virulence of the passaged virus for 21-day-old mice following intracranial and intraperitoneal inoculation. Six independent passage series were carried out: four in the presence of mouse hyperimmune ascitic fluid and two without antibody. Changes were observed in the E protein deduced amino acid sequence for each of the six 10th passage stocks sequenced. Eleven changes were observed in total for the six stocks sequenced; these were at residues 117, 118, 390, 423, and 460. Nine of the changes were nonconservative. Five of the six passaged variants were altered at Asp 390 which is part of an Arg-Gly-Asp (RGD) sequence. This change resulted from adaptation to SW13 cells rather than from antibody selection. The RGD sequence (and residue 423) falls within a region which is highly conserved between flaviviruses and is strongly hydrophilic. All five variants which were altered at Asp 390 were attenuated in 21-day-old mice following i.p. inoculation. We propose that the domain of E encompassing the RGD sequence is an important determinant of flavivirus pathogenicity.


Utility of Continuous EEG Monitoring in Noncritically lll Hospitalized Patients.
Continuous EEG (cEEG) monitoring is used in the intensive care unit (ICU) setting to detect seizures, especially nonconvulsive seizures and status epilepticus. The utility and impact of such monitoring in non-ICU patients are largely unknown. Hospitalized patients who were not in an ICU and underwent cEEG monitoring in the first half of 2011 and 2014 were identified. Reason for admission, admitting service (neurologic and nonneurologic), indication for cEEG, comorbid conditions, duration of recording, EEG findings, whether an event/seizure was recorded, and impact of EEG findings on management were reviewed. We evaluated the impact of the year of recording, admitting service, indication for cEEG, and neurologic comorbidity on the yield of recordings based on whether an event was captured and/or a change in antiepileptic drug management occurred. Two hundred forty-nine non-ICU patients had cEEG monitoring during these periods. The indication for cEEG was altered mental status (60.6%), observed seizures (26.5%), or observed spells (12.9%); 63.5% were on neuro-related services. The average duration of recording was 1.8 days. EEG findings included interictal epileptiform discharges (14.9%), periodic lateralized discharges (4%), and generalized periodic discharges (1.6%). Clinical events were recorded in 28.1% and seizures in 16.5%. The cEEG led to a change in antiepileptic drug management in 38.6% of patients. There was no impact of type of admitting service; there was no significant impact of indication for cEEG. In non-ICU patients, cEEG monitoring had a relatively high yield of event/seizures (similar to ICU) and impact on management. Temporal trends, admitting service, and indication for cEEG did not alter this.


[Total replacement of the lower lid].
Extensive eyelid neoplasms sometimes necessitate total excision of the lid. Similar situations can be found in post-traumatic injuries. The lower lid is the more frequent site of malignancy. A convenient method of total lower lid replacement is the use of a medial pedicle rotation flap of the cheek. Because of the firmer consistency of this cheek flap a tarsal plate replacement is not required as in other methods. Inner lining of the flap is accomplished by mobilization of conjunctiva of the lower fornix. The technique of the operation and its results are described.


[Drainage-free ureterocutaneostomy].
Drainage-free cutaneous fistula of the ureter is suggested to assure permanent extravesical outlet of the urine in patients with incurable tumor-induced obstruction of the pelvic segment of the ureter. Fistulous orifice is formed with the aid of a triangular flap sitting on a pedicle; the flap is placed into a longitudinal incision in the stump of the drained ureter. Fifteen ureteral fistulas were formed in nine patients. Fourteen of them functioned reliably for several years without causing renal complications.


Methods for the Watch the Spot Trial. A Pragmatic Trial of More- versus Less-Intensive Strategies for Active Surveillance of Small Pulmonary Nodules.
Small pulmonary nodules are most often managed by surveillance imaging with computed tomography (CT) of the chest, but the optimal frequency and duration of surveillance are unknown. The Watch the Spot Trial is a multicenter, pragmatic, comparative-effectiveness trial with cluster randomization by hospital or health system that compares more- versus less-intensive strategies for active surveillance of small pulmonary nodules. The study plans to enroll approximately 35,200 patients with a small pulmonary nodule that is newly detected on chest CT imaging, either incidentally or by screening. Study protocols for more- and less-intensive surveillance were adapted from published guidelines. The primary outcome is the percentage of cancerous nodules that progress beyond American Joint Committee on Cancer seventh edition stage T1a. Secondary outcomes include patient-reported anxiety and emotional distress, nodule-related health care use, radiation exposure, and adherence with the assigned surveillance protocol. Distinctive aspects of the trial include: 1) the pragmatic integration of study procedures into existing clinical workflow; 2) the use of cluster randomization by hospital or health system; 3) the implementation and evaluation of a system-level intervention for protocol-based care; 4) the use of highly efficient, technology-enabled methods to identify and (passively) enroll participants; 5) reliance on data collected as part of routine clinical care, including data from electronic health records and state cancer registries; 6) linkage with state cancer registries for complete ascertainment of the primary study outcome; and 7) intensive engagement with a diverse group of patient and nonpatient stakeholders in the design and execution of the study.


Warfarin therapy does not increase bleeding in patients undergoing heart transplantation.
Historically, warfarin has been discontinued or rapidly reversed with fresh frozen plasma in patients awaiting heart transplantation because of concerns regarding excessive bleeding. Because preoperative warfarin may have effects on bleeding after cardiac operations, we reviewed our experience to determine the risks in patients undergoing heart transplantation while maintained on warfarin. The records of consecutive adult patients undergoing heart transplantation from January 1996 to December 1998 were reviewed. Preoperative and 24-hour postoperative data were obtained, including patient demographics; hematologic laboratory values; medication use; repeat or primary sternotomy data; allogeneic blood product administration; and chest tube drainage. Multivariate linear and logistic regression analyses were performed using these variables to determine risk factors for bleeding after heart transplantation. Ninety adult patients, mean age 50 years, underwent orthotopic heart transplantation during the 36-month period. No relationships existed between preoperative international normalized ratio (INR, mean = 1.83 +/- 0.1, p = 0.84) or postoperative INR (mean = 2.2 +/- 0.9, p = 0.63) and chest tube drainage (mean = 721 +/- 63 mL). Relationships were observed between total blood product administration and preoperative INR (partial r = 0.30, p = 0.01) and postoperative INR (partial r = -0.37, p = 0.002); however, preoperative INR did not correlate (p = 0.29) when perioperative use of fresh frozen plasma was factored as a covariate. Inverse relationships were evident between postoperative INR and total blood product exposures, as well as transfusions of platelets (partial r = -0.26, p = 0.03), fresh frozen plasma (partial r = -0.28, p = 0.02), and red cells (partial r = -0.25, p = 0.04). Although we noted no correlations between INR and chest tube output, inverse relationships were observed with transfusion requirements in the first 24 hours after transplantation. Preoperative warfarin may be safely continued in patients awaiting heart transplantation.


Chromosome 11 abnormalities in Bowen disease of the vulva.
Chromosomal cytogenetic abnormalities are common in tumor cells and are often the basis for more detailed chromosomal mapping of tumor suppressor and oncogenes. Chromosome 11 abnormalities are frequently recognized in various neoplasms. We report a case of Bowen disease (squamous cell carcinoma in situ) of the vulva with an isolated 11p cytogenetic abnormality. A chromosome 11 paint confirmed two copies of chromosome 11 in all analyzed metaphases. An 11p subtelomeric probe confirmed an abnormality of 11p15-->pter indicative of a deletion. Previous studies of invasive vulvar cancers also frequently show 11p cytogenetic abnormalities, but never as an isolated finding. The patient suffered from other diseases that may also be related to this locus. Breakage and p53 studies were normal. It is possible that an 11p abnormality in Bowen's disease is a precursor in the evolution of invasive vulva cancer.


Use of left atrial appendage occlusion among older cardiac surgery patients with preoperative atrial fibrillation: a national cohort study.
Patients with atrial fibrillation (AF) undergoing cardiac surgery are at substantially increased risk for stroke. Increasing evidence has suggested that surgical left atrial appendage occlusion (S-LAAO) may have the potential to substantially mitigate this stroke risk; however, S-LAAO is performed in a minority of patients with AF undergoing cardiac surgery. We sought to identify factors associated with usage of S-LAAO. In a nationally-representative, contemporary cohort (07/2011-06/2012) of older patients undergoing cardiac surgery with preoperative AF (n = 11,404) from the Medicare-linked Society of Thoracic Surgeons Adult Cardiac Surgery Database, we evaluated patient and hospital characteristics associated with S-LAAO use by employing logistic and linear regression models. In this cohort (average age, 76 years; 39% female), 4177 (37%) underwent S-LAAO. Neither S-LAAO nor discharge anticoagulation was used in 25% ("unprotected" patients). The overall propensity for S-LAAO decreased significantly with increasing CHA2DS2-VASc (congestive heart failure; hypertension; age 75 years or older; diabetes mellitus; stroke, transient ischemic attack, or thromboembolism; vascular disease; age 65 to 74 years; sex category (female)) score (ptrend < 0.001). There was substantial variability in S-LAAO use across geographic regions, and S-LAAO was more commonly performed at academic and higher-volume valve surgery centers. Substantial variability in use of S-LAAO exists. In many instances, the procedure is being deferred in the patients that may be poised to benefit the most (i.e., those with increased CHA2DS2-VASc score-defined stroke risk).


Effects of dynorphin1-13 on opiate binding and dopamine and GABA uptake in stroked cat brain.
We previously reported that the opioid peptide dynorphin1-13 improves survival chances in stroked cats. Some evidence also suggests that changes in dopamine and gamma-aminobutyric acid (GABA) uptake may be associated with stroke. In the present study, therefore, we determined binding of the opiate [3H]ethylketocyclazocine (EKC), as well as dopamine and GABA uptake in various brain regions of control, stroked and dynorphin1-13-treated stroked cats. Cats were stroked by middle cerebral artery occlusion. In the EKC binding study, the Kd of the high-affinity site of the occluded cortex was significantly increased, relative to that of both the unoccluded side and control cortex. Dynorphin1-13 treatment reversed this effect, lowering the Kd to control level. In the dopamine uptake study, the Km was decreased and Vmax was increased significantly in unoccluded cortex, compared with that in the occluded cortex or in control cortex. Again, dynorphin1-13 reversed these effects, raising the Km and lowering the Vmax. However, the Km of occluded cortex was also increased so that it became significantly higher than that of control cortex. The Km of unoccluded subcortex in stroked cats treated with dynorphin1-13 was significantly reduced compared with control. In the GABA uptake study, there was no significant change in any parameter. The change in opioid binding observed here and its reversal by dynorphin1-13 are consistent with the notion that the peptide's beneficial effect on stroke is mediated through opiate receptors. Since opioid systems in the brain are known to have association with dopaminergic ones, the change in dopamine uptake could also be the result of an opioid effect.


Hyperphosphatemia-induced hyperparathyroidism in 5/6 nephrectomized rats: development of a new animal model.
We require a stable model to understand the molecular mechanism by which isolated hyperphosphatemia induces hyperparathyroidism secondary to chronic renal failure. The present study established a rat model of hyperphosphatemia-induced secondary hyperparathyroidism in chronic renal failure. Twenty-nine rats with 5/6 nephrectomy (Nx) were divided into three groups and were fed for 10 weeks on a high phosphate diet (1.2% phosphate) starting from three different post-Nx time points. Parathyroid hormone mRNA in parathyroid gland was measured by real-time PCR and parathyroid cell hyperplasia was tested by proliferating cell nuclear antigen (PCNA) assay. The 10 rats fed a high phosphate diet starting from the fourth week post-Nx had isolated hyperphosphatemia and excess synthesis/secretion of parathyroid hormone, and hyperplasia of the parathyroid glands were induced (r = 0.86 - 0.97, P < 0.001), but the levels of serum calcium and 1, 25 (OH)2D3 did not change. A rat model of hyperphosphatemia-induced secondary hyperparathyroidism in chronic renal failure was established by 5/6 Nx and 10 weeks-high phosphate diet starting from the fourth week post-Nx.


Post-mortem findings in familial partial lipodystrophy, Dunnigan variety.
Familial partial lipodystrophy, Dunnigan variety (FPLD), is an autosomal dominant disorder due to missense mutations in the lamin A/C gene and is characterized by gradual loss of subcutaneous fat from the extremities and trunk, fat accumulation in the head, neck and intra-abdominal areas, insulin resistance and its metabolic complications. We studied autopsy findings in two patients with FPLD to determine fat distribution and organ involvement. Patient 1, a 66-year-old woman with the R482Q mutation, had diabetes mellitus, dyslipidaemia, and coronary artery disease and died suddenly. Autopsy confirmed the typical body fat distribution and further revealed excess fat deposition in the subpectoral regions extending to the axillae, in the axillary lymph nodes and in the retroperitoneum. Atherosclerotic vascular disease including old infarcts of the myocardium, temporal lobe and kidneys were noted. Severe amyloidosis of the pancreatic islets and grouped muscle atrophy of the quadriceps and diaphragmatic muscles were present. Patient 2, a 29-year-old woman belonging to a pedigree with the R62G mutation, died of hyperlipidaemia-induced acute pancreatitis. Autopsy of patient 2 revealed extensive pancreatitis, hepatic steatosis and polycystic ovaries. Our study confirms typical body fat distribution and describes new sites of excess fat deposition. Our data show predisposition to atherosclerosis and polycystic ovaries and suggest that pancreatic amyloidosis may underlie development of hyperglycaemia in FPLD patients.


Low-salt water reduces intestinal permeability in atopic patients.
Clinical remission of atopic dermatitis (AD) after intake of a low-salt water has recently been reported. We here investigated the effects of a low-salt water in AD patients with increased intestinal permeability to lactulose. From an initial group of 75 atopic patients, who undertook a treatment in a medical spa center, 12 were included because of abnormal urinary excretion of lactulose (>0.6%), which is absorbed in the enterocytic interspaces, at baseline. The excretion of mannitol with an extraenterocytic absorption was also studied as control. During 18 days, the patients followed a medical spa treatment course, including topical application and oral ingestion of a low-mineral water. Patients were asked not to modify their usual food regimen during the cure. At the end of treatment (day 18), the determination of the excretion of both sugars in urine was repeated. At baseline, the mean urine excretion of lactulose in the study population was 1.21+/-0.08 SEM. At the end of treatment (day 18), the lactulose concentration in urine diminished dramatically by 55% (mean 0.55+/-0.09 SEM, p = 0.0005). Urine mannitol was also found to be reduced over the cure period, although to a lesser extent (30%, p = 0.04). This study indicates that low-mineral water normalizes the intestinal permeability of patients with AD.


Physician peer review: have we gone far enough or too far?
The authors discuss the long history of physician peer review and offer insight on the process, while presenting factors that have lead to increased physician non-peer review. The question at hand--have we gone far enough ... or too far?


Acute kidney injury associated with trimethoprim/sulfamethoxazole.
Trimethoprim/sulfamethoxazole effectively treats community-acquired soft tissue infections and urinary tract infections, both of which occur in patients with risk factors for renal impairment. We systematically studied the adverse renal effects of trimethoprim/sulfamethoxazole in a middle-aged veteran population. We reviewed complete electronic records for all patients who, during a 3 year period, had received ≥6 days of treatment with trimethoprim/sulfamethoxazole and for whom a baseline and follow-up determination of serum creatinine and blood urea nitrogen (BUN) were available. Of 573 patients who met inclusion criteria, 64 (11.2%) had increases in both serum creatinine and BUN that met predetermined criteria for acute kidney injury (AKI): in 33 (5.8%), AKI was judged likely due to trimethoprim/sulfamethoxazole; in 28 (4.9%), possibly due to trimethoprim/sulfamethoxazole; and in 3 (0.52%), unrelated to trimethoprim/sulfamethoxazole. Five additional patients (0.9%) had elevations only in serum creatinine. In nearly all cases likely due to trimethoprim/sulfamethoxazole, AKI resolved promptly after discontinuation of therapy, but one patient required dialysis. Pyuria appeared in only 2 of 37 patients who had urinalyses; eosinophiluria was not observed. In a multivariate model, patients with hypertension and diabetes mellitus had increased risk for renal insufficiency, especially if these conditions were considered poorly controlled. In a middle-aged male inpatient population treated for a minimum of 6 days, AKI is much more common with trimethoprim/sulfamethoxazole therapy than previously reported. Intrinsic renal impairment rather than interstitial nephritis or competition for creatinine clearance appears responsible for the great majority of cases, and neither an effect of dose nor duration was detected in a univariate analysis. Impairment is transient if therapy is discontinued.


Spontaneous pneumothorax: outpatient management with intercostal tube drainage.
In a series of 104 episodes of pneumothorax 75 percent of episodes were managed successfully on an outpatient basis by observation (23.1 percent) or by intercostal tube drainage using a flutter valve (51.9 percent). The patients for whom this treatment was not successful were admitted to hospital; 17 of them (16.3 percent of 104) were treated surgically. Bleb suturing with a stapling device and dry sponge abrasion of the pleura was the operation of choice.


Drugs, the criminal law, and the administration of justice.
Are criminal laws against the sale and use of drugs such as heroin and cocaine helpful in maintaining a liberal community? Answering this question is partly a matter of political philosophy, but the answer also depends on judgments about practical effects. Although it is clear that drug laws tend to worsen the conduct and condition of individuals who continue to use drugs, and strain the institutions of the criminal justice system, it is also plausible that these same laws succeed in reducing overall levels of drug use by suppressing the supply and helping sustain the community norm that disapproves of drug use.


Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches.
Bipolar disorder (type 1) is a serious and chronic psychiatric illness that can be difficult to treat. Many bipolar patients have refractory depressive episodes. Racemic ketamine, a glutamate modulator with prominent dissociate and psychedelic properties, has been demonstrated to have rapid acting antidepressant and anti-obsessional effects which may be useful for treating the symptoms of bipolar depression. Most of the existing research literature on unipolar and bipolar depression has looked at racemic ketamine in the sub-psychedelic dose range given by infusion as a stand-alone treatment (without concurrent psychotherapy). This article expands on the existing research by articulating three different paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The authors use composite clinical vignettes to illustrate different ways of working with ketamine to treat bipolar depression, and discuss a variety of clinical considerations for using ketamine with this population, including route, dose, frequency, chemical mitigators, and adverse events. Note that the conceptual paradigms could be applied to any ketamine treatment, with broad applicability beyond bipolar treatment.


Pattern of brain tissue loss associated with freezing of gait in Parkinson disease.
To investigate whether a specific pattern of gray matter (GM) tissue loss is associated with freezing of gait (FOG) in patients with Parkinson disease (PD). Seventeen patients with PD with FOG (PD-FOG), 20 patients with PD with no FOG (PD-noFOG), and 34 healthy control subjects were recruited. PD-FOG and PD-noFOG patients were matched on an individual basis for age, disease duration, and Hoehn and Yahr stage. Patients were also administered a comprehensive neuropsychological battery focused on executive functions. The extent and distribution of GM atrophy were assessed using voxel-based morphometry. In patients with PD, the severity of FOG correlated with frontal executive deficits. Compared with healthy control subjects, PD-FOG patients showed a distributed pattern of GM atrophy including the dorsolateral prefrontal, medial, and lateral temporal, inferior parietal, and occipital cortices. PD-noFOG patients showed only small regions of GM atrophy in the bilateral frontal and temporal cortex. The left inferior frontal gyrus, left precentral gyrus, and left inferior parietal gyrus were more atrophic in PD-FOG patients relative to both healthy control subjects and PD-noFOG patients. In PD-FOG patients, the severity of FOG was associated with GM volumes of the frontal and parietal cortices bilaterally. GM frontal and parietal atrophy occur in PD-FOG patients. FOG in PD seems to share with executive dysfunction and perception deficits a common pattern of structural damage to the frontal and parietal cortices.


Molecular mechanisms of growth depression in broiler chickens (Gallus Gallus domesticus) mediated by immune stress: a hepatic proteome study.
Immunological stress decreases feed intake, suppresses growth and induces economic losses. However, the underlying molecular mechanism remains unclear. Label-free liquid chromatography and mass spectrometry (LC-MS) proteomics techniques were employed to investigate effects of immune stress on the hepatic proteome changes of Arbor Acres broilers (Gallus Gallus domesticus) challenged with Escherichia coli lipopolysaccharide (LPS). Proteomic analysis indicated that 111 proteins were differentially expressed in the liver of broiler chickens from the immune stress group. Of these, 28 proteins were down-regulated, and 83 proteins were up-regulated in the immune stress group. Enrichment analysis showed that immune stress upregulated the expression of hepatic proteins involved in defense function, amino acid catabolism, ion transport, wound healing, and hormone secretion. Furthermore, immune stress increased valine, leucine and isoleucine degradation pathways. The data suggests that growth depression of broiler chickens induced by immune stress is triggered by hepatic proteome alterations, and provides a new insight into the mechanism by which immune challenge impairs poultry production.


Wrenchnolol derivative optimized for gene activation in cells.
Naturally occurring transcription factors usually have two independent domains, a DNA-binding domain and an activation domain. In designing a synthetic small molecule that mimics a transcription factor, each of the two domains needs to be replaced by small-molecule counterparts. Results of the present study show that derivatives of wrenchnolol, a synthetic molecule that interacts with Sur-2 coactivator, serve as activation modules and stimulate gene transcription in vitro and in cells when tethered to a DNA-binding molecule. Thirteen derivatives of wrenchnolol were chemically synthesized and tested for their ability to activate transcription in vitro and in cells. When tethered to the GAL4 DNA-binding domain, one derivative increased transcription of a GAL4-responsive reporter gene in cells 9-fold. This optimized derivative also induced up to 45% myogenesis of C2C12 cells when tethered to the DNA-binding domain of myogenic transcription factor MyoD. This optimized derivative may serve as a starting point for designing biological tools or components of fully synthetic transcription factors that permit selective up-regulation of genes.


Responses of microbial tolerance to heavy metals along a century-old metal ore pollution gradient in a subarctic birch forest.
Heavy metals are some of the most persistent and potent anthropogenic environmental contaminants. Although heavy metals may compromise microbial communities and soil fertility, it is challenging to causally link microbial responses to heavy metals due to various confounding factors, including correlated soil physicochemistry or nutrient availability. A solution is to investigate whether tolerance to the pollutant has been induced, called Pollution Induced Community Tolerance (PICT). In this study, we investigated soil microbial responses to a century-old gradient of metal ore pollution in an otherwise pristine subarctic birch forest generated by a railway source of iron ore transportation. To do this, we determined microbial biomass, growth, and respiration rates, and bacterial tolerance to Zn and Cu in replicated distance transects (1 m-4 km) perpendicular to the railway. Microbial biomass, growth and respiration rates were stable across the pollution gradient. The microbial community structure could be distinguished between sampled distances, but most of the variation was explained by soil pH differences, and it did not align with distance from the railroad pollution source. Bacterial tolerance to Zn and Cu started from background levels at 4 km distance from the pollution source, and remained at background levels for Cu throughout the gradient. Yet, bacterial tolerance to Zn increased 10-fold 100 m from the railway source. Our results show that the microbial community structure, size and performance remained unaffected by the metal ore exposure, suggesting no impact on ecosystem functioning.


Value of contrast-enhanced ultrasonography in assessing the activity of idiopathic retroperitoneal fibrosis: a prospective study.
We aimed to evaluate changes in the contrast-enhanced ultrasound (CEUS) parameters in patients with idiopathic retroperitoneal fibrosis (RPF) before and after treatment, and to analyse the value of CEUS to assess RPF activity. We performed a prospective study that included patients with idiopathic RPF who were treated for RPF at our hospital from April 2016 to April 2019. All patients underwent CEUS examination and some of them underwent positron emission tomography/computed tomography (PET/CT) examination simultaneously. CEUS parameters included tube wall and peripheral thickness, arterial wall intensity, and lumen intensity. The changes in CEUS parameters before and after treatment were evaluated, and their correlations with the standardised uptake value (SUVmax), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed. Thirty-one active idiopathic RPF patients were enrolled, of whom 11 underwent PET/CT examination before treatment. Tube wall and peripheral thickness (r=0.743, p<0.01) and arterial wall intensity (r=0.702, p<0.05) both correlated significantly with SUVmax. Lumen intensity did not correlate significantly with SUVmax (r=0.544, p=0.084). The correlation coefficients between lesion thickness and ESR levels were 0.508 (p=0.037), between lesion thickness and CRP levels were 0.575 (p=0.016). Arterial wall intensity and lumen intensity were not significantly correlated with ESR or CPR levels. Tube wall and peripheral thickness, arterial wall intensity, decreased significantly after treatment (p=0.001), while the lumen intensity was not significantly changed after treatment. Our findings suggest that CEUS, a radiation-free and repeatable detection method, is effective for assessing idiopathic RPF disease activity.


Gastroesophageal reflux and sclerotherapy strictures.
The development of esophageal stricture is common following endoscopic variceal sclerotherapy (EVS). Gastroesophageal reflux may be at least partly responsible. Twelve randomly selected male patients underwent chronic EVS for the management of bleeding esophageal varices. Six patients developed strictures during or after EVS, six did not. There were no significant differences between stricture and nonstricture patients during 24 hour esophageal pH monitoring. Three of the six stricture patients and four of the six nonstricture patients had an abnormal amount of reflux. Gastroesophageal reflux occurs frequently in patients undergoing EVS, and it is not likely to play a major role in EVS stricture formation.


Development and inter-laboratory validation of analytical methods for glufosinate and its two metabolites in foods of plant origin.
Glufosinate is widely used to control various weeds. Glufosinate and its main metabolites have become the focus of attention because of their high water solubility and persistence in aquatic systems. Quantification of the agrochemical product and its metabolite residues is essential for the safety of agricultural products. In this study, a highly specific, simple method was developed to directly determine glufosinate and its metabolite residues in 21 plant origin foods by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and it was validated on 11 foods in five laboratories. Finally, the repeatability limit, reproducibility limit, and uncertainty of the method were calculated based on these validated data and used to support the more accurate detection results. Four different chromatographic columns were used to analyze three target compounds, and the anionic polar pesticide column showed the optimum separation and peak shape. Composition of the mobile phase, extraction solvent, and the clean-up procedure were optimized. The developed method was validated on 21 plant origin foods. The average recoveries were 74-115% for all matrices. The validation results of five laboratories showed this method had a good repeatability (RSDr < 9.5%) and reproducibility (RSDR < 18.9%). The method validation parameters met the requirements of guidance established by the European Union (EU) and China for pesticide residue analysis. This methodology can be used for a routine monitoring that performs well for glufosinate and its metabolite residues.


Promises and Pitfalls of Anchoring Vignettes in Health Survey Research.
Data harmonization is a topic of growing importance to demographers, who increasingly conduct domestic or international comparative research. Many self-reported survey items cannot be directly compared across demographic groups or countries because these groups differ in how they use subjective response categories. Anchoring vignettes, already appearing in numerous surveys worldwide, promise to overcome this problem. However, many anchoring vignettes have not been formally evaluated for adherence to the key measurement assumptions of vignette equivalence and response consistency. This article tests these assumptions in some of the most widely fielded anchoring vignettes in the world: the health vignettes in the World Health Organization (WHO) Study on Global AGEing and Adult Health (SAGE) and World Health Survey (WHS) (representing 10 countries; n = 52,388), as well as similar vignettes in the Health and Retirement Study (HRS) (n = 4,528). Findings are encouraging regarding adherence to response consistency, but reveal substantial violations of vignette equivalence both cross-nationally and across socioeconomic groups. That is, members of different sociocultural groups appear to interpret vignettes as depicting fundamentally different levels of health. The evaluated anchoring vignettes do not fulfill their promise of providing interpersonally comparable measures of health. Recommendations for improving future implementations of vignettes are discussed.


Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity.
Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children. The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test. After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake. At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow-up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time.


Expression of the stress-related genes for glutathione S-transferase and ascorbate peroxidase in the most-glycinin-deficient soybean cultivar Tousan205 during seed maturation.
Global analysis of gene expression profiles in most-glycinin-deficient cultivar Tousan205, was performed by DNA microarray analysis. It was confirmed that Tousan205 lacks mRNA expression of three glycinin subunit precursor genes, G1 (A1aB1x), G2 (A2B1a), and G5 (A3B4), and lacks G4 (A5A4B3) protein. Most glycinin subunits were deficient in mature seeds of Tousan205. We compared the gene expression of Tousan205 with those of parent cultivar, Tamahomare, which was used for crossbreeding of Tousan205. As a result, Tousan205 exhibited higher expression of some seed maturation proteins, and stress-related genes such as glutathione S-transferase and ascorbate peroxidase. This result indicates the possibility that the decrease of main storage protein, glycinin causes stress in soybean.


Automated detection of focal seizures using subcutaneously implanted electrocardiographic device: A proof-of-concept study.
Phase 2 studies showed that focal seizures could be detected by algorithms using heart rate variability (HRV) in patients with marked autonomic ictal changes. However, wearable surface electrocardiographic (ECG) devices use electrode patches that need to be changed often and may cause skin irritation. We report the first study of automated seizure detection using a subcutaneously implantable cardiac monitor (ICM; Confirm Rx, Abbott). For this proof-of-concept (phase 1) study, we recruited six patients admitted to long-term video-electroencephalographic monitoring. Fifteen-minute epochs of ECG signals were saved for each seizure and for control (nonseizure) epochs in the epilepsy monitoring unit (EMU) and in the patients' home environment (1-8 months). We analyzed the ICM signals offline, using a previously developed HRV algorithm. Thirteen seizures were recorded in the EMU, and 41 seizures were recorded in the home-monitoring period. The algorithm accurately identified 50 of 54 focal seizures (sensitivity = 92.6%, 95% confidence interval [CI] = 85.6%-99.6%). Twelve of the 13 seizures in the EMU were detected (sensitivity = 92.3%, 95% CI = 77.2%-100%), and 38 of the 41 seizures in the out-of-hospital setting were detected (sensitivity = 92.7%, 95% CI = 84.7%-100%). Four false detections were found in the 141 control (nonseizure) epochs (false alarm rate = 2.7/24 h). Our results suggest that automated seizure detection using a long-term, subcutaneous ICM device is feasible and accurate in patients with focal seizures and autonomic ictal changes.


Development of learning and memory in Aplysia. II. Habituation and dishabituation.
The defensive withdrawal reflex of the mantle organs of Aplysia californica exhibits a variety of forms of both nonassociative and associative learning, which can exist in both short- and long-term forms. In addition, the reflex can be readily elicited and quantified as soon as the effector organs (siphon and gill) emerge at their respective developmental stages. Thus, this reflex system provides a useful preparation in which to study the development of learning and memory. In the present series of experiments we investigated the development of 2 forms of nonassociative learning, habituation and dishabituation, in the siphon withdrawal component of the reflex. This reflex response could be examined throughout the juvenile life of the animal (stages 9-12) since the reflex is functionally intact as soon as the siphon emerges in stage 9 (Rankin et al., 1987). We studied the development of habituation in stages 9-12 using tactile stimuli to the siphon delivered at interstimulus intervals (ISIs) of 1, 5, 10, and 30 sec. Habituation of siphon withdrawal was evident as early as juvenile stage 9. However, it existed in an immature form: Significant habituation was produced only with a very short (1 sec) ISI. No significant habituation occurred in response to 5 or 10 sec ISIs. Approximately 4 d later, in stage 10, significant habituation occurred to both 1 and 5 sec ISIs but not to a 10 sec ISI. Finally, approximately 1-2 weeks later, in stage 11, significant habituation occurred to 1, 5, and 10 sec ISIs but not to a 30 sec ISI, whereas stage 12 juveniles and adults (stage 13) readily habituated to a 30 sec ISI. Thus, there was a systematic developmental trend in the ability of the animals to habituate: Progressively older animals were capable of habituation to stimuli presented at progressively longer intervals. The systematic development of habituation was also evident by examining the amount of habituation exhibited to comparable ISIs by animals at different developmental stages. For all 4 ISIs examined, older animals showed significantly greater habituation than younger animals. Thus, our results show that habituation is present as soon as the siphon response system emerges and that it develops progressively throughout the juvenile life of the animal. Whereas habituation was present in the earliest developmental stage we examined (stage 9), dishabituation (in response to tail shock) did not emerge until 4-7 d later, in stage 10.(ABSTRACT TRUNCATED AT 400 WORDS)


An effectiveness study of a culturally enriched school-based CBT anxiety prevention program.
Anxiety disorders are prevalent in the school-aged population and are present across cultural groups. Scant research exists on culturally relevant prevention and intervention programs for mental health problems in the Aboriginal populations. An established cognitive behavioral program, FRIENDS for Life, was enriched to include content that was culturally relevant to Aboriginal students. Students (N = 533), including 192 students of Aboriginal background, participated in the cluster randomized control study. Data were collected three times over 1 year. A series of multilevel models were conducted to examine the effect of the culturally enriched FRIENDS program on anxiety. These analyses revealed that the FRIENDS program did not effectively reduce anxiety for the total sample or for Aboriginal children specifically. However, all students, regardless of intervention condition, Aboriginal status, or gender, reported a consistent decrease in feelings of anxiety over the 6-month study period.


Are HIV epidemics among men who have sex with men emerging in the Middle East and North Africa?: a systematic review and data synthesis.
Men who have sex with men (MSM) bear a disproportionately higher burden of HIV infection than the general population. MSM in the Middle East and North Africa (MENA) are a largely hidden population because of a prevailing stigma towards this type of sexual behavior, thereby limiting the ability to assess infection transmission patterns among them. It is widely perceived that data are virtually nonexistent on MSM and HIV in this region. The objective of this review was to delineate, for the first time, the evidence on the epidemiology of HIV among MSM in MENA. This was a systematic review of all biological, behavioral, and other related data on HIV and MSM in MENA. Sources of data included PubMed (Medline), international organizations' reports and databases, country-level reports and databases including governmental and nongovernmental organization publications, and various other institutional documents. This review showed that onsiderable data are available on MSM and HIV in MENA. While HIV prevalence continues at low levels among different MSM groups, HIV epidemics appear to be emerging in at least few countries, with a prevalence reaching up to 28% among certain MSM groups. By 2008, the contribution of MSM transmission to the total HIV notified cases increased and exceeded 25% in several countries. The high levels of risk behavior (4-14 partners on average in the last six months among different MSM populations) and of biomarkers of risks (such as herpes simplex virus type 2 at 3%-54%), the overall low rate of consistent condom use (generally below 25%), the relative frequency of male sex work (20%-76%), and the substantial overlap with heterosexual risk behavior and injecting drug use suggest potential for further spread. This systematic review and data synthesis indicate that HIV epidemics appear to be emerging among MSM in at least a few MENA countries and could already be in a concentrated state among several MSM groups. There is an urgent need to expand HIV surveillance and access to HIV testing, prevention, and treatment services in a rapidly narrowing window of opportunity to prevent the worst of HIV transmission among MSM in the Middle East and North Africa. Please see later in the article for the Editors' Summary.


[Coping matters in psychosis. Coping and the need for professional care in cases of subclinical psychosis].
Changes in the amount of care required in cases of subclinical psychosis are examined in relation to (1) the level of patient distress and (2) the level of dysfunctional coping. The Netherlands Mental Health Survey and Incidence Study (nemesis) is a longitudinal investigation into the occurrence of psychopathology in the general population. In the first two measurements of the nemesis study 4722 individuals had not been diagnosed as having a psychotic disorder according to dsm-iii-r. In the third measurement, 83 of those 4.722 were found to have had at least one subclinical psychotic experience. A panel of experts decided on the level of care that patients required. results Of the various types of psychotic experiences it was only 'passivity phenomena', hearing voices' and 'non-verbal hallucinations' which were associated with the need for care. These associations were largely explained by distress associated with the psychotic experience, with the exception of hearing voices. There were qualitative differences between the various types of coping: in particular, 'symptomatic coping' with psychotic experiences was associated with less perceived control over the psychotic experience (or = 0,79; 95% CI (confidence interval) 0,63-0,98) and an increased probability of the need for care (or = 6,07; 95% CI 1,95-18,95). Various types of psychotic experiences require different levels of care. The need for care can arise when psychotic experiences begin to cause patient distress and/or dysfunctional coping. These factors may well play a role in turning an individual with subclinical psychotic experiences into a psychiatric patient.


Obesity Severity, Dietary Behaviors, and Lifestyle Risks Vary by Race/Ethnicity and Age in a Northern California Cohort of Children with Obesity.
Identification of modifiable behaviors is important for pediatric weight management and obesity prevention programs. This study examined obesogenic behaviors in children with obesity in a Northern California obesity intervention program using data from a parent/teen-completed intake questionnaire covering dietary and lifestyle behaviors (frequency of breakfast, family meals, unhealthy snacking and beverages, fruit/vegetable intake, sleep, screen time, and exercise). Among 7956 children with BMI ≥ 95th percentile, 45.5% were females and 14.2% were 3-5, 44.2% were 6-11, and 41.6% were 12-17 years old. One-quarter (24.9%) were non-Hispanic white, 11.3% were black, 43.5% were Hispanic, and 12.0% were Asian/Pacific Islander. Severe obesity was prevalent (37.4%), especially among blacks, Hispanics, and older children, and was associated with less frequent breakfast and exercise and excess screen time, and in young children it was associated with consumption of sweetened beverages or juice. Unhealthy dietary behaviors, screen time, limited exercise, and sleep were more prevalent in older children and in selected black, Hispanic, and Asian subgroups, where consumption of sweetened beverages or juice was especially high. Overall, obesity severity and obesogenic behaviors increased with age and varied by gender and race/ethnicity. We identified several key prevalent modifiable behaviors that can be targeted by healthcare professionals to reduce obesity when counseling children with obesity and their parents.


MOF@PEDOT Composite Films for Impedimetric Pesticide Sensors.
Due to its deleterious effects on health, development of new methods for detection and removal of pesticide residues in primary and derived agricultural products is a research topic of great importance. Among them, imazalil (IMZ) is a widely used post-harvest fungicide with good performances in general, and is particularly applied to prevent green mold in citrus fruits. In this work, a composite film for the impedimetric sensing of IMZ built from metal-organic framework nanocrystallites homogeneously distributed on a conductive poly(3,4-ethylene dioxythiophene) (PEDOT) layer is presented. The as-synthetized thin films are produced via spin-coating over poly(ethylene terephtalate (PET) substrate following a straightforward, cost-effective, single-step procedure. By means of impedance spectroscopy, electric transport properties of the films are studied, and high sensitivity towards IMZ concentration in the range of 15 ppb to 1 ppm is demonstrated (featuring 1.6 and 4.2 ppb limit of detection, when using signal modulus and phase, respectively). The sensing platform hereby presented could be used for the construction of portable, miniaturized, and ultrasensitive devices, suitable for pesticide detection in food, wastewater effluents, or the assessment of drinking-water quality.


Observational study of azithromycin in hospitalized patients with COVID-19.
The rapid spread of the disease caused by the novel SARS-CoV-2 virus has led to the use of multiple therapeutic agents whose efficacy has not been previously demonstrated. The objective of this study was to analyze whether there is an association between the use of azithromycin and the evolution of the pulmonary disease or the time to discharge, in patients hospitalized with COVID-19. This was an observational study on a cohort of 418 patients admitted to three regional hospitals in Catalonia, Spain. As primary outcomes, we studied the evolution of SAFI ratio (oxygen saturation/fraction of inspired oxygen) in the first 48 hours of treatment and the time to discharge. The results were compared between patients treated and untreated with the study drug through subcohort analyses matched for multiple clinical and prognostic factors, as well as through analysis of non-matched subcohorts, using Cox multivariate models adjusted for prognostic factors. There were 239 patients treated with azithromycin. Of these, 29 patients treated with azithromycin could be matched with an equivalent number of control patients. In the analysis of these matched subcohorts, SAFI at 48h had no significant changes associated to the use of azithromycin, though azithromycin treatment was associated with a longer time to discharge (10.0 days vs 6.7 days; log rank: p = 0.039). However, in the unmatched cohorts, the increased hospital stay associated to azithromycin use, was no significant after adjustment using Multivariate Cox regression models: hazard ratio 1.45 (IC95%: 0.88-2.41; p = 0.150). This study is limited by its small sample size and its observational nature; despite the strong pairing of the matched subcohorts and the adjustment of the Cox regression for multiple factors, the results may be affected by residual confusion. We did not find a clinical benefit associated with the use of azithromycin, in terms of lung function 48 hours after treatment or length of hospital stay.


Correlation of immediate skin test responses to antigens introduced by multi-test and intracutaneous routes.
The Multi-Test applicator is a disposable plastic device for the simultaneous prick-puncture administration of different antigens at eight sites, in a rapid, relatively painless and reproducible manner. To determine its utility in immediate or reaginic skin testing, it was compared with the intradermal technique in children and adults. Skin test responses to glycerinated inhalant antigens, 1:20 or 1:10 W/V, administered by Multi-Test were comparable to those obtained from the same antigens applied intradermally in aqueous dilutions of 1:1,000 or 1:1,500 W/V.


Glomerular basement membrane anionic charge site changes early in aminonucleoside nephrosis.
Alterations of glomerular basement membrane (GBM) anionic (charge sites, CSs) in the development of proteinuria in a model of idiopathic nephrotic syndrome in man (puromycin aminonucleoside nephrotic syndrome [PAN] in the rat) were assessed quantitatively and sequentially early after disease induction. GBM CSs (known to consist mainly of heparan sulfate-rich proteoglycans) were stained in vivo and, in a separate group of animals by an in vitro method, with the cationic marker polyethyleneimine (PEI) studied by electron microscopic examination. Four hours after administration of PAN, there was a significant decrease in GBM lamina rara externa CSs: 18 +/- 0.7 versus 22.0 +/- 2.2 per 1000 nm GBM in controls by PEI injection and 17.2 +/- 2.7 versus 21.1 +/- 1.6 per 1000 nm GBM in controls by PEI in vitro staining. This CS alteration coincided with changes in glomerular epithelial cell morphologic characteristics (increased cytoplasmic organelles and rough endoplasmic reticulum) and preceded the detection of foot process broadening (at 24 hours) and increased urinary albuminuria (suggested at 12-24 hours, statistically significant at 36-48 hours). These results suggest that GBM CS-heparan sulfate proteoglycan alterations consisting of either decreased number and/or less anionic charge occur early in PAN and support a role for glomerular epithelial cell maintenance of GBM CS for normal glomerular function.


A virtual source model for Monte Carlo modeling of arbitrary intensity distributions.
A photon virtual source model was developed for simulating arbitrary, external beam, intensity distributions using the Monte Carlo method. The source model consists of a photon fluence grid composed of a matrix of square elements, located 25-cm downstream from the linear accelerator target. Each particle originating from the fluence map is characterized by the seven phase space parameters, position (x, y, z), direction (u, v, w), and energy. The map was reconstructed from fluence and energy spectra acquired by modeling components of the linear accelerator treatment head using the Monte Carlo code MCNP4B. The effect of contaminant electrons is accounted for by the use of a sub-source derived from a phase-space simulation of a 25-MV linac treatment head using the code BEAM. The BEAM sub-source was incorporated into the MCNP4B phase-space model and is sampled using a field-size dependent sampling ratio. A Gaussian blurring kernel is convolved with the photon fluence map to account for the finite focal spot size and scattering effects from structures such as the flattening filter and MLC leaves. Depth dose and profile source calculations for 6-MV and 25-MV photon beams, for 5 x 5 cm2, 10 x 10 cm2, and 15 x 15 cm2 field sizes, are in good agreement with measurement and are well within acceptability criteria suggested by the AAPM Task Group Report No. 53. Irregular field calculations compared with film measurement and with a 3-D pencil beam algorithm show that the source model is capable of accurately simulating arbitrary MLC fields.


Prefrontal cortical dysfunction in abstinent cocaine abusers.
The anterior cingulate cortex (ACC) and lateral prefrontal (LPFC) cortex are brain regions important to executive cognitive functions (ECF). We determined ACC and LPFC function in 23-day abstinent cocaine abusers using positron emission tomography (PET H(2)(15)O) during performance of a modified version of the Stroop Task. Cocaine abusers showed less activation than non-drug-using comparison subjects in the left ACC and the right LPFC and greater activation in the right ACC. Average amount of cocaine used per week was negatively correlated with activity in the rostral ACC and right LPFC. Disruption of ECF in substance abusers could interfere with attempts to stop drug use and undermine treatment. Since impairment in ECF may be a common feature of various neuropsychiatric disorders, these findings have applicability beyond the neurobiology of addiction.


Flavor Profile of Chinese Liquor Is Altered by Interactions of Intrinsic and Extrinsic Microbes.
The flavor profile of Chinese liquor is the result of the metabolic activity of its microbial community. Given the importance of the microbial interaction, a novel way to control the liquor's flavor is by regulating the composition of the community. In this study, we efficiently improved the liquor's flavor by perturbing the intrinsic microbial metabolism with extrinsic microbes. We first constructed a basic microbial group (intrinsic) containing Saccharomyces cerevisiae, Wickerhamomyces anomalus, and Issatchenkia orientalis and added special flavor producers (extrinsic), Saccharomyces uvarum and Saccharomyces servazzii, to this intrinsic group. Upon the addition of the extrinsic microbes, the maximum specific growth rates of S. cerevisiae and I. orientalis increased from 6.19 to 43.28/day and from 1.15 to 14.32/day, respectively, but that of W. anomalus changed from 1.00 to 0.96/day. In addition, most volatile compounds known to be produced by the extrinsic strains were not produced. However, more esters, alcohols, and acids were produced by S. cerevisiae and I. orientalis. Six compounds were significantly different by random forest analysis after perturbation. Among them, increases in ethyl hexanoate, isobutanol, and 3-methylbutyric acid were correlated with S. cerevisiae and I. orientalis, and a decrease in geranyl acetone was correlated with W. anomalus. Variations in ethyl acetate and 2-phenylethanol might be due to the varied activity of W. anomalus and S. cerevisiae. This work showed the effect of the interaction between the intrinsic and extrinsic microbes on liquor flavor, which would be beneficial for improving the quality of Chinese liquor.


Radical surgery for gastric cancer. A review of the Japanese experience.
Overall results after operations for gastric cancer in Japan are far superior to results obtained in the US and Europe. We have reviewed the Japanese literature in an effort to determine what factors explain this difference. It appears that the survival differences are due mainly to a greater frequency of early gastric cancer in Japan; meticulous histopathologic evaluation of the surgical specimens, resulting in more accurate pathologic staging; and the presumed benefit of extended nodal dissection when it extends outside of the level of node-positive disease. Although patients with both apparent and confirmed direct adjacent organ invasion can be helped by resection of those organs, extended resections of uninvolved pancreas and spleen do not improve rate of survival beyond the benefit of improved nodal dissection. Overall, there would appear to be justification for reexamining extended nodal dissection for gastric cancer in the US. Opportunities for a meaningful national study are significant.


Probing the cytoadherence of malaria infected red blood cells under flow.
Malaria is one of the most widespread and deadly human parasitic diseases caused by the Plasmodium (P.) species with the P. falciparum being the most deadly. The parasites are capable of invading red blood cells (RBCs) during infection. At the late stage of parasites' development, the parasites export proteins to the infected RBCs (iRBC) membrane and bind to receptors of surface proteins on the endothelial cells that line microvasculature walls. Resulting adhesion of iRBCs to microvasculature is one of the main sources of most complications during malaria infection. Therefore, it is important to develop a versatile and simple experimental method to quantitatively investigate iRBCs cytoadhesion and binding kinetics. Here, we developed an advanced flow based adhesion assay to demonstrate that iRBC's adhesion to endothelial CD36 receptor protein coated channels is a bistable process possessing a hysteresis loop. This finding confirms a recently developed model of cell adhesion which we used to fit our experimental data. We measured the contact area of iRBC under shear flow at different stages of infection using Total Internal Reflection Fluorescence (TIRF), and also adhesion receptor and ligand binding kinetics using Atomic Force Microscopy (AFM). With these parameters, we reproduced in our model the experimentally observed changes in adhesion properties of iRBCs accompanying parasite maturation and investigated the main mechanisms responsible for these changes, which are the contact area during the shear flow as well as the rupture area size.


Molecular reordering processes on ice (0001) surfaces from long timescale simulations.
We report results of long timescale adaptive kinetic Monte Carlo simulations aimed at identifying possible molecular reordering processes on both proton-disordered and ordered (Fletcher) basal plane (0001) surfaces of hexagonal ice. The simulations are based on a force field for flexible molecules and span a time interval of up to 50 μs at a temperature of 100 K, which represents a lower bound to the temperature range of earth's atmosphere. Additional calculations using both density functional theory and an ab initio based polarizable potential function are performed to test and refine the force field predictions. Several distinct processes are found to occur readily even at this low temperature, including concerted reorientation (flipping) of neighboring surface molecules, which changes the pattern of dangling H-atoms, and the formation of interstitial defects by the downwards motion of upper-bilayer molecules. On the proton-disordered surface, one major surface roughening process is observed that significantly disrupts the crystalline structure. Despite much longer simulation time, such roughening processes are not observed on the highly ordered Fletcher surface which is energetically more stable because of smaller repulsive interaction between neighboring dangling H-atoms. However, a more localized process takes place on the Fletcher surface involving a surface molecule transiently leaving its lattice site. The flipping process provides a facile pathway of increasing proton-order and stabilizing the surface, supporting a predominantly Fletcher-like ordering of low-temperature ice surfaces. Our simulations also show that eventual proton-disordered patches on the surface may induce significant local reconstructions. Further, a subset of the molecules on the Fletcher surface are susceptible to forming interstitial defects which might provide active sites for various chemical reactions in the atmosphere.


Analysis of the effects of hydroquinone and arbutin on the differentiation of melanocytes.
Hydroquinone (HQ) is a chemical compound that inhibits the functions of melanocytes and has long been known for its skin-whitening effect. According to previous studies, the Tyrosinase (Tyr) activity inhibitory effect and melanocyte-specific cell toxicity are known depigmenting mechanisms; however, details of the underlying mechanisms are unknown. Arbutin (Arb) is also known for its Tyr activity inhibitory effect and is commonly used as a skin-whitening agent. However, the detailed depigmenting mechanism of Arb is also not yet fully understood. Few studies have attempted to elucidate the effects of HQ and Arb on undifferentiated melanocytes. In this study, we examined the effects of HQ and Arb throughout each stage of differentiation of melanocytes using a mouse embryonic stem cell (ESC) culture system to induce melanocytes. The results showed that HQ in particular downregulated the early stage of differentiation, in which neural crest cells were generated, and the late stage of differentiation, in which melanogenesis became active. On the other hand, Arb had no effect on the differentiation of melanocytes, and only suppressed melanogenesis by specifically suppressing elevations in Tyr expression in the late stage of differentiation.


Recent Advances in Investigation, Prevention, and Management of Healthcare-Associated Infections (HAIs): Resistant Multidrug Strain Colonization and Its Risk Factors in an Intensive Care Unit of a University Hospital.
Active screening for resistant multidrug strain carriers remains an important component of infection control policy in any healthcare setting indifferent of financial and logistical costs. The objective of our study was to determine the spectrum of bacterial colonization individually among intensive care unit patients. A retrospective observational study was performed in the Intensive Care Unit of Emergency Clinical County Hospital of Oradea during 2017. Medical records of the patients were used for evaluation of source of ICU admission, previous antibiotic therapy, comorbidities, and length of hospital stay. Nasal and groin swabs for MRSA detection and rectal swabs for ESBL, VRE, and CRE detection were collected upon ICU admission of all patients in the first 24 hours and after 7 days. Swab samples were processed for isolation and identification of these resistant multidrug strains. Bacterial colonization on admission was detected in a quarter of patients included in the study. Carbapenemase-producing bacteria were the most common colonizers (21.16%). On admission, 12.06% of patients have been colonized by ESBL-producing members of the family Enterobacterales. Risk factors for colonization on admission to the ICU were chronic liver diseases and chronic renal failure for ESBL infection and chronic liver disease for CRE in male patients. Evaluation of Carmeli's score for male patients showed association only with CRE colonization. Chronic renal failure was found as risk factor for ESBL colonization in female patients. The prevalence of MRSA was 5.23% and less than 1% for VRE. There was no association between any risk factors studied and the presence of S. aureus or VRE upon admission. The 7-day ICU stay also proved to be an increased risk for ESBL and CRE infection.


[THE AVERAGE DURATION OF TREATMENT OF THE INJURED WITH DIFFERENT FORMS OF ACUTE INTOXICATIONS OF CHEMICAL ETIOLOGY].
The article presents materials relate to analysis of average duration of the injured of Omsk under different forms of acute chemical intoxications during 2001-2013. It was established that during analyzed period as a result of implementation of new organizational technologies occurred reliable. decreasing of duration of treatment of patients with light, medium and severe forms of acute chemical intoxications. Under severe complicated forms with lethal outcome no reliable dynamics of average duration of treatment of patients were established.


Assessment of complement clauses: a comparison between elicitation tasks and language sample data.
The aim of this study was to determine whether data from specifically designed elicitation tasks and commonly-used language sampling techniques provided the same information about children's production of complement clauses. It was predicted that elicitation tasks would yield more examples of complement clauses and children would use a wider range of verbs to form complement clauses in elicitation tasks than in language samples. A group of 20 pre-school children aged between 3;11-5;3 years were investigated. Each child completed two elicitation tasks, prompting the production of two of the major forms of complement clauses. A language sample of 100 utterances was also collected from each child. The results demonstrated that the two methods of data collection do not provide the same information about children's production of complement clauses. Significantly more examples of both types of complement clauses investigated were produced in the elicitation tasks. Similarly, children used a greater range of verbs in the elicitation tasks. Thus, language sample data under-estimate pre-school children's competency with complement clauses. Accurate and efficient methods of assessment of children's language structures are vital for speech-language pathologists to base their management decisions on. Elicitation tasks offer a viable alternative to language sampling.


Earthing: health implications of reconnecting the human body to the Earth's surface electrons.
Environmental medicine generally addresses environmental factors with a negative impact on human health. However, emerging scientific research has revealed a surprisingly positive and overlooked environmental factor on health: direct physical contact with the vast supply of electrons on the surface of the Earth. Modern lifestyle separates humans from such contact. The research suggests that this disconnect may be a major contributor to physiological dysfunction and unwellness. Reconnection with the Earth's electrons has been found to promote intriguing physiological changes and subjective reports of well-being. Earthing (or grounding) refers to the discovery of benefits-including better sleep and reduced pain-from walking barefoot outside or sitting, working, or sleeping indoors connected to conductive systems that transfer the Earth's electrons from the ground into the body. This paper reviews the earthing research and the potential of earthing as a simple and easily accessed global modality of significant clinical importance.


Lichen sclerosus et atrophicus in children.
The symptoms, findings, associated conditions, and treatment of lichen sclerosus et atrophicus were studied in 10 girls and one boy. Lichen sclerosus et atrophicus is a benign but chronic condition of the anogenital area of girls and, less frequently, of boys. The characteristic lesions are hypo-pigmented plaques in a figure-of-8 pattern surrounding the vulva and anus and often involving the natal cleft. The affected hypopigmented skin is sharply demarcated from the normal skin. Hemorrhagic, bullous lesions are uncommon. Fissures and ulcers are seen on the labia, between the labia, and on the perineum, anus, and natal cleft in many children and on the glans penis in boys. Lichen sclerosus et atrophicus causes painful defecation and anal and vulval bleeding. In two patients, one girl and one boy, anal stenosis due to lichen sclerosus et atrophicus and laxative treatment developed. Lichen sclerosus et atrophicus mimics sexual abuse and has led to false accusation and investigations. The anogenital lesions cleared in three patients at the ages of 9, 11, and 12 years, but lesions can persist into adulthood.


Non-metastatic Ewing's sarcoma: results in 98 patients treated with neoadjuvant chemotherapy.
From June 1983 to December 1987, 98 patients with non-metastatic Ewing's sarcoma of bone were treated by a protocol of neoadjuvant chemotherapy consisting of two months of preoperative chemotherapy with vincristine, adriamycin, and cyclophosphamide followed by local treatment and one year of chemotherapy aimed at preventing recurrence using the same drugs plus dactinomycin. Local treatment consisted of surgery in 39 cases (40%), radiation in 34 (34%), and both surgery and radiation in 25 (26%). After an average follow-up of five years, 51 patients (52%) had remained continuously disease-free (CDF), 46 had developed metastasis, of which 20 with local recurrence, and one had developed a radioinduced sarcoma. The site of the tumor (61% of patients with Ewing's sarcoma of the extremities were CDF vs. 35% with tumor of the pelvis) and the kind of local treatment (61% of patients who underwent surgery with or without radiation therapy were CDF vs. 35% of patients treated with radiation therapy alone) were important prognostic factors. These results are similar to those obtained in 59 patients treated from 1979 to 1982 (average follow-up, 10 years) using the same drugs administered according to adjuvant chemotherapy procedure as well as those reported in the only other large study on this subject in the literature (the multi-institution German study CESS-81). The authors conclude that even though neoadjuvant chemotherapy makes surgery possible and easier in Ewing's sarcoma, it does not significantly increase survival when compared to traditional adjuvant treatment.


Assessment of the European Society of Cardiology 0-Hour/1-Hour Algorithm to Rule-Out and Rule-In Acute Myocardial Infarction.
The new European Society of Cardiology guidelines to rule-in and rule-out acute myocardial infarction (AMI) in the emergency department include a rapid assessment algorithm based on high-sensitivity cardiac troponin and sampling at 0 and 1 hour. Emergency department physicians require high sensitivity to confidently rule-out AMI, whereas cardiologists aim to minimize false-positive results. High-sensitivity troponin I and T assays were used to measure troponin concentrations in patients presenting with chest-pain symptoms and being investigated for possible acute coronary syndrome at hospitals in New Zealand, Australia, and Canada. AMI outcomes were independently adjudicated by at least 2 physicians. The European Society of Cardiology algorithm performance with each assay was assessed by the sensitivity and proportion with AMI ruled out and the positive predictive value and proportion ruled-in. There were 2222 patients with serial high-sensitivity troponin T and high-sensitivity troponin I measurements. The high-sensitivity troponin T algorithm ruled out 1425 (64.1%) with a sensitivity of 97.1% (95% confidence interval [CI], 94.0%-98.8%) and ruled-in 292 (13.1%) with a positive predictive value of 63.4% (95% CI, 57.5%-68.9%).The high-sensitivity troponin I algorithm ruled out 1205 (54.2%) with a sensitivity of 98.8% (95% CI, 96.4%-99.7%)) and ruled-in 310 (14.0%) with a positive predictive value of 68.1% (95% CI, 62.6%-73.2%). The sensitivity of the European Society of Cardiology rapid assessment 0-/1-hour algorithm to rule-out AMI with high-sensitivity troponin may be insufficient for some emergency department physicians to confidently send patients home. These algorithms may prove useful to identify patients requiring expedited management. However, the positive predictive value was modest for both algorithms.


Importance of Anthropometric Measurements to Determine Cardiometabolic Diseases in Obstructive Sleep Apnea Syndrome.
Obesity is considered a major risk factor for obstructive sleep apnea syndrome (OSAS). This study aimed to examine the correlation between anthropometric measurements, which have been recently defined and are indicative of abdominal obesity and cardiometabolic diseases, OSAS severity, and polysomnography (PSG) parameters in patients with OSAS. This retrospective cohort study included patients who underwent all-night polysomnography with a prediagnosis of OSAS. These patients were categorized as having mild (5-15), moderate (15-30), and severe (>30) OSAS according to the apnea-hypopnea index (AHI). The anthropometric measurements used in the study consisted of waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), (waist/hip)-to-height ratio (WHHR), a body shape index (ABSI), body adiposity index (BAI), abdominal volume index (AVI), and conicity index (CI). A total of 410 individuals were enrolled in the study (31 control subjects and 129 with mild, 101 with moderate, and 149 with severe OSAS). A significant difference was observed between groups in terms of all anthropometric measurements (p<0.05). The difference between the groups was significant in terms of diabetes mellitus, hypertension, and cardiovascular disease (p<0.05). There was a significant correlation between each of the anthropometric measurements and the PSG parameters. In the receiver operating characteristic analysis, cutoff values that predicted severe OSAS were ABSI>0.08, BAI>28.29, AVI>25.54, and CI>1.37. Multiple regression analyses demonstrated that age, sex, and AVI were independent predictors that determine OSAS presence. Anthropometric parameters that are indicators of abdominal obesity were found to be robustly correlated with cardiometabolic diseases and the severity of OSAS.


Relation between coronary artery stenosis assessed by visual, caliper, and computer methods and exercise capacity in patients with single-vessel coronary artery disease. The Veterans Affairs ACME Investigators.
Practitioners often assume a close relation between angiographic coronary artery stenosis and patient functional capacity. To test this unproven hypothesis, we analyzed the relation between coronary artery stenosis measured by different methods and maximal treadmill exercise tolerance in patients with single-vessel disease before and after intervention by percutaneous transluminal coronary angioplasty (PTCA). Coronary angiography and maximal exercise testing off anti-ischemic medication were performed before random assignment of 227 patients with single-vessel coronary artery disease to PTCA or drug therapy. Six months later, angiography and exercise testing were repeated with patients assigned to PTCA off anti-ischemic therapy so that the altered coronary stenosis was the only consistent variable. Patients assigned to drug therapy were exercised on drug therapy. Coronary stenosis was assessed visually by the local investigator and quantitatively by blinded caliper and computer methods in central laboratories. Variabilities of caliper and computer measurements were established in a subset read twice. Visually estimated stenosis > or = 90% at baseline was associated with shorter exercise duration (7.9 versus 9.2 minutes, P < .04). Similar segregation at baseline was not observed with caliper or computer methods. Regardless of the method of measurement used, correlation between changes of lesion severity and exercise duration from baseline to follow-up was poor. Patients were angiographically classified as "better," "unchanged," or "worse" if follow-up stenosis was below, within, or above 2 SD of mean technical variability from baseline (+/- 18.8%, caliper, +/- 14.6%, computer). Exercise duration for PTCA patients improved among those with better lesions (+2.4 minutes, n = 50, P = .001) but also among those with unchanged lesions (+1.9 minutes, n = 41, P < or = .001). Unchanged medically treated patients improved less (+0.5 minutes, n = 86, P = .04). Results were similar when patients were angiographically classified by minimum lumen diameter. Handheld calipers and quantitative coronary angiography are equivalent techniques for making anatomic measurements. Neither method identified patients having reduced exercise capacity at baseline as well as visual estimation. The relation between changes of coronary stenosis and exercise duration is highly variable, at least in part because of the insensitivity of angiographic methods for detecting small but potentially important changes. Minimal anatomic improvement 6 months after PTCA does not preclude a good functional outcome. Contrary to common belief, angiographic stenosis does not correlate well with functional capacity, even in patients with single-vessel disease.


Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir.
Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagen. Here we show that favipiravir (T-705) is a potent mutagenic agent for hepatitis C virus (HCV) during its replication in human hepatoma cells. T-705 leads to an excess of G → A and C → U transitions in the mutant spectrum of preextinction HCV populations. Infectivity decreased significantly in the presence of concentrations of T-705 which are 2- to 8-fold lower than its cytotoxic concentration 50 (CC50). Passaging the virus five times in the presence of 400 μM T-705 resulted in virus extinction. Since T-705 has undergone advanced clinical trials for approval for human use, the results open a new approach based on lethal mutagenesis to treat hepatitis C virus infections. If proven effective for HCV in vivo, this new anti-HCV agent may be useful in patient groups that fail current therapeutic regimens.


Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States.
Outcomes for patients with metastatic bladder cancer (mBC) are generally poor and progressively worse following first-line (1L) chemotherapy. To evaluate treatment patterns, survival outcomes, and characteristics of a large, real-world US population of elderly patients with advanced mBC receiving 1L and second-line (2L) treatment retrospectively. We identified patients with advanced mBC (aged ≥66 years)-newly diagnosed between January 1, 2004, and December 31, 2011-in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program-Medicare linked database and assessed their palliative systemic chemotherapy treatments and survival outcomes. Of 1703 eligible patients, 42% received 1L chemotherapy; 1L-treated patients tended to be younger and healthier than nontreated patients. Only 27% of 1L-treated patients received cisplatin-based chemotherapy, most commonly cisplatin-gemcitabine. Cisplatin-treated patients were younger and had fewer comorbidities than non-cisplatin-treated patients. Thirty-five percent of 1L-treated patients subsequently received 2L chemotherapy. Patients received a variety of 2L agents as combination chemotherapy (52%) or single-agent chemotherapy (39%). Median overall survival durations in 1L-treated and 2L-treated patients were 8.5 and 7.9 months, respectively. Results from this retrospective SEER-Medicare database analysis underscore the historical inadequacies of 1L and 2L treatments in elderly patients with advanced mBC. Few patients were treated with 1L chemotherapy, a minority of whom received 1L cisplatin-based chemotherapy, and even fewer received 2L chemotherapy. These findings highlight the disconnect between 1L treatment in clinical trials and treatment in the real-world setting and the lack of standard approaches to 2L treatment in the United States.


The diagnostic value of the serum irisin level in patients with acute pericarditis and acute myopericarditis.
This preliminary study aims to examine a change in the blood levels of irisin in patients with acute pericarditis (AP) and acute myopericarditis (AMP) and examine the diagnostic value of the serum irisin level in AP and AMP. 10 patients, who applied to the emergency service and cardiology clinic with chest pain and who were diagnosed with AP and 5 patients, who were diagnosed with AMP as a result of routine examinations, were included in the study. The basal laboratory parameters, echocardiography findings and serum irisin levels of the patients and during check one month later were examined. While the basal irisin levels were found to be significantly low in the AMP group and high during the check (6.6 ± 1.58, 8.19 ± 1.43, respectively), no statistically significant difference was determined (p = 0.23). It was observed that the basal and control irisin levels did not vary significantly in the AP group (8.03 ± 1.6, 8.19 ± 1.43, respectively) (p = 0.84). In this preliminary study, the basal irisin levels were found to be significantly low in the AMP group, while there was no statistically significant difference between the basal irisin levels and control irisin levels in the AP and AMP groups (Tab. 5, Ref. 17).


Quality of reporting randomized controlled trials (RCTs) in diabetes in Iran; a systematic review.
To determine the quality of randomized controlled clinical trial (RCT) reports in diabetes research in Iran. Systematized review. We included RCTs conducted on diabetes mellitus in Iran. Animal studies, educational interventions, and non-randomized trials were excluded. We excluded duplicated publications reporting the same groups of participants and intervention. Two independent reviewers identify all eligible articles specifically designed data extraction form. We searched through international databases; Scopus, ProQuest, EBSCO, Science Direct, Web of Science, Cochrane Library, PubMed; and national databases (In Persian language) such as Magiran, Scientific Information Database (SID) and IranMedex from January 1995 to January of 2013 Two investigators assessed the quality of reporting by CONSORT 2010 (Consolidated Standards of Reporting Trials) checklist statemen.t,. Discrepancies were resolved by third reviewer consulting. One hundred and eight five (185) studies were included and appraised. Half of them (55.7 %) were published in Iranian journals. Most (89.7 %) were parallel RCTs, and being performed on type2 diabetic patients (77.8 %). Less than half of the CONSORT items (43.2 %) were reported in studies, totally. The reporting of randomization and blinding were poor. A few studies 15.1 % mentioned the method of random sequence generation and strategy of allocation concealment. And only 34.8 % of trials report how blinding was applied. The findings of this study show that the quality of RCTs conducted in Iran in diabetes research seems suboptimal and the reporting is also incomplete however an increasing trend of improvement can be seen over time. Therefore, it is suggested Iranian researchers pay much more attention to design and methodological quality in conducting and reporting of diabetes RCTs.