How accurate is multiparametric MR imaging in evaluation of prostate cancer volume?
To assess the factors influencing multiparametric (MP) magnetic resonance (MR) imaging accuracy in estimating prostate cancer histologic volume (Vh). A prospective database of 202 patients who underwent MP MR imaging before radical prostatectomy was retrospectively used. Institutional review board approval and informed consent were obtained. Two independent radiologists delineated areas suspicious for cancer on images (T2-weighted, diffusion-weighted, dynamic contrast material-enhanced [DCE] pulse sequences) and scored their degree of suspicion of malignancy by using a five-level Likert score. One pathologist delineated cancers on whole-mount prostatectomy sections and calculated their volume by using digitized planimetry. Volumes of MR true-positive lesions were measured on T2-weighted images (VT2), on ADC maps (VADC), and on DCE images [VDCE]). VT2, VADC, VDCE and the greatest volume determined on images from any of the individual MR pulse sequences (Vmax) were compared with Vh (Bland-Altman analysis). Factors influencing MP MR imaging accuracy, or A, calculated as A = Vmax/Vh, were evaluated using generalized linear mixed models. For both readers, Vh was significantly underestimated with VT2 (P < .0001, both), VADC (P < .0001, both), and VDCE (P = .02 and P = .003, readers 1 and 2, respectively), but not with Vmax (P = .13 and P = .21, readers 1 and 2, respectively). Mean, 25th percentile, and 75th percentile, respectively, for Vmax accuracy were 0.92, 0.54, and 1.85 for reader 1 and 0.95, 0.57, and 1.77 for reader 2. At generalized linear mixed (multivariate) analysis, tumor Likert score (P < .0001), Gleason score (P = .009), and Vh (P < .0001) significantly influenced Vmax accuracy (both readers). This accuracy was good in tumors with a Gleason score of 7 or higher or a Likert score of 5, with a tendency toward underestimation of Vh; accuracy was poor in small (<0.5 cc) or low-grade (Gleason score ≤6) tumors, with a tendency toward overestimation of Vh. Vh can be estimated by using Vmax in aggressive tumors or in tumors with high Likert scores.


Arrestin1 mediates light-dependent rhodopsin endocytosis and cell survival.
Arrestins are pivotal, multifunctional organizers of cell responses to GPCR stimulation, including cell survival and cell death. In Drosophila norpA and rdgC mutants, endocytosis of abnormally stable complexes of rhodopsin (Rh1) and fly photoreceptor Arrestin2 (Arr2) triggers cell death, implicating Rh1/Arr2-bearing endosomes in pro-cell death signaling, potentially via arrestin-mediated GPCR activation of effector kinase pathways. In order to further investigate arrestin function in photoreceptor physiology and survival, we studied Arr2's partner photoreceptor arrestin, Arr1, in developing and adult Drosophila compound eyes. We report that Arr1, but not Arr2, is essential for normal, light-induced rhodopsin endocytosis. Also distinct from Arr2, Arr1 is essential for light-independent photoreceptor survival. Photoreceptor cell death caused by loss of Arr1 is strongly suppressed by coordinate loss of Arr2. We further find that Rh1 C-terminal phosphorylation is essential for light-induced endocytosis and also for translocation of Arr1, but not Arr2, from dark-adapted photoreceptor cytoplasm to photosensory membrane rhabdomeres. In contrast to a previous report, we do not find a requirement for photoreceptor myosin kinase NINAC in Arr1 or Arr2 translocation. The two Drosophila photoreceptor arrestins mediate distinct and essential cell pathways downstream of rhodopsin activation. We propose that Arr1 mediates an endocytotic cell-survival activity, scavenging phosphorylated rhodopsin and thereby countering toxic Arr2/Rh1 accumulation; elimination of toxic Arr2/Rh1 in double mutants could thus rescue arr1 mutant photoreceptor degeneration.


Half-metallic alloys: electronic structure, magnetism and spin polarization.
Using the state-of-the-art screened Korringa-Kohn-Rostoker Green function method we study the electronic and magnetic properties of NiMnSb and similar Heusler alloys. We show that all these compounds are half-metals, e.g. the minority-spin band is semiconducting and the Fermi level falls within this gap resulting in 100% spin polarization at the Fermi level. The total spin moment M(t) shows the so-called Slater-Pauling behaviour and scales with the total valence charge Z(t) following the rule M(t) = Z(t) - 18 for half and M(t) = Z(t) - 24 for full Heusler alloys. These rules are connected to the origin of the gap. Finally we show that the inclusion of the spin-orbit interaction in our calculations kills the half-metallic gap but the spin-polarization at the Fermi level can be still very high, approximately 99% for NiMnSb, but much lower for a half-metallic compound like zinc-blende MnBi (77%).


Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells.
The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (NAs) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside)-induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5'-nucleotidases (50-100%). The ratio 5'-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5'-nucleotidase/deoxycytidine kinase ratio might be an important factor in predicting resistance to NAs. Implications of this finding for combining anthracyclines or vinca alkaloids with NAs toward leukemic cells are discussed.


Tiptoeing to chromosome tips: facts, promises and perils of today's human telomere biology.
The past decade has witnessed an explosion of knowledge concerning the structure and function of chromosome terminal structures-telomeres. Today's telomere research has advanced from a pure descriptive approach of DNA and protein components to an elementary understanding of telomere metabolism, and now to promising applications in medicine. These applications include 'passive' ones, among which the use of analysis of telomeres and telomerase (a cellular reverse transcriptase that synthesizes telomeres) for cancer diagnostics is the best known. The 'active' applications involve targeted downregulation or upregulation of telomere synthesis, either to mortalize immortal cancer cells, or to rejuvenate mortal somatic cells and tissues for cellular transplantations, respectively. This article reviews the basic data on structure and function of human telomeres and telomerase, as well as both passive and active applications of human telomere biology.


Psychoacoustic tinnitus loudness and tinnitus-related distress show different associations with oscillatory brain activity.
The phantom auditory perception of subjective tinnitus is associated with aberrant brain activity as evidenced by magneto- and electroencephalographic studies. We tested the hypotheses (1) that psychoacoustically measured tinnitus loudness is related to gamma oscillatory band power, and (2) that tinnitus loudness and tinnitus-related distress are related to distinct brain activity patterns as suggested by the distinction between loudness and distress experienced by tinnitus patients. Furthermore, we explored (3) how hearing impairment, minimum masking level, and (4) psychological comorbidities are related to spontaneous oscillatory brain activity in tinnitus patients. Resting state oscillatory brain activity recorded electroencephalographically from 46 male tinnitus patients showed a positive correlation between gamma band oscillations and psychoacoustic tinnitus loudness determined with the reconstructed tinnitus sound, but not with the other psychoacoustic loudness measures that were used. Tinnitus-related distress did also correlate with delta band activity, but at electrode positions different from those associated with tinnitus loudness. Furthermore, highly distressed tinnitus patients exhibited a higher level of theta band activity. Moreover, mean hearing loss between 0.125 kHz and 16 kHz was associated with a decrease in gamma activity, whereas minimum masking levels correlated positively with delta band power. In contrast, psychological comorbidities did not express significant correlations with oscillatory brain activity. Different clinically relevant tinnitus characteristics show distinctive associations with spontaneous brain oscillatory power. Results support hypothesis (1), but exclusively for the tinnitus loudness derived from matching to the reconstructed tinnitus sound. This suggests to preferably use the reconstructed tinnitus spectrum to determine psychoacoustic tinnitus loudness. Results also support hypothesis (2). Moreover, hearing loss and minimum masking level correlate with oscillatory power in distinctive frequency bands. The lack of an association between psychological comorbidities and oscillatory power may be attributed to the overall low level of mental health problems in the present sample.


Responses to Positive Affect: A Self-Report Measure of Rumination and Dampening.
Rumination in response to dysphoric moods has been linked to the onset and maintenance of depressive symptoms; however, responses to positive moods have received less attention despite the theoretical roles of both positive and negative affect in mood disorders. The purpose of the present study was to develop a self-report measure of ruminative and dampening Responses to Positive Affect (RPA), which we called the RPA Questionnaire. In two psychometric studies, the three subscales of the RPA (Dampening, Self-focused positive rumination, and Emotion-focused positive rumination) demonstrated acceptable structural validity, internal consistency, and preliminary evidence of convergent and incremental validity with concurrent measures of self-esteem, depressive rumination, and depressive and manic symptoms among undergraduates. The present results suggest that future research on mood disorders would benefit from measuring responses to both negative and positive moods.


Discrimination and Psychological Distress: Gender Differences among Arab Americans.
Despite the existing knowledge on the association between discrimination and poor mental health, very few studies have explored gender differences in this association in Arab Americans. The current study aimed to investigate whether gender moderates the association between the experience of discrimination and psychological distress in a representative sample of Arab Americans in Michigan. Using data from the Detroit Arab American Study (DAAS), 2003, this study recruited Arab Americans (337 males, 385 females) living in Michigan, United States. The main independent variable was discrimination. The main outcome was psychological distress. Covariates included demographic factors (age), socioeconomic status (education, employment, and income), and immigration characteristics (nativity and years living in United States). Gender was the focal moderator. We used multivariable regression with and without discrimination × gender interaction term. In the pooled sample, discrimination was positively associated with psychological distress [B = 0.62, 95% confidence interval (CI) = 0.22-1.03, p = 0.003]. We found a significant gender × discrimination interaction in the pooled sample (B = 0.79, 95% CI = 0.01-1.59, p = 0.050), suggesting a stronger association in males than females. In our gender-specific model, higher discrimination was associated with higher psychological distress among male (B = 0.87, 95% CI = 0.33-1.42, p = 0.002) but not female (B = 0.18, 95% CI = -0.43 to 0.78, p = 0.567) Arab Americans. While discrimination is associated with poor mental health, a stronger link between discrimination and psychological symptoms may exist in male compared to female Arab Americans. While efforts should be made to universally reduce discrimination, screening for discrimination may be a more salient component of mental health care for male than female Arab Americans.


Binding characteristics of IgA 16.4.12E, a monoclonal antibody with specificity for the nonreducing terminal epitope of alpha-(1----6)-dextrans. Comparisons between IgA hybridoma 16.4.12E and myeloma W3129.
IgA 16.4.12E is a murine monoclonal antibody obtained following immunization with isomaltohexose linked to keyhole limpet hemocyanin. We have studied its interaction with methyl alpha-D-glucopyranoside and its derivatives bearing deoxy or deoxyfluoro groups, and with the methyl alpha-glycosides of a series of isomalto-oligosaccharides, some bearing deoxy or deoxy-fluoro groups at selected positions. From the data it is concluded that the antibody binds optimally to 4 sequential glucopyranosyl residues and that the protein subsite possessing the major affinity binds the terminal, nonreducing glucosyl group of that antigenic epitope. All the hydroxyl groups of that terminal glucosyl group are involved in hydrogen bonding, some in a donating and some in an accepting capacity. In the last part of the paper we report the construction of a possible model of the antibody, derived from its known amino acid sequence and the known crystalline structures of two closely related antibodies. It shows a pronounced cavity in the general immunoglobulin combining area which is flanked by 2 solvent-exposed tryptophanyl residues. A model recently reported for anti-dextran IgA W3129 shows a similar cavity with one such residue. Guided by hydrogen bonds, experimentally deduced from the comparison of the affinities of variously derivatized ligands, we suggest a speculative fitting for the nonreducing terminus of the dextran antigen, in the respective cavities of both IgA 16.4.12E and W3129.


Botulinum neurotoxin and dendrotoxin as probes for studies on transmitter release.
Acceptors for BoNT have been detected autoradiographically on the terminal membrane of motor nerves at a density of approximately 150/micron2 and shown to mediate toxin internalization, a process deemed essential for its inhibition of transmitter release. DTX, a protein with pronounced central neurotoxicity, was shown to induce convulsive states in hippocampal slices from guinea-pig. Synaptic transmission was facilitated and spontaneous epileptiform activity produced in intact cell populations. Voltage clamp analysis of hippocampal neurones revealed that DTX specifically attenuated a transient voltage-dependent K+ conductance (A-current) and this could account for the excitatory effects observed. Proteinaceous acceptors with high affinity for DTX were identified on brain synaptosomal membranes and found to contain a 65 000 Mr polypeptide. Their location in rat brain regions was established and contrasted with that of the binding sites for beta-bungarotoxin. These findings indicate the usefulness of DTX as a probe for a protein associated with one variety of K+ channel while the larger subunit of BoNT was found to interact with a membraneous component that resides at cholinergic nerve terminals and, hence, is likely to have a unique role.


Prevention of pancreatic acinar cell carcinoma by Roux-en-Y Gastric Bypass Surgery.
Roux-en-Y Gastric Bypass Surgery (RYGB) prevents the occurrence of pancreatic cell acinar carcinoma (ACC) in male and female Ngn3-Tsc1-/- mice. Ngn3 directed Cre deletion of Tsc1 gene induced the development of pancreatic ACC. The transgenic mice with sham surgery demonstrated a cancer incidence of 96.7 ± 3.35% and survival rate of 67.0 ± 1.4% at the age of 300 days. Metastasis to liver and kidney was observed in 69.7 ± 9.7% and 44.3 ± 8.01% of these animals, respectively. All animals with RYGB performed at the age of 16 weeks survived free of pancreatic ACC up to the age of 300 days. RYGB significantly attenuated the activation of mTORC1 signaling and inhibition of tumor suppressor genes: p21, p27, and p53 in pancreatic ACC. Our studies demonstrate that bariatric surgery may limit the occurrence and growth of pancreatic ACC through the suppression of mTORC1 signaling in pancreas. RYGB shows promise for intervention of both metabolic dysfunction and organ cancer.


Case report: A community case study of the human-animal bond in animal-assisted therapy: the experiences of psychiatric prisoners with therapy dogs.
Prisoners frequently experience chronic loneliness and lack social support, which can exacerbate their struggles with incarceration. According to attachment theory, individuals who are insecurely attached may be more likely to develop unstable relationships and engage in antisocial behavior as adults. In 2015 an animal-assisted therapy (AAT) program was implemented in a Canadian forensic psychiatric facility/prison, a "hybrid" facility that adheres to federal legislation regarding correctional services but follows provincial mental health legislation. The program centers on the development of a human-animal bond (HAB), which serves as a connection between the animals and prisoners. The HAB also addresses issues related to toxic masculinity, which are often present among men incarcerated in correctional facilities, including psychiatric prisons. An instrumental community case study design involving 6 prisoners at a forensic psychiatric facility/prison over 24 AAT sessions between 2015-2019 was undertaken. Interviews with the prisoners and their mental health clinicians were thematically analyzed to explore how the HAB was experienced as a form of attachment. Four themes emerged: safety, physical touch, reciprocity, and acceptance. These themes suggest that the therapy dogs have the potential to serve as a surrogate attachment figure for prisoners, mitigating their experiences of disconnection and fostering their development of interpersonal connections. This suggests attachment theory underpins the HAB and highlights the contribution of AAT practice and research in forensic psychiatric facilities/prisons. This study also suggests that the program's offering of prosocial support and nurturance/caring aligns with the specific criminogenic risks and needs identified within Correctional Service Canada's Risk-Need-Responsivity (RNR) model for rehabilitation. Continued research and attention should be paid to AAT programs as a valuable addition to the range of support networks available to prisoners in psychiatric or non-psychiatric institutions.


A leukemic change as an initial manifestation of the common variant type of ALK-positive anaplastic large cell lymphoma in a patient with lung adenocarcinoma.
We report an 81-year-old man who had leukemic presentation of ALK-positive anaplastic large cell lymphoma (ALCL) as an initial manifestation. He had been well after chemotherapy and irradiation for the advanced lung adenocarcinoma, but suddenly suffered from severe lactic acidosis and hypotension. The peripheral blood smear and bone marrow aspiration revealed the infiltration of atypical large cells with horseshoe-shaped or lobulated nuclei. The detection of CD30 expression and the t (2;5) (p23;q35) translocation in these cells was confirmatory of a diagnosis of common variant ALK-positive ALCL in a leukemic phase. He deteriorated rapidly and died before administration of the chemotherapy. An adequate, prompt diagnosis is necessary for this rare disease status in oncologic emergency to improve the disease management.


[Pathologic urine findings related to medication].
We examined urine specimens from 144 consecutive patients attending a rheumatological department. Transient abnormal findings were frequent, but most urine samples normalized spontaneously. We found no association with use of non-steroidal anti-inflammatory drugs, but there was an association between pathological urine findings and the combined use of such drugs and systemic steroids.


Making health continuous: implications of different methods on the measurement of inequality.
In most national surveys, health is measured as a categorical variable. However, in order to be able to calculate socio-economic inequalities in health, a continuous variable is needed. The recently developed interval regression approach was shown to outperform to other approaches like ordered probit. In this research we investigate the impact of using different sets of external data to estimate health inequalities: the EQ-index and the Canadian HUI. We found that the concentration index differs, but the income-related health mobility index and its decomposition are highly similar.


Activation of hypoxia-inducible factor-1 ameliorates postischemic renal injury via inducible nitric oxide synthase.
Hypoxia-inducible factor-1 (HIF-1) could ameliorate renal ischemia reperfusion injury (IRI), but the underlying mechanism remains elusive. In the current study, we aim to investigate the possible role of prolyl hydroxylases inhibitor dimethyloxalylglycine (DMOG) in inducing delayed preconditioning-like effects against IRI. Mice were divided into four groups (n = 6): sham group; IRI group; DMOG group: pretreated with DMOG 24 h before IRI; and GW274150 + DMOG group: pretreated with DMOG followed by iNOS inhibitor GW274150 treatment 24 h before IRI. The results showed that the protein level of HIF-1a and the expression of its targets inducible nitric oxide synthase (iNOS), erythropoietin, and heme oxygenase-1 were obviously increased after administration of DMOG. Histological analysis of renal function showed improvement in tubulointerstitial injury due to ischemia by delayed preconditioning with DMOG. GW274150 antagonized the delayed renal protection afforded by DMOG as reflected by deteriorated renal dysfunction, aggravated histological injury, increased renal cell apoptosis, and increased vimentin expression in the kidney. In conclusion, our data demonstrate that DMOG pretreatment induces delayed renal protection against IRI in mice and the beneficial effects are mitigated by pharmacological inhibition of iNOS, suggesting that the protective effects derived from HIF-1 activation via DMOG in the kidney are partially mediated by iNOS.


POTENTIATION OF SOME CATECHOL AMINES BY PHENOXYBENZAMINE, GUANETHIDINE AND COCAINE.
In rabbit isolated atria, cocaine, guanethidine and phenoxybenzamine increased the changes in rate and force of contractions caused by noradrenaline and adrenaline, but did not potentiate isoprenaline. The most likely explanation for this result is that the drugs interfere with one of the mechanisms in the heart by which noradrenaline and adrenaline, but not isoprenaline, are inactivated; a probable mechanism would be the uptake of noradrenaline into storage sites in the tissue. Cocaine, guanethidine and phenoxybenzamine did not potentiate noradrenaline and adrenaline acting on the rabbit isolated duodenum and the rat uterus.


Can chemotherapy be omitted for patients with N0 or N1 endocrine-sensitive breast cancer treated with gonadotropin-releasing hormone agonist and tamoxifen?
Whether administering chemotherapy followed by tamoxifen plus a gonadotropin-releasing hormone (GnRH) agonist to treat patients with lower-risk hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer provides a greater benefit than administering tamoxifen plus GnRH agonist alone remains unclear. This study aimed to compare the outcomes of propensity score-matched (PSM) patients who underwent these 2 types of treatment plans. This retrospective study included patients treated at our institution between 2009 and 2019. Eligible patients had HR-positive, HER2-negative, invasive breast cancer who had undergone surgery. There were 579 patients with HR-positive, HER2-negative breast cancer who were treated with a GnRH agonist and tamoxifen; patients with pathologic N2 and those who received neoadjuvant chemotherapy were excluded. After 1:1 PSM of patients who underwent GnRH agonist treatment and tamoxifen with versus without chemotherapy, 122 patients from these 2 groups were analyzed. Survival rates were calculated using the Kaplan-Meier method and compared via the log-rank test. After PSM, there were no significant differences in several baseline characteristics between the 2 groups. After a median follow-up of 62.8 months, the patients in both groups demonstrated similar outcomes with no significant difference in disease-free survival (P = 0.596). Patients derived no significant survival benefit from undergoing a chemotherapy regimen before receiving tamoxifen and GnRH agonist therapy compared to forgoing such chemotherapy.


Utility of platelet transfusion in adult patients with traumatic intracranial hemorrhage and preinjury antiplatelet use: a systematic review.
Preinjury use of antiplatelet agents (e.g., clopidogrel and aspirin) is a risk factor for increased morbidity and mortality for patients with traumatic intracranial hemorrhage (tICH). Some investigators have recommended platelet transfusion to reverse the antiplatelet effects in tICH. This evidence-based medicine review examines the evidence regarding the impact of platelet transfusion on emergency department (ED) patients with preinjury antiplatelet use and tICH on patient-oriented outcomes. The MEDLINE, EMBASE, Cochrane Library, and other databases were searched. Studies were selected for inclusion if they compared platelet transfusion with no-platelet transfusion in the treatment of adult ED patients with preinjury antiplatelet use and tICH and reported rates of mortality, neurocognitive function, or adverse effects. We assessed the quality of the included studies using standard criteria. Five retrospective, registry-based studies were identified, which enrolled 635 patients cumulatively. Based on standard criteria, three studies were of low-quality evidence, and two studies were of very low-quality evidence. One study reported higher in-hospital mortality for patients with platelet transfusion (relative risk, 2.42; 95% confidence interval, 1.2-4.9); another showed a lower mortality rate for patients receiving platelet transfusion (relative risk, 0.21; 95% confidence interval, 0.05-0.95). Three studies did not show any statistical difference in comparing mortality rates between the groups. No studies reported intermediate or long-term neurocognitive outcomes or adverse events. Five retrospective registry studies with suboptimal methodologies provide inadequate evidence to support the routine use of platelet transfusion in adult ED patients with preinjury antiplatelet use and tICH. Systematic review, level III.


Prevalence of honorary and ghost authorship in Cochrane reviews.
To determine the prevalence of honorary and ghost authorship in Cochrane reviews, how authorship is assigned, and the ways in which authors and Cochrane editorial teams contribute. Using a Web-based, self-administered survey, corresponding authors for 577 reviews published in issues 1 and 2 from 1999 of The Cochrane Library were invited to report on the prevalence of honorary and ghost authors, contributions by authors listed in the byline and members of Cochrane editorial teams, and identification of methods of assigning authorship. Responses were received for 362 reviews (63% response rate), which contained 913 authors. One hundred forty-one reviews (39%) had evidence of honorary authors, 32 (9%) had evidence of ghost authors (most commonly a member of the Cochrane editorial team), and 9 (2%) had evidence of both honorary and ghost authors. The editorial teams contributed in a wide variety of ways to 301 reviews (83%). Authorship was decided by the group of authors (31%) or lead author (25%) in most reviews. Authorship order was assigned according to contribution in most reviews (76%). The 3 functions contributed to most by those listed in the byline were assessing the quality of included studies (83%), interpreting data (82%), and abstracting data from included studies (77%). A substantial proportion of reviews had evidence of honorary and ghost authorship. The Cochrane editorial teams contributed to most Cochrane reviews.


Pseudogenes in Human Cancer.
Recent advances in the analysis of RNA sequencing data have shown that pseudogenes are highly specific markers of cell identity and can be used as diagnostic and prognostic markers. Furthermore, genetically engineered mouse models have recently provided compelling support for a causal link between altered pseudogene expression and cancer. In this review, we discuss the most recent milestones reached in the pseudogene field and the use of pseudogenes as cancer classifiers.


Fast 3D shape screening of large chemical databases through alignment-recycling.
Large chemical databases require fast, efficient, and simple ways of looking for similar structures. Although such tasks are now fairly well resolved for graph-based similarity queries, they remain an issue for 3D approaches, particularly for those based on 3D shape overlays. Inspired by a recent technique developed to compare molecular shapes, we designed a hybrid methodology, alignment-recycling, that enables efficient retrieval and alignment of structures with similar 3D shapes. Using a dataset of more than one million PubChem compounds of limited size (< 28 heavy atoms) and flexibility (< 6 rotatable bonds), we obtained a set of a few thousand diverse structures covering entirely the 3D shape space of the conformers of the dataset. Transformation matrices gathered from the overlays between these diverse structures and the 3D conformer dataset allowed us to drastically (100-fold) reduce the CPU time required for shape overlay. The alignment-recycling heuristic produces results consistent with de novo alignment calculation, with better than 80% hit list overlap on average. Overlay-based 3D methods are computationally demanding when searching large databases. Alignment-recycling reduces the CPU time to perform shape similarity searches by breaking the alignment problem into three steps: selection of diverse shapes to describe the database shape-space; overlay of the database conformers to the diverse shapes; and non-optimized overlay of query and database conformers using common reference shapes. The precomputation, required by the first two steps, is a significant cost of the method; however, once performed, querying is two orders of magnitude faster. Extensions and variations of this methodology, for example, to handle more flexible and larger small-molecules are discussed.


A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days.
Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39-73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2-5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.


Gold Nanorods as Radiopharmaceutical Carriers: Preparation and Preliminary Radiobiological In Vitro Tests.
Low-energy electrons (Auger electrons) can be produced via the interaction of photons with gold atoms in gold nanorods (AuNRs). These electrons are similar to those emitted during the decay of technetium-99m (99mTc), a radioactive nuclide widely used for diagnostics in nuclear medicine. Auger and internal conversion (IC) electron emitters appropriately targeted to the DNA of tumors cells may, therefore, represent a new radiotherapeutic approach. 99mTc radiopharmaceuticals, which are used for diagnosis, could indeed be used in theragnostic fields when loaded on AuNRs and delivered to a tumor site. This work aims to provide a proof of concept (i) to evaluate AuNRs as carriers of 99mTc-based radiopharmaceuticals, and (ii) to evaluate the efficacy of Auger electrons emitted by photon-irradiated AuNRs in inducing radio-induced damage in T98G cells, thus mimicking the effect of Auger electrons emitted during the decay of 99mTc used in clinical settings. Data are presented on AuNRs' chemical characterization (with an aspect ratio of 3.2 and Surface Plasmon Resonance bands at 520 and 680 nm) and the loading of pharmaceuticals (after 99mTc decay) on their surface. Spectroscopic characterizations, such as UV-Vis and synchrotron radiation-induced X-ray photoelectron (SR-XPS) spectroscopies, were performed to investigate the drug-AuNR interaction. Finally, preliminary radiobiological data on cell killing with AuNRs are presented.


Recent Advances in Synthetic Membrane Transporters.
It is 25 years since the first report of a synthetic ion channel transporter. Today, dozens of molecular and supramolecular designs have been developed to facilitate ion and small molecule transport across a bilayer membrane. Presented here is a concise summary of the advances made over the past four years. The transporters are grouped into three mechanistic classes: mobile carrier, monomeric channel, and self-assembled pore. Common building blocks are crown ethers, steroids, cyclodextrins, peptides, curcubiturils, and calixarenes. The eventual goal is to produce functional supramolecular devices such as sensors, enzyme assays, and lead candidates for pharmaceutical development.


Expression of a synthetic gene encoding human insulin-like growth factor I in cultured mouse fibroblasts.
A synthetic gene encoding human insulin-like growth factor I (hIGF-I) was assembled and inserted into an expression vector containing the cytomegalovirus immediate early (CMV-IE) transcriptional regulatory region and portions of the bovine growth hormone gene. The recombinant plasmid encodes a 97 amino acid fusion protein containing the first 27 amino acids of the bovine growth hormone precursor and the 70 amino acids of hIGF-I. This plasmid, when transiently introduced into cultured mouse fibroblasts, directs synthesis of the fusion protein, subsequent proteolytic removal of the bovine growth hormone signal peptide, and secretion of hIGF-I into the culture medium. Conditioned medium from transfected cells inhibits binding of 125I-labeled IGF-I to type I IGF receptors on human placental membranes and to acid-stable human serum carrier proteins. The recombinant hIGF-I produced is biologically active, as monitored by the stimulation of DNA synthesis in vascular smooth muscle cells.


Drug interactions with phytotherapeutics in oncology.
Because 30 to 70% of tumour patients use complementary and alternative medicines; herb-drug combinations are particularly frequent in this population. Some of these combinations can critically alter exposure of anti-neoplastic and palliative treatment. This review summarises pharmacokinetic drug interactions caused by the herbal products most frequently used by tumour patients (garlic, ginkgo, ginseng, echinacea and St John's wort [SJW]). Herb-drug interactions, in general, and some interactions in particular (e.g., transporters, Phase II metabolism enzymes) are still poorly investigated and are difficult to evaluate because mixtures are administered with variable and often unspecified amounts of ingredients. Current evidence suggests that garlic and ginkgo can be safely co-administered, whereas CYP2C9 substrates (e.g., warfarin) should be monitored closely when ginseng therapy is started. Echinacea can induce drug metabolism mediated by CYP3A, but most likely relevant when administered with substances with a narrow therapeutic index or low oral bioavailability. The most relevant herbal perpetrator drug is SJW, which has substantial impact on CYP3A4- and CYP2C9-mediated metabolism and P-glycoprotein-mediated transport. This may lower exposure of co-administered drugs by up to 70%. Such an interaction is expected to occur with most of the tyrosine kinase inhibitors, but current evidence is limited.


Relation of estrogen receptor-alpha gene polymorphism and hormone replacement therapy to fall risk and muscle strength in early postmenopausal women.
Several factors may increase fracture risk, among them reduced bone mineral density (BMD), increased bone resorption, microarchitectural deterioration of bone, increased fall risk, and decreased muscle strength. We have previously reported that PvuII polymorphism of the estrogen receptor-alpha (ER alpha) gene is associated with bone loss rate, fracture risk, and response to hormone replacement therapy (HRT) in early postmenopausal Finnish women. We studied the influence of the ER alpha genotype on fall risk and muscle strength in a 5-year randomized HRT trial of 331 early postmenopausal women (subgroup of the population-based OSTPRE study, Kuopio, Finland). A 5-year postal inquiry in May 1994 included questions on falls during the previous 12 months. Grip strength was measured with dynamometer. The ER alpha gene polymorphism was analysed using PCR and PvuII restriction enzyme digestion. RESULTS. In all, 97 out of the 331 women reported falls. Half of those (56%) were slip falls, mostly during the winter season. In the HRT group, the ER alpha genotype was associated with fall risk (P = 0.002, logistic regression). The risk of falls (RR) was higher in women with the PP genotype than in those with the Pp (RR = 5.26, 95% CI 1.98-13.94, P = 0.001) or the pp (RR = 3.84, 95% CI 1.46-10.12, P = 0.007) genotype. When the falls were divided into slip (environment-related) and non-slip (endogenous) falls, the non-slip falls were associated with the genotype (P = 0.004), but the slip falls were not so clearly (P = 0.061). When all falls and non-slip falls were adjusted to the number of chronic health disorders and the variable time-since-menopause, the difference between the genotypes persisted (P = 0.003 and P = 0.010, respectively). In the non-HRT group, the ER alpha genotype was not associated with fall risk. The baseline or the 5-year grip strength values were not influenced by the ER alpha genotype. In conclusion, ER alpha polymorphism is associated with fall risk, especially with non-slip falls, in early postmenopausal Finnish women during the HRT. We have previously reported that, during HRT, women with the P allele have decreased fracture risk and that they may preferentially derive benefit from the positive effect of HRT on BMD. This suggests that the influence of ER alpha polymorphism may depend on the target tissue (bone versus the nervous system). In these early postmenopausal, non-osteoporotic and relatively healthy women, the increased fall risk associated with the PP genotype was not associated with increased fracture risk, possibly due to improved bone strength during the HRT although falls generally predispose to fractures.


Photodegradation of diafenthiuron in water.
Diafenthiuron, 1-tert-butyl-3-(2,6-di-isopropyl-4-phenoxyphenyl)thiourea, is an effective insecticide and acaricide. Sunlight degradation of diafenthiuron in various aqueous solutions and pure hexane yielded two major identified products: 1-tert-butyl-3-(2,6-di-isopropyl-4-phenoxyphenyl)-carbodiimide (CGA-140,408) and 1-tert-butyl-3-(2,6-di-isopropyl-4-phenoxy-phenyl)urea (CGA-177,960). CGA-140,408 was further photo-transformed into CGA-177,960 by sunlight. Direct photolysis appeared to be a major photolysis pathway of diafenthiuron in the environment. Photodegradation of CGA-140,408 and CGA-177,960 was enhanced in humic acid water, paddy water and aqueous acetone solutions, and followed first-order kinetics. Isopropanol (a radical quencher) and de-aeration strongly inhibited the photolysis of these chemicals, which suggested oxygen radical-mediated reactions.


Ouabain, a circulating hormone secreted by the adrenals, is pivotal in cardiovascular disease. Fact or fantasy?
Substantial evidence points to the presence in human plasma of an inhibitor of the sodium/potassium pump which plays a central role in the pathophysiology of circulatory disorders, including essential hypertension. Studies from the 1980/90s claimed that this inhibitor was identical or very similar in structure to plant-derived ouabain and was synthesized by the adrenal cortex. However, the physical evidence in studies reporting isolation and identification of ouabain in human plasma appears insecure on closer examination. Additionally, reported circulating levels of immunoreactive ouabain in humans vary greatly, the ability of the human adrenal glands to secrete ouabain is questionable and the original commercial assay for measuring immunoreactive ouabain is no longer available. We submit that the position of ouabain as an endogenous, adrenally produced regulator of the sodium pump is of such importance that the current evidence needs either to put on a more secure footing or to lose its current status.


DNA-lipid systems. A physical chemistry study.
It is well known that the interaction of polyelectrolytes with oppositely charged surfactants leads to an associative phase separation; however, the phase behavior of DNA and oppositely charged surfactants is more strongly associative than observed in other systems. A precipitate is formed with very low amounts of surfactant and DNA. DNA compaction is a general phenomenon in the presence of multivalent ions and positively charged surfaces; because of the high charge density there are strong attractive ion correlation effects. Techniques like phase diagram determinations, fluorescence microscopy, and ellipsometry were used to study these systems. The interaction between DNA and catanionic mixtures (i.e., mixtures of cationic and anionic surfactants) was also investigated. We observed that DNA compacts and adsorbs onto the surface of positively charged vesicles, and that the addition of an anionic surfactant can release DNA back into solution from a compact globular complex between DNA and the cationic surfactant. Finally, DNA interactions with polycations, chitosans with different chain lengths, were studied by fluorescence microscopy, in vivo transfection assays and cryogenic transmission electron microscopy. The general conclusion is that a chitosan effective in promoting compaction is also efficient in transfection.


Activation-induced T cell death exacerbates Trypanosoma cruzi replication in macrophages cocultured with CD4+ T lymphocytes from infected hosts.
Activation-induced cell death (AICD) of CD4+ T lymphocytes was described in infection with Trypanosoma cruzi, but a role for AICD in modulating parasite spread in host cells has not been investigated. In this study, replication of T. cruzi in vitro in murine macrophage (Mphi) monolayers was investigated. Long term (5 to 13 day) replication of infective (trypomastigote) T. cruzi forms was blocked by supernatants from activated (anti-TCR) CD4+ T cells of infected mice or by rIFN-gamma. However, when CD4+ T cells from infected mice were cocultured with Mphi and activated by anti-TCR, marked exacerbation of trypomastigote growth in Mphi ensued. The deleterious effect required contact between T cells and infected Mphi. Both anti-Fas and TCR activation killed a proportion of CD4+ T cells. Ly-6 activation did not induce AICD and did not exacerbate parasite growth. However, Fas-mediated killing of T cells before Ly-6 activation led to exacerbated parasite growth. Although a minor population, Fas-susceptible cells were the major source of IFN-gamma production by activated T cells. Addition of a neutralizing anti-Fas ligand antibody blocked 50 to 60% of CD4+ T cell AICD and reduced trypomastigote growth in T/Mphi cocultures stimulated by anti-TCR. The results demonstrate that in CD4+ T cells from infected mice, the onset of AICD selectively ablates IFN-gamma production and up-regulates parasite replication in Mphi in vitro. These findings suggest a deleterious role for AICD in T. cruzi infection.


Local cooling in spinal cord injury.
Eight patients with acute spinal cord injury at different levels were treated by local cooling. Early laminectomy was performed and the subdural space was irrigated with saline at 5degreesC for about two hours. In addition to this treatment, five patients, after closure of the operative wound, received local epidural cooling that was prolonged for a few days. All patients before treatment had a complete loss of function of the spinal cord below the injured segment. Four of these regained some sensory and motor functions and two were able to walk. Somatosensory cortical evoked responses were consistent with the results obtained, thus demonstrating their prognostic value. The clinical application of local spinal cord hypothermia in order to minimize the catastrophic effects of spinal cord trauma is discussed. The results obtained in these eight patients agree with the several experimental observations and seem to justify the application of this procedure to human beings.


Hydrazone-palladium catalyzed annulation of 1-allyl-2-bromobenzene derivatives with internal alkynes.
Annulation of 1-allyl-2-bromobenzene derivatives with internal alkynes using a hydrazone-palladium catalyst system proceeded smoothly and gave the corresponding polysubstituted naphthalene derivatives in good to high yields.


Comparison of colonic and ileal propulsive capabilities under conditions requiring hydrostatic work.
The intrinsic ability of cat colonic segments to do hydrostatic work to expel fluid was investigated in vitro and compared with the propulsive ability of ileal segments evaluated under identical conditions. Colonic segments spontaneously produced propulsive complexes at an average interval of 4.8 min when basal intraluminal pressure was set at 5 cmH2O. These complexes produced a net ejection of fluid in the aboral direction. When the capacitance of the evaluation system was set at 0.025 ml/cmH2O, colonic segments ejected only 5% of their content. This percentage increased to 23% when evaluation capacitance was increased to 0.125 ml/cmH2O. Peak aboral pressure associated with these complexes was approximately 37 cmH2O at both capacitances. Ileal segments aborally ejected almost twice as much fluid (44% of their luminal content) as did colonic segments at a capacitance of 0.025 ml/cmH2O even though ileal luminal content was five times less than colonic content. The aborally ejected volume per complex did not change when ileal segments were evaluated at two different capacitances even though higher pressures were required to eject fluid at the lower capacitance than at the higher capacitance. These results indicate that the propulsive behavior of ileal and colonic segments has some qualitative aspects that are similar but that only the propulsive ability of colonic segments is pressure limited under the conditions tested. Possible mechanisms that might produce this limitation are considered.


[Preparation of subtilisin BPN' and dextran conjugates].
The conditions for subtilishine BPN' binding with bromocyanogen activated dextranes have been selected. The dependence of the enzyme activity and stability from pH and temperature levels has been studied. The stability of a modified enzyme during storage in solution is increased as compared with that of the native enzyme due to a decrease in the autolysis rate. On the basis of diffusion coefficients and sedimentation constants of conjugates, absolute values of their molecular weights have been computed.


Lean mass as a determinant of bone mineral density of proximal femur in postmenopausal women.
To verify which component of body composition (BC) has greater influence on postmenopausal women bone mineral density (BMD). Four hundred and thirty women undergoing treatment for osteoporosis and 513 untreated women, except for calcium and vitamin D. Multiple linear regression analysis was performed in order to correlated BMD at lumbar spine (LS), total femur (FT), femoral neck (FN) with body mass (BM), total lean mass (LM) and total fat mass (FM), all determined by DXA. BM significantly correlated with all bone sites in untreated and treated women (r = 0.420 vs 0.277 at LS; r = 0.490 vs 0.418 at FN, r = 0.496 vs 0.414 at FT, respectively). In untreated women, the LM correlated better than FM with all sites, explaining 179% of LS; 32.3% of FN and 30.2% of FT; whereas FM explained 13.2% of LS; 277% of FN, 23.4% of FT In treated women, correlations with BC were less relevant, with the LM explaining 6.7% of BMD at LS; 15.2% of FN, 16% of FT, whereas the FM explained 8.1% of LS; 179% of FN and 176% of FT. LM in untreated women was better predictor of BMD than FM, especialy for distal femur, where it explained more than 30% of the BMD, suggesting that maintaining a healthy muscle mass may contribute to decrease osteoporosis risk. Treatment with anti-osteoporotic drugs seems to mask these relationships. Arch Endocrinol Metab. 2018;62(4):431-7.


Spatial distribution of podoconiosis in relation to environmental factors in Ethiopia: a historical review.
An up-to-date and reliable map of podoconiosis is needed to design geographically targeted and cost-effective intervention in Ethiopia. Identifying the ecological correlates of the distribution of podoconiosis is the first step for distribution and risk maps. The objective of this study was to investigate the spatial distribution and ecological correlates of podoconiosis using historical and contemporary survey data. Data on the observed prevalence of podoconiosis were abstracted from published and unpublished literature into a standardized database, according to strict inclusion and exclusion criteria. In total, 10 studies conducted between 1969 and 2012 were included, and data were available for 401,674 individuals older than 15 years of age from 229 locations. A range of high resolution environmental factors were investigated to determine their association with podoconiosis prevalence, using logistic regression. The prevalence of podoconiosis in Ethiopia was estimated at 3.4% (95% CI 3.3%-3.4%) with marked regional variation. We identified significant associations between mean annual Land Surface Temperature (LST), mean annual precipitation, topography of the land and fine soil texture and high prevalence of podoconiosis. The derived maps indicate both widespread occurrence of podoconiosis and a marked variability in prevalence of podoconiosis, with prevalence typically highest at altitudes >1500 m above sea level (masl), with >1500 mm annual rainfall and mean annual LST of 19-21°C. No (or very little) podoconiosis occurred at altitudes <1225 masl, with annual rainfall <900 mm, and mean annual LST of >24°C. Podoconiosis remains a public health problem in Ethiopia over considerable areas of the country, but exhibits marked geographical variation associated in part with key environmental factors. This is work in progress and the results presented here will be refined in future work.


Ion Distribution and Hydration Structure in the Stern Layer on Muscovite Surface.
Based on molecular dynamics simulations of eight ions (Na+, K+, Rb+, Cs+, Mg2+, Ca2+, Sr2+, and Ba2+) on muscovite mica surfaces in water, we demonstrate that experimental data on the muscovite mica surface can be rationalized through a unified picture of adsorption structures including the hydration structure, cation heights from the muscovite surface, and state stability. These simulations enable us to categorize the inner-sphere surface complex into two different species: an inner-sphere surface complex in a ditrigonal cavity (IS1) and that on top of Al (IS2). By considering the presence of the two inner-sphere surface complexes, the experimental finding that the heights of adsorbed cations from the muscovite surface are proportional to the ionic radius for K+ and Cs+ but inversely proportional to the ionic radius for Ca2+ and Ba2+ was explained. We find that Na+, Ca2+, Sr2+, and Ba2+ can form both IS1 and IS2; K+, Rb+, and Cs+ can form only IS1; and Mg2+ can form only IS2. It is suggested that the formation of IS1 and IS2 is governed by the charge density of the ions. Among the eight ions, we also find that the hydration structure for the outer-sphere surface complexes of divalent cations differs from that of the monovalent cations by one adsorbed water molecule (i.e., a water molecule located in a ditrigonal cavity).


Treatment of angular cheilitis. The significance of microbial analysis, antimicrobial treatment, and interfering factors.
This prospective study evaluated the significance of microbial analysis and antimicrobial treatment for the cure of angular cheilitis. Furthermore, various etiologic factors were investigated for their relative effect on the healing process. The study included 1) an open trial with 50 patients infected by Candida albicans and/or Staphylococcus aureus, and 2) an intraindividual comparison of eight patients with bilateral lesions infected by Candida albicans as the only detected pathogen. After a base-line examination the patients received ointments containing nystatin and/or fusidic acid, on the basis of the outcome of an initial microbial analysis. The patients were evaluated clinically, photographed, and examined for microorganisms at different time intervals. Ninety-six per cent of the patients who participated in the open trial had no sign of infection after 42 days of treatment. Lesions in the double-blind study, treated with nystatin, were healed after 28 days, whereas lesions that received placebo persisted throughout the treatment period. Increasing age, dry skin, and extended skinfolds at the corner of the mouth were factors closely related to the length of the healing process.


A nonlinear anisotropic viscoelastic model for the tensile behavior of the corneal stroma.
Tensile strip experiments of bovine corneas have shown that the tissue exhibits a nonlinear rate-dependent stress-strain response and a highly nonlinear creep response that depends on the applied hold stress. In this paper, we present a constitutive model for the finite deformation, anisotropic, nonlinear viscoelastic behavior of the corneal stroma. The model formulates the elastic and viscous response of the stroma as the average of the elastic and viscous response of the individual lamellae weighted by a probability density function of the preferred in-plane lamellar orientations. The result is a microstructure-based model that incorporates the viscoelastic properties of the matrix and lamellae and the lamellar architecture in the response of the stroma. In addition, the model includes a fully nonlinear description of the viscoelastic response of the lamellar(fiber) level. This is in contrast to previous microstructure-based models of fibrous soft tissues, which relied on quasilinear viscoelastic formulations of the fiber viscoelasticity. Simulations of recent tensile strip experiments show that the model is able to predict, well within the bounds of experimental error and natural variations, the cyclic stress-strain behavior and nonlinear creep behavior observed in uniaxial tensile experiments of excised strips of bovine cornea.


A peptide-based fluorescence resonance energy transfer assay for Bacillus anthracis lethal factor protease.
A fluorescence resonance energy transfer assay has been developed for monitoring Bacillus anthracis lethal factor (LF) protease activity. A fluorogenic 16-mer peptide based on the known LF protease substrate MEK1 was synthesized and found to be cleaved by the enzyme at the anticipated site. Extension of this work to a fluorogenic 19-mer peptide, derived, in part, from a consensus sequence of known LF protease targets, produced a much better substrate, cleaving approximately 100 times more efficiently. This peptide sequence was modified further on resin to incorporate donor/quencher pairs to generate substrates for use in fluorescence resonance energy transfer-based appearance assays. All peptides cleaved at similar rates with signal/background ranging from 9-16 at 100% turnover. One of these substrates, denoted (Cou)Consensus(K(QSY-35)GG)-NH(2), was selected for additional assay optimization. A plate-based assay requiring only low nanomolar levels of enzyme was developed for screening and inhibitor characterization.


Design of biological filter for iron and manganese removal from water.
The technology core of biological removal of iron and manganese by contact oxidation is iron and manganese oxidizing bacteria. This article made a study on down flow and up flow filtration, the results show that down flow filtration of the homogenous filter medium is more adapted to the reproduction of biotic formation. Homogeneous filter increase the depth of effective biological filter and the biomass that develop the bio-chemical capability of the biological filter. Homogeneous filter increase removal capability of Fe/Mn and alleviate the formation of sludge cake, which can get a quite backwash. Down flow homogeneous biological filter can solve some engineering problems of heterogeneous up flow filtration. The down flow homogeneous biological filter is more adapted to the removal of Fe/Mn in groundwater.


Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis.
Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis in a model of severe acute limb ischemia. Young adult (3-months-old) and aged (18-months-old) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with a laser Doppler scan and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis. Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n = 15: 20.4 +/- 1.9%, vs aged, n = 20: 19.6 +/- 1.3%; P = .72, analysis of variance [ANOVA]); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35 +/- 6% vs 17 +/- 4%, P = .046; day 14, 60 +/- 5% vs 27 +/- 7%, P = .0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3 +/- 0.3 vs 4.3 +/- 0.4; P = .0021). Aged mice had increased capillary density (day 7, 12.9 +/- 4.4 vs 2.8 +/- 0.3 capillaries/hpf; P = .02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1 +/- 0.9 vs 2.5 +/- 1.9 cells; P = .007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs 9; P = .01), as seen on angiography. After severe hind limb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia.


A unique MRI presentation of fungal infection in the brain.
Fungal infections of CNS are common in certain geographic locations. MRI with or without contrast is a useful prediagnostic tool. However, the findings may sometimes be misleading. In this case report, the authors present unusual imaging findings in the MRI of fungal infection in an immunocompetent host, whereby hyper-intense signals were seen on T2-weighted images and patchy post-contrast enhancement was observed with surrounding edema. These findings were suggestive of a neoplastic lesion but it was identified as aspergillosis on subsequent histopathology. This unusual MRI finding of CNS highlights the need to consider fungal infection as a differential diagnosis of all mass lesions on MRI, irrespective of their signal characteristics.


Treatment of type II endoleaks associated with left subclavian artery coverage during thoracic aortic stent grafting.
Increasing experience with thoracic aortic stent grafts has led to a more aggressive approach to thoracic aortic pathologies in the distal aortic arch and proximal descending thoracic aorta. To increase the length of the proximal landing zone, it is sometimes necessary to cover the left subclavian artery with the thoracic stent-graft, introducing the risk of retrograde filling of the excluded aorta from the left subclavian artery. It is currently unclear how best to manage these patients to prevent persistent risk of aneurysm expansion or rupture. We report our experience with a minimally invasive endovascular repair of the covered left subclavian artery. We reviewed prospectively gathered data on all investigational device exemption-approved patients undergoing thoracic aortic stent grafting at the Arizona Heart Institute from 2000 to 2006 (n = 289 patients). Patients had surveillance with a contrast-enhanced computed tomography scan on the first postoperative day and during follow-up at 1, 6, and 12 months. A total of 289 patients received thoracic stent grafts during the study: Medtronic Talent (Medtronic, Minneapolis, Minn) (n = 25) or Gore TAG (WL Gore & Associates Inc, Flagstaff, Ariz) (n = 261). The left subclavian artery was covered in 23% of patients (n = 66), of whom 17% had preoperative carotid-subclavian bypass (n = 11/66). Among patients with left subclavian artery coverage, the 30-day mortality was 6.1% (n = 4), procedure-related strokes developed in 3 patients (n = 3, 4.6%), and the incidence of left arm claudication was 7.6% (n = 5), necessitating postoperative carotid-subclavian bypass in 2 patients. Twelve patients (18%) had a type I (n = 6) or II (n = 7) endoleak. Coverage of the left subclavian artery accounted for 71% of the type II endoleaks (n = 5), whereas patent intercostals accounted for the rest (n = 2). Type II endoleaks associated with left subclavian artery coverage were successfully treated by retrograde coil embolization from the left brachial artery (n = 3) or left subclavian artery ligation (n = 1). Coverage of the left subclavian artery during thoracic aortic stent grafting is associated with a low incidence of arm complications and type II endoleaks. All type II endoleaks were successfully treated by retrograde coil embolization or ligation of the left subclavian artery. Successful treatment of endoleaks may reduce the risk of aneurysm expansion or rupture.


Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation.
The modulation of canonical macroautophagy/autophagy for therapeutic benefit is an emerging strategy of medical and pharmaceutical interest. Many drugs act to inhibit autophagic flux by targeting lysosome function, while others were developed to activate the pathway. Here, we report the surprising finding that many therapeutically relevant autophagy modulators with lysosomotropic and ionophore properties, classified as inhibitors of canonical autophagy, are also capable of activating a parallel noncanonical autophagy pathway that drives MAP1LC3/LC3 lipidation on endolysosomal membranes. Further, we provide the first evidence supporting drug-induced noncanonical autophagy in vivo using the local anesthetic lidocaine and human skin biopsies. In addition, we find that several published inducers of autophagy and mitophagy are also potent activators of noncanonical autophagy. Together, our data raise important issues regarding the interpretation of LC3 lipidation data and the use of autophagy modulators, and highlight the need for a greater understanding of the functional consequences of noncanonical autophagy.


Stroke Classification: Critical Role of Unusually Large von Willebrand Factor Multimers and Tissue Factor on Clinical Phenotypes Based on Novel "Two-Path Unifying Theory" of Hemostasis.
Stroke is a hemostatic disease associated with thrombosis/hemorrhage caused by intracranial vascular injury with spectrum of clinical phenotypes and variable prognostic outcomes. The genesis of different phenotypes of stroke is poorly understood due to our incomplete understanding of hemostasis and thrombosis. These shortcomings have handicapped properly recognizing each specific stroke syndrome and contributed to controversy in selecting therapeutic agents. Treatment recommendation for stroke syndromes has been exclusively derived from the result of laborious and expensive clinical trials. According to newly proposed "two-path unifying theory" of in vivo hemostasis, intracranial vascular injury would yield several unique stroke syndromes triggered by 3 distinctly different thrombogenetic mechanisms depending upon level of intracranial intravascular injury and character of formed blood clots. Five major phenotypes of stroke occur via thrombogenetic paths: (1) transient ischemic attack due to focal endothelial damage limited to endothelial cells (ECs), (2) acute ischemic stroke due to localized ECs and subendothelial tissue (SET) damage extending up to the outer vascular wall, (3) thrombo-hemorrhagic stroke due to localized vascular damage involving ECs and SET and extending beyond SET to extravascular tissue, (4) acute hemorrhagic stroke due to major localized intracranial hemorrhage/hematoma into the brain tissue or space between the coverings of the brain associated with vascular anomaly or obtuse trauma, and (5) encephalopathic stroke due to disseminated endotheliopathy leading to microthrombosis within the brain. New classification of stroke phenotypes would assist in selecting rational therapeutic regimen for each stroke syndrome and designing clinical trials to improve clinical outcome.


Dermoscopy of acquired pigmentary disorders: a comprehensive review.
Dermoscopy has traditionally been used for the diagnosis of neoplasms and more recently in the evaluation of inflammatory conditions. Recent observational studies have suggested a role for dermoscopy in identifying and differentiating acquired pigmentary disorders. This comprehensive review will summarize the growing literature on the use of dermoscopy for pigmentary disorders. A literature review was performed on PubMed dating from inception to October 2020. The following pigmentary disorders were included in this study: melasma, solar lentigines, poikiloderma of Civatte, exogenous ochronosis, lichen planus pigmentosus, erythromelanosis follicularis faciei et colli, pigmented contact dermatitis, Riehl's melanosis, postinflammatory hyperpigmentation, erythema dyschromicum perstans, ashy dermatosis, confluent and reticulated papillomatosis, acanthosis nigricans, pityriasis versicolor, tinea versicolor, idiopathic guttate hypomelanosis, and vitiligo. Search terms used included each pigmentary disorder along with the terms "dermoscopy" or "dermatoscopy." Relevant case reports and case series were included. Many pigmentary disorders have unique and distinguishable features on dermoscopy. Given that these disorders can be clinically challenging for clinicians and emotionally distressing for patients, dermoscopy provides an additional, useful tool in the evaluation and assessment process.


[A case of cystic pheochromocytoma].
A case of cystic pheochromocytoma is reported. A 64-year-old man was referred to our hospital because of right flank pain and gross hematuria. Excretory urography showed an inferior displacement of his right kidney, and right suprarenal mass was suspected. CT and ultrasonographic findings suggested that the most likely diagnosis was cystic adrenal tumor. Right adrenal tumor was removed through a transverse abdominal incision on October 15, 1986. During the procedure, the blood pressure rose to 260/100 mmHg at the time of tumor manipulation. The histological diagnosis was pseudocystic pheochromocytoma. Pathogenesis of cystic adrenal tumor is discussed briefly.


Phytotoxic sesterterpene, 11-epiterpestacin, from Bipolaris sorokiniana NSDR-011.
The structure of siccanol, a phytotoxic sesterterpene of fungal origin, was analyzed after chemical conversion by NMR spectroscopy. Siccanol was found to be an epimer of terpestacin that has been isolated from Arthrinium sp., and was thus renamed 11-epiterpestacin. Its stereochemistry was also identical with that of fusaproliferin, a structurally related mycotoxin from Fusarium proliferatum. Therefore, this sesterterpene may also be referred to as 24-deacetyl fusaproliferin. The phytotoxicity of 11-epiterpestacin was almost equal to that of terpestacin, but significantly higher than that of fusaproliferin.


Diversity of human rotavirus G and P genotypes in Panama, Costa Rica, and the Dominican Republic.
In this study 2,089 fecal samples from patients with gastroenteritis were analyzed from different hospitals in Panama, Costa Rica, and the Dominican Republic during the period comprised between December 2002 and July 2003. One hundred samples per country from the positives to the enzyme-linked immunosorbent assay (ELISA) kit were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) to determine the G and P genotypes: in Panama, Costa Rica, and Dominican Republic the combinations G and P have a great diversity and unusual genotypes. These results highlight an unexpected diversity among rotavirus strains in these countries and emphasize the need for further serologic and genetic surveys on more rotavirus strains in Central America and the Caribbean. In this context, the next generation of rotavirus vaccines will need to provide adequate protection against diseases caused by unusual genotypes. These results represent the second report of rotavirus genotypes in Costa Rica and first-time reports of rotavirus genotypes in Panama and the Dominican Republic.


Clinical validation of the nursing diagnosis Risk for Aspiration among patients who experienced a cerebrovascular accident.
the study's objective was the clinical validation of the nursing diagnosis Risk for Aspiration among patients who experienced cerebrovascular accidents (CVA). a prospective cohort study was conducted with 24 patients hospitalized due to a CVA. The instrument used to collect the data addressed the risk factors for respiratory aspiration, validated by concept analysis and by experts. the most frequent risk factors for respiratory aspiration were: dysphagia (54.2%) and impaired physical mobility (41.7%). The prevalence of the nursing diagnosis Risk for Aspiration was 58.3% and the prevalence of respiratory aspiration over the span of 48 hours (monitoring period) was 37.5%. Risk factors for dysphagia and impaired physical mobility were significantly associated with respiratory aspiration. the risk factors dysphagia and impaired physical mobility are good predictors of the nursing diagnosis Risk for Aspiration. This study contributed to improving the NANDA-I Taxonomy and the systematization of the nursing process.


Realizing your marketing influence, Part 3: professional certification as a marketing tool.
This is the last in a series of articles guiding nursing administrators from broad marketing strategy to tactics and specific applications. The first article laid the foundation for developing a market-driven strategic plan. The second focused on marketing from the inside out. This final article explores the benefits of specialty nurse certification as a strategy for nursing administrators to retain and recruit the most qualified nurses and to differentiate their services from those of competitors. The article includes findings from the American Association of Critical-Care Nurses' proprietary research, suggestions on how to support certification, and a case study of one hospital's experience in conducting a CCRN certification drive as part of their critical care nurse competency program.


Sampling rare event energy landscapes via birth-death augmented dynamics.
A common problem that affects simulations of complex systems within the computational physics and chemistry communities is the so-called sampling problem or rare event problem where proper sampling of energy landscapes is impeded by the presences of high kinetic barriers that hinder transitions between metastable states on typical simulation time scales. Many enhanced sampling methods have been developed to address this sampling problem and more efficiently sample rare event systems. An interesting idea, coming from the field of statistics, was introduced in a recent work [Lu, Lu, and Nolen, Accelerating Langevin sampling with birth-death, arXiv:1905.09863] in the form of a novel sampling algorithm that augments overdamped Langevin dynamics with a birth-death process. In this work, we expand on this idea and show that this birth-death sampling scheme can efficiently sample prototypical rare event energy landscapes, and that the speed of equilibration is independent of the barrier height. We amend a crucial shortcoming of the original algorithm that leads to incorrect sampling of barrier regions by introducing an alternative approximation of the birth-death term. We establish important theoretical properties of the modified algorithm and prove mathematically that the relevant convergence results still hold. We investigate via numerical simulations the effect of various parameters, and we investigate ways to reduce the computational effort of the sampling scheme. We show that the birth-death mechanism can be used to accelerate sampling in the more general case of underdamped Langevin dynamics that is more commonly used in simulating physical systems. Our results show that this birth-death scheme is a promising method for sampling rare event energy landscapes.


A randomized matched-pairs study of feasibility, acceptability, and effectiveness of systems consultation: a novel implementation strategy for adopting clinical guidelines for Opioid prescribing in primary care.
This paper reports on the feasibility, acceptability, and effectiveness of an innovative implementation strategy named "systems consultation" aimed at improving adherence to clinical guidelines for opioid prescribing in primary care. While clinical guidelines for opioid prescribing have been developed, they have not been widely implemented, even as opioid abuse reaches epidemic levels. We tested a blended implementation strategy consisting of several discrete implementation strategies, including audit and feedback, academic detailing, and external facilitation. The study compares four intervention clinics to four control clinics in a randomized matched-pairs design. Each systems consultant aided clinics on implementing the guidelines during a 6-month intervention consisting of monthly site visits and teleconferences/videoconferences. The mixed-methods evaluation employs the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Quantitative outcomes are compared using time series analysis. Qualitative methods included focus groups, structured interviews, and ethnographic field techniques. Seven clinics were randomly approached to recruit four intervention clinics. Each clinic designated a project team consisting of six to eight staff members, each with at least one prescriber. Attendance at intervention meetings was 83%. More than 80% of staff respondents agreed or strongly agreed with the statements: "I am more familiar with guidelines for safe opioid prescribing" and "My clinic's workflow for opioid prescribing is easier." At 6 months, statistically significant improvements were noted in intervention clinics in the percentage of patients with mental health screens, treatment agreements, urine drug tests, and opioid-benzodiazepine co-prescribing. At 12 months, morphine-equivalent daily dose was significantly reduced in intervention clinics compared to controls. The cost to deliver the strategy was $7345 per clinic. Adaptations were required to make the strategy more acceptable for primary care. Qualitatively, intervention clinics reported that chronic pain was now treated using approaches similar to those employed for other chronic conditions, such as hypertension and diabetes. The systems consultation implementation strategy demonstrated feasibility, acceptability, and effectiveness in a study involving eight primary care clinics. This multi-disciplinary strategy holds potential to mitigate the prevalence of opioid addiction and ultimately may help to improve implementation of clinical guidelines across healthcare. ClinicalTrials.gov (NCT02433496). https://clinicaltrials.gov/ct2/show/NCT02433496 Registered May 5, 2015.


Neural Correlates of Attentional Modulation of Prepulse Inhibition.
Prepulse inhibition (PPI) refers to the suppression of the startle reflex when the intense startling stimulus is shortly (20-500 ms) preceded by a weak non-startling stimulus (prepulse). Although the main neural correlates of PPI lie in the brainstem, previous research has revealed that PPI can be top-down modulated by attention. However, in the previous attend-to-prepulse PPI paradigm, only continuous prepulse but not discrete prepulse (20 ms) could elicit attentional modulation of PPI. Also, the relationship between the attentional enhancement of PPI and the changes in early cortical representations of prepulse signals is unclear. This study develops a novel attend-to-prepulse PPI task, when the discrete prepulse is set at 150 ms at a lead interval of 270 ms, and reveals that the PPI with attended prepulse is larger than the PPI with ignored prepulse. In addition, the early cortical representations (N1/P2 complex) of the prepulse show dissociation between the attended and ignored prepulse. N1 component is enhanced by directed attention, and the attentional increase of the N1 component is positively correlated with the attentional enhancement of PPI, whereas the P2 component is not affected by attentional modulation. Thus, directed attention to the prepulse can enhance both PPI and the early cortical representation of the prepulse signal (N1).


Effectiveness of inositol, metformin and their combination in women with PCOS undergoing assisted reproduction: systematic review and meta-analysis.
Our study aims to compare the effect of metformin, inositol and their combinations on the efficiency in improving outcomes of assisted reproductive technologies in women with PCOS. PubMed, The Cochrane Library, ClinicalTrials.gov, Embase, MEDLINE. The search was performed on studies published before November 14, 2021, to identify articles evaluating the effectiveness of treatment metformin and inositol on ART outcomes. The systematic review was conducted according to the PRISMA 2020 checklist and registered in the PROSPERO 2021 CRD42021287887. Randomized controlled trials (RCTs) in English that compared metformin or inositol or metformin + inositol treatment with placebo or no treatment in women with PCOS undergoing assisted reproduction were included. In addition, RCTs with comparison combination and single metformin or inositol treatment were also included. 35 RCTs were included for qualitative analysis reporting on 4668 participants. In group of Metformin treatment were included 1891 patients, in Myo-inositol group - 281, in inositol + metformin group were included 110 participants and in control group (placebo or absence of treatment) - 1865 women with PCOS. 5 meta-analyses were performed. CPR in comparison of metformin and placebo in 1312 patients were higher in metformin group (RR = 1.30, 95% CI: 1.12 to 1.50, p = 0.0004). OHSS was less in metformin (RR = 0.34, 95% CI: 0.17 to 0.69, p = 0.003). However, LBR were not statistically significant (RR = 1.12, 95% CI: 0.93 to 1.36, p = 0.24). In comparison of inositol and no treatment there was also no difference in CPR (RR = 1.37, 95% CI: 0.79 to 2.38, p = 0.26). As for metformin and inositol meta-analysis in 220 patients with PCOS, CPR were higher in inositol group (RR = 1.52, 95% CI: 1.05 to 2.18, p = 0.03). Combination treatment included only two RCTs and was illegible for meta-analysis. To our knowledge, it is the first meta-analysis that estimates inositol treatment compared to metformin. Based on our systematic review and meta-analysis, metformin seems to be a good option for improving ART outcomes in women with PCOS. However, it is not clear whether inositol usage is adequate. Nevertheless, we need more clinical trials of good quality to answer all questions thoroughly.


Drosophila retrotransposon promoter includes an essential sequence at the initiation site and requires a downstream sequence for full activity.
We describe a 98-base-pair region (-38 to +60) in the long terminal repeat of the Drosophila gypsy retrotransposon that is sufficient for accurate normal-level transcription. We find that, unlike most RNA polymerase II (pol II) promoters, the gypsy promoter includes downstream sequences that are required for full activity. Also unlike most pol II promoters, the gypsy promoter, which lacks a TATA motif, was found to have an essential sequence at the transcription initiation site, mutation of which abolishes transcription. These three uncommon features of the gypsy promoter may be characteristic of a subset of pol II promoters, exemplified by certain retrotransposons and developmental genes of Drosophila and by Tdt, the mouse terminal deoxynucleotidyl-transferase (TdT) gene.


Electron binding energies and Dyson orbitals of OnH2n+1 +,0,- clusters: Double Rydberg anions, Rydberg radicals, and micro-solvated hydronium cations.
Ab initio electron propagator methods are employed to predict the vertical electron attachment energies (VEAEs) of OH3 +(H2O)n clusters. The VEAEs decrease with increasing n, and the corresponding Dyson orbitals are diffused over exterior, non-hydrogen bonded protons. Clusters formed from OH3 - double Rydberg anions (DRAs) and stabilized by hydrogen bonding or electrostatic interactions between ions and polar molecules are studied through calculations on OH3 -(H2O)n complexes and are compared with more stable H-(H2O)n+1 isomers. Remarkable changes in the geometry of the anionic hydronium-water clusters with respect to their cationic counterparts occur. Rydberg electrons in the uncharged and anionic clusters are held near the exterior protons of the water network. For all values of n, the anion-water complex H-(H2O)n+1 is always the most stable, with large vertical electron detachment energies (VEDEs). OH3 -(H2O)n DRA isomers have well separated VEDEs and may be visible in anion photoelectron spectra. Corresponding Dyson orbitals occupy regions beyond the peripheral O-H bonds and differ significantly from those obtained for the VEAEs of the cations.


Behavioral Monitoring of Sexual Offenders Against Children in Virtual Risk Situations: A Feasibility Study.
The decision about unsupervised privileges for sexual offenders against children (SOC) is one of the most difficult decisions for practitioners in forensic high-security hospitals. Facing the possible consequences of the decision for the society, a valid and reliable risk management of SOCs is essential. Some risk management approaches provide frameworks for the construction of relevant future risk situations. Due to ethical reasons, it is not possible to evaluate the validity of constructed risk situations in reality. The aim of the study was to test if behavioral monitoring of SOCs in high-immersive virtual risk situations provides additional information for risk management. Six SOCs and seven non-offender controls (NOC) walked through three virtual risk situations, confronting the participant with a virtual child character. The participant had to choose between predefined answers representing approach or avoidance behavior. Frequency of chosen answers were analyzed in regards to knowledge of the participants about coping skills and coping skills focused during therapy. SOCs and NOCs behavior differed only in one risk scenario. Furthermore, SOCs showed in 89% of all cases a behavior not corresponding to their own belief about adequate behavior in comparable risk situations. In 62% of all cases, SOCs behaved not corresponding to coping skills they stated that therapists focused on during therapy. In 50% of all cases, SOCs behaved in correspondence to coping skills therapists stated that they focused on during therapy. Therapists predicted the behavior of SOCs in virtual risk situations incorrect in 25% of all cases. Thus, virtual risk scenarios provide the possibility for practitioners to monitor the behavior of SOCs and to test their decisions on unsupervised privileges without endangering the community. This may provide additional information for therapy progress. Further studies are necessary to evaluate the predictive and ecological validity of behavioral monitoring in virtual risk situations for real life situations.


The interactive effect of health status on work patterns among urban Puerto Rican women.
This paper aims to integrate two existing bodies of literature on the sociology of work and health. Using data from a study conducted in New York City in 1980 of 40 Puerto Rican women, a conceptual model is proposed for additional research in the area. The findings are discussed within the context of the larger structural and socioeconomic status of this particular racial/ethnic group. The findings clearly indicate that health status is related to work patterns and economic as well as social resources. Of the respondents who reported a major health event in their lives, 80 percent had a discontinuous work history. Children's health was also a major determinant of work status. The results of this study clearly reveal the need for research that will take into account the interplay between economic conditions, structural work factors, and the process by which women evaluate their roles and fulfill their function as economic and health caretakers of the family.


Blood flow resistance with vibration and its effect on blood cell migration.
The present study investigated the effect of transverse vibration on the hemo-rheological characteristics of blood flow using a newly designed pressure-scanning capillary viscometer. As a transverse vibration was applied, aggregated blood cells become disaggregated. Frequency of vibration was found to be the main parameter causing hemo-rheological changes. For RBC suspension in a non-aggregating medium (Dextran 40), increasing frequency of vibration caused decreased flow resistance. Meanwhile, flow resistance for whole blood increased with frequency of vibration. These seemingly contradictory results could be interpreted without conflict when a comprehensive mechanism of cell migration under vibration is elucidated. The present study confirmed that vibration diminishes RBC aggregation, which triggers two different cell migration mechanisms and subsequently resulted in either increasing or decreasing the flow resistance.


Augmentation of venous drainage by a venous anastomosis for pedicled flaps.
Recently several studies have addressed the venous problem and confirmed that venous ischemia is more injurious to tissue viability than arterial ischemia of equivalent duration. There are different methods of managing venous-compromised pedicled flaps. Between June 1996 and November 2003, our center treated two submental, five Becker, nine posterior interosseous, three distally based sural, and three colon pedicled flaps (22 flaps in total), which had venous congestion either at the time of flap elevation or immediately after inset of the flap. These cases of venous congestion were managed with an immediate additional venous anastamosis. After vein anastomosis, venous congestion reduced gradually, then improved, and finally disappeared completely in the postoperative follow-up days with all flaps surviving in their entirety. Reexploration was not required for the microsurgical venous anastomosis. In conclusion, flap necrosis resulting from venous congestion causes prolonged hospitalization, multiple debridements, and additional procedures to cover the exposed structures. Additional vein anastomosis, which is a simple, rapid, and reliable auxiliary procedure, may increase complete flap survival and lead to successful end results, both functional and cosmetic.


Biliptysis Revealing a Bilio-Bronchial Fistula.
The presence of a bilio-bronchial fistula (BBF) of hydatid origin is considered a serious complication as it can lead to significant injuries at the abdominal, diaphragmatic, and thoracic levels. Here, we report the case of a 70-year-old patient presenting with biliptysis as a symptom and whose thoracic and abdominal CT scan confirmed the presence of a right BBF. The management consisted of an initial endoscopic sphincterotomy, followed by an exclusive left thoracotomy surgery to treat lung, liver, and diaphragmatic injuries. Fortunately, the evolution was favorable with the disappearance of the biliptysis. To diagnose a BBF, it is crucial to conduct a precise assessment, focusing mainly on imaging to accurately locate the injury before any surgical intervention.


Nosocomial rabies: investigation of contacts of human rabies cases associated with a corneal transplant.
In October 1978 in Boise, Idaho, a woman died of rabies after receiving a corneal transplant from a man, who in retrospect was also found to have died of rabies. Investigation of 203 contacts of these two patients identified 94 who were felt to have had sufficient risk of exposure to justify being given rabies post-exposure prophylaxis. Nurses, physicians, respiratory therapists, and family members were at greatest risk. We discuss the problems encountered in determining risk of exposure for contacts of humans with rabies.


Bilateral Sequential NAION following Cataract Extraction: Case Report and Review of the Literature.
We report a 64-year-old patient who developed nonarteritic ischemic optic neuropathy (NAION) in both eyes following cataract extraction. The cataract surgeries in both eyes were uneventful and performed within a year, and NAION occurred a few months postoperatively in both eyes. A review of the literature on this rare complication is provided. This case report serves to raise awareness among cataract surgeons about this potential complication associated with irreversible visual loss, and especially about its high risk of bilaterality.


Phe1-substituted beta-casomorphin-5 analogues with analgesic activity.
The antinociceptive potency of linear and cyclic beta-casomorphin-5 (CM-5) analogues, modified in position 1 by substitution of the tyrosine (Tyr) by the phenylalanine (Phe) residue, was studied using the vocalization test. With the exception of the linear [Phe1,D-Orn2]CM-5, the Phe1-substituted linear and cyclic casomorphin analogues exhibit remarkable analgesic potency compared to morphine, although the opioid receptor affinity and the opioid activity in vitro is diminished compared to the corresponding Tyr-containing analogues. The analgesic effect of the compounds is mediated by activation of opioid receptors, because it can be antagonized with naloxone. Furthermore, it was demonstrated that the [Phe1,D-Orn2,D-Pro4]CM-5, which was about sixfold more potent than morphine, developed cross-tolerance to morphine.


Origin of the old testament plagues: explications and implications.
Analyses of past disasters may supply insights to mitigate the impact of recurrences. In this context, we offer a unifying causative theory of Old Testament plagues, which has present day public health implications. We propose the root cause to have been an aberrant El Niño-Southern Oscillation teleconnection that brought unseasonable and progressive climate warming along the ancient Mediterranean littoral, including the coast of biblical Egypt, which, in turn, initiated the serial catastrophes of biblical sequence - in particular arthropod-borne and arthropod-caused diseases. Located beyond the boundary of focal climate change, inland Goshen would not have been similarly affected. Implicit in this analysis is a framework to consider a possibility of present day recurrence of similar catastrophes and their impact upon essential public services.


Risk associated with central catheters for malignant tumor patients: a systematic review and meta-analysis.
The risk of venous thrombosis and mortality associated with central catheter (PICC/CICC) for malignant tumor patients is not definite. So, we carried out a systematic review and meta-analysis to evaluate it. Among patients with comparing PICC with CICC, odds ratio (OR) or risk ratio (RR) was calculated with a random effect model meta-analysis. The result of the stratification analysis of 7 studies (PICC vs CICC) supported the theory that CICCs were associated with a decrease in the odds ratio of thrombosis compared with PICCs. 7 of 15 studies provided the information about the compared mortality rate of the patients. The result showed that CICCs were associated with a decrease in the odds ratio of thrombosis compared with PICCs (OR = 0.45, 95% CI:0.32-0.62, p < 0.0001, I2 = 0%,Tau2 = 0.00). Meta-analysis of 8 studies of 2639 patients showed that pharmacological deep vein thrombosis prophylaxis drugs could decrease the risk of mortality of malignant tumor patients with CICCs (RR = 0.58, 95% CI:0.48-0.71, Z = 5.32, p < 0.0001, I2 = 71%). We found that PICCs are associated with a raised risk of deep vein thrombosis, and pharmacological deep vein thrombosis prophylaxis drugs is a beneficial factor in decreasing the incidence of thrombosis, while warfarin may decrease the risk of mortality of malignant tumor patients with CICCs.


Twelve-month experience with the GORE® TIGRIS® Vascular Stent in the superficial femoral and popliteal arteries.
The aim of this paper was to report the continued mid-term follow-up of the first patients world-wide treated with the GORE(®) TIGRIS(®) Vascular Stent, a dual component stent consisting of a nitinol wire frame combined with a fluoropolymer-interconnecting structure. From December 2011 until November 2012, 32 consecutive patients (20 men, mean age 72.8 years) with 40 atherosclerotic femoropopliteal lesions (5% occlusions) underwent angioplasty and implantation of a GORE(®) TIGRIS(®) Vascular Stent. The patients were scheduled for follow-up at 3, 6 and 12 months after stent implantation for duplex ultrasound and assessment of Rutherford-Becker class (RBC) and Ankle-Brachial Index (ABI). Here we report the completed 6-month follow-up and, for the first time, a 12-month follow-up. The median follow-up was 418 days. During the 12-month follow-up 4 patients died. Restenosis or reocclusion of the stent in this time period was observed in 5 lesions (12.5%), resulting in a cumulative primary patency rate of 85.5±6.0%. The ABI increased pre-interventionally from 0.65±0.18 to 0.91±0.18 (P<0.0001) at the 12-month visit. The median RBC improved from 3 to 1 (P<0.0001). No stent thrombosis related to discontinuation of dual antiplatelet therapy 4 weeks after the index procedure was observed. The mid-term follow-up of the dual component GORE(®) TIGRIS(®) Vascular Stent showed promising results with high 12-month primary patency rates after femoropopliteal endovascular interventions. These first clinical data are very promising compared to other stent concepts in the superficial femoral and popliteal artery.


Distribution of the anterior, posterior, and total corneal astigmatism in healthy eyes.
To evaluate the magnitude and axis orientation of the anterior, posterior, and total corneal astigmatism in normal healthy eyes of an Iranian population. In a prospective cross-sectional study, ophthalmic and anterior segment parameters of 153 healthy eyes of 153 subjects were evaluated by Galilei dual Scheimpflug analyzer. The magnitude and axis orientation [with-the-rule (WTR), against-the-rule (ATR), and oblique] of the anterior, posterior, and total corneal astigmatism measurements (ACA, PCA, and TCA) were compared according to the age, sex, and other ophthalmic parameters. The mean ± SD age of the study population was 30 ± 5.9 years. The mean magnitude was 1.09 ± 0.76 diopters (D) for ACA, 0.30 ± 0.13 D for PCA, and 1.08 ± 0.77 D for TCA. Males had a significantly higher magnitude of PCA than females (p = 0.041). Most eyes had a WTR anterior astigmatism and an ATR posterior astigmatism. The WTR astigmatism had a higher mean magnitude compared to the ATR and oblique astigmatism in all the astigmatism groups, with a significant difference in the ACA and TCA groups (p < 0.05). PCA magnitude exceeded 0.50 D in only 7.8% of the subjects. ACA, PCA, and TCA were significantly correlated with each other and also had a significant correlation with the anterior and posterior maximum corneal elevation measurements (p < 0.001). The results of this study although are limited due to the small number of participants and confined to our demographics, provided information regarding a population that was not described before and may be helpful in obtaining optimum results in astigmatism correction in refractive surgery or designing new intraocular lenses.