New positive and negative regulators for general control of amino acid biosynthesis in Saccharomyces cerevisiae.
The biosynthesis of most amino acids in Saccharomyces cerevisiae is coregulated. Starvation for a single amino acid results in the derepression of amino acid biosynthetic enzymes in many unrelated pathways. This phenomenon, known as general control, is mediated by both positive (GCN) and negative (GCD) regulatory genes. In this paper we describe the identification and characterization of several new regulatory genes for this system, GCN6, GCN7, GCN8, GCN9, and GCD5. A mutation in the negative regulator GCD5 was isolated on the basis of its suppression of a gcn2 mutation. The effect of gcd5 is a posttranscriptional increase in histidine biosynthetic enzyme activity. Suppressors of gcd5 which are deficient in derepression were in turn isolated. Eight such mutations, defining four new positive regulatory genes (GCN6 through GCN9), were obtained. These mutations are recessive, confer sensitivity to multiple amino acid analogs, and result in decreased mRNA levels for genes under general control. The GCN6 and GCN7 gene products were shown to be positive regulators for transcription of the GCN4 gene, the most direct-acting positive regulator thus far identified. The interaction of GCN6 and GCN7 with GCN4 is fundamentally different from that of previously isolated GCN genes. It should also be noted that these gcn selections gave a completely different nonoverlapping set of mutations from earlier selections which relied on analog sensitivity. Thus, we may have identified a new class of GCN genes which are functionally distinct from GCN1 through GCN5.


Nano polystyrene induced changes in anxiety and learning behaviour are mediated through oxidative stress and gene disturbance in mouse brain regions.
It is widely reported now that nanoplastic particles have potential neurotoxic effects and may disturb central nervous system (CNS) function. However, the mechanism behind these toxic effects still needs to be elucidated. In the current study, we investigated the effects of polystyrene nanoplastics (PS-NPs) on changes in learning, memory, and anxiety-related behavior in mice based on some selected biochemical, molecular, and histopathological changes in three important brain regions (Cortex, Hypothalamus, and Hippocampus). Male mice were orally administered daily with two doses of 50 nm PS-NPs (0.2 mg/ml and 1 mg/ml) for 8 weeks. We observed decreased expression of neurotransmitter-related genes (VAChT, GAD, and SYP) in the cortex, hypothalamus, and hippocampus areas of the mouse brain. Other biochemical variables including, antioxidant enzymes, biomarkers for oxidative stress, and acetylcholinesterase activity showed significant alterations in all three brain regions. Molecular and neurochemical data thus suggest significant neurobehavioral changes following sub-chronic exposure to PS-NPs which may lead to enhanced anxiety-related and spatial learning and memory-related impairments by affecting limbic areas of the brain.


Platelet-to-lymphocyte, neutrophil-to-lymphocyte and lymphocyte-to-monocyte ratios are related to cancer-related fatigue and quality of life in patients with cancer: a cross-sectional study.
To explore the association of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) with cancer-related fatigue (CRF) and quality of life (QOL) in cancer patients. A cross-sectional study. A grade A tertiary hospital in Wuhan, China. A total of 236 participants were recruited. Participants who were diagnosed with cancer received chemotherapy and/or radiotherapy, and aged ≥18 years were included in this study. The PLR, NLR and LMR were calculated based on the absolute lymphocyte count, neutrophil count, platelet count and monocyte count. The CRF and QOL of patients after the first chemotherapy/radiotherapy were evaluated. The median values (IQR) of PLR, NLR and LMR were 174.51 (126.14-261.02), 2.84 (1.64-5.24) and 2.56 (1.30-3.72), respectively. Univariate analysis indicated that high PLR (≥ 174.51), high NLR (≥ 2.84) and low LMR (< 2.56) at baseline significantly correlated with CRF and poor QOL after the first chemotherapy/radiotherapy (p<0.005). Multiple linear regression analysis indicated that elevated PLR might be an independent risk factor for CRF (p<0.001) and QOL (p=0.010) in cancer patients. PLR, NLR and LMR are associated with CRF and QOL in cancer patients. High PLR may predict severe CRF and poor QOL. Further studies are needed to validate these findings based on the expanded sample size.


Hemodilution with other blood reinfusion techniques in total hip arthroplasty.
Acute normovolemic hemodilution has been reported to result in blood savings varying from 18% to 90%. Very few of these are randomized prospective studies. This study attempts to determine the blood transfusion savings if acute normovolemic hemodilution is used in combination with autologous predonated blood and cell saver. Thirty-three patients undergoing total hip arthroplasty were assigned randomly to one of two groups (control, n = 16; hemodilution, n = 17). Patients in both groups entered an autologous predonation program if cleared medically and were placed on Cell Saver intraoperatively and in the postanesthesia care unit. In addition, the hemodilution group underwent acute normovolemic hemodilution preoperatively. Only 41% of the patients in the hemodilution group required any autologous blood transfusion as compared with 75% of the control group. In addition, the hemodilution group required a mean lower quantity of autologous blood transfusion (41% of the estimated blood loss) as compared with the control group (71%). The net anesthesia time increased by an average of 11.4 minutes in the hemodilution group. Acute normovolemic hemodilution is a safe procedure even in an older patient population. Hemodilution resulted in fewer patients needing autologous predonated blood transfusions. The major benefit of hemodilution was seen when predonation was not possible.


Air Trapping Is Associated with Heterozygosity for Alpha-1 Antitrypsin Mutations in Patients with Asthma.
Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder involving lungs, characterized by low serum concentration of the protein alpha-1 antitrypsin (AAT) also called proteinase inhibitor (PI). Asthma is common in AATD patients, but there are only few data on respiratory function in asthmatic patients with AATD. The aim of the study was to evaluate lung function in asthmatic outpatients with mutation in the SERPINA1 gene coding for AAT versus asthmatic subjects without mutation. We performed the quantitative analysis of the serum concentration of AAT in 600 outpatients affected by mild to moderate asthma from the University Hospital of Parma, Italy. Fifty-seven of them underwent the genetic analysis subsequently; they were subdivided into mutated and non-mutated subjects. All the mutated patients had a heterozygous genotype, except 1 (PI*SS). We assessed the lung function through a flow-sensing spirometer and the small airway parameters through an impulse oscillometry system. The values of forced vital capacity (% predicted) and those of the residual volume to total lung capacity ratio (%) were, respectively, lower and higher in patients mutated versus patients without mutation, showing a significantly greater air trapping (p = 0.014 and p = 0.017, respectively). Moreover, patients with mutation in comparison to patients without mutation showed lower forced expiratory volume in 3 s (% predicted) and forced expiratory volume in 6 s (L) spirometric values, reflecting a smaller airways contribution. In asthmatic patients, heterozygosity for AAT with PI*MZ and PI*MS genotypes was associated with small airway dysfunction and with lung air trapping.


Identifying secreted biomarkers of dopaminergic ventral midbrain progenitor cells.
Ventral midbrain (VM) dopaminergic progenitor cells derived from human pluripotent stem cells have the potential to replace endogenously lost dopamine neurons and are currently in preclinical and clinical development for treatment of Parkinson's Disease (PD). However, one main challenge in the quality control of the cells is that rostral and caudal VM progenitors are extremely similar transcriptionally though only the caudal VM cells give rise to dopaminergic (DA) neurons with functionality relevant for cell replacement in PD. Therefore, it is critical to develop assays which can rapidly and reliably discriminate rostral from caudal VM cells during clinical manufacturing. We performed shotgun proteomics on cell culture supernatants from rostral and caudal VM progenitor cells to search for novel secreted biomarkers specific to DA progenitors from the caudal VM. Key hits were validated by qRT-PCR and ELISA. We identified and validated novel secreted markers enriched in caudal VM progenitor cultures (CPE, LGI1 and PDGFC), and found these markers to correlate strongly with the expression of EN1, which is a predictive marker for successful graft outcome in DA cell transplantation products. Other markers (CNTN2 and CORIN) were found to conversely be enriched in the non-dopaminergic rostral VM cultures. Key novel ELISA markers were further validated on supernatant samples from GMP-manufactured caudal VM batches. As a non-invasive in-process quality control test for predicting correctly patterned batches of caudal VM DA cells during clinical manufacturing, we propose a dual ELISA panel measuring LGI1/CORIN ratios around day 16 of differentiation.


Prediction of clinical outcome with estrogen and progestin receptor concentrations and their relationships to clinical and histopathological variables in endometrial cancer.
Concentrations of cytosol estrogen (ERC) and cytosol progestin (PRC) receptors were assayed in malignant tissue specimens of 230 patients with endometrial cancer, and those of nuclear estrogen and nuclear progestin receptors, and 17 beta-hydroxysteroid dehydrogenase activities in about 100 specimens. Endometrial cancer was at an early stage in 205 and advanced in 25 patients. As a supplement to surgical and radiation therapy, all patients received p.o. medroxyprogesterone acetate (100 mg a day) for 2 years. The follow-up time varied from 12 to 96 months (median, 42 months). Concentrations of ERC, PRC, nuclear estrogen, and nuclear progestin receptors in endometrial cancer tissue were significantly lower in clinical stages III-IV than in clinical stage I. In clinical stage I, ERC and PRC appeared in significantly lower concentrations in anaplastic than in moderately and well differentiated malignancies. The concentrations of these receptors were increased in obese patients, and the activity of 17 beta-hydroxysteroid dehydrogenase was increased in patients younger than 50 years, suggesting that endogenous female steroid hormones modify the pattern of female steroid receptors in malignant endometrium. In clinical stage I, 13 of 153 patients with adequate therapy contracted a recurrent disease. Poor prognosis was predicted by anaplastic structure of the malignancy (P less than 0.001), low tissue concentrations (0-30 fmol/mg protein) of ERC alone (P = 0.006), PRC alone (P = 0.010), and ERC and PRC simultaneously (P = 0.004). All 101 patients who simultaneously had ERC and PRC in concentrations higher than 30 fmol/mg protein remained disease free for 2 years, whereas all recurrences in patients with receptor-poor tumors appeared during the 2 years of medroxyprogesterone acetate treatment. In clinical stage II, with 30 patients, no prognosis indicators predicted the clinical outcome, whereas in clinical stages III + IV, with 25 patients, low ERC concentrations were associated with a worsened prognosis (P = 0.045). Conclusively, cytosol and nuclear estrogen and nuclear progestin receptor concentrations and 17 beta-hydroxysteroid dehydrogenase activity give valuable information about the endocrine associations in endometrial cancer. Cytosol estrogen and cytosol progestin receptors appeared to be useful predictors of recurrent disease. They also have the potential to distinguish between patients expected to benefit from adjuvant progestin therapy and those expected to be unresponsive to the same treatment.


Homocysteine plasma levels as a marker of clinical severity in septic patients.
Homocysteine and sepsis are both associated with inflammation and endothelial activation. Therefore this study was aimed to evaluate if the plasma homocystein level is related with the septic patient clinical severity. Severe sepsis or septic shock patients, with less than 48 hours from organ dysfunction start, were admitted to this prospective observational study. Homocysteine levels were determined by the time of study admission and then on the Days 3, 7 and 14. The homocysteine association with the Sequential Organ Failure Assessment (SOFA) score was evaluated using the Sperman test, and its association with mortality using the Mann-Whitney test. A p<0.05 value was considered statistically significant. Twenty one patients were enrolled, and 60 blood samples were collected to measure total homocysteine [median 6.92 (5.27 - 9.74 μmol/L)]. The Sperman correlation test showed no association between homocysteine and SOFA ( r=0.15 and p=0.26). Also no correlation was found for the homocysteine level by the study admission time and the difference between the Day 3 SOFA score versus by study admission (deltaSOFA) (r=0.04 and p=0.87). Homocysteine variation between the Day 3 and the study admission (deltaHmc) and SOFA score variation in the same period were not correlated (r=-0.11 and p=0.66). Homocysteine by the study admission was not correlated with death in intensive care unit rate (p= 0.46) or in-hospital death rate (p = 0.13). This was also true for deltaHmc (p=0.12 and p=0.99, respectively). Baseline homocysteine levels and its variations within the first dysfunction days were not related with septic patients' worsened organ function parameters or mortality.


PPM Ir-f-phamidol-Catalyzed Asymmetric Hydrogenation of γ-Amino Ketones Followed by Stereoselective Cyclization for Construction of Chiral 2-Aryl-pyrrolidine Pharmacophores.
Transition metal catalysts with a million turnovers and excellent selectivity are rarely reported but are crucial for the industrial manufacture of optical pure pharmaceuticals, natural products, and fine chemicals. In this paper, we report an unprecedented aninoic Ir-f-phamidol catalyst for asymmetric hydrogenation of γ-amino ketones followed by stereoselective cyclization for construction of valuable chiral 2-aryl-pyrrolidine pharmacophores. The Ir-f-phamidol catalyst showed up to 1,000,000 TON and >99% ee, as well as excellent tolerance of substrates and protecting groups, providing various chiral amino alcohol intermediates. Upon optimization of the conditions, the stereoselective cyclization reaction was highly smooth and efficient (quantitative conversions, 92 to >99% ee). Finally, this solution was applied in the preparation of high-value chiral entities containing such chiral 2-aryl-pyrrolidine pharmacophores.


Nanoparticle-based artificial RNA silencing machinery for antiviral therapy.
RNA interference is a fundamental gene regulatory mechanism that is mediated by the RNA-induced silencing complex (RISC). Here we report that an artificial nanoparticle complex can effectively mimic the function of the cellular RISC machinery for inducing target RNA cleavage. Our results show that a specifically designed nanozyme for the treatment of hepatitis C virus (HCV) can actively cleave HCV RNA in a sequence specific manner. This nanozyme is less susceptible to degradation by proteinase activity, can be effectively taken up by cultured human hepatoma cells, is nontoxic to the cultured cells and a xenotransplantation mouse model under the conditions studied, and does not trigger detectable cellular interferon response, but shows potent antiviral activity against HCV in cultured cells and in the mouse model. We have observed a more than 99% decrease in HCV RNA levels in mice treated with the nanozyme. These results show that this nanozyme approach has the potential to become a useful tool for functional genomics, as well as for combating protein-expression-related diseases such as viral infections and cancers.


A nexus model of the temporal-parietal junction.
The temporal-parietal junction (TPJ) has been proposed to support either specifically social functions or non-specific processes of cognition such as memory and attention. To account for diverse prior findings, we propose a nexus model for TPJ function: overlap of basic processes produces novel secondary functions at their convergence. We present meta-analytic evidence that is consistent with the anatomical convergence of attention, memory, language, and social processing in the TPJ, leading to a higher-order role in the creation of a social context for behavior. The nexus model accounts for recent examples of TPJ contributions specifically to decision making in a social context and provides a potential reconciliation for competing claims about TPJ function.


Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.
Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication that can follow liver surgery or transplantation. We have investigated the involvement of the endocannabinoid system in hepatic I/R injury using an in vivo mouse model. Here we report that I/R triggers several-fold increases in the hepatic levels of the endocannabinoids anandamide and 2-arachidonoylglycerol, which originate from hepatocytes, Kupffer, and endothelial cells. The I/R-induced increased tissue endocannabinoid levels positively correlate with the degree of hepatic damage and serum TNF-alpha, MIP-1alpha, and MIP-2 levels. Furthermore, a brief exposure of hepatocytes to various oxidants (H2O2 and peroxynitrite) or inflammatory stimuli (endotoxin and TNF-alpha) also increases endocannabinoid levels. Activation of CB2 cannabinoid receptors by JWH133 protects against I/R damage by decreasing inflammatory cell infiltration, tissue and serum TNF-alpha, MIP-1alpha and MIP-2 levels, tissue lipid peroxidation, and expression of adhesion molecule ICAM-1 in vivo. JWH133 also attenuates the TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and the adhesion of human neutrophils to HLSECs in vitro. Consistent with the protective role of CB2 receptor activation, CB2-/- mice develop increased I/R-induced tissue damage and proinflammatory phenotype. These findings suggest that oxidative/nitrosative stress and inflammatory stimuli may trigger endocannabinoid production, and indicate that targeting CB2 cannabinoid receptors may represent a novel protective strategy against I/R injury. We also demonstrate that CB2-/- mice have a normal hemodynamic profile.


Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial.
Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma. This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed. Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7-15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3-20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0-79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure). Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients. Jiangsu Hengrui Medicine.


Auditory Processing in Children with Migraine: A Controlled Study.
Background This study aimed to investigate central auditory processing performance in children with migraine and compared with controls without headache. Methods Twenty-eight children of both sexes, aged between 8 and 12 years, diagnosed with migraine with and without aura, and a control group of the same age range and with no headache history, were included. Gaps-in-noise (GIN), duration pattern test (DPT), synthetic sentence identification (SSI) test, and nonverbal dichotic test (NVDT) were used to assess central auditory processing performance. Results Children with migraine performed significantly worse in DPT, SSI test, and NVDT when compared with controls without headache; however, no significant differences were found in the GIN test. Conclusions Children with migraine demonstrate impairment in the physiologic mechanism of temporal processing and selective auditory attention. In our short communication, migraine could be related to impaired central auditory processing in children.


Phenolic glycolipid-1 of Mycobacterium leprae binds complement component C3 in serum and mediates phagocytosis by human monocytes.
Previous studies from this laboratory have demonstrated that Mycobacterium leprae, an obligate intracellular bacterial parasite, enters human mononuclear phagocytes via complement receptors on these host cells and bacterium-bound C3. The present study investigates the role of M. leprae surface molecules in C3 fixation and phagocytosis. By enzyme-linked immunosorbent assay, C3 binds selectively to phenolic glycolipid-1 (PGL-1), a major surface molecule of the leprosy bacillus. C3 fixation to PGL-1 is serum concentration dependent and is abolished in heat-inactivated serum or serum containing ethylenediaminetetraacetic acid. C3 fixation is also abolished in serum containing ethyleneglycol-bis (beta-aminoethyl ether)N,N,N'-tetraacetic acid and MgCl2 indicating that isolated PGL-1 fixes C3 via the classical complement pathway. The capacity of PGL-1 to fix C3 is dependent upon its terminal trisaccharide since sequential removal of monosaccharide units of the trisaccharide results in a stepwise reduction in C3 fixation. Deacylation of PGL-1 also abolishes C3 fixation. C3 fixes to the trisaccharide of PGL-1 that is chemically linked to bovine serum albumin via the chemical carrier, 8-methoxycarbonyloctanol. PGL-1 mediates C3 fixation to polystyrene microspheres, and PGL-1 and C3 together mediate ingestion of polystyrene microspheres by human monocytes, wherein these inert test particles reside in membrane-bound phagosomes. Thus, complement receptors on mononuclear phagocytes, complement component C3, and PGL-1 comprise a three-component receptor-ligand-acceptor molecule system for mediating phagocytosis of M. leprae.


Particle-based photodynamic therapy based on indocyanine green modified plasmonic nanostructures for inactivation of a Crohn's disease-associated Escherichia coli strain.
Particle-based photodynamic therapy (PPDT) holds great promise in theranostic applications. Herein, we demonstrate that PPDT based on gold nanorods coated with an indocyanine green (ICG)-loaded silica shell allows for the inactivation of the Crohn's disease-associated adherent-invasive Escherichia coli strain LF82 (E. coli LF82) under pulsed laser light irradiation at 810 nm. Fine-tuning of the plasmonic structures together with maximizing the photosensitizer loading onto the nanostructures allowed optimizing the singlet oxygen generation capability and the PPDT efficiency. Using a nanoparticle concentration low enough to suppress photothermal heating effects, 6 log10 reduction in E. coli LF82 viability could be achieved using gold nanostructures displaying a plasmonic band at 900 nm. An additional modality of nanoparticle-based photoinactivation of E. coli is partly observed, with 3 log10 reduction of bacterial viability using Au NRs@SiO2 without ICG, due to the two-photon induced formation of reactive oxygen species. Interaction of the particles with the bacterial surface, responsible for the disruption of the bacterial integrity, together with the generation of moderate quantities of singlet oxygen could account for this behavior.


A machine learning approach for computation of cardiovascular intrinsic frequencies.
Analysis of cardiovascular waveforms provides valuable clinical information about the state of health and disease. The intrinsic frequency (IF) method is a recently introduced framework that uses a single arterial pressure waveform to extract physiologically relevant information about the cardiovascular system. The clinical usefulness and physiological accuracy of the IF method have been well-established via several preclinical and clinical studies. However, the computational complexity of the current L2 optimization solver for IF calculations remains a bottleneck for practical deployment of the IF method in real-time settings. In this paper, we propose a machine learning (ML)-based methodology for determination of IF parameters from a single carotid waveform. We use a sequentially-reduced Feedforward Neural Network (FNN) model for mapping carotid waveforms to the output parameters of the IF method, thereby avoiding the non-convex L2 minimization problem arising from the conventional IF approach. Our methodology also includes procedures for data pre-processing, model training, and model evaluation. In our model development, we used both clinical and synthetic waveforms. Our clinical database is composed of carotid waveforms from two different sources: the Huntington Medical Research Institutes (HMRI) iPhone Heart Study and the Framingham Heart Study (FHS). In the HMRI and FHS clinical studies, various device platforms such as piezoelectric tonometry, optical tonometry (Vivio), and an iPhone camera were used to measure arterial waveforms. Our blind clinical test shows very strong correlations between IF parameters computed from the FNN-based method and those computed from the standard L2 optimization-based method (i.e., R≥0.93 and P-value ≤0.005 for each IF parameter). Our results also demonstrate that the performance of the FNN-based IF model introduced in this work is independent of measurement apparatus and of device sampling rate.


Ultrathin CsPbX3 Nanowire Arrays with Strong Emission Anisotropy.
1D nanowires of all-inorganic lead halide perovskites represent a good architecture for the development of polarization-sensitive optoelectronic devices due to their high absorption efficient, emission yield, and dielectric constants. However, among as-fabricated perovskite nanowires with the lateral dimensions of hundreds nanometers so far, the optical anisotropy is hindered and rarely explored owing to the invalidating of electrostatic dielectric mismatch in the physical dimensions. Here, well-aligned CsPbBr3 and CsPbCl3 nanowires with thickness T down to 15 and 7 nm, respectively, are synthesized using a vapor phase van der Waals epitaxial method. Strong emission anisotropy with polarization ratio up to ≈0.78 is demonstrated in the nanowires with T < 40 nm due to the electrostatic dielectric confinement. With the increasing of thickness, the polarization ratio remarkably reduces monotonously to ≈0.17 until T ≈140 nm; and further oscillates in a small amplitude owing to the wave characteristic of light. These findings not only represent a demonstration of perovskite-based polarization-sensitive light sources, but also advance fundamental understanding of their polarization properties of perovskite nanowires.


[Anesthetic management of a patient with Mulvihill-Smith syndrome].
Mulvihill-Smith syndrome is a rare disease that belongs to progeroid syndromes. This syndrome is characterized by a senile face with an underdeveloped lower half, short stature, microcephaly, multiple pigmented nevi, immunodeficiency, hearing loss, and high-pitched voice. We report anesthetic management of a 27-year-old woman, 138 cm and 27 kg, with this syndrome, who underwent removal of mandibular cyst, partial resection of tongue and keratoplasty. Anesthesia was induced with fentanyl, propofol and vecuronium. There was difficulty in maintaining adequate ventilation with a face mask for children, and we used a mask for infants. Her Cormack grade was rated 3 but her trachea could be intubated assisted by BURP procedure. Anesthesia was maintained with sevoflurane, nitrous oxide and oxygen supplemented with fentanyl. The changes of blood pressure during anesthesia were extraordinary, suggesting the presence of advanced arteriosclerosis. The postoperative course was uneventful, with stable hemodynamics, and the patient was discharged from the hospital on 9th postoperative day. Anesthesia for Mulvihill-Smith syndrome should be performed with caution for the potential risk of difficult airway and unstable hemodynamics.


[Bilateral synovial chondromatosis of the first metatarsophalangeal joint: a case report. ].
Synovial chondromatosis is a rare pathology of unknown aetiology. It originates from the chondroid metaplasia of the connective tissue of the synovial membrane. Consequently, cartilaginous nodules develop in the affected joints, first calcifying and then ossifying. The bursae mucosae, the vaginae tendinis and the para-articular connective tissue are less frequently affected. The most common locations of this pathology are the knee, the hip, the shoulder, the elbow and the ankle. The small joints are rarely affected, even less the bilateral involving of joints, above all of hand or foot, is exceptional. In a clinical and radiological valuation, it is difficult to distinguish synovial chondromatosis from osteoarthritis and from degenerative arthopathies in general. A sure diagnosis can be obtained only by means of a histological examination. We here report a case of synovial chondromatosis bilaterally located on the first metatarsophalangeal joint. Clinical and radiological features were similar to those of hallux rigidus, a typical and peculiar metatarsophalangeal joint pathology. The diagnostic suspicion arose during surgery, and was subsequently confirmed by histological examination. During the following visits, the patient did not present any painful symptomatology.


Coverage and effectiveness of Kyasanur forest disease (KFD) vaccine in Karnataka, South India, 2005-10.
Kyasanur forest disease (KFD), a tick-borne viral disease with hemorrhagic manifestations, is localised in five districts of Karnataka state, India. Annual rounds of vaccination using formalin inactivated tissue-culture vaccine have been conducted in the region since 1990. Two doses of vaccine are administered to individuals aged 7-65 years at an interval of one month followed by periodic boosters after 6-9 months. In spite of high effectiveness of the vaccine reported in earlier studies, KFD cases among vaccinated individuals have been recently reported. We analysed KFD vaccination and case surveillance data from 2005 to 2010. We calculated KFD incidence among vaccinated and unvaccinated populations and computed the relative risk and vaccine effectiveness. During 2005-2010, a total of 343,256 individuals were eligible for KFD vaccination (details of vaccination for 2008 were not available). Of these, 52% did not receive any vaccine while 36% had received two doses and a booster. Of the 168 laboratory-confirmed KFD cases reported during this 5-year period, 134 (80%) were unvaccinated, nine each had received one and two doses respectively while 16 had received a booster during the pre-transmission season. The relative risks of disease following one, two and booster doses of vaccine were 1.06 (95% CI = 0.54-2.1), 0.38 (95% CI = 0.19-0.74) and 0.17 (95% CI = 0.10-0.29) respectively. The effectiveness of the vaccine was 62.4% (95% CI = 26.1-80.8) among those who received two doses and 82.9% (95% CI = 71.3-89.8) for those who received two doses followed by a booster dose as compared to the unvaccinated individuals. Coverage of KFD vaccine in the study area was low. Observed effectiveness of the KFD vaccine was lower as compared to the earlier reports, especially after a single dose administration. Systematic efforts are needed to increase the vaccine coverage and identify the reasons for lower effectiveness of the vaccine in the region.


Candida albicans biofilms: a developmental state associated with specific and stable gene expression patterns.
Like many bacteria, yeast species can form biofilms on several surfaces. Candida albicans colonizes the surfaces of catheters, prostheses, and epithelia, forming biofilms that are extremely resistant to antifungal drugs. We have used transcript profiling to investigate the specific properties of C. albicans biofilms. Biofilm and planktonic cultures produced under different conditions of nutrient flow, aerobiosis, or glucose concentration were compared by overall gene expression correlation. Correlation was much higher between biofilms than planktonic populations irrespective of the growth conditions, indicating that biofilm populations formed in different environments display very similar and specific transcript profiles. A first cluster of 325 differentially expressed genes was identified. In agreement with the overrepresentation of amino acid biosynthesis genes in this cluster, Gcn4p, a regulator of amino acid metabolism, was shown to be required for normal biofilm growth. To identify biofilm-related genes that are independent of mycelial development, we studied the transcriptome of biofilms produced by a wild-type, hypha-producing strain and a cph1/cph1 efg1/efg1 strain defective for hypha production. This analysis identified a cluster of 317 genes expressed independently of hypha formation, whereas 86 genes were dependent on mycelial development. Both sets revealed the activation of the sulfur-amino acid biosynthesis pathway as a feature of C. albicans biofilms.


[Antigenicity study of cefpirome sulfate].
Immunological properties of cefpirome sulfate (CPR) were examined. The immunogenicity and challenging ability of CPR were examined in guinea pigs by active systemic anaphylaxis (ASA) and homologous 4-hr passive cutaneous anaphylaxis (PCA) tests. The animals given CPR alone intraperitoneally for sensitization and their sera were negative for ASA or PCA reactions, like the results with reference substances, ceftazidime (CAZ) and cephalothin sodium (CET). When each antibiotic plus Freund's complete adjuvant (FCA) was used for sensitization, ASA reactions were observed with CPR, cephaloridine (CER), CET, and cefazolin sodium (CEZ), and PCA reactions, with CPR and CET. CPR had the ability to challenge the ASA and PCA reactions. CER and CET also showed the ability to challenge ASA or PCA reactions, though at low incidences. The cross-reactivity of CPR with commercially available antibiotics was examined by heterologous PCA test and by passive hemagglutination test and its inhibition test. The antiserum used was from rabbits immunized with each antibiotic-ovalbumin conjugate plus FCA, and the antigen was each antibiotic-bovine serum albumin conjugate. CPR cross-reacted markedly with cefotaxime sodium (CTX) having the same side chain at position 7 and showed weak, unidirectional reactions with CAZ and CET. In the in vitro direct Coombs test, the positive reactions noted with CPR were stronger than those with latamoxef sodium, equal to those with CEZ and slighter than those with CTX, CET and benzylpenicillin potassium. In conclusion, in the safety evaluation of CPR, its antigenic potential may not be a problem, like the cases of other antibiotics.


A 12-month survey of the gastro-intestinal helminths of antelopes, gazelles and giraffids kept at two zoos in Belgium.
Faecal egg count patterns and clinical signs associated with gastro-intestinal (GI) nematodes of 107 zoo ruminants were monitored at fortnightly intervals for 1 year. The ruminants in this study were kept under different husbandry conditions at two sites of the Royal Zoological Society of Antwerp, the Antwerp Zoo and the Animal Park Planckendael. Artiodactylids involved were Arabian oryx (Oryx leucoryx), scimitar-horned oryx (Oryx dammah), bongos (Tragelaphus euryceros isaaci), sitatungas (Tragelaphus spekii gratus), common eland (Taurotragus oryx), impala (Aepyceros melampus), slender-horned gazelles, (Gazella leptoceros), blue wildebeest (Connochaetes taurinus taurinus), Kordofan giraffes (Giraffe camelopardalis antiquorum) and okapi (Okapia johnstoni). Nematode eggs were recovered from 586 of 1606 (36.5%) individual faecal samples, using flotation techniques. Infection levels were distinctly low at Antwerp Zoo, probably due to zero grazing and daily dung removal. At Planckendael, the herds of Arabian oryx, scimitar-horned oryx and slender-horned gazelles showed markedly higher egg counts than the other herds, with more than 10% of the faecal egg counts having more than 100 eggs per gram (epg) and maximum faecal egg counts of 600, 750 and 1350 epg, respectively. Faecal egg counts increased during the mid-grazing season (July) and peaked at the end of the grazing season (October). No clinical signs, such as loss of faecal consistency, could be correlated with faecal egg counts (P > 0.05). With the exception of significantly more Nematodirus spp. eggs that were present in juvenile eland, no differences in faecal egg counts could be found between the sexes and different age groups. Abomasa and intestines of 17 animals that died during the survey were available for total worm counts. In one Arabian oryx, four slender-horned gazelles and one sitatunga low burdens ranging from 200 to 14,300 were found. Nematode species recovered were Camelostrongylus mentulatus from the abomasa and Trichostrongylus retortaeformis, Nematodirus fillicollis, Capillaria spp. and Trichuris spp. from the intestines. Our findings suggest different nematode infection levels between herds, which are mainly due to husbandry conditions but to a lesser extent to species- or individual susceptibility. Identification of ungulates that are highly infected and knowledge of the seasonal variation of their helminths can contribute greatly to a well-adjusted species-specific management and helminth control program.


How Do People with Experience of Infertility Value Different Aspects of Assistive Reproductive Therapy? Results from a Multi-Country Discrete Choice Experiment.
Assistive reproductive therapies can help those who have difficulty conceiving but different forms of assistive reproductive therapies are associated with different treatment characteristics. We undertook a large, multinational discrete choice experiment to understand patient preferences for assistive reproductive therapies. We administered an online discrete choice experiment with persons who had experience with subfertility or assistive reproductive therapies in the USA, UK, the Nordic region (Denmark, Norway, Sweden, Finland), Spain, and China. Attributes encouraged trade-offs between effectiveness, risk of adverse effects, treatment (dis)comfort, (in)convenience, cost per cycle and shared decision making. We used multinomial logit and mixed-logit models to estimate preferences and attribute importance by country/region, and estimated willingness to pay for changes in attribute levels. A total of 7565 respondents participated. Mixed logit had a better fit than multinomial logit across all samples. Preferences moved in expected directions across all samples, but the relative importance of attributes differed between countries. Willingness to pay was greatest for improvements in effectiveness and a greater degree of shared decision making, and we observe a substantial 'option value' independent of treatment characteristics. Unexpectedly, preferences over cost were insignificant in the Chinese sample, limiting the use of willingness to pay in this sample. Respondents balanced concerns for effectiveness with other considerations, including the cost and (dis)comfort of treatment, and the degree of shared decision making, but there is also substantial option value independent of treatment characteristics, demonstrating value of assistive reproductive therapies to individuals with experience of subfertility. We hypothesise that price insensitivity in the Chinese sample may reflect a degree of social desirability bias.


A decomposition of electrocortical activity as a function of spatial frequency: a weighted multidimensional scaling analysis.
In this study, we examined the usefulness of weighted multidimensional scaling (WMDS) to decompose electrocortical activity of multiple brain sources. This electrocortical activity was evoked by checkerboard stimuli of four different spatial frequencies (0.75, 1.5, 3.0, and 6.0 cpd), presented to 12 participants under passive viewing conditions. Visual evoked potentials (VEPs) were recorded with a high density montage of 60 electrodes. These data were analyzed by using WMDS, resulting in four different dimensions, each of which can be considered equivalent to a potential scalp distribution, i.e. dipole source. The first of these dipole sources, which were determined by brain electrical source analysis (BESA), was predominantly activated by higher spatial frequencies, the second and third were predominantly activated by lower spatial frequencies, while the third and fourth sources were characterized by hemispheric asymmetry. Moreover, the neural activity of these brain sources was characterized by different patterns as a function of spatial frequency and time. The results suggest that visual processing of spatial frequencies comprises relatively separate subsystems with different spatiotemporal response characteristics.


Sinus elevation by in situ utilization of bone scrapers: technique and results.
The objective was to present a novel technique for antrostomy performed before sinus elevation in atrophic maxilla for subsequent implant placement. The study included 10 sinus elevations performed by the proposed technique in nine consecutive patients presenting with inadequate posterior maxillary height. The technique is described, calculating the antrostomy surface area, volume of bone tissue obtained and final height attained in each case. A total of 16 implants were placed. All ten elevations were accomplished. Mean antrostomy surface area was 0.55 mm2, mean bone volume obtained was 0.56 cm3 and mean height attained was 11.7 mm from a baseline mean height of 5.6 mm. Out of the 16 implants, 14 were inserted immediately after the elevation and 2 were inserted in a second step, after ossification; 93.7% of the implants were osseointegrated at 6 months after prosthesis placement. The use of bone scrapers to create antrostomy for sinus elevation is a simple and very safe procedure. It provides a variable amount of particulate bone graft that is easily handled and highly useful for packing the cavity that will elevate the sinus membrane.


Post-traumatic stress disorder: case report.
Following exposure to a major traumatic event like the August seventh 1998 Nairobi bomb blast various reactions occur, some of which result in stress-related psychiatric disorders. We have described one such case, and used it to illustrate the salient features of post-traumatic stress disorder. We have outlined the diagnostic categories of the post-traumatic disorders and discussed the different treatment modalities applicable.


[Effectiveness of eradication anti-helicobacter therapy in patients with duodenal ulcer in different drug dosage regimens].
46 patients having exacerbation of duodenal ulcer in the presence of Helicobacter pylori (HP) were studied for efficacy of HP eradication treatment which comprised omeprazole (40 mg/day), colloid bismuth subcitrate (480 mg/day) and metronidazole (1000 mg/day) for 2 weeks. According to the dosage regimen the patients were divided into two groups. Patients of group 1 received the drugs in fractions, of group 2--in a single daily doses. The eradication therapy in both dosage regimen was high (73 and 88%, respectively). Thus, it is proved that single daily doses of actibacterial drugs can be also used in clinical practice for conduction of eradication therapy.


[The criteria of threshold effects of environmental pollutants].
A set of criteria, indices and methods applicable to determining the threshold doses and concentrations of chemical substances was critically examined, analyzed and summarized. A differentiated notion for the hazard effect threshold and for threshold effects, with due respect for which the daily doses and norms are substantiated for various environmental objects, is described. An original interpretation of the hygienic evaluation of an enhanced enzyme activity, mainly of the microsomal hepatic enzymes, is suggested; it is noteworthy, that this aspect was often regarded as a physiological response to the detoxication of chemicals. An advantage of calculating the reference doses as compared to other mathematical methods of determining the threshold values is demonstrated. The article is intended to promote and enhance the safety of hygienic regulation, which is a basis for the state environmental monitoring.


Acupuncture for pain and dysfunction after neck dissection: results of a randomized controlled trial.
To determine whether acupuncture reduces pain and dysfunction in patients with cancer with a history of neck dissection. The secondary objective is to determine whether acupuncture relieves dry mouth in this population. Patients at a tertiary cancer center with chronic pain or dysfunction attributed to neck dissection were randomly assigned to weekly acupuncture versus usual care (eg, physical therapy, analgesia, and/or anti-inflammatory drugs, per patient preference or physician recommendation) for 4 weeks. The Constant-Murley score, a composite measure of pain, function, and activities of daily living, was the primary outcome measure. Xerostomia, a secondary end point, was assessed using the Xerostomia Inventory. Fifty-eight evaluable patients were accrued and randomly assigned from 2004 to 2007 (28 and 30 patients on acupuncture and control arms, respectively). Constant-Murley scores improved more in the acupuncture group (adjusted difference between groups = 11.2; 95% CI, 3.0 to 19.3; P = .008). Acupuncture produced greater improvement in reported xerostomia (adjusted difference in Xerostomia Inventory = -5.8; 95% CI, -0.9 to -10.7; P = .02). Significant reductions in pain, dysfunction, and xerostomia were observed in patients receiving acupuncture versus usual care. Although further study is needed, these data support the potential role of acupuncture in addressing post-neck dissection pain and dysfunction, as well as xerostomia.


Maternal serum interleukin-6 during pregnancy and during term and preterm labor.
To determine the normal concentrations of maternal serum interleukin-6 during the second and third trimesters of pregnancy and the different stages of term and preterm labor, and to examine the clinical usefulness of measuring this cytokine in the serum of women in preterm labor to diagnose asymptomatic intrauterine infections. Maternal serum interleukin-6 concentrations were measured cross-sectionally in 315 gravidas in their second and third trimesters and during term and preterm labor. Placentas from women who delivered preterm were examined for histologic chorioamnionitis. At term, women in labor had significantly elevated median maternal serum interleukin-6 concentrations compared with those at term not in labor (4.7 pg/mL versus 2.2 pg/mL, P < .001). Women admitted in preterm labor who delivered had significantly higher median interleukin-6 concentrations than did those in preterm labor who responded to tocolysis (9.3 pg/mL versus 1.9 pg/mL, P < .001). Women in preterm labor who delivered preterm with evidence of chorioamnionitis had significantly higher serum concentrations of interleukin-6 than did those in preterm labor who delivered in the absence of chorioamnionitis (15.9 pg/mL versus 4.6 pg/mL, P = .006). Compared with antepartum gravidas, those in term or preterm labor had significantly higher concentrations of maternal serum interleukin-6 concentrations; extremely elevated levels were found in patients whose preterm labor was associated with intrauterine infection.


Tumor detection in the bladder wall with a measurement of abnormal thickness in CT scans.
Virtual cystoscopy is a developing technique for bladder cancer screening. In a conventional cystoscopy, an optical probe is inserted into the bladder and an expert reviews the appearance of the bladder wall. Physical limitations of the probe place restrictions on the examination of the bladder wall. In virtual cystoscopy, a computed tomography (CT) scan of the bladder is acquired and an expert reviews the appearance of the bladder wall as shown by the CT. The task of identifying tumors in the bladder wall has often been done without extensive computational aid to the expert. We have developed an image processing algorithm that aids the expert in the detection of bladder tumors. Compared with an expert observer reading the CT, our algorithm achieves 89% sensitivity, 88% specificity, 48% positive predictive value, and 98% negative predictive value.


Voluntary Modulation of Evoked Responses Generated by Epidural and Transcutaneous Spinal Stimulation in Humans with Spinal Cord Injury.
Transcutaneous (TSS) and epidural spinal stimulation (ESS) are electrophysiological techniques that have been used to investigate the interactions between exogenous electrical stimuli and spinal sensorimotor networks that integrate descending motor signals with afferent inputs from the periphery during motor tasks such as standing and stepping. Recently, pilot-phase clinical trials using ESS and TSS have demonstrated restoration of motor functions that were previously lost due to spinal cord injury (SCI). However, the spinal network interactions that occur in response to TSS or ESS pulses with spared descending connections across the site of SCI have yet to be characterized. Therefore, we examined the effects of delivering TSS or ESS pulses to the lumbosacral spinal cord in nine individuals with chronic SCI. During low-frequency stimulation, participants were instructed to relax or attempt maximum voluntary contraction to perform full leg flexion while supine. We observed similar lower-extremity neuromusculature activation during TSS and ESS when performed in the same participants while instructed to relax. Interestingly, when participants were instructed to attempt lower-extremity muscle contractions, both TSS- and ESS-evoked motor responses were significantly inhibited across all muscles. Participants with clinically complete SCI tested with ESS and participants with clinically incomplete SCI tested with TSS demonstrated greater ability to modulate evoked responses than participants with motor complete SCI tested with TSS, although this was not statistically significant due to a low number of subjects in each subgroup. These results suggest that descending commands combined with spinal stimulation may increase activity of inhibitory interneuronal circuitry within spinal sensorimotor networks in individuals with SCI, which may be relevant in the context of regaining functional motor outcomes.


Influence of advanced age on Mycobacterium bovis BCG vaccination in guinea pigs aerogenically infected with Mycobacterium tuberculosis.
Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only tuberculosis (TB) vaccine currently available, but its efficacy against adult pulmonary TB remains controversial. BCG induces specific immune responses to mycobacterial antigens and may elicit protective immunity against TB. TB remains a major public health problem, especially among the elderly, yet the efficacy of BCG in the elderly is unknown. We investigated the ability of BCG vaccination to prevent TB in young (6-week-old), middle-aged (18-month-old), and old (60-month-old) guinea pigs. BCG-Tokyo vaccination reduced the growth of Mycobacterium tuberculosis H37Rv in all three groups. By use of an enzyme-linked immunospot (ELISPOT) assay, antigen-specific gamma interferon (IFN-γ)-producing cells were detected in the 60-month-old guinea pigs after a booster vaccination with BCG-Tokyo. Our findings suggest that BCG-Tokyo has a protective effect against tuberculosis infection regardless of age.


Modeling Interactions between Transposable Elements and the Plant Epigenetic Response: A Surprising Reliance on Element Retention.
Transposable elements (TEs) compose the majority of angiosperm DNA. Plants counteract TE activity by silencing them epigenetically. One form of epigenetic silencing requires 21-22 nt small interfering RNAs that act to degrade TE mRNA and may also trigger DNA methylation. DNA methylation is reinforced by a second mechanism, the RNA-dependent DNA methylation (RdDM) pathway. RdDM relies on 24 nt small interfering RNAs and ultimately establishes TEs in a quiescent state. These host factors interact at a systems level, but there have been no system level analyses of their interactions. Here, we define a deterministic model that represents the propagation of active TEs, aspects of the host response and the accumulation of silenced TEs. We describe general properties of the model and also fit it to biological data in order to explore two questions. The first is why two overlapping pathways are maintained, given that both are likely energetically expensive. Under our model, RdDM silenced TEs effectively even when the initiation of silencing was weak. This relationship implies that only a small amount of RNAi is needed to initiate TE silencing, but reinforcement by RdDM is necessary to efficiently counter TE propagation. Second, we investigated the reliance of the host response on rates of TE deletion. The model predicted that low levels of deletion lead to few active TEs, suggesting that silencing is most efficient when methylated TEs are retained in the genome, thereby providing one explanation for the large size of plant genomes.


Interaction of clusterin and matrix metalloproteinase-9 and its implication for epithelial homeostasis and inflammation.
Uncontrolled increases of matrix metalloproteinase-9 (MMP-9) activity have been causally linked to epithelial barrier disruption and severe symptoms of inflammatory diseases such as dry eye (DE). The data presented here show that the anti-inflammatory, cytoprotective intracellular and extracellular chaperone protein clusterin (CLU) interacts with MMP-9 both inside and outside epithelial cells. CLU bound very strongly to active MMP-9, with an affinity constant K(D) of 2.63 nmol/L. Unexpectedly, CLU had a much higher affinity for pro-MMP-9 than for active MMP-9 or pro-MMP-2, requiring the N-terminal propeptide domain of pro-MMP-9. The significance of the interaction between CLU and MMP-9 was demonstrated by the observation that CLU prevents stress-induced MMP-9 aggregation and inhibits MMP-9 enzymatic activity. Furthermore, CLU inhibited MMP-9-mediated disintegration of the tight junction structure formed between human epithelial cells. Additionally, CLU inhibited enzymatic activities of MMP-2, MMP-3, and MMP-7. Treatment with proinflammatory cytokines, which are known to increase MMP-9 transcription under inflammatory conditions, reduced the expression of CLU in human epithelial cells. Similarly, in a mouse model of human DE, inflammatory stress depleted CLU in the ocular surface epithelium but allowed MMP-9 to prevail therein. The present results thus provide novel insights into previously unrecognized mechanisms by which CLU maintains fluid-epithelial interface homeostasis, thereby preventing the onset of inflammatory conditions, especially where MMP-9 is actively involved.


Insights from the study of heart rate variability.
Indices of heart rate variability (HRV) provide a window onto autonomic modulation of the heart. HRV indices, determined in either the time or frequency domain, are closely related and reflect parasympathetic, mixed sympathetic, and parasympathetic and circadian rhythms. In population studies, decreased HRV has had predictive value for mortality among healthy adults. It is a well-established risk factor for arrhythmic events and mortality among post-myocardial-infarction patients but has only moderate sensitivity and specificity. Decreased HRV has had mixed predictive success in congestive heart failure. Reduced HRV identifies diabetic patients with autonomic neuropathy. HRV in combination with other risk stratifiers, e.g. ejection fraction, can identify cardiac patients at especially high risk of mortality. Many but not all interventions associated with increased HRV are also associated with better survival rates.


Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin.
Postnatal handling increases glucocorticoid receptor expression in the rat hippocampus, thus altering the regulation of hypothalamic synthesis of corticotropin-releasing hormone and the hypothalamic-pituitary-adrenal response to stress. The effect on glucocorticoid receptor gene expression represents one mechanism by which the early environment can exert a long-term effect on neural development. The handling effect on hippocampal glucocorticoid receptor expression is dependent on peripheral thyroid hormone release and the activation of ascending serotonergic pathways. In primary hippocampal cell cultures, serotonin (5-HT) increases glucocorticoid receptor expression, and this effect appears to be mediated by increased cAMP levels. In the current studies we examined the in vivo effects of handling on hippocampal cAMP-protein kinase A (PKA) activity. In 7-d-old rat pups, we found that (1) postnatal handling increased adenylyl cyclase activity and hippocampal cAMP levels, (2) the effect of handling on cAMP levels was completely blocked by treatment with either propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, or the 5-HT receptor antagonist, ketanserin, and (3) handling also increased hippocampal PKA activity. We then examined the effects of handling on cAMP-inducible transcription factors. Handling rapidly increased levels of the mRNAs for nerve growth factor-inducible factor A (NGFI-A) (zif268, krox24) and activator protein-2 (AP-2) as well as for NGFI-A and AP-2 immunoreactivity throughout the hippocampus. Finally, we found that the effects of handling on NGFI-A and AP-2 expression were significantly reduced by concurrent treatment with either PTU or ketanserin, effects that paralleled those on cAMP formation. NGFI-A and AP-2 have been implicated in the regulation of glucocorticoid receptor expression during development. Thus, these findings suggest that postnatal handling might alter glucocorticoid receptor gene expression via cAMP-PKA pathways involving the activation of NGFI-A and AP-2.


Weighted variance FBAT: a powerful method for including covariates in FBAT analyses.
The family-based association test (FBAT), an extension of transmission/disequilibrium test, capitalizes on linkage disequilibrium to assess the association of genetic markers and traits in nuclear families. It does not permit a formal inclusion of covariates, although an offset under the FBAT -o option allows for an overall trait-intercept adjustment. The PBAT software provides additional features and permits the inclusion of covariates in the FBAT test statistic, but does not account for the parental genotype information when the traits are adjusted for the covariates. We propose the weighted variance FBAT (WVF) method to generate trait values adjusted for both parental genotypes and covariate values. WVF is expected to be more powerful, because the variance is minimized considering both of these factors simultaneously using a weighted Gauss-Newton algorithm. Two simulated parent/child trio data sets, both with a covariate and the second with a gene by covariate interaction, were simulated to compare WVF power with FBAT and PBAT for a quantitative trait. WVF is most powerful when levels of significance are greater and covariates have a larger influence, indicating WVF may be especially effective when multiple comparisons are an important consideration, such as with whole genome association studies. WVF will also improve the cost of an association study when environmental covariates are considered. A SAS program (www.SAS.com) for generating WVF residuals that can be input to the current versions of the FBAT (www.biostat.harvard.edu/fbat/fbat.html) and PBAT (www.biostat.harvard.edu/clange/default.htm) software is provided.


CASP5 assessment of fold recognition target predictions.
We present an overview of the fifth round of Critical Assessment of Protein Structure Prediction (CASP5) fold recognition category. Prediction models were evaluated by using six different structural measures and four different alignment measures, and these scores were compared to those assigned manually over a diverse subset of target domains. Scores were combined to compare overall performance of participating groups and to estimate rank significance. The methods used by a few groups outperformed all other methods in terms of the evaluated criteria and could be considered state-of-the-art in structure prediction. We discuss a few examples of difficult fold recognition targets to highlight the progress of ab initio-type methods on difficult structure analogs and the difficulties of predicting multidomain targets and selecting prediction models. We also compared the results of manual groups to those of automatic servers evaluated in parallel by CAFASP, showing that the top performing automated server structure predictions approached those of the best manual predictors.


Comparison of patient-specific inlet boundary conditions in the numerical modelling of blood flow in abdominal aortic aneurysm disease.
Three inlet boundary condition datasets were derived from phase-contrast MRI: (i) centre line velocity data converted to two-dimensional (2D) velocity profile using Womersley equations (Womersley), (ii) 2D velocity profile with one axial component of velocity (1CV), (iii) 2D velocity profile with three components of velocity (3CV). Computational fluid dynamics was performed using a rigid wall approach with geometry data extracted from the computed tomography dataset. Helical flow was present in the 1CV and 3CV simulations, with more complex patterns for the 3CV case. The Womersley method produced simplified flow patterns with an absence of helical flow. Mean values of quantitative indices (helical flow index, mean wall shear stress, oscillatory index) were compared with the 3CV inlet data. These were lower for both the Womersley inlet data (28%, 71%, 56%) and the 1CV inlet data (9%, 24%, 69%). It was concluded that inlet methods based on centre line velocity, such as might be obtained from Doppler ultrasound, lead to significantly simplified abdominal aortic aneurysm haemodynamics and thus are not recommended. Single velocity component (axial) data from MRI might suffice when general flow characteristics and spatial wall shear stress are required. Ideally 2D MRI velocity profiles with 3-velocity component data are preferred to fully account for helical flow.


Goniometric versus computerized angle measurement in assessing hallux valgus.
Digital workstations with high-resolution monitors are replacing standard radiographs for image evaluation and interpretation. Radiographic angles in the foot have been evaluated for interobserver and intraobserver reliability with plain films, but use of digital workstations has not been validated. Because the 1-2 intermetatarsal (IM) and hallux valgus (HV) angles help determine the most appropriate bunion procedure, the reliability of these measurements is important. The HV and 1-2 IM angles were evaluated on preoperative radiographs of 25 patients who subsequently underwent bunion procedures. A standardized technique using a film marker and goniometer on plain film was compared with use of a mouse and computerized angle measurement software at a digital workstation. Three foot and ankle surgeons conducted these measurements at various intervals. Completion of three readings of each radiograph in each format by each observer totaled 1,800 measurements. Computerized measurement gave better overall reliability. For the HV angle, interobserver agreement (measurements within 2 degrees) improved from 66% with plain films to 81% with the digital workstation (p < 0.001). Intraobserver agreement increased from 72% to 80%. The 1-2 IM angle was similarly reliable with both methods for inter- and intraobserver agreement. This study validates the use of computer-assisted angle measurement on digital radiographs for assessment of HV and 1-2 IM angles. Computerized measurement may result in more reliable readings because it eliminates the error inherent with use of a goniometer and facilitates adjustment of radiographic lines on the computer to ensure correct alignment.


[Capacity of activation of so-called deficient factors in hereditary blood coagulation disorders].
By factor-specific exchange-experiments it was proved that the lack of factor VIII activity in hemophilia A is not caused by an incapacity of activation or even lack of the factor, but by a defect of the pertaining activator resp. activator system. The same goes for factor IX in hemophilia B as well as factors VII, IX and X in family defect of the prothrombin-complex. In contrast, inactivity in the von Willebrand-Jünrgens-disease is obviously caused by a genuine lack of factor VIII.


Panax ginseng.
The herbal remedies referred to as "ginseng" are derived from the roots of several plants. One of the most commonly used and researched of the ginsengs is Panax ginseng, also called Asian or Korean ginseng. The main active components of Panax ginseng are ginsenosides, which have been shown to have a variety of beneficial effects, including anti-inflammatory, antioxidant, and anticancer effects. Results of clinical research studies demonstrate that Panax ginseng may improve psychologic function, immune function, and conditions associated with diabetes. Overall, Panax ginseng appears to be well tolerated, although caution is advised about concomitant use with some pharmaceuticals, such as warfarin, oral hypoglycemic agents, insulin, and phenelzine. Panax ginseng does not appear to enhance physical performance. Products with a standardized ginsenoside concentration are available.


Neuropsychological outcomes of army personnel following deployment to the Iraq war.
The effects of war-zone deployment on neuropsychological health remain poorly understood. Neuropsychological performance deficits serve as sensitive measures of neural dysfunction and are often associated with psychosocial and occupational problems. Previous studies have not conducted objective neuropsychological assessments both before and after a major war-zone deployment. To examine objective neuropsychological outcomes of Iraq War deployment in a large military cohort. The Neurocognition Deployment Health Study, a prospective, cohort-controlled study conducted at military installations. This report centers on 961 male and female active-duty Army soldiers drawn from the larger cohort. Deploying Army soldiers (n = 654) were examined prior to deployment to Iraq (April-December 2003) and shortly after return (within a mean of 73 days [median, 75 days]; January-May 2005) from Iraq deployment. A comparison group of soldiers (n = 307) similar in military characteristics but not deploying overseas during the study was assessed in sessions timed to be as close as possible to the assessment of deployers. Military unit sampling procedures facilitated representation of combat, combat support, and combat service support functions among both deployers and nondeployers. Individually administered, performance-based neuropsychological tasks. Estimates (beta; the unstandardized parameter estimate) for the absolute differences in adjusted mean outcome scores between deployed and nondeployed groups were determined using generalized estimating equations. Multiple linear regression analyses adjusted for battalion membership revealed that Iraq deployment, compared with nondeployment, was associated with neuropsychological compromise on tasks of sustained attention (beta = 0.11; P<.001), verbal learning (beta = -1.51; P = .003), and visual-spatial memory (beta = -3.82; P<.001). Iraq deployment was also associated with increased negative state affect on measures of confusion (beta = 1.40; P<.001) and tension (beta = 1.24; P<.001). In contrast, deployment was associated with improved simple reaction time (beta = 4.30; P = .003). Deployment effects remained statistically significant after taking into account deployment-related head injury and stress and depression symptoms. Deployment to Iraq is associated with increased risk of neuropsychological compromise. Findings point to the need to investigate further the impact of deployment on neural functioning. Public health implications include consideration of neuropsychological compromise in health prevention and postdeployment clinical and occupational management.


Structure of the transition state for folding of a protein derived from experiment and simulation.
Independent experimental and theoretical studies of the unfolding of barley chymotrypsin inhibitor 2 (CI2) are compared in an attempt to derive plausible three-dimensional structural models of the transition states. A very simple structure index is calculated along the sequence for the molecular dynamics-generated transition state models to facilitate comparison with the phi F values. The two are in good agreement overall (correlation coefficient = 0.87), which suggests that the theoretical models should provide a structural framework for interpretation of the phi F values. Both experiment and simulation indicate that the transition state is a distorted form of the native state in which the alpha-helix is weakened but partially intact and the beta-sheet is quite disrupted. As inferred from the phi f values and observed directly in the simulations, the unfolding of CI2 is cooperative and there is a "folding core" comprising a patch on the alpha-helix and a portion of the beta-sheet, nucleated by interactions between Ala16, Ile49 and other neighbouring residues. The protein becomes less structured radiating away from this core. Overall the data indicate that CI2 folds by a nucleation-collapse mechanism. In the absence of experimental information, we have little confidence that the molecular dynamics simulations are correct, especially when only one or a few simulations are performed. On the other hand, even though the experimentally derived phi values may reflect the extent of overall structure formation, they do not provide an actual atomic-resolution three dimensional structure of the transition state. By combining the two approaches, however, we have a framework for interpreting phi F values and can hopefully arrive at a more trustworthy model of the transition state. The process is in some ways similar to the combination of molecular dynamics and NMR data to solve the tertiary structure of proteins.


Behavioral and neurochemical consequences of lipopolysaccharide in mice: anxiogenic-like effects.
Systemic administration of lipopolysaccharide (LPS) induces sickness behaviors, as well as alterations of hypothalamic-pituitary-adrenal functioning commonly associated with stressors. In the present investigation, it was demonstrated that systemic LPS treatment induced a sickness-like behavioral profile (reduced active behaviors, soporific effects, piloerection, ptosis), which appeared to be dependent upon the novelty of the environmental context in which animals were tested. As well, LPS induced anxiogenic-like responses, including decreased time spent in the illuminated portion of a light-dark box, reduced open-arm entries in a plus-maze test, and decreased contact with a novel stimulus object in an open-field situation. The behavioral changes were accompanied by increased plasma ACTH and corticosterone levels. As well, LPS induced increased turnover of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the paraventricular nucleus (PVN), median eminence plus arcuate nucleus, hippocampus, as well as NE turnover within the locus coeruleus and DA turnover within the nucleus accumbens. Although these neurochemical variations were reminiscent of those elicited by stressors, LPS was not particularly effective in modifying DA activity within the prefrontal cortex or NE within the amygdala, variations readily induced by stressors. Whether the LPS-induced anxiogenic-like responses were secondary to the illness engendered by the endotoxin remains to be determined. Nevertheless, it ought to be considered that bacterial endotoxin challenge, and the ensuing cytokine changes, may contribute to emotionality and perhaps even anxiety-related behavioral disturbances.


A Rasch Model and Rating System for Continuous Responses Collected in Large-Scale Learning Systems.
An extension to a rating system for tracking the evolution of parameters over time using continuous variables is introduced. The proposed rating system assumes a distribution for the continuous responses, which is agnostic to the origin of the continuous scores and thus can be used for applications as varied as continuous scores obtained from language testing to scores derived from accuracy and response time from elementary arithmetic learning systems. Large-scale, high-stakes, online, anywhere anytime learning and testing inherently comes with a number of unique problems that require new psychometric solutions. These include (1) the cold start problem, (2) problem of change, and (3) the problem of personalization and adaptation. We outline how our proposed method addresses each of these problems. Three simulations are carried out to demonstrate the utility of the proposed rating system.


Effects of exercise training and hypercholesterolemia on adenosine activation of voltage-dependent K+ channels in coronary arterioles.
Coronary arterioles from hypercholesterolemic swine display attenuated adenosine-mediated vasodilatation that is attributable to the elimination of voltage-dependent K(+) (Kv) channel stimulation. For the present study, we tested the hypotheses that exercise training would correct impaired adenosine-induced dilatation in coronary arterioles from hypercholesterolemic pigs through restoration of adenosine activation of Kv channels and that vasodilatation to the receptor-independent adenylyl cyclase activator, forskolin, would also be attenuated in arterioles from hypercholesterolemic pigs. Pigs were randomly assigned to a control (NC) or high-fat, high-cholesterol (HC) diet for 20 wk. Four weeks after the diet was initiated, pigs from both groups were assigned to exercise training (Ex; 5 days/wk for 16 wk) or sedentary (Sed) protocols, resulting in four groups of pigs: NC-Sed, NC-Ex, HC-Sed, and HC-Ex. Arterioles ( approximately 150 mum) from both HC-Sed and HC-Ex pigs displayed impaired adenosine-mediated dilatation that was attributable to the elimination of 4-aminopyridine (4-AP; 1 mM)-sensitive Kv channel activation compared with NC counterparts. Arteriolar smooth muscle whole cell Kv currents were significantly reduced in HC-Sed compared with NC-Sed, although HC-Ex and NC-Ex did not differ. Forskolin-mediated dilatation was attenuated by 4-AP (1 mM) and in a concentration-dependent manner by tetraethylammonium (TEA; 0.1-1 mM) in NC-Sed but not HC-Sed. Further, TEA-sensitive Kv currents were diminished in cells of HC-Sed compared with NC-Sed pigs. Quantitative RT-PCR revealed similar expression levels of Kv3.1 and 3.3 in arterioles of NC-Sed and HC-Sed swine with undetectable expression of Kv1.1, 3.2, and 3.4. Taken together, these results suggest that hypercholesterolemia-mediated attenuation of adenosine-induced vasodilatation in coronary arterioles is not corrected by exercise training and is likely attributable to an impairment in the pathway coupling adenylyl cyclase with a highly TEA-sensitive Kv channel isoform(s).


North American male reference population for speed of sound in bone at multiple skeletal sites.
Alternatives to dual-energy X-ray absorptiometry (DXA) have been sought to increase access to low-cost osteoporosis risk assessment. Early quantitative ultrasound (QUS) systems measured speed of sound (SOS) and broadband ultrasound attenuation (BUA) at the calcaneus, and these were demonstrated to be good predictors of hip fracture risk. Recent studies have demonstrated the usefulness of other peripheral sites to assess bone status. The Sunlight Omnisense (Sunlight Medical, Rehovot, Israel) is a portable, inexpensive QUS device capable of multiple-site SOS measurement. To provide a robust male reference database, 588 healthy Caucasian males aged 20-90 yr were recruited from 6 centers across North America. SOS measurements were taken at the distal 1/3 radius, proximal third phalanx, midshaft tibia, and fifth metatarsal. A female reference database has previously been collected at North American sites. The results indicate that SOS in males exhibits an age-related decline beginning in the fifth decade at the radius, phalanx, and metatarsal, whereas the tibial SOS remains nearly constant until the ninth decade. Although females reach a higher-peak SOS than males at most sites, SOS is higher in males at all sites after the sixth decade, as a result of a more gradual decline in SOS. Longitudinal monitoring of healthy men should be performed to confirm these cross-sectional results.


Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004-2008.
Rates of overdose deaths involving prescription drugs increased rapidly in the United States during 1999-2006. However, such mortality data do not portray the morbidity associated with prescription drug overdoses. Data from emergency department (ED) visits can represent this morbidity and can be accessed more quickly than mortality data. To better understand recent national trends in drug-related morbidity, CDC and the Substance Abuse and Mental Health Services Administration (SAMHSA) reviewed the most recent 5 years of available data (2004-2008) on ED visits involving the nonmedical use of prescription drugs from SAMHSA's Drug Abuse Warning Network (DAWN). This report describes the results of that review, which showed that the estimated number of ED visits for nonmedical use of opioid analgesics increased 111% during 2004-2008 (from 144,600 to 305,900 visits) and increased 29% during 2007-2008. The highest numbers of ED visits were recorded for oxycodone, hydrocodone, and methadone, all of which showed statistically significant increases during the 5-year period. The estimated number of ED visits involving nonmedical use of benzodiazepines increased 89% during 2004-2008 (from 143,500 to 271,700 visits) and 24% during 2007-2008. These findings indicate substantial, increasing morbidity associated with the nonmedical use of prescription drugs in the United States during 2004-2008, despite recent efforts to control the problem. Stronger measures to reduce the diversion of prescription drugs to nonmedical purposes are warranted.


Suture Selection to Minimize Postoperative Postinflammatory Hyperpigmentation in Patients With Skin of Color During Mohs Micrographic Surgery.
The effects of suture selection on postinflammatory hyperpigmentation (PIH) in patients with skin of color who have had Mohs micrographic surgery (MMS) are limited. During the COVID-19 pandemic, fast-absorbing gut sutures reduced the need for in-person follow-up visits without increasing the frequency of postoperative complications. Although absorbable gut sutures are popular, they are highly reactive and can induce inflammation in patients with skin of color. Choosing less inflammatory, nonabsorbable sutures can improve the cosmetic outcome for patients with skin of color who undergo MMS.


A mechanism for the inhibition of neural progenitor cell proliferation by cocaine.
Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation. Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2alpha and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A. Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.


Foot-and-mouth disease: an assessment of the risks facing New Zealand.
Although New Zealand has never had a case of foot-and-mouth disease (FMD), the threat that this disease poses to the economy of this country has long been recognised. The unprecedented global spread of FMD caused by the type-O PanAsia strain, culminating in the outbreak that occurred in the United Kingdom in early 2001, has refocussed the concerns of biosecurity agencies worldwide. The 3 lines of defence against exotic disease incursions in this country are border controls, surveillance and incursion response capability. This article reviews the pathogenesis, virus survival, routes of infection and methods of spread of FMD virus, and in the light of recent international developments, presents a summary of the major risks of introduction and dissemination of FMD virus and the risk-management measures in place for this country.


Histone deacetylase inhibitors induce reactivation of herpes simplex virus type 1 in a latency-associated transcript-independent manner in neuronal cells.
Histone acetylation is implicated in the regulation of herpes simplex virus type 1 (HSV-1) latency. However, the role of histone acetylation in HSV-1 reactivation is less clear. In this study, the well-established model system, quiescently infected, neuronally differentiated PC12 (QIF-PC12) cells, was used to address the participation of histone acetylation in HSV-1 reactivation. In this model, sodium butyrate and trichostatin A (TSA), two histone deacetylase inhibitors, stimulated production of infectious HSV-1 progeny from a quiescent state. To identify viral genes responsive to TSA, the authors analyzed representative alpha, beta, and gamma viral genes using quantitative real-time polymerase chain reaction. Only the latency-associated transcript (LAT) accumulated in response to TSA treatment, under culture conditions that restricted virus replication and spread. This led the authors to evaluate the importance of LAT expression on TSA-induced reactivation. In QIF-PC12 cells, the LAT deletion mutant virus dLAT2903 reactivated equivalently with its wild-type parental strain (McKrae) after TSA treatment, as well as forskolin and heat stress treatment. Both viruses also reactivated equivalently from latently infected trigeminal ganglia explants from rabbits. In contrast, there was a marked reduction in the recovery of dLAT2903, as compared to wild-type virus, from the eyes of latently infected rabbits following epinephrine iontophoresis. These combined in vitro, ex vivo, and in vivo data suggest that LAT is not required for reactivation from latently infected neuronal cells per se, but may enhance processes that allow for the arrival of virus at, or close to, the site of original inoculation (i.e., recrudescence).


Bromination of L-tryptophan in a Fermentative Process With Corynebacterium glutamicum.
Brominated compounds such as 7-bromo-l-tryptophan (7-Br-Trp) occur in Nature. Many synthetic and natural brominated compounds have applications in the agriculture, food, and pharmaceutical industries, for example, the 20S-proteasome inhibitor TMC-95A that may be derived from 7-Br-Trp. Mild halogenation by cross-linked enzyme aggregates containing FAD-dependent halogenase, NADH-dependent flavin reductase, and alcohol dehydrogenase as well as by fermentation with recombinant Corynebacterium glutamicum expressing the genes for the FAD-dependent halogenase RebH and the NADH-dependent flavin reductase RebF from Lechevalieria aerocolonigenes have recently been developed as green alternatives to more hazardous chemical routes. In this study, the fermentative production of 7-Br-Trp was established. The fermentative process employs an l-tryptophan producing C. glutamicum strain expressing rebH and rebF from L. aerocolonigenes for halogenation and is based on glucose, ammonium and sodium bromide. C. glutamicum tolerated high sodium bromide concentrations, but its growth rate was reduced to half-maximal at 0.09 g L-1 7-bromo-l-tryptophan. This may be, at least in part, due to inhibition of anthranilate phosphoribosyltransferase by 7-Br-Trp since anthranilate phosphoribosyltransferase activity in crude extracts was half-maximal at about 0.03 g L-1 7-Br-Trp. Fermentative production of 7-Br-Trp by recombinant C. glutamicum was scaled up to a working volume of 2 L and operated in batch and fed-batch mode. The titers were increased from batch fermentation in CGXII minimal medium with 0.3 g L-1 7-Br-Trp to fed-batch fermentation in HSG complex medium, where up to 1.2 g L-1 7-Br-Trp were obtained. The product isolated from the culture broth was characterized by NMR and LC-MS and shown to be 7-Br-Trp.


SELF-INFLICTED LASER HANDHELD LASER-INDUCED MACULOPATHY: A NOVEL OCULAR MANIFESTATION OF FACTITIOUS DISORDER.
To report a case of factitious self-inflicted handheld laser-induced maculopathy. A 29-year-old man presented to our clinic complaining of a step-wise progressive loss of vision that abruptly began in his left eye but then became bilateral. He underwent comprehensive ocular examination, including visual acuity testing, biomicroscopic, dilated funduscopic examination, structural optical coherence tomography, en face structural optical coherence tomography, optical coherence tomography angiography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography. Visual acuity was 20/200 in both eyes. Although the multimodal imaging was highly consistent with handheld laser-induced maculopathy, the patient continued to deny this behavior. Self-inflicted handheld laser-induced maculopathy may be a novel manifestation of factitious disorder. Clinical suspicion for this should remain high in the presence of the signature multimodal retinal findings despite denial by the patient. This category of patients could benefit from psychiatric referral, to prevent further ocular or extra-ocular self-injury.


Can bifocals slow myopia progression?
Retrospective studies have suggested that in children with near point esophoria, bifocals can slow myopia progression by about 50 percent. A prospective study was conducted to test this hypothesis. Thirty-two children, all with near point esophoria, were randomly divided into either correction with single-vision or with bifocal lenses containing a +1.25 D and. Axial length and refraction were measured under cycloplegia every 6 months for 18 months. Twenty-eight children completed the study. Myopia progressed at an equal rate in both groups for the first 12 months. Progression was much faster during the first 6 months, which was during the school year, than during the second 6 months, which included all of the summer vacation (0.64 D/yr vs 0.29 D/yr). During the last 6 months, myopia progressed rapidly for children in single-vision lenses (0.80 D/yr) but slowly for those in bifocals (0.37 D/yr). A repeated-measure analysis of variance showed that season of the year had a significant effect on myopia progression (p > 0.002) and that the effect differed for the two treatment groups (p > 0.043). Over the whole 18-month study, myopia progressed at rate of 0.57 D/yr for those in single-vision lenses and 0.39 D/yr in those in bifocals (p = 0.26). Bifocals seemed to slow myopia progression in these children with near-point esophoria, although a longer-term study with more subjects is needed to confirm this finding. Myopia progressed more rapidly during the school year than during summer vacation.


[Cardio-oncology and cardio-obstetrics : crucial role of a multidisciplinary approach].
In this clinical case, we describe the cardio-oncological history and the complexity of the management of a patient presenting a breast cancer diasgnosed during pregnancy followed by a postpartum cardiomyopathy. A multidisciplinary approach is mandatory.


Stabilization of Prussian blue with polyaniline and carbon nanotubes in neutral media for in vivo determination of glucose in rat brains.
This study demonstrates a new electrochemical microbiosensor for selective in vivo monitoring of glucose in rat brains. The microbiosensor is prepared by using Prussian blue (PB)/polyaniline (PANI)/multi-walled carbon nanotubes (MWNTs) as the electrocatalyst for the reduction and determination of H2O2 generated from the glucose oxidase (GOx)-based enzymatic catalytic reaction. PANI and MWNTs are used to stabilize PB nanoparticles in physiological solutions. As a result, the as-formed three-dimensional (3D) PB/PANI/MWNT nanostructure exhibits a stable and large electrochemical response compared to the PB-modified electrode. The use of PB/PANI/MWNTs in this work to replace "natural peroxidase" (i.e., horseradish peroxidase) used in the existing microbiosensors enables the method developed here to be facile but selective for in vivo measurements of glucose virtually interference-free from ascorbic acid and other electroactive species coexisting in the brain. This property, along with the good linearity and stability toward glucose, makes this microbiosensor competent for continuous in vivo monitoring of the changes of glucose in rat brains during intraperitoneal injection of insulin. The method demonstrated here can be applied to develop other oxidase-based microbiosensors for other neurochemicals, which would be helpful for understanding the chemical process involved in some physiological and pathological events.


The decision-making process for unplanned admission to hospital unveiled in hospitalised older adults: a qualitative study.
The hazards of hospitalisation, and the growing demand for goal-oriented care and shared decision making, increasingly question whether hospitalisation always aligns with the preferences and needs of older adults. Although decision models are described comprehensively in the literature, little is understood about how the decision for hospitalisation is made in real life situations, especially under acute conditions. The aim of this qualitative study was to gain insight into how the decision to hospitalise was made from the perspective of the older patient who was unplanned admitted to hospital. Open interviews were conducted with 21 older hospitalised patients and/or their next of kin about the decision-making process leading to hospitalisation. Data were analysed according to the Constructivist Grounded Theory approach. Although a period of complaints preceded the decision to unplanned hospitalisation, ranging from hours to years, the decision to hospitalise was always taken acutely. In all cases, there was an acute moment in which the home as a care environment was no longer considered adequate. This conclusion was based on a combination of factors including factors related to complaints, general practitioner and home environment. Three parties were involved in this assessment: the patient, his next of kin and the general practitioner. At the same time, a very positive value was attributed towards the hospital. Depending on the assessment of the home as care environment by the various parties, there were four routes to hospitalisation: referral, shared, demanding and bypassing. For all participants, the decision to hospitalisation was taken acutely, even if the problems evoking admission were not acute, but present for a longer period. Participants saw admission as inevitable, due to the negative perceptions of the care environment at home at that moment, combined with the positive expectations of hospital care. Advance care planning, nor shared decision making were rarely seen in these interviews. An ethical dilemma occurred when the next of kin consented to hospitalisation against the wishes of the patient. More attention for participation of older adults in decision making and their goals is recommended.


Gene shuffling-generated and natural variants of the tomato resistance gene Cf-9 exhibit different auto-necrosis-inducing activities in Nicotiana species.
Tomato Cf genes encode membrane-bound proteins with extracellular leucine-rich repeats, and confer resistance to the fungal tomato pathogen Cladosporium fulvum, and a hypersensitive response (HR) to C. fulvum-derived race-specific elicitors. Several Cf genes, including Cf-4 and Cf-9, are members of the highly homologous Hcr9 (homologues of C. fulvumresistance gene Cf-9) gene family. Hcr9s evolve mainly by sequence exchange between paralogues, by which novel Cf genes may be generated. To mimic this aspect of natural evolution, we generated chimeras between multiple Hcr9s in vitro by gene shuffling. The shufflants were tested for novel specificities by transient expression in Nicotiana benthamiana. Many shufflants induced an HR in the absence of fungal elicitors and were designated auto-activators. We also identified two natural Hcr9 auto-activators in the wild tomato species Lycopersicon peruvianum, which induced an HR upon expression in N. benthamiana. The Hcr9 auto-activators exhibit different auto-necrosis-inducing specificities in five selected species of the Nicotiana genus, and they were shown to function in the same signalling pathway as Cf-9. Auto-activating alleles of nucleotide binding site-leucine-rich repeat genes and the protein kinase Pto were previously described. The auto-activators described here, belonging to the Cf-like structural class of resistance genes, shed light on this important phenotype and may be used as tools to unravel the mechanisms by which this class of resistance proteins function.


Introduction of cost display reduces laboratory test utilization.
To study the effects on the number of laboratory tests ordered after introduction of cost display (showing the cost in the computerized test ordering system at test ordering and test result delivery) and cost charge (requiring all primary healthcare centers to pay full laboratory costs of the ordered tests). The study included cost display for secondary healthcare centers (inpatient hospitals, emergency departments, and outpatient specialist providers) as well as publicly and privately operated primary healthcare centers (sites of nonemergency, nonspecialist healthcare). After 3 months, cost charge was introduced by management for all primary healthcare centers. Information on laboratory test cost was appended to the laboratory test name in the test ordering system, resulting in cost display both at the moment of test ordering and at the presentation of the test result. Numbers of laboratory tests were obtained from the laboratory information system and calculated as tests per physician visit. Cost charge was managed through the established laboratory invoicing system. In the publicly operated primary healthcare centers, neither of the interventions had any effect on laboratory test volume, nor did cost display have an effect in the privately operated primary healthcare centers. However, introduction of cost charge significantly decreased laboratory test ordering in the privately operated primary healthcare centers. In contrast, secondary healthcare centers lowered test volumes when cost display was introduced. The results support cost awareness and cost charge as means of reducing laboratory utilization. However, the outcome varies with the setting.