Effect of switching from cyclosporine to tacrolimus on exhaled nitric oxide and pulmonary function in patients with chronic rejection after lung transplantation.
Previous studies have demonstrated that shifting immunosuppressive therapy from cyclosporine (CyA) to tacrolimus (FK) may arrest the decline in forced expiratory volume in 1 second (FEV(1)) during chronic rejection after lung transplantation. Exhaled nitric oxide (eNO) has been shown to be elevated during chronic rejection. We report the concomitant stabilization of FEV(1) and decrease in eNO after changing from CyA to FK therapy in patients with chronic rejection after lung transplantation. We used a prospective design. The study included 10 lung transplant patients (5 men and 5 women), mean age 44 +/- 14 years at time of transplantation, with a progressive decline in FEV(1) that was attributed to chronic rejection. Four patients underwent heart-lung transplantation and 3 had a sequential single and 3 a single-lung transplantation. The switch from CyA to FK occurred at 36 +/- 23 months after transplantation (Time 0). The eNO was measured using a chemiluminescence analyzer, according to standardized European Respiratory Society (ERS) criteria. At Time 0, there were 6 patients in bronchiolitis obliterans syndrome (BOS) Stage 0-p, with a mean decline in FEV(1) of 15 +/- 3%; 2 in BOS Stage 1; and 2 in BOS Stage 2. Compared with the best post-operative FEV(1), there was a progressive and significant decline until Time 0, from 2.56 +/- 0.9 liters to 2.03 +/- 0.94 liters (p = 0.0047). Thereafter, FEV(1) stabilized: 2.03 +/- 0.94 liters at Time 0 and 2.05 +/- 0.94 liters 6 months later (p = non-significant). Concomitantly, there was a gradual increase in eNO during the 6 months before Time 0, from 11.4 +/- 2.5 ppb at the time of best FEV(1) to 20.5 +/- 14.8 ppb at Time 0. After switching, there was a non-significant decline in eNO, from 20.5 +/- 14.8 ppb to 14.9 +/- 5.4 ppb. There was no significant difference in eNO levels between the patients in BOS Stage 0-p and patients in higher BOS stages at either timepoint in the study. This study illustrates that a switch from CyA to FK can stabilize pulmonary function in lung transplant patients with chronic rejection. This stabilization of FEV(1) is accompanied by a decrease in eNO, indicating that this treatment shift can reduce inflammation of airways during the course of chronic rejection. Consequently, measuring eNO may be extremely valuable in guiding the treatment of chronic rejection after lung transplantation.


Management of neonatal hip instability and dysplasia.
The diagnosis and treatment of neonatal hip instability and dysplasia is controversial. Different countries have different algorithms and guidelines on which hips should be screened or treated. German speaking countries have introduced universal ultra sound hip screening programmes resulting in relatively high splintage rates in certain centres. Some Scandinavian centres have organised selective screening programmes with serial ultrasound observation of hip instabilities, leading to comparatively low splintage rates. Though most experts would treat clinical hip instability (confirmed by ultrasound evaluation), the natural history and epidemiology of dysplasia is less well understood. The treatment regimes for neonatal dysplasia are varied with wide differences in the rates of splintage. 'Late' dislocation may be secondary to prenatal dislocation (teratogenic), neonatal hip instability or to persistent major dysplasia of the hip. The term 'missed' dislocation should not be used as this suggests negligence on the part of the examiner, when this may not be the case. Which splint to use (rigid or dynamic), at what age, and for how long, are questions currently unresolved as no proper controlled trials have been undertaken. However, a sensible treatment algorithm can be advocated. Complications secondary to splintage are rare, though nerve damage, avascular necrosis of the hip, redislocation and skin problems have been described.


Cellular and molecular mechanisms of new onset seizure generation.
New onset epilepsy and seizures are common neurological disorders in aged people, second only to stroke and dementia. They are frequently related to other pathological conditions including stroke, trauma, tumors and neurological diseases whereas in about one-third of cases the origin is unknown. Besides the origin, the cellular and molecular events that suddenly trigger seizures are poorly defined. Using an acute model of seizure generation that better resembles new onset seizures, we studied GABAergic interneurons and astrocytes during seizure generation. We found that seizures are preceded by a GABAergic rhythmic hyperactivity that synchronizes pyramidal neurons by inducing a rebound spiking that favors seizures' onset. Furthermore, the intense activity in GABAergic interneurons evokes Ca2+ elevations in astrocytes that, by releasing glutamate, further excite neuronal network. Elucidating the cellular and molecular events that generate seizures may reveal new targets for treatment of new onset seizures and epilepsy.


On nickel contents in urine and hair in a case of exposure to nickel carbonyl.
In an accidental case of exposure to nickel carbonyl with a few persons weak symptoms of illness were observed. Rapid and simple methods of flameless atomic absorption spectroscopy were applied for the determination of nickel in urinary samples and in sections of bundled hairs. The measurements showed in some cases remarkable increased Ni values well above normal levels. The data obtained will be amply discussed and can be used in part for a rough estimation of the biological half life of inhaled Ni.


Lipid composition of SV40-induced transplantable hamster tumor.
The analysis of the lipid composition of the SV40-induced transplantable hamster tumor has shown that: (a) the total phospholipid content in the tumor is lower than that usually found in normal tissues and similar to that reported for other neoplasms; (b) except for a lower percentage of diphosphatidylglycerol, the phospholipid composition is comparable with that reported for normal tissues; (c) the fatty acid profiles of the various glycerophospholipid classes are characterized by high proportions of oleic acid; and (d) phosphatidylethanolamine contains proportions of alkenyl side chains which are consistent with the amounts of plasmalogenic phospholipids found in other neoplasms.


Abnormalities of central contrast sensitivity in glaucoma.
The detectability of foveally presented low-contrast flickering stimuli was determined for glaucoma patients, ocular hypertensives, and normal control subjects. Two types of stimuli, a homogeneous flickering field, and a counterphase flickering grating of low spatial frequency, were presented on a screen subtending 4 degrees of visual angle. The average of the contrast sensitivities to these two simuli (defined as the dynamic response coefficient) was consistently lower in glaucomatous than in normotensive eyes. The dynamic response coefficient was also below normal in half the ocular hypertensive eyes.


Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer.
It has been reported that the mutations of epidermal growth factor receptor (EGFR) are detected in lung cancers. Studies of EGFR mutations in large numbers of patients' tumors with clinical data including response to EGFR tyrosine kinase directed therapy are needed to develop a robust database for clinical use. The purpose of the present study is to gain further insights into the significance of EGFR mutation in non-small cell lung cancer (NSCLC). We investigated the clinicopathologic significance of tyrosine kinase domain (exons 18-21) EGFR mutations in 120 patients with primary NSCLC and the correlation between EGFR mutation and sensitivity to gefitinib in an additional 20 NSCLC patients treated with gefitinib. In addition, onocogenic KRAS mutations and RASSF1A promoter methylation were determined in the same samples. EGFR mutation was detected in 29 of 120 (24%) tumors. All of the 29 (40%) mutations occurred in 72 adenocarcinomas. EGFR mutation was significantly more frequent in females (47%) than males (12%, P < 0.0001), in younger patients (38%) than older patients (10%, P = 0.0005), in nonsmokers (47%) than smokers (13%, P < 0.0001), and in well-differentiated tumors (39%) than moderately and poorly differentiated tumors (7%, P < 0.0001). Mutation of the EGFR gene was preferentially observed in advanced disease. Furthermore, EGFR mutations were detected in 11 of 14 (79%) responders, whereas none of six (0%) nonresponders had the mutation (P = 0.0022). These results in Japanese (East Asian) patients indicated that EGFR mutation plays an important role in pathogenesis of lung adenocarcinoma.


Pregnancy and Gestational Diabetes Mellitus (GDM) in North American Indian Adolescents and Young Adults (AYA): Implications for Girls and Stopping GDM.
To provide an updated synopsis of the research and clinical practice findings on pregnancy and gestational diabetes mellitus (GDM) in American Indian and Alaska Native (AIAN) adolescents and to describe the newly developed "Stopping GDM," an early intervention, culturally tailored risk reduction program for AIAN girls and their mothers. Five research articles met our inclusion criteria. Three retrospective quantitative studies published in the past 10 years corroborated a 1.5 to 2 times higher prevalence for GDM for all age groups in the AIAN population as compared to other ethnic groups, and that the percentage of GDM cases attributable to overweight and obesity was highest for AIs (52.8%). Moreover, First Nations women across all age groups had more adverse pregnancy risk factors than non-First Nations women. Out of the five selected articles, two were qualitative research articles: one examined AIAN women's experiences of having GDM or type 2 diabetes (T2D) during pregnancy and the other appraised the understanding of GDM and reproductive health of at-risk AIAN girls. There is a paucity of research published on this topic. AIAN females are at high risk for developing GDM. Early, culturally responsive interventions and cohort follow-up studies are needed among adolescents and young adults, using technology that appeals to this age group.


Sustainable Redox Mediation for Lithium-Oxygen Batteries by a Composite Protective Layer on the Lithium-Metal Anode.
A synergic combination of a soluble -redox mediator and a protected Li metal -electrode to prevent the self-discharge of the redox mediator is realized by -exploiting a 2,2,6,6-tetramethylpiperidinyl 1-oxyl (TEMPO) redox mediator and an Al2 O3 /PVdF-HFP composite -protective layer (CPL). Stabilization of Li metal by simple CPL coating is effective at -suppressing the chemical reduction of the oxidized TEMPO and opens up the possibility of sustainable redox mediation for robust cycling of Li-O2 batteries.


Effect of propylgallate on a dipalmitoylphosphatidylglycerol and calcium mixture.
Effect of propylgallate (PrG) on the thermotropic behavior of mixtures of dipalmitoylphosphatidylglycerol (DPPG) and Ca2+ was studied by means of differential scanning calorimetry (DSC). In the case of DPPG or DPPG/Ca (molar ratio, 15 : 1), the transition temperature (Tm) of the main transition and the subtransition decreased from 40 degrees C to 29 degrees C and from 29 degrees C to 20 degrees C, respectively, with an increase in the concentration of PrG. The addition of PrG to the DPPG/Ca mixture induced a shoulder on the high temperature side in the reheating scan. Neither PrG nor low concentrations of Ca2+ bind to the Lc phase of DPPG. When the molar ratio of DPPG to Ca was 1 : 1, the subtransition did not occur, that is, only the main transition (Tm = 90 degrees C) appeared. The Tm of the main transition was slightly affected by PrG. On the addition of PrG, another metastable endothermic transition peak (Tm = 78 degrees C) appeared. It is concluded that Ca2+ and PrG inhibit each other's binding.


Differential effect of colchicine upon the entry of proteins into myelin and myelin related membranes.
Brain slices from 20 day old rats were incubated with radioactive aminoacids in the presence and absence of 500 microM colchicine and the appearance of labeled proteins in myelin and in a myelin-like fraction (SN4 fraction) was measured. In the presence of the inhibitor, the entry of proteolipid proteins was decreased to 55% in myelin and to 45% in SN4 fraction with reference to control values while the entry of basic proteins and other minor protein components was unaffected in both fractions. The synthesis of proteolipid proteins was not affected by the presence of colchicine; moreover, a slight accumulation of these proteins was observed in microsomes. The results suggest that the microtubular system is involved in the transport of proteolipid proteins from their site of synthesis to their site of deposition and that the various types of myelin proteins follow different transport routes to enter into this special type of membrane.


The effects of glutamate and GABA (gamma-amino-butyric-acid) on spontaneous acetylcholine release at the neuromuscular junction in Xenopus laevis embryo cell cultures.
The miniature endplate currents (MEPC's) were recorded at the neuromuscular junction of Xenopus laevis embryo neuron-muscle co-cultured cells. These MEPC's were due to the spontaneous release of acetylcholine from the nerve terminal. After perfusion with glutamate (10 mumol/L), both frequency and amplitude of the MEPC's increased. After washing away of glutamate, this effect persisted. We named this phenomena "Long-Term Facilitation". GABA (20 mumol/L) on the other hand had an inhibitory effect on both frequency and amplitude of the MEPC's. After washing away of GABA, the MEPC frequency and amplitude increased. We named this effect "Post-Potentiation". Local perfusion experiments furthermore indicated that the effect of glutamate was restricted to the neuromuscular junction, the effect of GABA was restricted to the soma.


Dioxindole in asymmetric catalytic synthesis: direct access to 3-substituted 3-hydroxy-2-oxindoles via 1,4-additions to nitroalkenes.
The asymmetric Michael addition of dioxindoles to β-substituted nitroalkenes is reported. The bifunctional primary amine-thiourea A, by means of a non-covalent-based mode of catalysis, secures direct access to 3-substituted 3-hydroxyoxindole derivatives with high stereocontrol.


HPA axis disturbance in obsessive-compulsive disorder.
Twenty nondepressed outpatients with DSM-III obsessive-compulsive disorder entered a 10-week placebo-controlled study of clomipramine and underwent a 1-mg dexamethasone suppression test (DST) at baseline; 11 had a repeat DST at the end of treatment: Nonsuppression was rare. When compared to 82 previously described outpatients with panic disorder studied in a similar fashion, OCD patients had postdexamethasone cortisol values that were substantially lower and more stable over time. Results within the OCD group closely resembled those from a group of never-ill controls.


Excretory/secretory antigens from a bovine filarial parasite cross react with human antifilarial antibodies.
Certain excretory/secretory proteins released by adult females of the bovine filarial parasite, Setaria digitata, along with the release of microfilariae when chromatographically analysed has three major protein fractions of molecular weights 70 kD (ESF1), 16.5 kD (ESF2) and 11 kD (ESF3). Of these ESF2 and ESF3 cross reacted with antibodies from Wuchereria bancrofti infected humans. ESF2 was more specific and accurate in detecting human filarial infection. Similar proteins secreted by human filarial parasites could be targets for combating the disease by cure or control.


Plant Cryopreservation: A Look at the Present and the Future.
Cryopreservation is known as an applied aspect of cryobiology or the study of life at low temperatures [...].


Mediterranean visceral leishmaniasis associated with acute lymphoblastic leukemia (ALL).
We report a case of Mediterranean visceral leishmaniasis (MVL) associated with acute lymphoblastic leukemia (ALL) from the South of Iran. The patient, a 12-year-old girl, was known to be a case of ALL and had bone pain and prolonged fever on referral. A trephine biopsy revealed a hypocellular marrow with many amastigotes. Moreover, by specific polymerase chain reaction (PCR) on peripheral blood, a 145 bp band corresponding to kDNA from the genus Leishmania was detected and the species was identified as Leishmania infantum using nested PCR. The patient was treated successfully with two courses of amphotericin B plus IFN-gamma. To our knowledge this is first report of MVL/ALL from Iran and possibly the world.


RNA and protein expression of herpesvirus entry mediator (HVEM) is associated with molecular markers, immunity-related pathways and relapse-free survival of patients with AML.
Immune checkpoint molecules are highly relevant as potential prognostic markers and therapeutic targets in malignant diseases. HVEM belongs to the TNF receptor family and provides stimulatory as well as inhibitory signals depending on the ligand. Abnormal HVEM expression has been described in various malignancies, but the role in AML is unknown. Here we report extensive data on HVEM surface protein expression analyzed by flow cytometry on bone marrow leukemic cells of 169 AML patients at diagnosis. An independent cohort of 512 AML patients was analyzed for HVEM mRNA expression in bone marrow samples by Affymetrix microarrays. Consistently for both cohorts and methods, we show that HVEM was differentially expressed and that expression levels were associated with defined genetic markers. HVEM expression was lower in cases with FLT3-ITD (p = 0.001, p < 0.001), with mutations in NPM1 (p = 0.001, p < 0.001) or with the combination of NPM1 mutation and FLT3 wild type (p = 0.049, p = 0.050), while a biallelic mutation in CEBPA correlated positively with higher HVEM expression (p = 0.015, p < 0.001). In a differential gene expression analysis, we found 13 genes including HOXA9, MEIS1 and MN1 that were closely associated with HVEM expression. Besides, four gene sets closely linked to immunity were enriched in HVEM (high) samples. Finally, high expression of HVEM was associated with a trend toward longer relapse-free survival. The results of this study provide new information on the potential significance of HVEM in AML.


[Secondary pulmonary hypertension due to pulmonary tumor thrombotic microangiopathy diagnosed by open lung biopsy].
A 67-year-old woman was admitted with progressive exertional dyspnea. Arterial blood gas analysis showed severe hypoxia. A chest radiograph and a computed tomography showed bilateral interstitial infiltrations and patchy ground-grass opacities. Initially, she was given antibiotics with no effect. Since transthoracic echocardiography revealed right ventricular overload, cardiac catheterization was performed, which showed pulmonary hypertension. Pulmonary angiography revealed irregular filling defects along with pulmonary peripheral sites. Open lung biopsy was performed to establish a definitive diagnosis and to treat the diffuse lung disease. Microscopically, multiple tumor thrombi of mucinous adenocarcinoma were found in small sized pulmonary artery. Primary sites of malignancy has not been found in spite of postoperative examinations.


von Willebrand factor is a cofactor for thrombin-catalyzed cleavage of the factor VIII light chain.
The proteolytic activation of highly purified, heterodimeric porcine factor VIII and factor VIII-von Willebrand factor complex by thrombin was compared at I 0.17, pH 7.0, 22 degrees C. During the activation of factor VIII, heavy-chain cleavage is necessary to activate the procoagulant function, whereas light-chain cleavage is required to dissociate factor VIII from von Willebrand factor. The kinetics of activation of free factor VIII and factor VIII-von Willebrand factor complex were identical. The steady-state kinetics of thrombin-catalyzed heavy-chain cleavages and light-chain cleavage of factor VIII either free or in complex with von Willebrand factor were studied using sodium dodecyl sulfate-polyacrylamide gel radioelectrophoresis and scanning densitometry of fragments derived from 125I-labeled factor VIII. Association of factor VIII with von Willebrand factor resulted in an 8-fold increase in the catalytic efficiency (kcat/Km) of light-chain cleavage (from 7 x 10(6) to 54 x 10(6) M-1 s-1). The catalytic efficiencies of heavy-chain cleavage at position 372 (approximately 6 x 10(6) M-1 s-1) and position 740 (approximately 100 x 10(6) M-1 s-1) were not affected by von Willebrand factor. We conclude that von Willebrand factor promotes cleavage of the factor VIII light chain by thrombin which is followed by rapid dissociation of the complex, so that the rate-limiting step becomes heavy-chain cleavage at position 372. This accounts for the observation that von Willebrand factor has no effect on the kinetics of activation of factor VIII by thrombin.


Comparison of dual- and triple-freeze protocols for pulmonary cryoablation in a Tibet pig model.
The purpose of this study was to compare a dual-freeze protocol with a triple-freeze protocol for pulmonary cryoablation in a porcine lung model. Five dual- (10-5-10-5) and five triple-freeze (5-5-5-5-10-5) cryoablations were performed on an exposed operation field in normal porcine lung. Changes in the temperature of the cryoprobes and the diameter of the iceballs were measured during the ablation and pathologic changes in the cryozones (zones of tissue destruction) were reviewed 7 days after the procedure. The diameter of the iceball surface differed between the two protocols. Pathologically, the triple-freeze protocol was associated with a longer complete necrosis zone than the dual-freeze protocol, though the two protocols produced cryolesions and cryozones of similar length, and in both cases there were five areas of tissue destruction. With the same duration of freezing (20 min), the triple-freeze protocol may be better for pulmonary cryoablation than the dual-freeze protocol.


Induction of platelet-derived growth factor A and B chains and over-expression of their receptors in human pancreatic cancer.
Expression of platelet-derived growth factor (PDGF) and PDGF receptors was examined in cultured human pancreatic cancer cells, in the normal human pancreas and in pancreatic adenocarcinomas. mRNA transcripts encoding PDGF A and B chains, and PDGF receptor beta (PDGFR beta) were present in PANC-I and HPAF human pancreatic cancer cells. Transforming growth factor beta I (TGF-beta I), but not PDGF-AA or -BB, enhanced PDGF A and B chain mRNA levels in both cell lines. In the normal human pancreas PDGF A chain mRNA levels were relatively abundant, whereas PDGF B chain mRNA levels were not detected and PDGF receptor alpha (PDGFR alpha) and beta mRNA transcripts were present at low levels. PDGF immunoreactivity was present in islet cells, and PDGFR alpha was present in acinar cells, whereas PDGFR beta was present in acinar cells and in the connective tissue. In the pancreatic cancers, PDGF A chain mRNA transcripts were also abundant, and 6 of 13 samples exhibited the PDGF B chain mRNA transcript. In addition, there was a 7-fold increase in the levels of PDGFR alpha and PDGFR beta in the cancer samples by comparison with the normal pancreas. By immunohistochemistry, PDGF and both PDGF receptors were present in the cancer cells, and PDGFR beta was abundant in fibroblasts and endothelial cells within the connective tissue.


Thermal reaction and luminescence of long-lived N 2D in N2 ice.
Photochemistry of an N2 ice and thermal reaction of the irradiated sample were studied with vacuum-ultraviolet (VUV) light from a synchrotron. Concurrent detection of infrared absorption and visible emission spectra provide evidence for the generation of energetic products N (2D) and N (2P) atoms, N2 (A) molecule and linear-N3 (l-N3) radical after excitation of icy N2 at 121.6 nm. Irradiation at 190 nm is shown to be an effective way to eliminate the l-N3 radical. After the photolysis and photoelimination of the l-N3, we initiate synthesis of l-N3 via the thermal ramping of the sample in temperature range 3.5 to 20 K. In addition, the emission from the N (2D) atom was observed during the thermal ramping process. These behaviors indicate that a long-lived N (2Dlong) atom is generated in the VUV-photolyzed N2 ice. A comparison of the variations of the visible emission of N (2D) and the infrared absorption of l-N3 with time indicates that the long-lived N (2Dlong) dominated the thermal synthesis of l-N3 The results have enhanced suggestion and understanding of the conversion for nitrogen species in cold astrophysical environments with VUV irradiation.


Health literacy and behavioral health factors in adults.
This study was to examine the relationship between health literacy (HL) and health behaviors in the South Bohemia Region in the Czech Republic (CR) and compare them to HL and health behaviors in the Visegrád group countries (Czech Republic, Hungary, Poland, and Slovakia). The paper reports the results from the research in the CR. A quantitative descriptive study. The sample was stratified by sex and age and included a representative sample of 303 adults. The data were collected using the combination of a country-specific questionnaire with the HLS-EU-16 standardized questionnaire. Exercise was significantly associated with perceived health and HL; those with a lower level of HL did not exercise during the previous month. Based only on full answers (N = 251), inadequate HL was identified in 17.5% of the respondents (44), marginal HL in 31.5% (77), and adequate HL in 51% (128) of the respondents. Nearly 49% of the participants evaluated their health as 'good', 25.7% rated their health as 'very good' and 'satisfactory' by 25.7%. But 41.6% experienced one or more chronic diseases, 37.6% had some limitations to their health, and 20.5% smoked. For alcohol consumption, 26% drank weekly and 23% drank two to three times a month. Exercise varied from never (29.7%) to daily (7.9%). Based on our results, we conclude that health behavior risk factors are still present in the South Bohemia region of the CR regardless of levels of HL reported on the HLS-EU-16.


The effect of indwelling catheter on OH-proline in the urethral wound: an experimental study.
To investigate the effect of catheterization on urethral wound healing by measuring OH-proline. Eighteen male New Zealand albino rabbits were divided equally into three groups. In the control group, urethral tissue samples were taken from the ventral penile surface. In group II, the ventral penile surface was incised and primarily repaired by 6/0 polydioxanone. In group III, the incised urethra was repaired by 6/0 polydioxanone and a urethral catheter was inserted. Tissue samples were taken on the 20th postoperative day in groups II and III. Tissue OH-proline levels were measured by the method of Bergman and Loxley. The Kruskal-Wallis statistical test was used for evaluation. OH-proline values as microg/mg dry tissue were 16.43+/-2.68 in the control group, 14.47+/-1.82 in group II and 14.63+/-0.63 in group III. There was no significant difference between the three groups (P>0.05). Use of a urethral catheter does not appear to have a direct effect on collagen synthesis in wound healing.


Energy cost of fever in children on total parenteral nutrition.
The aim of the study was to measure the changes in energy expenditure (EE) and respiratory quotient (RQ) induced by fever in children receiving total parenteral nutrition (TPN). Ten children aged 1-16 years (weight for height: 104.5 +/- 13%) were included. They underwent two EE recordings of 3 h duration using indirect calorimetry, during a febrile (38.9 +/- 0.5 degrees C) and afebrile conditions, after parameters (nutritional intake, ambient temperature) being equal. The EE, (febrile phase) was significantly higher than the EE(2) (afebrile) (2.13 +/- 0.48 vs 1.78 +/- 0.42 kcal/kg/h; P < 0.01). Increase in EE was significantly correlated with body temperature (r = 0.92, P < 0.001). The slope of the regression line indicates an increase of 16.2% in EE per degree of fever. By dividing the individual increase in EE by the individual increase in temperature, the energy expenditure during fever is 11.3% per unit rise ( degrees C). During the febrile phase urinary nitrogen excretion was significantly higher (280 +/- 90 vs 210 +/- 70 mg/kg fat free mass/day, P < 0.02). The RQ during the febrile phase (0.90 +/- 0.13) did not differ significantly from mean RQ during the afebrile phase (0.95 +/- 0.07). Fever due to infection or inflammatory process is partly responsible for an hypermetabolic state including increased EE.


[Cerebral hemisphere blood volume, venous filling and emptying in patients with arterial hypertension who have suffered from Chernobyl accident depending on sex and age].
Reliable differences in cerebral hemisphere blood vessels filling and tonus of microcirculation system have been found between men and women of different ages with arterial hypertension, who have suffered from Chernobyl accident with the help of tetrapolar impedance plethysmography method (rheoanalysator PAS-01). Cerebral hemisphere blood vessels filling in women of all ages has been shown to be higher for sure than in men and the tonus of pre- and postcapillaries under developing arterial hypertension gets lower with age.


Peripheral Blood Cell Variables Related to Systemic Inflammation in Patients With Unresectable or Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.
Systemic inflammatory response (SIR) plays a central role in the prognosis of unresectable or metastatic pancreatic ductal adenocarcinoma (mPDAC), and many SIR-related peripheral blood cell (PBC)-derived variables have been proposed as prognostic factors. The study aims to perform a systematic review and, for the more studied PBC-derived variables, a meta-analysis. A systematic review from 2000 to 2020 on 2 databases by predefined criteria was performed for PBC-derived variables in patients with mPDAC receiving chemotherapy in relation with overall survival. Eligible studies were selected by inclusion criteria, and only the PBC variables reported in at least 10 studies were evaluated by meta-analysis. Three hundred and eighty articles were found, and 28 studies were selected. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were reported in 28 and 10 articles, respectively. The subsequent meta-analyses supported the prognostic effect for both, NLR (hazard ratio, 2.10; 95% confidence interval, 1.87-2.37) and PLR (hazard ratio, 1.22; 95% confidence interval, 1.08-1.37). Heterogeneity was significant for NLR (I2 = 62%) and low for PLR (I2 = 24%). Among SIR-related PBC-derived variables, NLR is the most suitable prognostic factor for future clinical trials of patients with mPDAC.


A study on the influences of a hygrothermal environment on the compressive strength and failure criteria of asphalt mixtures based on true triaxial tests.
Based on a high-pressure servo static and dynamic true triaxial test machine (tawz-500/300), uniaxial and true triaxial tests of AC-25C asphalt mixtures under different heat moisture coupling treatments were performed, and the triaxial compressive strength value was determined by mathematical treatment. The test results show that in the range of 20-60 °C, the uniaxial and triaxial compressive strength of the AC-25C asphalt mixture decreases with increasing drying and soaking environment temperature. In the temperature range of 20-40 °C, the drying temperature sensitivity and soaking temperature sensitivity of the asphalt mixture with compressive strength and failure strain value as indices are the maximum. The increase in the intermediate principal stress can improve the triaxial compressive strength, and the increase reaches the maximum when the environmental treatment temperature is 40 °C. The maximum stress ratio is in the range of σ2/σ3 = 0.25 to σ2/σ3 = 0.5. The failure forms of uniaxial tension and triaxial tension are mainly caused by tensile stress. The influence of temperature, humidity and stress ratio on triaxial failure strength is analysed. The relationship between the failure strength and temperature coefficient k is established using a variety of failure criteria, which can provide an experimental and theoretical basis for the mechanical analysis of asphalt mixtures under complex stress states.


Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have".
Biotinidase recycles the vitamin biotin. Biotinidase deficiency is an autosomal recessively inherited neurocutaneous disorder. The symptoms of the disorder can be successfully treated or prevented by administering pharmacological doses of biotin. The biotinidase gene (BTD) has been cloned and sequenced; its genomic organization has been determined and more than 150 mutations have been identified. The disorder meets the major criteria for newborn screening and is being universally adopted in the United States and in many countries around the world. Newborn screening will limit our understanding about the natural history of the disorder. Regardless, the disorder is an ideal example of an inherited metabolic disorder that if untreated can result in major disabilities, but if identified early can be readily treated by the oral administration of a vitamin.


Initial testing of an electronic application of the simplified modified Rankin Scale questionnaire (e-smRSq).
To facilitate modified Rankin scale (mRS) assessments, we developed and tested a smartphone/web application of the simplified mRS questionnaire (e-smRSq). The e-smRSq guides raters towards a final score according to the smRSq algorithm, and offers hints for scoring based on the conventional mRS concepts. Initially, three experienced mRS certified raters prepared 30 vignettes of unstructured stroke patient interviews, and determined consensus reference scores. Using the e-smRSq, 16 raters of varied professional backgrounds without mRS training scored the mRS for 24 randomly selected vignettes. Subsequently, 5 certified and 5 uncertified raters using the e-smRSq scored 23 mRS certification vignettes developed and used in the Strategies to Innovate Emergency Care Clinical Trials Network-Neurological Emergencies Treatment Trials (SIREN-NETT). Cohen's and Fleiss's kappa (κ), weighted kappa (κw), and intra-class correlation (ICC) compared rater scores with reference scores and assessed interrater reliability. For the 16 initial raters using the e-smRSq with 24 vignettes, the κ (Fleiss) was 0.62 and ICC 0.87 (CI 0.80-0.93). Comparing raters' scores with reference scores, Cohen's κ was 0.68 and κw 0.90. For the 10 subsequent raters using the e-smRSq on SIREN-NETT vignettes, κ (Fleiss) was 0.8 and ICC 0.95 (CI 0.91-0.97). Comparing all 10 raters scores with SIREN-NETT reference scores, Cohen's κ was 0.88 and κw 0.97. There was no significant difference between certified and uncertified raters. The e-smRSq appears to have good reproducibility and validity metrics among both certified and non-certified mRS raters, possibly owing to its simplicity. Further testing in stroke patients in warranted.


Effect of homocysteine on the L-arginine/nitric oxide synthase/nitric oxide pathway in human platelets.
Recent evidence indicates that chronic hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis, thrombosis, and other cardiovascular diseases. This may be secondary to impaired fibrinolysis, or increased platelet reactivity. L-Arginine/ nitric oxide synthase/nitric oxide (NO) plays an important role in the regulation of platelet function. The present study was undertaken to determine the effect of homocysteine (HCY) on the L-arginine/NO pathway of human platelets. Washed human platelets were incubated in the presence or absence of HCY for 2h at 37 degrees C followed by a measurement of indices of the L-arginine/NO pathway. HCY caused a concentration-dependent reduction in the platelet uptake of L-[3H]arginine. HCY also caused a concentration-dependent decrease in nitrite production concurrent with a decrease in cyclic guanosine monophosphate, whereas NO synthase activity of the platelets, measured as conversion of L-[3H]arginine to L-[3H]citrulline, remained unchanged on incubation with HCY. These observations indicate that the L-arginine/NO pathway is involved in the mechanism responsible for the effects of HCY on platelets by diminishing NO production through decreased uptake of L-arginin


[Experience of a young graduate nurse overseas].
A young, recently graduated nurse chose, as her first job, a position on the archipelago of Saint-Pierre and Miquelon. Through her dual perspective as a young graduate and a native of metropolitan France, we discover the nursing care and the questions she raises, between the proximity resulting from the demographics of the islands and the young teams with a high staff turnover.


E-learning use in the review of neonatal resuscitation program in physicians: a scoping review.
To determine if e-learning interventions are efficient to review Neonatal Resuscitation Program (NRP) and to prevent performance deterioration in neonatal resuscitation of already-certified healthcare professionals. In this scoping review, we searched for manuscripts published until June 2020 in five databases. We included all studies on e-learning use for NRP review in already-certified healthcare providers. Among 593 abstracts retrieved, 38 full-text articles were assessed for eligibility. Five studies were included. Four studies evaluated the effectiveness of e-learning interventions immediately or months after their completion by providers. These interventions did not consistently enhance their NRP knowledge and their performance. One study showed that a growth mindset can influence positively neonatal resuscitation performance after an e-learning simulation. There is not enough evidence to conclude that e-learning interventions can prevent neonatal resuscitation knowledge and performance decay in already-certified providers. More research is needed on the use of e-learning simulation-based scenarios to improve NRP retention.


Lp(a) phenotypes, other lipoprotein parameters, and a family history of coronary heart disease in middle-aged males.
In a study of 95 presumably healthy, 40-42-year old males from Northen Sweden, the Lp(a) phenotype distribution differed between those who had, and those who did not have one or more close relatives (parent or sib) with coronary heart disease. In the former group, 60% of the males were Lp(a+), as opposed to 28% in the latter group. Thus, in the homogeneous population sample studied, analysis of the normal inherited Lp(a) variation permitted the identification of distinct subpopulations, with respect to familial occurrence of coronary heart disease. None of a series of other parameters distinguished such sub-populations. The results reported are in agreement with our previous finding of a close association between phenotype Lp(a+) and risk of contracting coronary heart disease.


Students' Perception of Newly Experimented "Rangoli Art" in Anatomy Education: A Pilot Study.
Art and drawing have a well-established history with the teaching and learning of anatomy, as symbolized by Leonardo Da Vinci's Vitruvian Man. However, its efficacy relatively declined in modern anatomy education. The purpose of this study was to survey students' views regarding the "anatomy Rangoli-making activity" and to discern if this art form may be implicated in anatomy education. In this group activity, the basic anatomical drawing of the specific structure was made on the floor, and then the different structures in the illustration were filled with relevant powdered Rangoli colors. The present study was conducted on seventy-eight first-year medical students who were willing to participate in the study. A mixed questionnaire regarding their opinion on the "anatomy Rangoli-making activity" was designed and feedback was taken from the students. The majority of the students replied that the Rangoli-making activity was interesting, promoted team spirit, and improved confidence to draw and understand the concept of the diagrams. The students agreed that it is an innovative method of anatomy learning. Almost 99% of students suggested incorporating such art activities in anatomy learning for future students. The enthusiastic response of the students to this activity is encouraging to introduce such art base activities in anatomy education and learning. Future multicenter studies on this learning method may be planned to check its efficacy.


Layers of complexity in interpreting evidence on effectiveness.
There has been growing attention to using evidence on effectiveness to guide public health and health improvement policies, strategies, programmes and actions 'on the ground'. However, there has been insufficient recognition of the complexity attached to interpreting such evidence and translating it into action. In this paper, a randomized controlled trial is used as an illustrative case study to uncover layers of that complexity. It is suggested that these layers should be taken into account in designing, executing, analysing and reporting primary evaluative studies and reviews; formulating recommendations for action; and developing more fully fit-for-purpose approaches to evidence-informed public health and health improvement.


[Mechanism of activation of the photosensitizing effect of water-soluble analogs of chlorophyll when bound to a polymer].
It has been shown that the order of mixture of photoreduction components of methylene red with ascorbic acid sensitized with clorine e in an aqueous solution of polyvinilpyrrolidone markedly affects the rate and depth of the reaction. The data obtained support the hypothesis that the intensificiation of the sensitized reaction in the presence of polymer is conditioned by joint polymer binding of the reaction components. This binding facilitates the interaction between the electron donor or acceptor with the light-excited pigment.


Factors Influencing The Six-Month Mortality Rate In Patients With A Hip Fracture: DEJAVNIKI, KI VPLIVAJO NA ŠESTMESEČNO STOPNJO UMRLJIVOSTI PRI BOLNIKIH Z ZLOMOM KOLKA.
There are several potential risk factors in patients with a hip fracture for a higher rate of mortality that include: comorbid disorders, poor general health, age, male gender, poor mobility prior to injury, type of fracture, poor cognitive status, place of residence. The aim of this study was to assess the influence of potential risk factors for six-month mortality in hip fracture patients. The study included all patients with a hip fracture older than 65 who had been admitted to the Clinic for orthopaedic surgery during one year. One hundred and ninety-two patients were included in the study. Six months after admission due to a hip fracture, 48 patients had died (6-month mortality rate was 25%). The deceased were statistically older than the patients who had survived. Univariate regression analysis indicated that six variables had a significant effect on hip fracture patients' survival: age, mobility prior to the fracture, poor cognitive status, activity of daily living, comorbidities and the place where they had fallen. Multivariate regression modelling showed that the following factors were independently associated with mortality at 6 months post fracture: poor cognitive status, poor mobility prior to the fracture, comorbid disease. Poor cognitive status appeared to be the strongest mortality predictor. The employment of brief tests for cognitive status evaluation would enable orthopaedists to have good criteria for the choice of treatment for each patient screened.


Psychological aspects of HIV infection in children.
Despite advances in the pharmaceutical treatment of HIV disease, there are still an increasing number of people living with the disease, and an increasing number of children and adolescents are personally affected by the epidemic. The psychological effects on these children are significant and relate not only to a parent's degree of illness and the threat of death but also to the association of the disease with substance abuse and the pervasive effects of the stigma that surround it. To intervene optimally on behalf of these children, programs must be multidisciplinary and take a holistic approach to address specific social and psychological issues and ensure stability in a child's care giving.


[Radiation sensitivity testing and late neurological complications following radiosurgery for AVM: the use of SF2 from fibroblasts as a predictive factor].
To identify SF2 as a prognostic factor of late complications from radiosurgery in patients treated for AVM. Five patients with AVM treated in three canadian institutions and who suffered clinically significant neurological sequelaes secondary to radiosurgery were identified. Their fibroblasts were cultured and their radiation sensitivity tested to determine the SF2 for each patient. Patients who developed a neurological complication from radionecrosis, secondary to radiosurgery had an SF2 different than the two control patients with AVM and no complications and also from a group of five cancer patients without late radiation complications (P = 0.005). Radiosurgery is an elective procedure. The identification of a subgroup of patients who are radiosensitive and at a higher risk of radiation induced complications can allow the treatment team to reduce the risk of such complications. SF2 as a new predictive factor should be incorporated in predictive models of risk from treatment of AVM by radiosurgery. This work needs to be confirmed in a larger cohort of patients.


Infectious hematopoietic necrosis virus (IHNV) nucleoprotein amino acid residues affect viral virulence and immunogenicity in rainbow trout (Oncorhynchus mykiss).
This study compared the N protein sequences of genotype J with other genotypes of IHNV to select amino acid residues that may be related to the change in viral virulence. The recombinant viruses containing different mutation sites were rescued by alanine scanning mutagenesis and the reverse genetic system. The nine recombinant virus strains obtained in this work were named rIHNV-N85, rIHNV-N102, rIHNV-N146, rIHNV-N380, rIHNV-N85-102-146, rIHNV-N85-102-380, rIHNV-N85-146-380, rIHNV-N102-146-380, and rIHNV-N85-102-146-380. Pathogenicity and immunity assays were performed to determine the role of virulence sites. The result of the pathogenicity test showed that the survival rates of rIHNV-N85, rIHNV-N102, rIHNV-N85-102-146, and rIHNV-N85-102-380 groups were 52.5%, 55%, 67.5%, and 57.5%, while the survival rate of wild-type (wt) IHNV HLJ-09 group was only 10%. The replication ability of recombinant viruses with substitutions at positions 85 and 102 was significantly inhibited in vivo and in vitro. The qRT-PCR result indicated that the cytokines of IFN1, IL-8, and IL-1β expression levels were increased in rIHNV-N85, rIHNV-N102, rIHNV-N85-102-146, and rIHNV-N85-102-380 groups. In addition, these four recombinant viruses could cause the rainbow trout to produce anti-IHNV-specific antibodies immunoglobulin M (IgM) earlier, confirming that 85 and 102 amino acid residues of N protein affected the virulence and immunogenicity of IHNV. All these results suggest that mutations of the N protein virulence sites reduce virulence while retaining immunogenicity. This also provides a new idea for studying the virulence mechanism of rhabdoviruses and preparing attenuated vaccines.


Validation of various extraction techniques for the quantitative analysis of polycyclic aromatic hydrocarbons in sewage sludges using gas chromatography-ion trap mass spectrometry.
A new GC-ion trap MS method has been developed for the determination of polycyclic aromatic hydrocarbons (PAHs) in sewage sludge samples. The sludge samples were extracted with Soxhlet, Soxtec, and pressurized liquid extraction (PLE) using 1:1 (v/v) dichloromethane (DCM):n-hexane solvent mixture. A multi-layer clean-up (silica/Al2O3) column were used, followed by gel permeation chromatography (GPC) to eliminate the interfering organic compound as well as the lipids. The extracts were quantified with GC-EI-SIS and GC-EI-MS-MS. The method was successfully applied to determine the concentration of PAHs present in sewage sludge samples collected from four waste water treatment plants (WWTPs). The method recovery values varied from 61.5 to 90.5%, 65.0 to 91.8% and 60.0 to 93.4% for Soxtec extraction, Soxhlet extraction and PLE extraction, respectively. The total concentrations of the 16 PAHs in the sewage sludge samples were found to vary from 1.56 to 6.18 mg/kg. The concentration of PAHs in WWTPs did not significantly vary.


A Review of the Clinical Trial Landscape in Psoriasis: An Update for Clinicians.
As our understanding of the pathogenesis of psoriasis has evolved over the past two decades, so has the number of treatment options. The introduction of biologic agents targeting specific cytokines in the interleukin (IL)-23/IL-17 pathway has proven successful in promoting skin clearance among patients. However, their use is often limited owing to cost, parenteral administration, and possible reduced efficacy over time. Topical therapies have also seen limited advancement, with agents such as corticosteroids and vitamin D derivatives remaining the mainstay of treatment, despite side effects limiting their long-term use. New therapeutic agents are needed to improve disease management for patients. In this review, we summarize pipeline and recently approved therapies undergoing clinical trials for psoriasis during a 12-month search period (30 June 2021 to 30 June 2022) using ClinicalTrials.gov. New-generation biologics and oral small molecules in phase II or III development were included, and pivotal data identified through various search modalities (PubMed, conference presentations, etc.) evaluating each drug candidate will be discussed. Topical therapies will also be discussed in line with recent US Food and Drug Administration approvals. As new therapies continue to enter the treatment landscape, long-term data and comparative trials will be needed to better understand their place among existing therapeutic agents.


Acute change of lung function to short-term exposure to ambient air pollutants with and without physical activity: A real-world crossover study.
Physical activity (PA) would increase the inhalation rate and thereby inhaled dose of air pollutants. However, it's still uncertain whether the effects of air pollutants on lung function are attenuated by PA, especially in the high-polluted areas. We aimed to disentangle the interaction between air pollution and PA on lung function among healthy adults. In this study, a real-world crossover study was conducted among 74 healthy adults. Each participant underwent both rest and 15-min intermittent moderate PA exposure scenarios (consisting of 15min stationary bike riding alternating with 15min of rest), which lasted for 2 h. On the same day, the participants among active and inactive group were exposed to the same air pollution. We have monitored the fine particulate matter (PM2.5), particulate matter less than 10 μm (PM10), particulate matter less than 1 μm (PM1), black carbon (BC), nitrogen dioxide (NO2), and ozone (O3) continuously during 2-h exposure. Lung function were measured at five times points for each visit (before, immediately, 3 h, 5 h, and 24 h after the 2-h exposure scenario). Mixed-effects models were applied to explore the effects of air pollution, PA, and their interaction on lung function. The participants had a mean (standard deviation (SD)) age of 19.9 (0.9) years. The average concentration [mean ± SD] of PM2.5, PM10, PM1, BC, NO2, and O3 were 59.4 ± 45.1 μg/m3, 122.8 ± 109.0 μg/m3, 38.8 ± 29.2 μg/m3, 1.94 ± 1.17 μg/m3, 59.5 ± 26.6 μg/m3, and 74.0 ± 30.3 μg/m3, respectively. Overall, greater increasement in lung function were observed among active group compared with inactive group at all timepoints. In fully adjusted models, we observed the benefits of PA and detrimental effects of air pollutants on lung function. Our results suggested that PA, compared to rest, alleviated the detrimental effects of air pollutants on lung function. We also stressed the importance of timing of measurements for capturing association. In conclusion, our observations suggested that PA might alleviate the associations between various pollutant exposures and lung function, which would drive further research towards potential pathway.


Preparation by irradiation of a solid support for enzyme immunoassay.
Reagents (immobilized anti-alpha-fetoprotein discs) having a porous structure were prepared for enzyme immunoassay of alpha-fetoprotein by radiation polymerization at low temperatures. Discs were attached to sticks for easy handling. The activity (determined by absorbance at 492 nm) of the discs varied with the hydrophilic properties and size of the disc. The discs are sufficiently sensitive and precise for enzyme immunoassay of alpha-fetoprotein.


Impact of a Prior Cancer Diagnosis on Quality of Care and Survival Following Acute Myocardial Infarction: Retrospective Population-Based Cohort Study in England.
An increasing proportion of patients with cancer experience acute myocardial infarction (AMI). We investigated differences in quality of AMI care and survival between patients with and without previous cancer diagnoses. A retrospective cohort study using Virtual Cardio-Oncology Research Initiative data. Patients aged 40+ years hospitalized in England with AMI between January 2010 and March 2018 were assessed, ascertaining previous cancers diagnosed within 15 years. Multivariable regression was used to assess effects of cancer diagnosis, time, stage, and site on international quality indicators and mortality. Of 512 388 patients with AMI (mean age, 69.3 years; 33.5% women), 42 187 (8.2%) had previous cancers. Patients with cancer had significantly lower use of ACE (angiotensin-converting enzyme) inhibitors/angiotensin receptor blockers (mean percentage point decrease [mppd], 2.6% [95% CI, 1.8-3.4]) and lower overall composite care (mppd, 1.2% [95% CI, 0.9-1.6]). Poorer quality indicator attainment was observed in patients with cancer diagnosed in the last year (mppd, 1.4% [95% CI, 1.8-1.0]), with later stage disease (mppd, 2.5% [95% CI, 3.3-1.4]), and with lung cancer (mppd, 2.2% [95% CI, 3.0-1.3]). Twelve-month all-cause survival was 90.5% in noncancer controls and 86.3% in adjusted counterfactual controls. Differences in post-AMI survival were driven by cancer-related deaths. Modeling improving quality indicator attainment to noncancer patient levels showed modest 12-month survival benefits (lung cancer, 0.6%; other cancers, 0.3%). Measures of quality of AMI care are poorer in patients with cancer, with lower use of secondary prevention medications. Findings are primarily driven by differences in age and comorbidities between cancer and noncancer populations and attenuated after adjustment. The largest impact was observed in recent cancer diagnoses (<1 year) and lung cancer. Further investigation will determine whether differences reflect appropriate management according to cancer prognosis or whether opportunities to improve AMI outcomes in patients with cancer exist.


Nogo/RTN4 isoforms and RTN3 expression protect SH-SY5Y cells against multiple death insults.
Among the members of the reticulon (RTN) family, Nogo-A/RTN4A, a prominent myelin-associated neurite growth inhibitory protein, and RTN3 are highly expressed in neurons. However, neuronal cell-autonomous functions of Nogo-A, as well as other members of the RTN family, are unclear. We show here that SH-SY5Y neuroblastoma cells stably over-expressing either two of the three major isoforms of Nogo/RTN4 (Nogo-A and Nogo-B) or a major isoform of RTN3 were protected against cell death induced by a battery of apoptosis-inducing agents (including serum deprivation, staurosporine, etoposide, and H2O2) compared to vector-transfected control cells. Nogo-A, -B, and RTN3 are particularly effective in terms of protection against H2O2-induced increase in intracellular reactive oxygen species levels and ensuing apoptotic and autophagic cell death. Expression of these RTNs upregulated basal levels of Bax, activated Bax, and activated caspase 3, but did not exhibit an enhanced ER stress response. The protective effect of RTNs is also not dependent on classical survival-promoting signaling pathways such as Akt and Erk kinase pathways. Neuron-enriched Nogo-A/Rtn4A and RTN3 may, therefore, exert a protective effect on neuronal cells against death stimuli, and elevation of their levels during injury may have a cell-autonomous survival-promoting function.


Dopamine release at the time of a predicted aversive outcome causally controls the trajectory and expression of conditioned behavior.
Dopamine release in the nucleus accumbens (NAc) is causally linked to adaptive aversive learning, and its dysregulation is a core phenotype in anxiety and stress disorders. Here, we record NAc core dopamine during a task where mice learn to discriminate between cues signaling two types of outcomes: (1) footshock presentation and (2) footshock omission. We show that dopamine release is evoked by footshock omission. This dopamine response is largest when the omission is unexpected and decreases over learning, and artificially increasing this signal disrupts discrimination learning. Conversely, optogenetic inhibition of dopamine responses to the footshock itself impairs learning. Finally, theory-driven computational modeling suggests that these effects can be explained by dopamine signaling the perceived saliency of predicted aversive events. Together, we elucidate the role of NAc dopamine in aversive learning and offer potential avenues for understanding the neural mechanisms involved in anxiety and stress disorders.


Single molecule force spectroscopy reveals a weakly populated microstate of the FnIII domains of tenascin.
The native states of proteins exist as an ensemble of conformationally similar microstates. The fluctuations among different microstates are of great importance for the functions and structural stability of proteins. Here, we demonstrate that single molecule atomic force microscopy (AFM) can be used to directly probe the existence of multiple folded microstates. We used the AFM to repeatedly stretch and relax a recombinant tenascin fragment TNfnALL to allow the fibronectin type III (FnIII) domains to undergo repeated unfolding/refolding cycles. In addition to the native state, we discovered that some FnIII domains can refold from the unfolded state into a previously unrecognized microstate, N* state. This novel state is conformationally similar to the native state, but mechanically less stable. The native state unfolds at approximately 120 pN, while the N* state unfolds at approximately 50 pN. These two distinct populations of microstates constitute the ensemble of the folded states for some FnIII domains. An unfolded FnIII domain can fold into either one of the two microstates via two distinct folding routes. These results reveal the dynamic and heterogeneous picture of the folded ensemble for some FnIII domains of tenascin, which may carry important implications for the mechanical functions of tenascins in vivo.


Impact of a Formulation Containing Unusual Polyunsaturated Fatty Acids, Trace Elements, Polyphenols and Plant Sterols on Insulin Resistance and Associated Disturbances.
To evaluate the effect of a lipid-based formulation containing unusual polyunsaturated fatty acids, trace elements, polyphenols and plant sterols on insulin resistance and its associated disturbances among adults at risk of diabetes. This was an 8-week, three-arm, open-label randomized clinical trial. We studied individuals aged ≥ 18 years old with diabetes risk given by a body mass index ≥ 25 kg/m2 or a FinnRisc score ≥ 13/20. Participants were randomly assigned to receive: 7 ml sunflower oil (control group), 3.5 ml of the study formulation + 3.5 ml of sunflower oil (low-dose group) or 7 ml of study formulation (high-dose group). We randomized 25 individuals. After one withdrawal in the high-dose group, the study sample comprised nine patients in the control, nine in the low-dose and six in the high-dose groups. The insulin sensitivity increased significantly and in a dose-dependent fashion, up to 10% in the high-dose group. At week 8 the low-dose group exhibited lower glycemic excursions during the oral glucose tolerance test (OGTT), especially 1 h after the glucose challenge (32 mg/dl or 23% lower vs. control group). The incremental area under the glucose curve in the OGTT was 17.1% lower in the low-dose group vs. the control group. Waist circumference increased in the control group, remained constant in the low-dose group and decreased in the high-dose group. C-reactive protein decreased in both formulation groups, up to 50% in the high-dose group. Participants in the formulation groups exhibited increased secretion of GLP-1 and plasma irisin at week 8 vs. the control group. The formulation induced favorable changes in insulin sensitivity, glucose tolerance, abdominal obesity and inflammation. These effects and their durability will need to be assessed in larger studies. NCT03512665. Team Foods Colombia.


Asthma control and steroid doses 5 years after early or delayed introduction of inhaled corticosteroids in asthma: a real-life study.
We evaluated asthma control and medication use 5 years after introduction of an inhaled corticosteroid (budesonide via Turbuhaler) in 462 patients with persistent asthma and symptoms of different duration. An early treatment group with symptoms for <2 years (group A) was compared with a delayed treatment group (group B) (median duration 5 years and 3 months). Most patients received budesonide 400 microg twice daily as initial dose. We report 5-year follow-up data on 404 patients (group A n = 253; group B n = 151) and on a few more patients after treatment for 6 months, 1 year and 3 years. At 5 years the mean maintenance doses of budesonide were 412 microg (A) and 825 microg (B), respectively (P<0.001). Nevertheless, treatment goals (normal lung function, normal exercise tolerance, minimal use of reliever medication, no asthma exacerbations) were all statistically significantly more frequently achieved in group A. At 5 years group B patients also used significantly more additional asthma medications, e.g. inhaled long-acting beta2-agonists by 64% compared with 6% in group A. In group A 43 patients (17%) had been able to stop budesonide treatment compared to five patients (3%) in group B. A subgroup of group B patients with higher mean baseline FEV1 values than group A showed nevertheless significantly poorer response. No treatment-related serious adverse events were reported. Budesonide was well tolerated in both groups. Duration of asthma symptoms when starting treatment with an inhaled corticosteroid is an important determinant for the response. Early treatment gives significantly better airway function and asthma control than delayed treatment and at lower maintenance doses.


Prevention of HIV-1 infection by phthalocyanines.
The ability of selected phthalocyanines and metallophthalocyanines to block HIV infection has been evaluated in an epithelial HeLa-CD4 cell line with an integrated LTR-beta-galactosidase gene. Sulfonated phthalocyanine itself (PcS), as well as its copper, nickel, and vanadyl chelates, were the most effective in blocking viral infection. These compounds were also very effective in blocking the fusion activity of the viral Env proteins. All of these compounds are expected to bind axial ligands weakly or not at all. In contrast, sulfonated phthalocyanines bearing metals expected to bind axial ligands more tightly (aluminum, cobalt, chromium, iron, silicon, and zinc) were less effective in blocking HIV infection and also less effective at inhibiting fusion. A number of active compounds were found to block binding of gp120 to CD4. Selected cationic and carboxy phthalocyanines, as well as porphyrazines, were also evaluated. Our results indicate that at least some of the compounds render the virus noninfectious, i.e. that they are virucidal. These compounds have potential as microbicides that might be used to provide protection against sexually transmitted HIV.


Antibiotic optimization in the difficult-to-treat patient with complicated intra-abdominal or complicated skin and skin structure infections: focus on tigecycline.
Complicated intra-abdominal and skin and skin structure infections are widely varied in presentation. These infections very often lead to an increase in length of hospital stay, with a resulting increase in costs and mortality. In addition, these infections may be caused by a wide variety of bacteria and are often polymicrobial with the possibility of the presence of antimicrobial-resistant strains, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum β-lactamase strains (Escherichia coli, Klebsiella pneumoniae), and K. pneumoniae carbapenemase-producing strains. In combination with patients' immunosuppression or comorbidities, the treatment and management options for initial therapy success are few. Tigecycline, a new glycylcyline antimicrobial from the tetracycline drug class, represents a viable option for the successful treatment of these infections. It has been shown to have activity against a wide variety of bacteria, including the antimicrobial-resistant strains. As with all tetracycline drugs, it is not recommended for pregnant or nursing women. The potential side effects are those typical of tetracycline drugs: nausea, vomiting, and headaches. Drug-drug interactions are not expected, and renal function monitoring is not necessary.


Experimental crossbreeding reveals strain-specific variation in mortality, growth and personality in the brown trout (Salmo trutta).
Although hybridization between populations with low genetic diversity may induce heterosis, it can also lead to reduced fitness of hybrid offspring through outbreeding depression and loss of local adaptations. Using a half-sib mating design, we studied on brown trout (Salmo trutta) how hybridization of migratory hatchery-strain females with males from various strains would affect early mortality, growth and personality in F1 offspring. No differences in mortality or alevin body length were found between the crossing groups by the end of the yolk-sac stage. At later developmental stages, higher mortality and slower growth in one of the geographically distant hybrid groups indicated potential outbreeding depression. The personality component indicating boldness and exploration tendency showed fairly low genetic variation and no phenotypic differences among the crossing groups while the personality component related to freezing behavior indicated stronger freezing responses in the purebred and local cross strain when compared to the two other strains. However, the purebred hatchery strain possessed stronger additive genetic tendency for boldness and explorative behavior, and weaker genetic tendency for freezing behavior, when compared to the wild × hatchery hybrid group. Our results add to the cumulating evidence of risks related to the stocking of fish strains from non-native origins.


Association between blastocyst morphology and live birth rate following frozen-thawed single blastocyst transfer: Results from a 5-year retrospective analysis of 2593 cryopreserved blastocysts.
Our aim was to investigate associations between blastocyst morphology parameters and live birth outcome and to make possible additional recommendations for existing embryo selection strategies. This retrospective cohort study included 2593 frozen-thawed single blastocyst transfers (SBT) cycles from 2012 to 2016. Multivariable logistic regression model was used to analyze the independent predictive effectiveness of blastocyst parameters for live birth rate (LBR). The participants enrolled in the present study were 32 (28-35) years old with a median body mass index of 21.20 (19.60-23.40) kg/m2 , among whom 1058 (40.8%) women had live births. Among the three blastocyst morphology parameters, we found only inner cell mass grade and trophectoderm cell grade had significant effects on LBR (P < 0.001). When adjusting for potential confounders in a multivariable logistic regression model, the expansion and hatching (EH) stage of blastocoel also showed obvious correlation with LBR. Blastocysts at EH stage 4-5 had a significantly higher LBR than that at stage 3 (P < 0.05). Additionally, the timing of blastulation was also an important predictor of LBR. Blastocysts vitrified on day 6 and day 7 yielded a lower LBR than that vitrified on day 5 (P < 0.001). The timing of blastulation and all blastocyst morphology parameters were associated with LBR independently. Although the most important parameter for predicting clinical outcomes remains undetermined, the timing of blastulation was a stable predictor of live birth for frozen-thawed SBT.


Psychometric qualities of the Fatigue Assessment Scale in Croatian sarcoidosis patients.
Fatigue is an unspecific symptom, but a major problem in sarcoidosis patients. There is a need for a reliable and valid way to measure fatigue. The Fatigue Assessment Scale (FAS) has good psychometric properties in healthy and sarcoidosis samples in the Netherlands, but nothing is known about the psychometric qualities of the FAS in sarcoidosis samples from other countries. Therefore, we examined the reliability, construct, and content validity in Croatian sarcoidosis patients. Croatian sarcoidosis patients from a pulmonary outpatient clinic completed the FAS and a symptom inventory questionnaire. The internal consistency of the FAS was 0.91. Using exploratory factor analysis and Mokken scale analysis, the scale was unidimensional. A dichotomous fatigue item distinguished between individuals who scored high or low on the FAS. Concerning discriminant validity, individuals reporting health complaints were more tired. The FAS correlated moderately with a number of neurological and psychological problems. Females and lower educated individuals reported more fatigue. The Croatian translation of the FAS has good reliability and validity in a sarcoidosis sample. Future research is needed to explore the psychometric qualities (i) of the Croatian FAS in healthy individuals and (ii) of the FAS in other languages.


Impact of robotic assistance on precision of vitreoretinal surgical procedures.
To elucidate the merits of robotic application for vitreoretinal maneuver in comparison to conventional manual performance using an in-vitro eye model constructed for the present study. Capability to accurately approach the target on the fundus, to stabilize the manipulator tip just above the fundus, and to perceive the contact of the manipulator tip with the fundus were tested. The accuracies were compared between the robotic and manual control, as well as between ophthalmologists and engineering students. In case of manual control, ophthalmologists were superior to engineering students in all the 3 test procedures. Robotic assistance significantly improved accuracy of all the test procedures performed by engineering students. For the ophthalmologists including a specialist of vitreoretinal surgery, robotic assistance enhanced the accuracy in the stabilization of manipulator tip (from 90.9 µm to 14.9 µm, P = 0.0006) and the perception of contact with the fundus (from 20.0 mN to 7.84 mN, P = 0.046), while robotic assistance did not improve pointing accuracy. It was confirmed that telerobotic assistance has a potential to significantly improve precision in vitreoretinal procedures in both experienced and inexperienced hands.


Cationic nanoplastic causes mitochondrial dysfunction in neural progenitor cells and impairs hippocampal neurogenesis.
Nanoplastics (NPs) exposure to humans can occur through various routes, including the food chain, drinking water, skin contact, and respiration. NPs are plastics with a diameter of less than 100 nm and have the potential to accumulate in tissues, leading to toxic effects. This study aimed to investigate the neurotoxicity of polystyrene NPs on neural progenitor cells (NPCs) and hippocampal neurogenesis in a rodent model. Toxicity screening of polystyrene NPs based on their charge revealed that cationic amine-modified polystyrene (PS-NH3+) exhibited cytotoxicity, while anionic carboxylate-modified polystyrene (PS-COO-) and neutral NPs (PS) did not. NPCs treated with PS-NH3+ showed a significant reduction in growth rate due to G1 cell cycle arrest. PS-NH3+ increased the expression of cell cycle arrest markers p21 and p27, while decreasing cyclin D expression in NPCs. Interestingly, PS-NH3+ accumulated in mitochondria, leading to mitochondrial dysfunction and energy depletion, which caused G1 cell cycle arrest. Prolonged exposure to PS-NH3+ in C17.2 NPCs increased the expression of p16 and senescence-associated secretory phenotype factors, indicating cellular senescence. In vivo studies using C57BL/6 mice demonstrated impaired hippocampal neurogenesis and memory retention after 10 days of PS-NH3+ administration. This study suggests that NPs could deplete neural stem cell pools in the brain by mitochondrial dysfunction, thereby adversely affecting hippocampal neurogenesis and neurocognitive functions.


Small omphalocele with umbilical evagination of the bladder: a distinct entity?
A neonatal case of umbilical evagination of the bladder combined with a small omphalocele is presented. This rare congenital malformation has previously been described in only three cases. Umbilical evagination can be understood as a disturbance of development of both the vitelline and allantoic ducts, resulting in a non-descended but otherwise normal bladder opening to the inferior margin of a small omphalocele. Diagnosis is made by clinical inspection and ultrasound. Since other malformations are not present, this entity may be regarded as a minor form of a lower midline defect with excellent prognosis.


New developments in antibacterial choice for lower respiratory tract infections in elderly patients.
Elderly patients are at increased risk of developing lower respiratory tract infections compared with younger patients. In this population, pneumonia is a serious illness with high rates of hospitalisation and mortality, especially in patients requiring admission to intensive care units (ICUs). A wide range of pathogens may be involved depending on different settings of acquisition and patient's health status. Streptococcus pneumoniae is the most common bacterial isolate in community-acquired pneumonia, followed by Haemophilus influenzae, Moraxella catarrhalis and atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae. However, elderly patients with comorbid illness, who have been recently hospitalised or are residing in a nursing home, may develop severe pneumonia caused by multidrug resistant staphylococci or pneumococci, and enteric Gram-negative bacilli, including Pseudomonas aeruginosa. Moreover, anaerobes may be involved in aspiration pneumonia. Timely and appropriate empiric treatment is required in order to enhance the likelihood of a good clinical outcome, prevent the spread of antibacterial resistance and reduce the economic impact of pneumonia. International guidelines recommend that elderly outpatients and inpatients (not in ICU) should be treated for the most common bacterial pathogens and the possibility of atypical pathogens. The algorithm for therapy is to use either a selected beta-lactam combined with a macrolide (azithromycin or clarithromycin), or to use monotherapy with a new anti-pneumococcal quinolone, such as levofloxacin, gatifloxacin or moxifloxacin. Oral (amoxicillin, amoxicillin/clavulanic acid, cefuroxime axetil) and intravenous (sulbactam/ampicillin, ceftriaxone, cefotaxime) beta-lactams are agents of choice in outpatients and inpatients, respectively. For patients with severe pneumonia or aspiration pneumonia, the specific algorithm is to use either a macrolide or a quinolone in combination with other agents; the nature and the number of which depends on the presence of risk factors for specific pathogens. Despite these recommendations, clinical resolution of pneumonia in the elderly is often delayed with respect to younger patients, suggesting that optimisation of antibacterial therapy is needed. Recently, some new classes of antibacterials, such as ketolides, oxazolidinones and streptogramins, have been developed for the treatment of multidrug resistant Gram-positive infections. However, the efficacy and safety of these agents in the elderly is yet to be clarified. Treatment guidelines should be modified on the basis of local bacteriology and resistance patterns, while dosage and/or administration route of each antibacterial should be optimised on the basis of new insights on pharmacokinetic/pharmacodynamic parameters and drug interactions. These strategies should be able to reduce the occurrence of risk factors for a poor clinical outcome, hospitalisation and death.


Bone marrow edema in the knee in osteoarthrosis and association with total knee arthroplasty within a three-year follow-up.
The purpose of this study was to determine if a correlation exists between magnetic resonance imaging (MRI) findings of bone marrow edema (BME) in osteoarthrosis (OA) of the knee joint and need for total knee arthroplasty (TKA) within a follow-up period of 3 years. The entire database of knee MR studies over a 3-year period was used to select individuals with knee OA. A chart review was conducted to identify and include only those who had a 3-year follow-up appointment from the time of the initial MR study. There were 25 patients in the OA-only group (four men and 21 women; age range, 28-75; average age, 49.3 years). The OA and BME group had 48 patients (23 men and 25 women; average age, 55.5 years). The MRs were reviewed and interpreted by a musculoskeletal radiologist and were classified into one of four patterns of BME: none, focal, global, or cystic pattern. Meniscal tear and degree of cartilage loss were also assessed. Subjects who had BME of any pattern type were 8.95 times as likely to progress rapidly to a TKA when compared to subjects with no BME (p = 0.016). Subjects with a global pattern of BME were 5.45 times as likely to have a TKA compared to subjects with focal, cyst, or no BME (p < 0.05). Subjects with a global edema pattern were 13.04 times as likely to have a TKA than subjects with no marrow edema in the knee (p < 0.01). There was no correlation of TKA with meniscal tear or cartilage loss. The group of subjects who had a TKA were 12.6 years older than those who did not have a TKA (p < 0.001). However, the BME results were still significant after accounting for the age difference. Our classification of patterns into global, focal, cystic, and absence of BME is an attempt to further define edema in osteoarthrosis and how it relates to clinical progression. Patients with BME and OA have an increased risk of TKA as opposed to OA and no marrow edema. The BME pattern with the worst prognosis for the knee is the global pattern.


Effectiveness of geriatric evaluation and care. One-year results of a multicenter randomized clinical trial.
The aim of this study was to demonstrate the effectiveness of outpatient elderly care based on Comprehensive Geriatric Assessment (CGA). Eleven hospital Geriatric Evaluation and Management units (GEMs) systematically screened 1386 inpatients over a 10-month period, using the same uniform selection plan which included 15 programmed exclusion-inclusion criteria and a standard CGA. At the end of this screening, 152 eligible frail elderly patients were randomized to either a comprehensive outpatient GEMs program (intervention group: N=79) or to usual care by their family doctors (control group: N=73). We did not find any statistically significant difference between the two groups at entry. During the one-year follow-up period, 6 GEMs patients (7.6%) and 12 controls (17.1%) died, without significant differences between the two survival curves. Only three patients (all controls) ultimately dropped out, and eight (3 unit patients and 5 controls) entered a nursing home. GEMs patients were significantly more likely to have individual improvement in mental status (p=0.006), morale (p=0.024) and functional level (p=0.023), compared to controls. Even though intervention participants spent fewer days in hospital and nursing home (p<0.05), they received much more home care and day-hospital assistance (p<0.001), which explains why total expenditure on health care was the same in the two groups. We conclude that: 1) a standardized selection plan may contribute to identify the older inpatients in need of CGA; and 2) CGA-based outpatient care may be clinical- and cost-effective if directly managed by GEMs, and may provide targeted older patients with more substantial benefits than standard care, without inflating health care expenses.


Economics and violence against children, findings from the Violence Against Children Survey in Nigeria.
This study seeks to assess the impact of economic factors on sexual, emotional, and physical violence on Nigerian children and adolescents aged 13-24 years. Data collected from the Nigerian Violence Against Children Survey (VACS), a national, cross-sectional household survey of females and males aged 13-24 years were used to examine sexual, emotional, and physical violence victimization. Data were collected on household economic status, e.g., flooring and roofing materials, transportation. A poverty index was developed using the Simple Poverty Scorecard™ for Nigeria to determine the impact that economic factors have on these violence measures. Children aged 13-17 years in households with high economic status (ES) were 1.81, 1.78, and 4.91 times, more likely to experience sexual, emotional, and physical violence, respectively, within the last 12 months than those in the lowest ES. Individuals aged 18-24 years in households with high ES were 1.62 and 1.41 times more likely to experience emotional and physical violence, respectively, prior to age 18 than those in the lowest ES. Individuals aged 18-24 years in households with middle or high ES were 1.65 and 1.96, respectively, times more likely to experience physical violence prior to age 18 than those in the lowest ES. Highest tertile ES was significantly associated with sexual, emotional, and physical violence among Nigerians aged 13-24 years. Further research is needed to determine the cause of increased violence amongst high ES households. Targeted interventions towards this ES class are recommended to reduce violence against children in Nigeria.


Complementary values of static and dynamic scintigraphy, computerized tomography and angiography in the diagnosis of a partially thrombosed giant intracranial aneurysm.
The case history is presented of a 17 year-old male admitted with right hemiplegia and motor aphasia. Static and dynamic scintigraphy allowed prediction of a giant aneurysm in the deep left frontotemporal region, and this supposition was confirmed by CT and carotid angiography. CT also revealed the aneurysm to extend farther medially than the other two examinations had indicated, the medial portion of the aneurysm being thrombosed. Evaluation of the diagnostic information obtained from the three procedures, combined with the clinical data, makes possible a reconstruction of the probable course of events. The presenting signs were probably caused by a newly formed thrombus within the aneurysm. Death, which occurred after five days, was apparently due to subarachnoid hemorrhage.


Longitudinal Changes of the Ruminal Microbiota in Angus Beef Steers.
The ruminal microbiota of Angus cows and steers were characterized using 16s rRNA gene sequencing, and the expression of their metabolic pathways was predicted. Samples were collected on weaning day from the steers and the cows, and subsequently on three other occasions from the steers. Results showed that microbial richness, evenness, and diversity decreased (p < 0.001) in the rumen of the steers as they were weaned and transitioned to a high-concentrate feedlot diet. However, on the day of weaning, microbial evenness was similar to that observed in the rumen of cows (p = 0.12). The abundance of archaea was similar (p = 0.59) between the cows and steers at weaning, but it decreased (p = 0.04) in the rumen of steers after weaning, and remained stable (p ≥ 0.44) for the remainder of their lives. Likewise, no difference (p = 0.51) in the abundance of Bacteroidetes was detected between the cows and the calves on the day they were weaned, but the abundance of this phylum increased (p = 0.001) and remained stable after that. These results suggest that cows may have a strong influence on the composition, and help modulate the ruminal microbiota of young calves; however, following weaning, their ruminal microbiotas tend to differentiate from that state observed at earlier ages.


Amplification of the inflammatory cellular redox state by human immunodeficiency virus type 1-immunosuppressive tat and gp160 proteins.
In the course of our studies on oxidative stress as a component of pathological processes in humans, we showed that microintrusion into cells with microcapillary and ultramicroelectrochemical detection could mimic many types of mechanical intrusion leading to an instant (0.1 s) and high (some femtomoles) burst release of H2O2. Specific inhibitors of NADPH enzymes seem to support the assumption that this enzyme is one of the main targets of our experiments. Also, human immunodeficiency virus type 1 (HIV-1) gp160 inhibits the cooperative response of uninfected T cells as well as Tat protein release by infected cells does. In this study, we analyzed in real time, lymphocyte per lymphocyte, the T-cell response following activation in relation to the redox state. We showed that the immunosuppressive effects of HIV-1 Tat and gp160 proteins and oxidative stress are correlated, since the native but not the inactivated Tat and gp160 proteins inhibit the cellular immune response and enhance oxidative stress. These results are consistent with a role of the membrane NADPH oxidase in the cellular response to immune activation.


Pollination ecology in the narrow endemic winter-flowering Primula allionii (Primulaceae).
Reduction of pollen flow can affect plant abundance and population viability and cause selection on plant mating system and floral traits. Little is known on the effect of this phenomenon in species naturally restricted to small and isolated habitats, that may have developed strategies to cope with long-term isolation and small population size. We investigated the pollination ecology of the endemic distylous winter-flowering P. allionii to verify the possible limitation of female fitness due to reduced pollinator visits. We recorded a higher production of pollen grains in long-styled morph, and a higher seed set in short-styled morph. The high intra-morph variability of sexual organ position may explain the hybridization phenomena allowing and easier intra-morph pollination. The fruit set is constant, although its winter-flowering period might decrease pollen transfer. Nevertheless, the lower competition for pollinators with neighbouring plants and the long-lasting anthesis may offset its reproductive success. Even if our results show no evidence of imminent threats, changes in plant-pollinator interactions might increase inbreeding, resulting in an increased extinction risk.


Treatment of Pain in Reptiles.
This chapter provides an overview of our current understanding of clinical analgesic use in reptiles. Currently, μ-opioid agonist drugs are the standard of care for analgesia in reptiles. Reptile pain is no longer considered a necessary part of recovery to keep the reptile from becoming active too early. Rather, treating pain allows for the reptile to begin normalizing their behavior. This recognition of pain and analgesia certainly benefits our reptile patients and greatly improves reptile welfare, but it also benefits our students and house officers, who will carry the torch and continue to demand excellence in reptile medicine.


Bayesian shrinkage estimation of high dimensional causal mediation effects in omics studies.
Causal mediation analysis aims to examine the role of a mediator or a group of mediators that lie in the pathway between an exposure and an outcome. Recent biomedical studies often involve a large number of potential mediators based on high-throughput technologies. Most of the current analytic methods focus on settings with one or a moderate number of potential mediators. With the expanding growth of -omics data, joint analysis of molecular-level genomics data with epidemiological data through mediation analysis is becoming more common. However, such joint analysis requires methods that can simultaneously accommodate high-dimensional mediators and that are currently lacking. To address this problem, we develop a Bayesian inference method using continuous shrinkage priors to extend previous causal mediation analysis techniques to a high-dimensional setting. Simulations demonstrate that our method improves the power of global mediation analysis compared to simpler alternatives and has decent performance to identify true nonnull contributions to the mediation effects of the pathway. The Bayesian method also helps us to understand the structure of the composite null cases for inactive mediators in the pathway. We applied our method to Multi-Ethnic Study of Atherosclerosis and identified DNA methylation regions that may actively mediate the effect of socioeconomic status on cardiometabolic outcomes.


Initial treatment of colic.
This article discusses some of the rationales for the medical management of colic during the initial treatment period. The issue of colic pain control and the masking of clinical signs that may indicate severe gastrointestinal disease is addressed. Therapeutic considerations related to dehydration, metabolic imbalances, hemostatic disorders, antimicrobial therapy, fecal consistency, gastrointestinal decompression, and regulation of intestinal motility are reviewed.


Impacts of PCB analytical interpretation uncertainties on dechlorination assessment and remedial decisions.
Laboratory analyses of polychlorinated biphenyls (PCBs) often do not quantitate the 209 individual PCB congeners, thereby requiring analyst interpretation to determine individual congener concentrations. Error introduced during this interpretation is subsequently propagated to calculated surrogate variables, such as the number of chlorines per biphenyl (CPB), and the molar dechlorination product ratio (MDPR), which are used to assess the extent of dechlorination and inform remedial decisions. The present work applies a Monte Carlo (MC) analysis to assess current methods for quantitating co-eluting congeners and the errors that could occur in individual congeners and derived CPB and MDPR estimates. Synthetic chromatograms, which were created using two alternative methods (random assignment and assignment based on relative proportions in Aroclors) for assigning mass to co-eluting congeners, were compared to their fully-quantitated counterparts. The percent error introduced in total PCB (∑PCB) concentration ranges from approximately -60% to +50%. Similarly, the errors associated with CPB and MDPR estimates range from approximately -20% to +20% and -120% to +30%, respectively. Uncertainties introduced during congener analysis and propagated to surrogate variables can thus be substantial, and should be considered in assessments of the extent of dechlorination and associated remedial decisions.


Effect of high sugar concentration on nitrogenase activity of Acetobacter diazotrophicus.
Acetobacter diazotrophicus is a nitrogen-fixing bacterium that growth inside sugar cane plant tissue where the sucrose concentration is approximately 10%. The influence of high sugar content on nitrogenase was measured in the presence of oxygen and of nitrogen added in the form of ammonium and amino acids. In all parameters analyzed, 10% sucrose protected nitrogenase against inhibition by oxygen, ammonium, some amino acids, and also to some extent by salt stress. The oxygen concentration at which inhibition occurred increased from 2 kPa in 1% glucose or gluconic acid, to 4 kPa (0.4 atm) in 10% sucrose. Nitrogenase activity was partially inhibited by increased ammonium levels (2.0, 5.0, and 10.0 mM) in the presence of 1% sucrose, but the cells maintained their nitrogenase activity at 10% sucrose. This could be explained by the slow ammonium assimilation by the cells in the presence of high sucrose concentrations, i.e., independent of its concentration between 2 and 10 mM, the assimilation of ammonium was reduced to one-third in cells grown with 10% sucrose. Some amino acids were also tested in the presence of 1 and 10% sucrose. Cells grown in 1% sucrose had their nitrogenase activity reduced by 50-98% in the presence of glutamic acid, glutamine, alanine, asparagine, or threonine, whereas with 10% sucrose, nitrogenase activity was increased by glutamic acid and was reduced by only 61-73% by the other amino acids. The effect of NaCl concentrations (0.0, 0.25, 0.5, 0.75, or 1.0%) was also studied at the two concentrations of sucrose. Nitrogenase activity and growth of A. diazotrophicus, which was visualized by the pellicle formation in semi-solid medium, showed sensitivity even to low NaCl concentrations, which was somewhat relieved at the higher sucrose level. These observations indicate different osmotolerance mechanisms for sucrose and salt.


Radiomics-based classification models for HBV-related cirrhotic patients with covert hepatic encephalopathy.
The significant abnormalities of precuneus (PC), which are associated with brain dysfunction, have been identified in cirrhotic patients with covert hepatic encephalopathy (CHE). The present study aimed to apply radiomics analysis to identify the significant radiomic features in PC and their subregions, combine with clinical risk factors, then build and evaluate the classification models for CHE diagnosis. 106 HBV-related cirrhotic patients (54 had current CHE and 52 had non-CHE) underwent the three-dimensional T1-weighted imaging. For each participant, PC and their subregions were segmented and extracted a large number of radiomic features and then identified the features with significant discriminative power as the radiomics signature. The logistic regression analysis was employed to develop and evaluate the classification models, which are constructed using the radiomics signature and clinical risk factors. The classification model (R-C model) achieved best diagnostic performance, which incorporated radiomics signature (4 radiomic features from right PC), venous blood ammonia, and the Child-Pugh stage. And the area under the receiver operating characteristic curve values (AUC), sensitivity, specificity, and accuracy values were 0.926, 1.000, 0.765, and 0.848, in the testing set. Application of the radiomics nomogram in the testing set still showed a good predictive accuracy. This study presented the radiomic features of the right PC, as a potential image marker of CHE. The radiomics nomogram that incorporates the radiomics signature and clinical risk factors may facilitate the individualized prediction of CHE.


Incorporating the length-dependent passive-force generating muscle properties of the extrinsic finger muscles into a wrist and finger biomechanical musculoskeletal model.
Dynamic movement trajectories of low mass systems have been shown to be predominantly influenced by passive viscoelastic joint forces and torques compared to momentum and inertia. The hand is comprised of 27smallmass segments. Because of the influence of the extrinsic finger muscles, the passive torques about each finger joint become a complex function dependent on the posture of multiple joints of the distal upper limb. However, biomechanical models implemented for the dynamic simulation of hand movements generally don't extend proximally to include the wrist and distal upper limb. Thus, they cannot accurately represent these complex passive torques. The purpose of this short communication is to both describe a method to incorporate the length-dependent passive properties of the extrinsic index finger muscles into a biomechanical model of the upper limb and to demonstrate their influence on combined movement of the wrist and fingers. Leveraging a unique set of experimental data, that describes the net passive torque contributed by the extrinsic finger muscles about the metacarpophalangeal joint of the index finger as a function of both metacarpophalangeal and wrist postures, we simulated the length-dependent passive properties of the extrinsic finger muscles. Dynamic forward simulations demonstrate that a model including these properties passively exhibits coordinated movement between the wrist and finger joints, mimicking tenodesis, a behavior that is absent when the length-dependent properties are removed. This work emphasizes the importance of incorporating the length-dependent properties of the extrinsic finger muscles into biomechanical models to study healthy and impaired hand movements.


Clinical and pathological study of two patients with progressive supranuclear palsy and Alzheimer's changes. Antigenic determinants that distinguish cortical and subcortical neurofibrillary tangles.
Two cases with classical clinical manifestations of progressive supranuclear palsy (PSP) showed severe progressive dementia as an additional clinical feature. Neuropathological study demonstrated typical features of PSP in the brainstem. Additionally, histological criteria of Alzheimer's disease (AD) were observed. A topographic and immunohistological study (with neurofilament subunit and Tau and Ubiquitin antibodies) of the distribution of neurofibrillary tangles (NFTs) was performed in order to compare the characteristics of NFTs from cortex and brainstem. NFTs from cortex were positive with all antibodies used and were predominantly distributed in cortical layers III and V and affected medium size neurons. Brainstem NFTs were positive only for neurofilament subunits and Tau. Cortical and brainstem NFTs showed immunohistological differences. Cortical NFTs in our two cases had a similar distribution as in control AD cases. On the basis of our observations we believe (1) that cortical tangles in our PSP cases are related to Alzheimer's disease and (2) that the cortical NFTs of PSP and AD are morphologically and immunohistologically distinct. Mechanisms concerned with the production of cortical and brainstem NFTs in PSP and AD are discussed.