A Quantitative Curriculum Mapping of the Faculty of Pharmacy of Yeditepe University, Turkey: A Process to Assess the Consistency of a Curriculum with the Mission and Vision of an Institution and National Requirements.
The changing role of the pharmacist led to some improvements of pharmacy education worldwide these last years. Curricula have evolved and the content-based education has been converted into a competency-based education. The definition of a global practice-based competency framework by the International Pharmaceutical Federation (FIP) and the European Pharmacy Competencies Framework by the European the Quality Assurance in European Pharmacy Education and Training (PHAR-QA) project helps Universities to keep in with these changes. The National Council of Deans of Faculties of Pharmacy in Turkey also defined 169 competencies with their sub-competencies that have to be reached upon the completion of a pharmacy education program, yet it did not indicate how the faculties can measure if their curricula are consistent with these competencies. This study aims to provide a method for a quantitative mapping of a given curriculum in order to analyze if a curriculum fulfills the requirements defined by the National Deans Council. It also helps to easily determine the weaknesses and strengths of a program. Moreover, with this study, the consistency of the content of the courses with the mission and vision defined by an institution can be easily determined. Thus, this study can also be a useful tool for the revision and enhancement of a program according to institutional targets.


Insulin up-regulates heme oxygenase-1 expression in 3T3-L1 adipocytes via PI3-kinase- and PKC-dependent pathways and heme oxygenase-1-associated microRNA downregulation.
Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has antioxidant, antiinflammatory, and antiapoptotic effects in many physiological systems. HO-1 activity in obese mice is lower than in controls, and a sustained increase in HO-1 protein levels ameliorates insulin resistance and compensatory hyperinsulinemia. In the present study, we explored the regulatory effect of insulin on HO-1 expression in 3T3-L1 adipocytes and the underlying mechanism. We investigated the time- and dose-effect of insulin on HO-1 expression in 3T3-L1 adipocytes. Using specific inhibitors acting on insulin signaling pathways, we clarified the involvement of insulin downstream signaling molecules in insulin-regulated HO-1 expression. We also investigated the involvement of microRNAs (miRNAs) in insulin-regulated HO-1 expression using microarray and real-time RT-PCR assays. In an in vivo study, we performed insulin/glucose coinfusion in rats to increase circulating insulin levels for 8 h, then measured adipocyte HO-1 expression. Insulin caused a significant increase in HO-1 expression that was time- and dose-dependent, and this effect was blocked by inhibition of phosphatidylinositol 3 (PI3)-kinase activation using LY294002 (50 μM) or of protein kinase C activation using Ro-318220 (2 μM), but not by an Akt inhibitor, triciribine (10 μM). Furthermore, incubation of 3T3-L1 adipocytes with 100 nm insulin resulted in a significant decrease in levels of the miRNAs mir-155, mir-183, and mir-872, and this effect was also blocked by pretreatment with LY294002 or Ro-318220, but not triciribine. An in vivo study in rats showed that 8 h of a hyperinsulinemic euglycemic state resulted in a significant increase in adipocyte HO-1 expression. In conclusion, insulin increases HO-1 protein expression in 3T3-L1 adipocytes via PI3-kinase and protein kinase C-dependent pathways and miRNAs down-regulation.


Pathology of Neointimal Calcification in Very Late Restenosis After Bare Metal Stent Implantation for Superficial Femoral Artery.
A 60-year-old man, who had claudication in his right limb due to total occlusion of the right superficial femoral artery, received bare metal stents. Although the bare metal stents in the superficial femoral artery did not show restenosis 5 years after stent implantation, angiography revealed significant in-stent restenosis when he developed right critical limb ischemia at 8 years post implantation. Ballooning for in-stent lesions did not result in full expansion. His right limb was amputated above the knee due to progressive limb ischemia. In the pathological findings in the superficial femoral artery, marked calcification was observed in the entire circumference of the luminal surface of the neointima. However, lipid core formation was not identified in the neointima. Although several cracks following balloon angioplasty were observed at the superficial calcified layers, injury to neointimal tissue such as compression was not observed. The neointima exhibited heavy calcification in the very late phase of in-stent restenosis after bare metal stent implantation in superficial femoral artery. Therefore, balloon angioplasty in the very late phase of in-stent restenosis potentially results in underexpansion.


Communication between (L)-galactono-1,4-lactone dehydrogenase and cytochrome c.
l-galactono-1,4-lactone dehydrogenase (GALDH) catalyzes the terminal step of vitamin C biosynthesis in plant mitochondria. Here we investigated the communication between Arabidopsis thaliana GALDH and its natural electron acceptor cytochrome c (Cc). Using laser-generated radicals we observed the formation and stabilization of the GALDH semiquinone anionic species (GALDHSQ ). GALDHSQ oxidation by Cc exhibited a nonlinear dependence on Cc concentration consistent with a kinetic mechanism involving protein-partner association to form a transient bimolecular complex prior to the electron transfer step. Oxidation of GALDHSQ by Cc was significantly impaired at high ionic strength, revealing the existence of attractive charge-charge interactions between the two reactants. Isothermal titration calorimetry showed that GALDH weakly interacts with both oxidized and reduced Cc. Chemical shift perturbations for (1) H and (15) N nuclei of Cc, arising from the interactions with unlabeled GALDH, were used to map the interacting surface of Cc. For Arabidopsis Cc and yeast Cc, similar residues are involved in the interaction with GALDH. These residues are confined to a single surface surrounding the heme edge. The range of chemical shift perturbations for the physiological Arabidopsis Cc-GALDH complex is larger than that of the non-physiological yeast Cc-GALDH complex, indicating that the former complex is more specific. In summary, the results point to a relatively low affinity GALDH-Cc interaction, similar for all partner redox states, involving protein-protein dynamic motions. Evidence is also provided that Cc utilizes a conserved surface surrounding the heme edge for the interaction with GALDH and other redox partners. NMR assignment of the backbone amide resonances of Arabidopsis CcRED has been deposited in BMRB database (BMRB accession number 18828). L-galactono-1,4-lactone dehydrogenase (L-galactono-1,4-lactone: ferricytochrome c oxidoreductase, EC 220.127.116.11).


Spatially resolved solid-state 1H NMR for evaluation of gradient-composition polymeric libraries.
Polyurethane libraries consisting of films with composition gradients of aliphatic polyisocyanate and hydroxy-terminated polyacrylate resin were characterized using methods of (1)H NMR microimaging (i.e., magnetic resonance imaging, (MRI)) and solid-state NMR. Molecular mobilities and underlying structural information were extracted as a function of the relative content of each of the two components. Routine NMR microimaging using the spin-echo sequence only allows investigations of transverse relaxation of magnetization at echo times >2 ms. A single-exponential decay was found, which is likely due to free, noncross-linked polymer chains. The mobility of these chains decreases with increasing content of the aliphatic polyisocyanate. The concept of a 1D NMR profiler is introduced as a novel modality for library screening, which allows the convenient measurement of static solid-state NMR spectra as a function of spatial location along a library sample that is repositioned in the rf coil between experiments. With this setup the complete transverse relaxation function was measured using Bloch decays and spin echoes. For all positions within the gradient-composition film, relaxation data consisted of at least three components that were attributed to a rigid highly cross-linked resin, an intermediate cross-linked but mobile constituent, and the highly mobile free polymer chains (the latter is also detectable by MRI). Analysis of this overall relaxation function measured via Bloch decays and spin echoes revealed only minor changes in the mobilities of the individual fractions. Findings with respect to the most mobile components are consistent with the results obtained by NMR microimaging. The major effect is the significant increase in the rigid-component fraction with the addition of the hydroxy-terminated polyacrylate resin.


Analysis of cell type and radiographic presentation as predictors of the clinical course of patients with bronchioalveolar cell carcinoma.
Bronchioloalveolar carcinoma is a primary lung neoplasm of variable histopathologic, radiologic, and clinical expression. There are three cell types described in bronchioloalveolar carcinoma: Clara cells, mucin-producing cells, and alveolar type II epithelial cells. It is unclear whether these three tumor cell types are associated with a specific radiologic presentation and clinical course. In this study, we investigated whether tumor cell type, identified by transmission electron microscopy, correlated with a specific radiologic pattern, and whether tumor cell type or radiologic presentation correlated with the patient's clinical course and outcome. Transmission electron microscopy was used to restudy tissue blocks from the original surgical histopathologic specimens in 54 patients with primary bronchioloalveolar carcinoma diagnosed over a 10-year period (1980 to 1990). The pretreatment radiographs were reviewed in each case, and the first chest radiograph obtained at the time of the discovery of the tumor in each patient was compared with the results of the ultrastructural study. The medical records of each patient were examined to obtain pertinent radiologic, clinical, and patient outcome information. There were 32 Clara cell tumors, 10 mucin-producing cell tumors, and 1 alveolar type II epithelial cell tumor in this series. Eleven additional tumors had mixtures of two or more cell types. No statistically significant relationship was detected between tumor cell type and radiologic presentation or patient mortality pattern. There was increased mortality among patients who presented radiologically with segmental, lobar, multifocal, or diffuse disease compared with those patients exhibiting a solitary pulmonary nodule at presentation. Radiologic presentation, rather than tumor cell type, provides prognostic information that aids in predicting patient outcome.


Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.
Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.


Family caregivers' monitoring of medication usage: a qualitative study of Mexican-origin families with serious mental illness.
Despite the high level of involvement of many family caregivers of adults with serious mental illness such as schizophrenia, little is known about their experiences with and beliefs about monitoring the psychiatric medication usage of their relatives. We used consensual qualitative research methods to analyze narratives on this topic by 12 Mexican-descent caregivers (160 pages of transcripts). The caregivers predominantly represented parent (mother) caregivers with levels of psychological distress and burden that were similar to those of larger samples of Mexican-descent caregivers. They represented equally high and low Expressed Emotion. We found that (a) caregivers' high knowledge (awareness) of medication usage was either tied to a hands-on monitoring approach or inferred by either the absence or the presence of their relatives' symptoms, (b) caregivers struggled with reconciling the symptom stabilization benefits of medication with the medications' side effects and limitations, and (c) most caregivers received little to no assistance from other available family members. Theory development and possible interventions involving family-assisted support of psychiatric medication usage should assess and possibly address caregivers' struggles with medications' side effects and low levels of support from available family.


The influence of partial knee replacement designs on tensile strain at implant-bone interface.
Partial knee replacement (PKR) results in fast recovery and good knee mechanics and is ideal to treat medial knee osteoarthritis. Cementless PKR depends on bone growing into the implant surface for long-term fixation. Implant loosening may occur due to high tensile strain resulted from large mechanical loads during rehab exercises. The purpose of this study is to investigate whether external fixations such as superior screw and frontal flange could reduce the tensile strain at the implant-bone interface. Three medial PKRs were designed. The first PKR had no external fixations. A superior screw and a frontal flange were then added to the first PKR to form the second and third PKR designs, respectively. Finite element analysis was performed to examine the tensile strain at the implant-bone interface during weight-bearing exercises. The PKR with no external fixations exhibited high tensile strain at the anterior implant-bone interface. Both the screwed and flanged PKRs effectively reduced the tensile strain at the anterior implant-bone interface. Furthermore, the flanged PKR resulted in a more uniform reduction of the tensile strain than the screwed PKR. In conclusion, external fixations are necessary to alleviate tensile strain at the implant-bone interface during knee rehab exercises.


Prognostic Value of Shock Index, Modified Shock Index, and Age-Adjusted Derivatives in Prediction of In-Hospital Mortality in Patients with Acute Decompensated Heart Failure: Persian Registry of Cardiovascular Disease/ Heart Failure Study.
Introduction of simple bedside tools for assessing patients' condition in different settings improves triaging. However, these indices are less frequently used in heart failure. This study aims to evaluate the utility of shock index, age shock index, modified shock index, and age-modified shock index in the prediction of in-hospital mortality in acute decompensated heart failure individuals. We conducted this retrospective study on 3652 acute decompensated heart failure individuals in the context of Persian Registry of Cardiovascular Disease/heart failure. Shock index, age shock index, modified shock index, and age-modified shock index were assessed during admission. Receiver operating characteristic curve was used to define the optimum cut-off point. Odds ratio models were used for investigating the association of in-hospital mortality according to each specified cut-off value. Mean age was 70.12 ± 12.56 years (males: 62.6%). Optimum cut-off point for shock index, age shock index, modified shock index, and age-modified shock index were set to be 0.71 (sensitivity: 63%, specificity: 60%), 50.5 (sensitivity: 65%, specificity: 60%), 0.94 (sensitivity: 60%, specificity: 60%), and 66.7 (sensitivity: 62%, specificity: 60%), respectively. Participants with higher shock index derivatives in all domains had significantly higher likelihood of death. Compared to those with shock index, age shock index, modified shock index, and age-modified shock index values of less than cut-off points, adjusted model revealed patients with higher values had 2.59 (95% CI: 1.94-3.46, P<.001), 2.61 (95% CI: 1.95-3.48, P <.001), 2.14 (95% CI: 1.61-2.84, P <.001), and 2.28 (95% CI: 1.72- 3.03, P <.001) times increase in-hospital death risk, respectively. Shock index, age shock index, modified shock index, and age-modified shock index are simple bedside tools to reliably predict in-hospital mortality in acute decompensated heart failure patients to better prioritize high-risk subjects.


Thermal stress resistance of the brown alga Fucus serratus along the North-Atlantic coast: acclimatization potential to climate change.
Seaweed-dominated communities are predicted to disappear south of 45° latitude on North-Atlantic rocky shores by 2200 because of climate change. The extent of predicted habitat loss, however, could be mitigated if the seaweeds' physiology is sufficiently plastic to rapidly acclimatize to the warmer temperatures. The main objectives of this study were to identify whether the thermal tolerance of the canopy-forming seaweed Fucus serratus is population-specific and where temperatures are likely to exceed its tolerance limits in the next 200 years. We measured the stress response of seaweed samples from four populations (Norway, Denmark, Brittany and Spain) to common-garden heat stress (20 °C-36 °C) in both photosynthetic performance and transcriptomic upregulation of heat shock protein genes. The two stress indicators did not correlate and likely measured different cellular components of the stress response, but both indicators revealed population-specific differences, suggesting ecotypic differentiation. Our results confirmed that thermal extremes will regularly reach physiologically stressful levels in Brittany (France) and further south by the end of the 22nd century. Although heat stress resilience in photosynthetic performance was higher at the species' southern distributional edge in Spain, the hsp expression pattern suggested that this edge-population experienced reduced fitness and limited responsiveness to further stressors. Thus, F. serratus may be unable to mitigate its predicted northward shift and may be at high risk to lose its center of genetic diversity and adaptability in Brittany (France). As it is an important intertidal key species, the disappearance of this seaweed will likely trigger major ecological changes in the entire associated ecosystem.


Interdependence of stroke survivors' recovery and their relatives' attitudes and health: a contribution to investigating the causal effects.
One goal of the study was to test specific hypotheses concerning the interdependence of the stroke survivors' recovery and their caregiving partners' attitudes and health. The other aim was to find an applicable method for investigating causal effects on the rehabilitation of chronically sick persons in longitudinal studies with medium-sized samples. The recovery of 81 stroke survivors regarding the physical and mental functioning in everyday life and their caregiving partners' health and attitudes were assessed twice, once after the patients left the hospital and again one year later. We applied the structure equation modeling and the cross-lagged partial correlation analysis (CLPC) for testing causal effects. Particularly stroke victims' cognitive and emotional recovery seems to be influenced by psychosocial factors such as the caregiving partners' acceptance of a post-stroke life-situation. In contrast to this, the research suggests that the patients' recovery regarding physical functioning is not substantially affected by the partners, rather the patients' difficulties with motor functioning influence their partners' health. Caregivers merit attention as part of rehabilitation interventions. We recommend the CLPC for investigating causal effects in the complex interdependence of chronically sick persons' convalescence and their family members' health and state of mind in medium-sized samples.


Immunohistochemical study of ten cases of argyrophilic carcinoma (carcinoid) of the breast.
The significance of argyrophilia in human breast cancer is still a controversial issue. We tested immunohistochemically 10 cases of argyrophilic carcinomas of the breast and found evidence of immunoreactivity with neuroendocrine markers: chromogranin, NSE, gastrin, insulin and bombesin. Argyrophilia was demonstrated in breast cancers of the usual types and was found to be related to the secretory activity of neoplastic cells. Unfortunately, no adequate follow-up data are available to clarify the natural history of argyrophilic breast cancer. A clinical treatment different from that of conventional breast cancer is not at present justified.


Predictors of lethality in severe leptospirosis in urban Brazil.
To ascertain prognostic factors associated with fatal outcomes in severe leptospirosis, a retrospective case-control study was done using population-based surveillance data. Centralized death certificate reporting of leptospirosis mortality was combined with details of patients' hospitalizations, which were obtained from hospitals representing all sectors of São Paulo city. Among identified leptospirosis cases, 89 lethal cases and 281 survivor cases were analyzed. Predictors of death included age>40 years, development of oliguria, platelet count<70,000/microL, creatinine>3 mg/dL, and pulmonary involvement. The latter was the strongest risk factor with an estimated odds ratio of 6.0 (95% confidence interval: 3.0-12.0). Serologic findings with highest titer against Leptospira interrogans serovar Copenhageni did not show significant differences between survivors and non-survivors. Lung involvement was an important predictor of death in leptospirosis in São Paulo, of relevance in leptospirosis-endemic regions where this complication is common.


Alcohol and breast cancer: reconciling epidemiological and molecular data.
Breast cancer is the most diagnosed cancer in women worldwide. Epidemiological studies have suggested a possible causative role of alcohol consumption as a risk factor for breast cancer. However, such conclusions should be interpreted with considerable caution for several reasons. While epidemiological studies can help identify the roots of health problems and disease incidence in a community, they are by necessity associative and cannot determine cause and effect relationships. In addition, all these studies rely on self-reporting to determine the amount and type of alcoholic beverage consumed, which introduces recall bias. This is documented in a recent study which stated that the apparent increased risk of cancer among light-moderate drinkers may be "substantially due to underreporting of intake." Another meta-analysis about alcohol and breast cancer declared "the modest size of the association and variation in results across studies leave the causal role of alcohol in question." Furthermore, breast cancer develops over decades; thus, correlations between alcohol consumption and breast cancer cannot be determined in epidemiological studies with windows of alcohol exposure that captures current or recent alcohol intake, after clinical diagnosis. Numerous risk factors are involved in breast carcinogenesis; some are genetic and beyond the control of a woman; others are influenced by lifestyle factors. Breast cancer is a heterogeneous and polygenic disease which is further influenced by epigenetic mechanisms that affect the transciptomes, proteomes and metabolomes, and ultimately breast cancer evolution. Environmental factors add another layer of complexity by their interactions with the susceptibility genes for breast cancer and metabolic diseases. The current state-of-knowledge about alcohol and breast cancer association is ambiguous and confusing to both a woman and her physician. Confronting the huge global breast cancer issue should be addressed by sound science. It is advised that women with or without a high risk for breast cancer should avoid overconsumption of alcohol and should consult with their physician about risk factors involved in breast cancer. Since studies associating moderate alcohol consumption and breast cancer are contradictory, a woman and her physician should weigh the risks and benefits of moderate alcohol consumption.


A Rare Case of Primary Central Nervous System Lymphoma in an Adolescent Female Treated with High-Dose Methotrexate and Rituximab-Based Chemoimmunotherapy and Consolidation Whole Brain Radiotherapy.
Primary central nervous system lymphoma (PCNSL) is a rare pediatric brain tumor. A 16-year-old female patient presented to the clinic with complaints of multiple episodes of generalized tonic clonic seizures, nystagmus, and weakness on the left side of the body for 3 weeks. She had similar symptoms, waxing and waning for the last 2 years, responding to corticosteroids. Repeat magnetic resonance imaging (MRI) of the brain showed multiple areas of signal abnormalities involving the left temporal lobe, the basal ganglion, the thalamus, and the right frontal and occipital lobes with contrast enhancement in bitemporal lesions. With a clinico- radiological diagnosis of demyelinating disorder, she underwent an image-guided right frontal lobe biopsy, which revealed sheets of atypical lymphoid cells diffusely immunopositive for CD20 but negative for CD3, CD10, BCL-6, and MUM-1, suggesting diffuse large B-cell lymphoma, germinal center B-cell subtype. The systemic lymphoma workup was essentially normal. She received 5 cycles of chemoimmunotherapy with rituximab, high-dose methotrexate (HDMTX), vincristine, and procarbazine and had a complete radiological response (CR). This was followed by whole brain radiotherapy (WBRT) to a dose of 36 Gy in 20 fractions over 4 weeks. Subsequently she received 2 cycles of consolidation chemoimmunotherapy with rituximab and high-dose cytarabine. Serial brain MRI done 1, 4, and 8 months after completion of treatment showed persistence of the CR. At the last follow-up visit, 15 months from the date of diagnosis, she was disease free and asymptomatic. This report underlines the fact that PCNSL in adolescents may be effectively treated with a combination of HDMTX- and rituximab-based chemoimmunotherapy followed by consolidation with WBRT.


Construction of Covalent Organic Cages with Aggregation-Induced Emission Characteristics from Metallacages for Mimicking Light-Harvesting Antenna.
A series of covalent organic cages built from fluorophores capable of aggregation-induced emission (AIE) were elegantly prepared through the reduction of preorganized M2 (LA )3 (LB )2 -type metallacages, simultaneously taking advantage of the synthetic accessibility and well-defined shapes and sizes of metallacages, the good chemical stability of the covalent cages as well as the bright emission of AIE fluorophores. Moreover, the covalent cages could be further post-synthetically modified into an amide-functionalized cage with a higher quantum yield. Furthermore, these presented covalent cages proved to be good energy donors and were used to construct light-harvesting systems employing Nile Red as an energy acceptor. These light-harvesting systems displayed efficient energy transfer and relatively high antenna effect, which enabled their use as efficient photocatalysts for a dehalogenation reaction. This research provides a new avenue for the development of luminescent covalent cages for light-harvesting and photocatalysis.


Exploring the association between eating disorders and gender dysphoria in youth.
This study reviews the overlap between eating disorders (EDs) and gender dysphoria (GD) in an adolescent population. A retrospective chart review was conducted on a clinical population presenting for concerns of GD. It was noted that five of the 97 patients had been found to be suffering from an ED at presentation. An additional 10 patients were noted to have ED-related symptoms. Although ED risk was elevated in trans males and females, absolute risk was higher in trans males when compared to population based prevalence rates. Our results suggest that rates of EDs and ED-related symptoms are high in patients presenting with GD, and that standard screening for these symptoms should be considered in both populations at assessment and over the course of treatment.


Calf Endurance and Achilles Tendon Structure in Classical Ballet Dancers.
Optimal lower leg function is critical for ballet dancers to meet their occupational requirements. Achilles tendon injury is particularly detrimental to ballet dancers. While standardized measures have been validated and incorporated into clinical practice for use in people with Achilles tendon injury, normative ranges specific to the dancer population have not been described. The purpose of this pilot study was to observe the performance of pre-professional ballet students and professional ballet dancers on a well-established test battery for lower leg functional performance as well as ultra-sonographic evaluation of the structure of their Achilles tendons. The dancers in this study had significantly shorter Achilles tendons than non-dancers (p = 0.016). Dancers demonstrated significantly higher maximum heel-rise height on the heel-rise test for calf endurance (p < 0.001) but performed significantly less work than non-dancers (p = 0.014). The results of this study support the use of the heel-rise test as a tool for screening and to guide rehabilitation.


[The effect of calf blood dialysate on the excretion of estriol in placental insufficiency].
The efficacy of a dialysate of calf blood in the treatment of chronic placental insufficiency is assessed using the urinary oestriol elimination as parameter. Compared with a control group, those cases receiving 2 times 250 ml protein-free dialysate of calf blood (Solcoseryl) in saline solution over 9 days showed a significant increase in the daily quantity of urinary oestriol elimination already from the second day of treatment onwards. Other conventional procedures in the medical treatment of placental insufficiency are discussed. Some of these are known to have secondary effects or must be regarded as invasive.


Effect of diazepam and chlorpromazine on proliferative activity and vascular endothelial growth factor (VEGF) secretion from cultured endothelial HECa10 cells in vitro.
Diazepam and chlorpromazine - psychotropic agents widely used for the amelioration of anxiety, depression, and psychosis, have been found to affect cell proliferation. We have checked whether these drugs influence proliferation of endothelial cells and probably angiogenesis process. We have studied the effect of diazepam and chlorpromazine on proliferative activity and vascular endothelial growth factor (VEGF) release from murine endothelial HECa10 cells cultured in vitro. In conclusion, diazepam at concentration of 10(-4)M had inhibitory action on the proliferation of endothelial cells in cultures. Chlorpromazine at concentrations from 10(-7) to 10(-4)M diminished the proliferative activity and secretion of VEGF into supernatants of cultured cells.


Conjunctival cytologic features of primary Sjögren's syndrome.
To determine whether there are specific cytologic features associated with primary Sjögren's syndrome (SS), the authors evaluated impression cytology specimens from three conjunctival sites (temporal bulbar [TB], inferior bulbar [IB], and inferior tarsal [IT]) from 38 SS eyes, 34 eyes of aqueous tear-deficient patients without SS, 35 eyes of seborrheic blepharitis patients, and 17 eyes of normal controls in a masked fashion. The following features were observed more frequently in SS eyes than in the eyes of the other groups: squamous metaplasia of the TB and IB (P less than 0.05), extensive (greater than 75%) goblet cell loss of the TB (P less than 0.05), mucous aggregates of the bulbar conjunctiva (P less than 0.05), and inflammatory cells intercalated with epithelial cells on the IT conjunctiva (P less than 0.06). The conjunctival inflammatory cell infiltrate correlated with the presence of extensive squamous metaplasia (P less than 0.01) in SS specimens. The inflammatory cells on the IT conjunctival epithelium were found to consist predominantly of T-lymphocytes by immunofluorescent staining of cytologic specimens from six eyes. Based on these findings, the authors speculated that conjunctival squamous metaplasia, in addition to aqueous tear deficiency, may be due to primary involvement of the dysfunctional immune system of SS.


The role of liver biopsy in the workup of liver dysfunction late after SCT: is the role of iron overload underestimated?
Abnormalities in liver function tests are common in hematopoietic SCT (HSCT) recipients. We retrospectively investigated the role of liver biopsy in determining the cause of elevated liver enzymes and its impact on the management of patients in the post-HSCT setting. A total of 24 consecutive liver biopsies were obtained from 20 patients from September 2003 to December 2007. A definite histopathologic diagnosis was obtained in 91.7% of the biopsies. Iron overload (IO) was found in 75% and GVHD in 54.2% of the patients. The initial clinical diagnosis of GVHD was confirmed in 56.5% and refuted in 43.5% of the allogeneic HSCT recipients. The median number of post transplant transfusions, percent transferrin saturation and ferritin levels were found to be higher in patients who had histologically proven hepatic IO (p1=0.007, p2=0.003 and p3=0.009, respectively). Regression analysis showed a significant correlation between serum ferritin levels and histological grade of iron in the hepatocytes. Our data suggest that hepatic IO is a frequent finding in the post-HSCT setting, which contributes to hepatic dysfunction and it should be considered in the differential diagnosis, particularly in patients with high serum ferritin levels.


Assumed non-persistent environmental chemicals in human adipose tissue; matrix stability and correlation with levels measured in urine and serum.
The aim of this study was to (1) optimize a method for the measurement of parabens and phenols in adipose tissue, (2) evaluate the stability of chemical residues in adipose tissue samples, and (3) study correlations of these compounds in urine, serum, and adipose tissue. Samples were obtained from adults undergoing trauma surgery. Nine phenols and seven parabens were determined by isotope diluted TurboFlow-LC-MS/MS. The analytical method showed good accuracy and precision. Limits of detection (LOD) for parabens and phenols ranged from 0.05 to 1.83ng/g tissue. Good recovery rates were found, even when biological samples remained defrosted up to 24h. Benzophenone-3 (BP-3; range of values: <LOD-1.48ng/g tissue) and methylparaben (MeP; <LOD-1.78ng/g tissue) were detected in >70% of adipose tissue samples, while bisphenol-A (BPA; <LOD-3.28ng/g tissue) and 2-phenylphenol (2-PP; <LOD-0.78ng/g tissue) were detected in >40% of adipose tissue samples. In general, levels were similar between adipose tissue and serum, while a correlation between adipose tissue and urine was only found for BP-3. In conclusion, adipose tissue samples in this study were found to contain environmental chemicals considered to be non-persistent, whose levels were weakly or not at all correlated with the urine burden. Therefore, adipose tissue may potentially provide additional information to that obtained from other biological matrices. Further investigations are warranted to explore whether adipose tissue might be a suitable matrix for assessment of the consequences for human health of mid/long-term exposure to these chemicals.


Viral hepatitis among drug users in methadone maintenance: associated factors, vaccination outcomes, and interventions.
Drug users are at high risk of viral Hepatitis A, B, and C. The prevalence of Hepatitis A, Hepatitis B, and Hepatitis C, associated factors, and vaccine seroconversion among drug treatment program participants in a randomized controlled trial of hepatitis care coordination were examined. Of 489 participants, 44 and 47% required Hepatitis A/Hepatitis B vaccinations, respectively; 59% were Hepatitis C positive requiring linkage to care. Factors associated with serologic statuses, and vaccine seroconversion are reported; implications for strategies in drug treatment settings are discussed. Results suggest generalizable strategies for drug treatment programs to expand viral hepatitis screening, prevention, vaccination, and linkage to care.


Is there gender bias in the prehospital management of patients with acute chest pain?
Prior emergency department (ED) and inpatient studies have found that women with coronary artery disease are more frequently misdiagnosed and undertreated compared with men. This study was performed to determine whether there is a gender bias in the prehospital management of patients with acute chest pain. This study was performed in a large urban county emergency medical services (EMS) agency with approximately 40,000 patient contacts/year. The study population comprised consecutive patients > or = 45 years old with a chief complaint of atraumatic chest pain. Using chi2 analysis and the unpaired Student's t-test, male and female patient encounters were compared. This study had >80% power (alpha 0.05) to detect a 3% difference between populations. Data from 2,858 consecutive patient encounters were analyzed, with females comprising 1,508 (53%). Females were significantly older than males (67 +/- 13.1 vs. 62.7 +/- 12.3 years, p < 0.001). Male patients were more likely to receive aspirin (42.3% vs. 35.4%, p < 0.001) and 12-lead electrocardiograms (ECGs) (46.8% vs. 39.3%, p < 0.001) compared with female patients. The rates of transport refusal, oxygen, nitroglycerin, and narcotic administration did not differ between populations. Although females presenting to this urban EMS system with acute chest pain were older, they received significantly less aspirin and fewer 12-lead ECGs in the field. These results suggest strategies must be developed to ensure that appropriate therapy is provided to women presenting to EMS systems with acute cardiac ischemia.


Influence of cytomegalovirus infection on the recovery of humoral immunity after autologous bone marrow transplantation.
Recovery of B-cell number and function was studied in 23 patients with hematological malignancies treated with high-dose chemoradiotherapy followed by autologous bone marrow transplantation (auto-BMT) in relation to the presence or absence of cytomegalovirus (CMV) infection. B cells recovered rapidly after auto-BMT and specific antibodies to herpes viruses remained nearly unchanged. Both were independent of the CMV status of the patients. However, the capacity of peripheral blood B cells to differentiate in vitro into cytoplasmic immunoglobulin (Ig)-positive cells (plasma cells) on pokeweed mitogen stimulation in the presence of normal T-cell help was significantly better in CMV-negative patients than in CMV-positive patients after auto-BMT, but was decreased in both groups. Serum Ig levels were, in contrast, higher in CMV-positive patients than in CMV-negative patients after auto-BMT.


Evaluation of a test for Clostridium difficile toxins A and B for the diagnosis of neonatal swine enteritis.
A commercially available 1-hour enzyme immunoassay (EIA) for detecting the presence of Clostridium difficile toxins A and B was evaluated for use in diagnosis of C. difficile infections in neonatal swine. This test was compared with a tissue culture cytotoxicity assay, which is considered to be the reference standard for the detection of C. difficile toxins. Twenty-seven samples of colonic contents and 23 fecal samples were collected from freshly euthanized neonatal swine with a history of scours. Of the 50 specimens tested, 20 were positive by the EIA test and tissue culture and 24 were negative by both tests, for an overall correlation of 88%. The sensitivity and specificity of the EIA were 91% and 86%, respectively, and the positive and negative predictive values were 84% and 86%, respectively. The EIA test is considered suitable as an aid for the diagnosis of C. difficile enteritis because of the high correlation between EIA results and those of the tissue culture cytotoxicity assay.


Role of tromaril--a new anti-inflammatory drug in eye diseases.
In this clinical study, the role of enfenamic acid (Tromaril), a new anti-inflammatory and nonsteroidal drug, on various eye diseases such as trauma, on inflammatory diseases such as uveitis, and after cataract surgery was evaluated. The drug was administered to 30 patients (group A) while 29 patients (group B) were given a placebo. Twenty-one patients showed good response, and of these, 15 patients (76%) belonged to group A, to whom Tromaril had been administered. Of the patients who were given Tromaril, none showed any side effects in general. It can be concluded that Tromaril is a strong and effective anti-inflammatory drug for use in various eye diseases.


Case of Nontraumatic Rectus Sheath Hematoma from Muscle Training Mimicking Acute Abdomen.
Rectus sheath hematoma is an unusual but well-known clinical problem. Our hospital admitted a 54-year-old woman complaining of harsh right-sided hypogastric pain that started while muscle training. Computed tomography of the abdomen and pelvis demonstrated a right rectus sheath hematoma. As the hematoma did not increase, the patient was conservatively treated. Despite increased awareness of rectus sheath hematoma, its early diagnosis and treatment still present a challenge to emergency physicians. Swift acknowledgement of this rare cause of abdominal pain may avoid more intrusive examination, unnecessary hospitalization, and laparotomy. Careful consideration of the patient's medical history and a high index of suspicion are needed to diagnose this complication.


Lead and thallium tetrakis(imidazolyl)borates: modifying structure by varying metal and anion.
We are using the coordinating anions tetrakis(imidazolyl)borate and tetrakis(4-methylimidazolyl)borate to construct new metal-organic framework structures. In this report, we are exploring materials similar in composition to the previously reported layered network structure Pb[B(Im)(4)](NO(3))(nH(2)O). The metal in this compound can be replaced with isoelectronic Tl(I), affording Tl[B(Im)(4)], and the borate can be modified by using 4-methylimidazole, resulting in Pb[B(4-MeIm)(4)](NO(3)) and Tl[B(4-MeIm)(4)]. Like the parent Pb[B(Im)(4)](NO(3))(nH(2)O), Tl[B(Im)(4)] and Tl[B(4-MeIm)(4)] are layered network structures but both lack anions or solvent molecules in the interlayer spacing. The material Pb[B(4-MeIm)(4)](NO(3)), however, exhibits a 3D network structure that lacks an open topology, resulting from the increased stereochemical activity (greater steric bulk toward other ligands) of the 4-methylimidazole ring. Both of the Tl(I) solids display longer M-N bonds than observed in the analogous Pb(II) compounds; these lengths account for the decreased effect of the stereochemical activity of the 4-methylimidazole ring in Tl[B(4-MeIm)(4)].


Mechanomyography and Torque during FES-Evoked Muscle Contractions to Fatigue in Individuals with Spinal Cord Injury.
A mechanomyography muscle contraction (MC) sensor, affixed to the skin surface, was used to quantify muscle tension during repetitive functional electrical stimulation (FES)-evoked isometric rectus femoris contractions to fatigue in individuals with spinal cord injury (SCI). Nine persons with motor complete SCI were seated on a commercial muscle dynamometer that quantified peak torque and average torque outputs, while measurements from the MC sensor were simultaneously recorded. MC-sensor-predicted measures of dynamometer torques, including the signal peak (SP) and signal average (SA), were highly associated with isometric knee extension peak torque (SP: r = 0.91, p < 0.0001), and average torque (SA: r = 0.89, p < 0.0001), respectively. Bland-Altman (BA) analyses with Lin's concordance (ρC) revealed good association between MC-sensor-predicted peak muscle torques (SP; ρC = 0.91) and average muscle torques (SA; ρC = 0.89) with the equivalent dynamometer measures, over a range of FES current amplitudes. The relationship of dynamometer torques and predicted MC torques during repetitive FES-evoked muscle contraction to fatigue were moderately associated (SP: r = 0.80, p < 0.0001; SA: r = 0.77; p < 0.0001), with BA associations between the two devices fair-moderate (SP; ρC = 0.70: SA; ρC = 0.30). These findings demonstrated that a skin-surface muscle mechanomyography sensor was an accurate proxy for electrically-evoked muscle contraction torques when directly measured during isometric dynamometry in individuals with SCI. The novel application of the MC sensor during FES-evoked muscle contractions suggested its possible application for real-world tasks (e.g., prolonged sit-to-stand, stepping,) where muscle forces during fatiguing activities cannot be directly measured.


Malakoplakia of the prostate.
A case a malakoplakia of the prostate is reported, the fourth case in this site. The clinical features, histology and ultrastructure are described.


Selective effect of tempol on renal medullary hemodynamics in spontaneously hypertensive rats.
The present study assessed the short- and long-term effect of tempol, a membrane-permeable mimetic of superoxide dismutase, on renal medullary hemodynamics in spontaneously hypertensive rats (SHR). Tempol was given in the drinking water (1 mM) for 4 days or 7 wk (4-11 wk of age), and medullary blood flow (MBF) was measured over a wide range of renal arterial pressure by means of laser-Doppler flowmetry in anesthetized rats. In addition, the response of the medullary circulation to angiotensin II (5-50 ng x kg(-1) x min(-1) iv) was determined in SHR treated for 4 days with tempol. Compared with control SHR, short- and long-term treatment with tempol decreased arterial pressure by approximately 20 mmHg and increased MBF by 35-50% without altering total renal blood flow (RBF) or autoregulation of RBF. Angiotensin II decreased RBF and MBF dose dependently (approximately 30% at the highest dose) in control SHR. In SHR treated with tempol, angiotensin II decreased RBF (approximately 30% at the highest dose) but did not alter MBF significantly. These data indicate that the antihypertensive effect of short- and long-term administration of tempol in SHR is associated with a selective increase in MBF. Tempol also reduced the sensitivity of MBF to angiotensin II. Taken together, these data support the idea that tempol enhances vasodilator mechanisms of the medullary circulation, possibly by interacting with the nitric oxide system. Increased MBF and reduced sensitivity of MBF to angiotensin II may contribute to the antihypertensive action of tempol in SHR.


Care of the Patient with Chest Pain in the Observation Unit.
Care of the patient presenting to an emergency department (ED) with chest pain remains a common yet challenging aspect of emergency medicine. Acute coronary syndrome presents in nonspecific fashion. The development and evolution of the ED-based observation unit has helped to safely assess and diagnose those most at risk for an adverse cardiac event. Furthermore, there are several provocative testing modalities to help assess for coronary artery disease. This article serves to describe and discuss the modern ED-based observation unit approach to patients with chest pain and/or angina equivalents presenting to an ED.


Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers.
BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.


Demonstration of cross-reactive antibodies able to elicit lysis of both HIV-1- and HIV-2-infected cells.
A total of 100% of sera from a large number of HIV-1-infected patients contained antibodies able to elicit Antibody-dependent cellular cytotoxicity lysis of cells infected with the HIV-1 isolates IIIB or RF. Levels of activity could not be correlated with activities in ELISA or neutralizing antibody assays nor with the clinical status of the patients. Surprisingly, 8 of 156 patients sera could additionally elicit lysis of HIV-2-infected cells, and cold target competition assays demonstrated that the cross-reactivity was apparently mediated via recognition of common epitope(s) expressed on the surface of cells infected with either group of HIV. The ADCC mechanism was shown to be mediated by a CD16+ lymphocyte. This demonstration of an effector mechanism able to attack and eliminate cells infected with a wide range of HIV strains has obvious implications for development of putative vaccines.


Functional analysis of the transmembrane domain and activation cleavage of human corin: design and characterization of a soluble corin.
Corin is a cardiac transmembrane serine protease. In cell-based studies, corin converted pro-atrial natriuretic peptide (pro-ANP) to mature ANP, suggesting that corin is potentially the pro-ANP convertase. In this study, we evaluated the importance of the transmembrane domain and activation cleavage in human corin. We showed that a soluble corin that consists of only the extracellular domain was capable of processing recombinant human pro-ANP in cell-based assays. In contrast, a mutation at the conserved activation cleavage site, R801A, abolished the function of corin, demonstrating that the activation cleavage is essential for corin activity. These results allowed us to design, express, and purify a mutant soluble corin, EKsolCorin, that contains an enterokinase recognition sequence at the activation cleavage site. Purified EKsolCorin was activated by enterokinase in a dose-dependent manner. Activated EK-solCorin had hydrolytic activity toward peptide substrates with a preference for Arg and Lys residues in the P-1 position. This activity of EKsolCorin was inhibited by trypsin-like serine protease inhibitors but not inhibitors of chymotrypsin-like, cysteine-, or metallo-proteases. In pro-ANP processing assays, purified active EKsolCorin converted recombinant human pro-ANP to biologically active ANP in a highly sequence-specific manner. The pro-ANP processing activity of EKsolCorin was not inhibited by human plasma. Together, our data indicate that the transmembrane domain is not necessary for the biological activity of corin but may be a mechanism to localize corin at specific sites, whereas the proteolytic cleavage at the activation site is an essential step in controlling the activity of corin.


[Association between Porphyromonas gingivalis and scaling and root planning therapy].
Porphyromonas gingivalis (P. gingivalis) is considered to be major putative periodontal pathogens. The purpose of the study was to evaluate P. gingivalis and clinical effects of scaling and root planning (SRP) in 20 subjects after 3 months. Twenty periodontitis patients were selected. The mean age was (44.33 +/- 13.86) years old. Clinical assessments of probing depth (PD), clinical attachment loss (CAL) and bleeding on probing (BOP) were made prior to SRP and at 3 months post-therapy. Subgingival plaque samples were taken at each visit and analyzed using TaqMan real-time polymerase chain reaction for the presence and levels of P. gingivalis. The quantification for P. gingivalis was also performed with the help of the species-specific primers/probes and the serial dilution of the plasmid standards. Mean probing depth, mean clinical attachment loss and bleeding on probing showed significant reduction at 3 months (P<0.001). The prevalence and level of P. gingivalis were significantly reduced after SRP (P<0.001). A positive correlation was found between the numbers of P. gingivalis and PD at baseline (P<0.001). There were no correlation between the initial level of P. gingivalis at baseline and the clinical improvement after therapy. But the number of P. gingivalis at responding sites was more decreased than non-responding sites after SRP (P<0.05). SRP produced a good clinical improvement. The prevalence and level of P. gingivalis were significantly reduced after SRP. The effect of SRP may be determined by the degree of P. gingivalis is decreased. The real-time polymerase chain reaction can be used to evaluate the effect of periodontal therapy.


Development of donor-derived thymic lymphomas after allogeneic bone marrow transplantation in AKR/J mice.
The transplantation of bone marrow cells from BALB/c (but not C57BL/6 and C3H/HeN) mice was observed to lead to the development of thymic lymphomas (leukemias) in AKR/J mice. Two leukemic cell lines, CAK1.3 and CAK4.4, were established from the primary culture of two thymic lymphoma, and surface phenotypes of these cell lines found to be H-2d and Thy-1.2+, indicating that these lymphoma cells are derived from BALB/c donor bone marrow cells. Further analyses of surface markers revealed that CAK1.3 is L3T4+ Lyt2+ IL2R-, whereas CAK4.4 is L3T4- Lyt2- IL2R+. Both CAK1.3 and CAK4.4 were transplantable into BALB/c but not AKR/J mice, further indicating that these cells are of BALB/c bone marrow donor origin. The cells were found to produce XC+-ecotropic viruses, but xenotropic and mink cell focus-forming viruses were undetectable. Inasmuch as thymic lymphomas are derived from bone marrow cells of leukemia-resistant BALB/c strain of mice under the allogeneic environment of leukemia-prone AKR/J mice, this animal model may serve as a useful tool not only for the analysis of leukemic relapse after bone marrow transplantation but also for elucidation of the mechanism of leukemogenesis.


The influence of zinc on the blood serum of cadmium-treated rats through the rheological properties.
The blood rheological properties serve as an important indicator for the early detection of many diseases. This study aimed to investigate the influence of zinc (Zn) on blood serum of cadmium (Cd) intoxication-treated male rats through the rheological properties. The rheological parameters were measured in serum of control, Cd, and Cd+Zn groups at wide range of shear rates (225-1875 s(-1)). The rat blood serum showed a non-significant change in cadmium-treated rats' %torque and shear stress at the lower shear rates (200-600 s(-1)) while a significant increase was observed at the higher shear rates (650-1875 s(-1)) compared with the control. The rat blood serum viscosity increased significantly in the Cd-treated group at each shear rate compared with the control. The viscosity and shear rate exhibited a non-Newtonian behavior for all groups. The increase in blood serum viscosity in Cd-treated male rats might be attributed to destruction or changes in the non-clotting proteins, and other blood serum components. In Cd+Zn-treated rats, the rat blood serum viscosity values returned nearer to the control values at each shear rate. Our results confirmed that Zn displaced Cd or compete with the binding sites for Cd uptake.


Kinesin-1 structural organization and conformational changes revealed by FRET stoichiometry in live cells.
Kinesin motor proteins drive the transport of cellular cargoes along microtubule tracks. How motor protein activity is controlled in cells is unresolved, but it is likely coupled to changes in protein conformation and cargo association. By applying the quantitative method fluorescence resonance energy transfer (FRET) stoichiometry to fluorescent protein (FP)-labeled kinesin heavy chain (KHC) and kinesin light chain (KLC) subunits in live cells, we studied the overall structural organization and conformation of Kinesin-1 in the active and inactive states. Inactive Kinesin-1 molecules are folded and autoinhibited such that the KHC tail blocks the initial interaction of the KHC motor with the microtubule. In addition, in the inactive state, the KHC motor domains are pushed apart by the KLC subunit. Thus, FRET stoichiometry reveals conformational changes of a protein complex in live cells. For Kinesin-1, activation requires a global conformational change that separates the KHC motor and tail domains and a local conformational change that moves the KHC motor domains closer together.


Chronic domperidone fails to increase striatal spiperone binding sites despite hyperprolactinemia: comparison with chronic haloperidol.
Mice were administered the dopaminergic antagonists haloperidol or domperidone in their drinking water for 2 or 21 days. Serum prolactin levels and striatal 3H-spiperone-binding sites (D-2 receptors) were compared to vehicle-treated controls. While only domperidone elevated serum prolactin levels, only haloperidol increased the density of striatal 3H-spiperone-binding site. The failure of domperidone, a potent D-2 receptor antagonist, to increase striatal receptor number is attributed to its poor penetration of the blood-brain barrier. These results indicate that peripheral effects of neuroleptic drugs, including prolactin elevation, are not sufficient for the development of dopaminergic supersensitivity in the central nervous system.


Strategies for bioengineered scaffolds that support adipose stem cells in regenerative therapies.
Regenerative medicine possesses the potential to ameliorate damage to tissue that results from a vast range of conditions, including traumatic injury, tumor resection and inherited tissue defects. Adult stem cells, while more limited in their potential than pluripotent stem cells, are still capable of differentiating into numerous lineages and provide feasible allogeneic and autologous treatment options for many conditions. Adipose stem cells are one of the most abundant types of stem cell in the adult human. Here, we review recent advances in the development of synthetic scaffolding systems used in concert with adipose stem cells and assess their potential use for clinical applications.


How to control the blood glucose level in the surgical diabetic patient.
This report is a sequel to "Why Control Blood Glucose Levels?" (Arch Surg 111:229, 1976), which linked complications of diabetes mellitus to poor control. Hyperglycemia, increased gluconeogenesis, nitrogen wasting, and increased ketogenesis occur in the perioperative period, partly as a result of contrainvents are aggravated in the diabetic. Zones of levels of blood glucose control are charted, as well as the corresponding insulin needs for each of these zones. Intermediate insulins should provide basic coverage; regular insulin is recommended only as a supplement. Several blood glucose determinations per day are necessary to maintain control. The hazards of dependence on urine testing and the "sliding scale" for control are among a number of caveats discussed.


QSPR Prediction of Lipophilicity for Organic Compounds Using Random Forest Technique on the Basis of Simplex Representation of Molecular Structure.
The relationship between the octanol-water partition coefficient for more than twelve thousand organic compounds and their structures was investigated using a QSPR approach based on Simplex Representation of Molecular Structure (SiRMS). The dataset used in our study included 10973 compounds with experimental values of lipophilicity (LogKow ) for different chemical compounds. Random Forest (RF) method was used for statistical modeling at the 2D level of representation of molecular structure. Developed models are adequate and successfully validated with external test sets. Proposed models have clear interpretation due to the use of simplex representation of molecular structure and predict the LogKow values with the accuracy of the best modern models. Thus QSPR models proposed in this study represent powerful and easy-to use virtual screening tool that can be recommended for prediction of octanol-water partition coefficient.


CONTROVERSIAL ISSUES IN THE TREATMENT OF DYSLIPIDEMIAS IN PATIENTS WITH DIABETES MELLITUS.
Patients with diabetes mellitus have an elevated cardiovascular risk. Lipid-lowering therapy is a successful strategy to prevent atherosclerotic events in these patients. Therefore, almost all professional societies recommend statin therapy for patients with diabetes under certain conditions. Despite this broad consensus, a number of controversial issues remain. Thus, it remains unclear in which patients the lipid parameters should be determined in the fasting state and in which postprandial values are sufficient. It is also an open issue whether all patients with diabetes should receive statin therapy and which goals should be achieved. While the benefit of statin-ezetimibe and statin-PCSK9-inhibition combinations has been shown in large outcome trials, results of outcome trials involving statins with triglyceride lowering drugs have been ambiguous. Thus, it is currently unclear which patients benefit from such combinations. Finally, the best strategy to address severe hypertriglyceridemia in patients with diabetes is unclear. This article discusses these issues and aims to provide help and information to practicing physicians taking care of patients with diabetes mellitus. (REV INVEST CLIN. 2018;70:237-43).


Modelling COVID-19 dynamics and potential for herd immunity by vaccination in Austria, Luxembourg and Sweden.
Against the COVID-19 pandemic, non-pharmaceutical interventions have been widely applied and vaccinations have taken off. The upcoming question is how the interplay between vaccinations and social measures will shape infections and hospitalizations. Hence, we extend the Susceptible-Exposed-Infectious-Removed (SEIR) model including these elements. We calibrate it to data of Luxembourg, Austria and Sweden until 15 December 2020. Sweden results having the highest fraction of undetected, Luxembourg of infected and all three being far from herd immunity in December. We quantify the level of social interaction, showing that a level around 1/3 of before the pandemic was still required in December to keep the effective reproduction number Refft below 1, for all three countries. Aiming to vaccinate the whole population within 1 year at constant rate would require on average 1,700 fully vaccinated people/day in Luxembourg, 24,000 in Austria and 28,000 in Sweden, and could lead to herd immunity only by mid summer. Herd immunity might not be reached in 2021 if too slow vaccines rollout speeds are employed. The model thus estimates which vaccination rates are too low to allow reaching herd immunity in 2021, depending on social interactions. Vaccination will considerably, but not immediately, help to curb the infection; thus limiting social interactions remains crucial for the months to come.


Anisotropy of ongoing neural activity in the primate visual cortex.
The mammalian neocortex features distinct anatomical variation in its tangential and radial extents. This review consolidates previously published findings from our group in order to compare and contrast the spatial profile of neural activity coherence across these distinct cortical dimensions. We focus on studies of ongoing local field potential (LFP) data obtained simultaneously from multiple sites in the primary visual cortex in two types of experiments in which electrode contacts were spaced either along the cortical surface or at different laminar positions. These studies demonstrate that across both dimensions the coherence of ongoing LFP fluctuations diminishes as a function of interelectrode distance, although the nature and spatial scale of this falloff is very different. Along the cortical surface, the overall LFP coherence declines gradually and continuously away from a given position. In contrast, across the cortical layers, LFP coherence is discontinuous and compartmentalized as a function of depth. Specifically, regions of high LFP coherence fall into discrete superficial and deep laminar zones, with an abrupt discontinuity between the granular and infragranular layers. This spatial pattern of ongoing LFP coherence is similar when animals are at rest and when they are engaged in a behavioral task. These results point to the existence of partially segregated laminar zones of cortical processing that extend tangentially within the laminar compartments and are thus oriented orthogonal to the cortical columns. We interpret these electrophysiological observations in light of the known anatomical organization of the cortical microcircuit.


A Comparison of Oral and Intravenous Mouse Models of Listeriosis.
Listeria monocytogenes is one of several enteric microbes that is acquired orally, invades the gastric mucosa, and then disseminates to peripheral tissues to cause systemic disease in humans. Intravenous (i.v.) inoculation of mice with L. monocytogenes has been the most widely-used small animal model of listeriosis over the past few decades. The infection is highly reproducible and has been invaluable in deciphering mechanisms of adaptive immunity in vivo, particularly CD8⁺ T cell responses to intracellular pathogens. However, the i.v. model completely bypasses the gut phase of the infection. Recent advances in generating both humanized mice and murinized bacteria, as well as the development of a foodborne route of transmission has reignited interest in studying oral models of listeriosis. In this review, we analyze previously published reports to highlight both the similarities and differences in tissue colonization and host response to infection using either oral or i.v. inoculation.


Influence of mefloquine administration during early pregnancy on rat embryonic development.
Mefloquine (MQ) is a potent effective antimalarial drug against multiple drug-resistant Plasmodium falciparum. It has been proved that MQ can be given safely during the second and third trimesters. However, there is very limited information on the drug safety during the first trimester. The aim of the present work was to investigate the embryotoxicity and teratogenicity of MQ during critical periods of early development. Wistar rats were orally administered with a single dose of MQ (45 mg/kg bwt or 187 mg/kg bwt) on the 1st, 6th or 13th days of pregnancy. Cyclophosphamide (CPA) was chosen as a positive control. On the 21st day of gestation, standard parameters of reproductive performance and fetal examination were estimated. Malondialdehyde (MDA) level, glutathione reductase activity and glutathione (GSH) content were evaluated in placenta and liver homogenates of mothers and fetuses. The results indicated that MQ did not adversely affect the number of implantation, resorption, litter size and fetal body weight and length. Only groups treated with MQ on the 1st day of gestation exhibited significant decrease in fetal body weight. Examination of fetuses for external, visceral and skeletal changes showed minimal variations involving extension of lateral brain ventricles and renal pelvis and signs of delayed ossification. These variations were accompanied with significant elevation of MDA level and reduction of GSH content of fetal liver. Prenatal exposure to MQ at early pregnancy did not cause any embryolethal or teratogenic effect. It could slightly exacerbate minor variations.


Pattern of polymorphism after strong artificial selection in a domestication event.
The process of strong artificial selection during a domestication event is modeled, and its effect on the pattern of DNA polymorphism is investigated. The model also considers population bottleneck during domestication. Artificial selection during domestication is different from a regular selective sweep because artificial selection acts on alleles that may have been neutral variants before domestication. Therefore, the fixation of such a beneficial allele does not always wipe out DNA variation in the surrounding region. The amount by which variation is reduced largely depends on the initial frequency of the beneficial allele, p. As a consequence, p has a strong effect on the likelihood of detecting the signature of selection during domestication from patterns of polymorphism. These theoretical results are discussed in light of data collected from maize. Although the main focus of this article is on domestication, this model can also be generalized to describe selective sweeps from standing genetic variation.


Structural features and in vitro antiviral activities of sulfated polysaccharides from Sphacelaria indica.
Many viruses display affinity for cell surface heparan sulfate proteoglycans with biological relevance to virus entry. This raises the possibility of the application of sulfated polysaccharides in antiviral therapy. In this study, we have analyzed xylogalactofucan- and alginic acid-containing fractions from Sphacelaria indica, a marine alga. The xylogalactofucan that has apparent molecular mass of 26±5 kDa and negative specific rotation [α](D)(32) -71° (c 0.2, H(2)O) contains, inter alia, (1→3)-linked L-fucopyranosyl and D-galactopyranosyl residues. The algin (molecular mass: 21±5kDa) contains 41% guluronic and 59% mannuronic acid residues. The 50% inhibitory concentration (IC(50)) values of these macromolecules and their chemically sulfated derivatives against herpes simplex virus type 1 (HSV-1) were in the range of 0.6-10 μg ml(-1) and they lacked cytotoxicity at concentrations up to 200 μg ml(-1). The antiviral activity was dependent on the sulfate contents of the polysaccharides. The results support the feasibility of inhibiting HSV infection by direct interaction of polysaccharides with viral particles.


Hypoglycemia and hyperinsulinemia in rodent models of severe malaria infection.
Severe hypoglycemia developed during nonlethal Plasmodium chabaudi and lethal P. yoelii blood stage malaria infection in mice, always in association with hyperinsulinemia. Supernatants of lethal P. yoelii incubated overnight induced hypoglycemia and hyperinsulinemia in normal mice. In murine malaria, hypoglycemia may be largely secondary to increased insulin secretion.


A Novel Strategy for TNF-Alpha Production by 2-APB Induced Downregulated SOCE and Upregulated HSP70 in O. tsutsugamushi-Infected Human Macrophages.
Orientia (O.) tsutsugamushi-induced scrub typhus is endemic across many regions of Asia and the Western Pacific, where an estimated 1 million cases occur each year; the majority of patients infected with O. tsutsugamushi end up with a cytokine storm from a severe inflammatory response. Previous reports have indicated that blocking tumor necrosis factor (TNF)-α reduced cell injury from a cytokine storm. Since TNF-α production is known to be associated with intracellular Ca2+ elevation, we examined the effect of store-operated Ca2+ entry (SOCE) inhibitors on TNF-α production in O. tsutsugamushi-infected macrophages. We found that 2-aminoethoxydiphenyl borate (2-APB), but not SKF96365, facilitates the suppression of Ca2+ mobilization via the interruption of Orai1 expression in O. tsutsugamushi-infected macrophages. Due to the decrease of Ca2+ elevation, the expression of TNF-α and its release from macrophages was repressed by 2-APB. In addition, a novel role of 2-APB was found in macrophages that causes the upregulation of heat shock protein 70 (HSP70) expression associated with ERK activation; upregulated TNF-α production in the case of knockdown HSP70 was inhibited with 2-APB treatment. Furthermore, elevated HSP70 formation unexpectedly did not help the cell survival of O. tsutsugamushi-infected macrophages. In conclusion, the parallelism between downregulated Ca2+ mobilization via SOCE and upregulated HSP70 after treatment with 2-APB against TNF-α production was found to efficiently attenuate an O. tsutsugamushi-induced severe inflammatory response.


Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype.
AP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation-dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFNγ, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2-associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response.


Phosphatidic acid modulation of Kv channel voltage sensor function.
Membrane phospholipids can function as potent regulators of ion channel function. This study uncovers and investigates the effect of phosphatidic acid on Kv channel gating. Using the method of reconstitution into planar lipid bilayers, in which protein and lipid components are defined and controlled, we characterize two effects of phosphatidic acid. The first is a non-specific electrostatic influence on activation mediated by electric charge density on the extracellular and intracellular membrane surfaces. The second is specific to the presence of a primary phosphate group, acts only through the intracellular membrane leaflet and depends on the presence of a particular arginine residue in the voltage sensor. Intracellular phosphatidic acid accounts for a nearly 50 mV shift in the midpoint of the activation curve in a direction consistent with stabilization of the voltage sensor's closed conformation. These findings support a novel mechanism of voltage sensor regulation by the signaling lipid phosphatidic acid.


A novel inhibitor of indole-3-glycerol phosphate synthase with activity against multidrug-resistant Mycobacterium tuberculosis.
Tuberculosis (TB) continues to be a major cause of morbidity and mortality worldwide. The increasing emergence and spread of drug-resistant TB poses a significant threat to disease control and calls for the urgent development of new drugs. The tryptophan biosynthetic pathway plays an important role in the survival of Mycobacterium tuberculosis. Thus, indole-3-glycerol phosphate synthase (IGPS), as an essential enzyme in this pathway, might be a potential target for anti-TB drug design. In this study, we deduced the structure of IGPS of M. tuberculosis H37Rv by using homology modeling. On the basis of this deduced IGPS structure, screening was performed in a search for novel inhibitors, using the Maybridge database containing the structures of 60,000 compounds. ATB107 was identified as a potential binding molecule; it was tested, and shown to have antimycobacterial activity in vitro not only against the laboratory strain M. tuberculosis H37Rv, but also against clinical isolates of multidrug-resistant TB strains. Most MDR-TB strains tested were susceptible to 1 microg x mL(-1) ATB107. ATB107 had little toxicity against THP-1 macrophage cells, which are human monocytic leukemia cells. ATB107, which bound tightly to IGPS in vitro, was found to be a potent competitive inhibitor of the substrate 1-(o-carboxyphenylamino)-1-deoxyribulose-5'-phosphate, as shown by an increased K(m) value in the presence of ATB107. The results of site-directed mutagenesis studies indicate that ATB107 might inhibit IGPS activity by reducing the binding affinity for substrate of residues Glu168 and Asn189. These results suggest that ATB107 is a novel potent inhibitor of IGPS, and that IGPS might be a potential target for the development of new anti-TB drugs. Further evaluation of ATB107 in animal studies is warranted.


Erythema nodosum in chlamydial infections.
Twelve patients suffering from erythema nodosum who had diagnostic titres or seroconversions in chlamydial complement fixation test are described. Eleven had respiratory infections. The twelfth had sterile pyuria, symptoms of pelvic inflammatory disease and exceptionally high antibody titres against Chlamydia trachomatis in an immunofluorescence test. The simple chlamydial complement fixation test is recommended for the screening of cases of erythema nodosum.


Biological Activity of an Injectable Biphasic Calcium Phosphate/PMMA Bone Cement for Induced Osteogensis in Rabbit Model.
Polymethylmethacrylate (PMMA) bone cement is widely used in repair of vertebral fracture because of its good biomechanical properties and fast curing. However, the bioinertness of PMMA cement may cause interfacial loosening, fatigue, fracture, and ultimate failure. In this study, biphasic calcium phosphate (BCP) is introduced into PMMA cement to prepare an injectable composite bone cement (BCPx /PMMA) and the content of BCP is optimized to achieve appropriate rate of absorption that matches the bone regeneration. The compressive strength of BCPx /PMMA bone cement is found to comply with the International Standardization Organization standard 5833, and can promote biomineralization as well as adhesion, proliferation, and osteogenic differentiation of Sprague-Dawley rat bone marrow mesenchymal stem cells in vitro. Furthermore, in vivo test performed on a rabbit radius defect model demonstrates that the presence of BCP can significantly improve the osteogenic efficacy of PMMA cement. Therefore, it is anticipated that BCPx /PMMA bone cement, as a promising injectable biomaterial, is of great potential in bone tissue regeneration.


Study of platelet-rich fibrin combined with rat periodontal ligament stem cells in periodontal tissue regeneration.
The objective of this study was to investigate the advantages and feasibility of periodontal tissue regeneration using platelet-rich fibrin (PRF) combined with rat periodontal ligament stem cells (PDLSCs) for the first time. We first determined the effect of PRF on rat PDLSCs in vitro. We next conducted an in vivo study, in which a tissue engineering technique was performed to repair periodontal defects in five groups: a blank group, collagen group (implanted collagen membrane), collagen + cells group (implanted collagen membrane and rat PDLSCs), PRF group (implanted PRF membrane) and PRF + cells group (implanted PRF membrane and rat PDLSCs). PRF greatly enhanced cell proliferation, mRNA and protein expression levels of bone sialoprotein (BSP), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2) and activity of alkaline phosphatase (ALP) in vitro. Transplantation of PRF combined with rat PDLSCs resulted in higher expression of osteopontin (Opn), collagen I (COL1A) and RUNX2 at both 12 and 24 days after surgery. Micro-computed tomography and histological analysis showed substantially more new bone formation in the PRF + cells group at 24 days after surgery. Based on these results, we discuss the role of PRF in the proliferation and differentiation of rat PDLSCs and suggest that PRF combined with rat PDLSCs provides a valuable tool for periodontal tissue engineering.


Role of IFN-γ and IL-6 cytokines and their association in determining susceptibility to chronic idiopathic urticaria.
Chronic Idiopathic Urticaria (CIU) is a common skin disorder, which may occur spontaneously. The aim of the present study was to assess the serum levels of interferon (IFN)-γ and interleukin (IL)-6 and to examine the association of IFN-γ+874 T/A and IL-6-174 G/C cytokine gene polymorphisms. To accomplish this, ELISA-based cytokine serum levels of IFN-γ (n=30) and IL-6 (n=30) in CIU patients (n=100) and Healthy Controls (HC) (n=200) were performed. Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was performed to verify the positional significance. A significant (p<0.0001) increase in the serum cytokine levels of IFN-γ and IL-6 was recorded in CIU patients compared to HC. The AT and TT genotypes of IFN-γ and GG genotype of IL-6 were found to be significantly associated with CIU. In conclusion, our findings show a significant increase in the cytokine levels of IFN-γ and IL-6, highlighting their regulatory role in the development of disease. In addition to this, association studies have revealed that TT genotype of IFN-γ +874 T/A and GG genotype of IL-6-174 G/C were susceptible towards the CIU.


[Mood States in outpatients with lesional epilepsy at the neurosurgical clinic and improvement in mood States after lamotrigine addiction].
People with epilepsy have a high incidence of mood disorders that may affect their quality of life. Lamotrigine(LTG)is one of the antiepileptic drugs that are commercially available in Japan these days and its mood-stabilizing qualities were well known. First, 66 outpatients with epilepsy were evaluated for changes in mood states by the Profile of Mood States(POMS)and the Japanese-edition Beck Depression Inventory-Second Edition(BDI-II)on self report. The POMS questionnaire includes 30 items that address six components of mood. At baseline, one third of the outpatients with epilepsy had mood problems compared by POMS health reference. The mean BDI-II baseline score was 14.9±10.1, and one third of these epilepsy patients exhibited moderate or severe depression. Second, in the twelve patients with epilepsy, LTG was added to other antiepileptic drugs, and the POMS and BDI-II were administered at baseline and after addiction to LTG. 4 out of 8(50%)patients with simple partial seizure and 5 out of 8(62.5%)patients after the adjunctive therapy experienced at least a 50% reduction in the number of seizures compared with the self-reported baseline before the adjunctive therapy. The component scores of Depression-Dejection, Anger-Hostility and Confusion-Bewilderment in POMS were statistically improved in these patients completing adjunctive LTG(pared t-test, p<0.05). In these patients, the mean BDI-II baseline score was 25.8±13.1. Following administration of LTG, there was a significant decrease in the mean BDI-II scores(15.0±6.6)between baseline and the end of adjunctive LTG. This study suggests that, in addition to seizure control, LTG may have a mood-stabilizing effect and improve the quality of life in patients with epilepsy.


Role of Mast Cells in Shaping the Tumor Microenvironment.
Early mast cell (MC) infiltration has been reported in a wide range of human and animal tumors particularly malignant melanoma and breast and colorectal cancer. The consequences of their presence in the tumor microenvironment (TME) or at their margins still remain unclear as it is associated with a good or poor prognosis based on the type and anatomical site of the tumor. Within the tumor, MC interactions occur with infiltrated immune cells, tumor cells, and extracellular matrix (ECM) through direct cell-to-cell interactions or release of a broad range of mediators capable of remodeling the TME. MCs actively contribute to angiogenesis and induce neovascularization by releasing the classical proangiogenic factors including VEGF, FGF-2, PDGF, and IL-6, and nonclassical proangiogenic factors mainly proteases including tryptase and chymase. MCs support tumor invasiveness by releasing a broad range of matrix metalloproteinases (MMPs). MC presence within the tumor gained additional significance when it was assumed that controlling its activation by tyrosine kinase inhibitors (imatinib and masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) or controlling their interactions with other cell types may have therapeutic benefit.


Suppression of EDAG gene expression by phorbol 12-myristate 13-acetate is mediated through down-regulation of GATA-1.
EDAG, a hematopoietic tissue-specific protein, is involved in the regulation of proliferation, differentiation and apoptosis of hematopoietic cells. In this study, a dose-dependent inhibition of EDAG expression by PMA was observed in K562 cells. The responsive element for the PMA-induced inhibition was contained in the region between -211 and +32bp of the EDAG gene promoter. By oligonucleotide-directed mutagenesis, EMSA, ChIP and transient transfection assays, we found that two tandem repeat GATA-1 sites in the promoter of EDAG gene played an important role in the PMA-mediated down-regulation of the EDAG gene expression in K562 cells. The kinetics of EDAG expression during PMA induction showed that the levels of EDAG expression were down-regulated concomitantly with GATA-1 down-expression. Decreased GATA-1 expression by siRNA reduced expression of EDAG in K562 cells, and restored expression of GATA-1 significantly rescued EDAG expression from PMA-mediated suppression. Overexpression of EDAG in K562 cells inhibited the megakaryocytic differentiation induced by PMA which raised the interesting possibility that PMA induced K562 cells differentiation toward megakaryocytic phenotype through, at least in part, the inhibition of EDAG expression. In vivo analysis confirmed that EDAG was highly expressed in primitive progenitor cells and down-regulated in megakaryocytes which was consistent with the expression pattern of GATA-1. Furthermore, PKC and MAPK specific inhibitors treatment attenuated the down-regulation of EDAG induced by PMA. Taken together, these results suggest that the inhibition of the EDAG gene by PMA is mediated through down-regulation of transcription factor GATA-1 and involved the PKC/MAPK signaling pathway.


A Combined Procedure of Intrastromal Corneal Rings Explantation and Penetrating Keratoplasty in a Patient With Keratoconus: A Case Report.
Keratoconus is a non-inflammatory and degenerative corneal ectasia that determinate progressive steepening of paracentral cornea with development of irregular astigmatism and visual function deterioration. According to the stage of the pathology, different methods of correction can be used: rigid contact lenses may be used to alter corneal shape and partially correct astigmatism, corneal collagen cross-linking (CXL) and intrastromal corneal ring segment (ICRS) implantation can reinforce corneal stroma to slow disease progression. Late-stage treatment comprehend anterior lamellar keratoplasty or penetrating keratoplasty. We evaluated a 31-year-old patient who was subjected to bilateral ICRS implantation combined with CXL due to keratoconus. This led, after 9 months, to ring extrusion in his left eye, corneal thinning and microperforation into the aqueous chamber with residual irregular astigmatism of 4.50 D. cyl. 10°. The patient underwent ICRS explantation and PKP during the same surgical session. After 15 months of follow-up, the BCVA was 0.2 LogMAR with a residual astigmatism of 6.3 dpt.


An outbreak of psittacosis in a boys' boarding school.
In 1980, an outbreak of a mild illness involving twenty pupils and four adults in a boys' boarding school was identified serologically as psittacosis. Intensive epidemiological investigations did not uncover the source. It is suggested either that sources of chlamydia other than avian exist, which may produce a milder illness than the avian type, or that human-to-human spread of a mild form of chlamydiosis occurs.


Preoperative planning using virtual reality for percutaneous transseptal valve-in-valve transcatheter mitral valve replacement: a case report.
Virtual reality (VR) technology has been implemented as a pre-procedural planning tool for cardiovascular interventions to enable detailed evaluation of patient anatomy from different vantage points. Here, we employed a VR platform to preoperatively plan for percutaneous valve-in-valve transcatheter mitral replacement (ViV-TMVR) in a prohibitive surgical candidate. An 85-year-old male with a history of two prior sternotomies for bioprosthetic aortic valve (AV) and mitral valve (MV) 31 mm Medtronic Mosaic bioprosthesis presented with severe mitral regurgitation from a degenerative bioprosthetic MV. The patient was deemed a prohibitive surgical candidate for a third sternotomy and instead was recommended a percutaneous transseptal ViV-TMVR. An electrocardiogram-gated chest computed tomography (CT) provided a neo-left-ventricular outflow tract (neo-LVOT) of 1.89 cm2. This CT was reconstructed to create a 360° VR (360VR) model. A 29 mm SAPIEN three bioprosthetic valve, selected based on the already implanted MV, was placed inside the bioprosthetic MV and analysed in VR at different angles to ensure it would not obstruct the LVOT. The neo-LVOT measured in VR was 3.02 cm2, which would allow for sufficient blood flow without significant obstruction from the new SAPIEN three bioprosthetic valve. The patient tolerated the procedure well. This case demonstrates the utility of VR as a pre-procedural planning tool for interventional cardiology procedures. Preoperative planning in VR alleviated concerns regarding obstruction of the neo-LVOT and helped confirm safe implantation by clearly showing the three-dimensional spatial relationship between the implants and surrounding patient anatomy.


Understanding Objections to One Anastomosis (Mini) Gastric Bypass: A Survey of 417 Surgeons Not Performing this Procedure.
Despite published experience with thousands of patients, the uptake of One Anastomosis/Mini Gastric Bypass (OAGB/MGB) has been less than enthusiastic and many surgeons still harbour objections to this procedure. The purpose of this study was to understand these objections scientifically. Bariatric surgeons from around the world were invited to participate in a questionnaire-based survey on SurveyMonkey®. Surgeons already performing this procedure were excluded. Four hundred seventeen bariatric surgeons (from 42 countries) not currently performing OAGB/MGB took the survey. There were 211/414 (50.97%) and 188/414 (45.41%) respondents who expressed concerns that it will lead to an increased risk of gastric and oesophageal cancers respectively. A total of 62/416 (14.9%) and 201/413 (n = 48.6%) surgeons respectively felt that OAGB/MGB was associated with a higher early (30-day) and late complication rate compared to the RYGB. Moreover, 7.8% (n = 32/411) and 16.26% (n = 67/412) of the respondents were concerned that OAGB/MGB carried a higher early (30-day) and late mortality, respectively, in comparison with the RYGB. There were 79/410 (19.27%) and 88/413 (21.3%) respondents who were concerned that OAGB/MGB was not an effective procedure for weight loss and co-morbidity resolution, respectively. A total of 258/411 (62.77%) respondents reported that OAGB/MGB was not approved by their national society as a mainstream bariatric procedure; 51.0% of these surgeons would start performing this procedure if it was. Surgeons not performing OAGB/MGB cite a number of concerns for not performing this operation. This survey is the first scientific attempt to understand these objections scientifically.


The strong efficiency of the Escherichia coli gapA P1 promoter depends on a complex combination of functional determinants.
The Escherichia coli multi-promoter region of the gapA gene ensures a high level of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) production under various growth conditions. In the exponential phase of growth, gapA mRNAs are mainly initiated at the highly efficient gapA P1 promoter. In the present study, by using site-directed mutagenesis and chemical probing of the RPo (open complex) formed by Esigma70 (holoenzyme associated with sigma70) RNAP (RNA polymerase) at promoter gapA P1, we show that this promoter is an extended -10 promoter that needs a -35 sequence for activity. The -35 sequence compensates for the presence of a suboptimal -10 hexamer. A tract of thymine residues in the spacer region, which is responsible for a DNA distortion, is also required for efficient activity. We present the first chemical probing of an RPo formed at a promoter needing both a -10 extension and a -35 sequence. It reveals a complex array of RNAP-DNA interactions. In agreement with the fact that residue A-11 in the non-template strand is flipped out in a protein pocket in previously studied RPos, the corresponding A residue in gapA P1 promoter is protected in RPo and is essential for activity. However, in contrast with some of the previous findings on RPos formed at other promoters, the -12 A:T pair is opened. Strong contacts with RNAP occur both with the -35 sequence and the TG extension, so that the sigma4 and sigma2 domains may simultaneously contact the promoter DNA. RNAP-DNA interactions were also detected immediately downstream of the -35 hexamer and in a more distal upstream segment, reflecting a wrapping of RNAP by the core and upstream promoter DNA. Altogether, the data reveal that promoter gapA P1 is a very efficient promoter sharing common properties with both extended -10 and non-extended -10 promoters.


Approximations of density matrices in N-electron valence state second-order perturbation theory (NEVPT2). II. The full rank NEVPT2 (FR-NEVPT2) formulation.
In Paper I, the performances of pre-screening (PS), extended PS (EPS), and cumulant (CU) approximations to the fourth-order density matrix were examined in the context of second-order N-electron valence state perturbation theory (NEVPT2). It has been found that the CU, PS, and even EPS approximations with loose thresholds may introduce intruder states. In the present work, the origin of these "false intruder" states introduced by approximated density matrices is discussed. Canonical NEVPT2 implementations employ a rank reduction trick. By analyzing its residual error, we find that the omission of the rank reduction leads to a more stable multireference perturbation theory for incomplete active space reference wave functions. Such a full rank (FR)-NEVPT2 formulation is equivalent to the conventional NEVPT2 method for the complete active space self-consistent field/complete active space configuration interaction reference wave function. A major drawback of the FR-NEVPT2 formulation is the necessity of the fifth-order density matrix. To avoid the construction of the high-order density matrices, the combination of the FR-NEVPT2 with the CU approximation is studied. However, we find that the CU approximation remains problematic as it still introduces intruder states. The question of how to robustly and efficiently perform internally contracted multireference perturbation theories with approximate densities remains a challenging field of investigation.


A New Method for Syndrome Classification of Non-Small-Cell Lung Cancer Based on Data of Tongue and Pulse with Machine Learning.
To explore the data characteristics of tongue and pulse of non-small-cell lung cancer with Qi deficiency syndrome and Yin deficiency syndrome, establish syndrome classification model based on data of tongue and pulse by using machine learning methods, and evaluate the feasibility of syndrome classification based on data of tongue and pulse. We collected tongue and pulse of non-small-cell lung cancer patients with Qi deficiency syndrome (n = 163), patients with Yin deficiency syndrome (n = 174), and healthy controls (n = 185) using intelligent tongue diagnosis analysis instrument and pulse diagnosis analysis instrument, respectively. We described the characteristics and examined the correlation of data of tongue and pulse. Four machine learning methods, namely, random forest, logistic regression, support vector machine, and neural network, were used to establish the classification models based on symptom, tongue and pulse, and symptom and tongue and pulse, respectively. Significant difference indices of tongue diagnosis between Qi deficiency syndrome and Yin deficiency syndrome were TB-a, TB-S, TB-Cr, TC-a, TC-S, TC-Cr, perAll, and the tongue coating texture indices including TC-CON, TC-ASM, TC-MEAN, and TC-ENT. Significant difference indices of pulse diagnosis were t4 and t5. The classification performance of each model based on different datasets was as follows: tongue and pulse < symptom < symptom and tongue and pulse. The neural network model had a better classification performance for symptom and tongue and pulse datasets, with an area under the ROC curves and accuracy rate which were 0.9401 and 0.8806. It was feasible to use tongue data and pulse data as one of the objective diagnostic basis in Qi deficiency syndrome and Yin deficiency syndrome of non-small-cell lung cancer.