Baclofen inhibition of the hyperpolarization-activated cation current, Ih, in rat substantia nigra zona compacta neurons may be secondary to potassium current activation.
1. The properties of the hyperpolarization-activated cation current (Ih), and its modulation by gamma-aminobuturic acid-B (GABAB) receptor activation and protein kinase A, were investigated using whole cell voltage clamp of substantia nigra zona compacta principal neurons in rat midbrain slices in vitro. 2. At 30 degrees C, Ih activated between -75 and -155 mV, with a V1/2 of -115 mV. At 35 degrees C, the activation curve shifted positive by 10 mV. Ih had an estimated reversal potential of -27 mV. Ion substitution experiments showed that the current was carried by Na+ and K+. 3. Application of the GABAB receptor agonist baclofen (30 microM) induced an outward potassium current (GIRK), increased neuronal membrane conductance and inhibited Ih. The inhibition of Ih was voltage independent. Baclofen induced an 11-mV positive shift in the reversal potential of Ih. 4. Extracellular barium (300 microM) markedly reduced the baclofen-evoked outward current and associated increase in membrane conductance due to GIRK activation. There was also very little inhibition of Ih by baclofen in the presence of barium. When cesium was the major intracellular cation, both the increase in membrane conductance due to GIRK activation and the inhibition of Ih evoked by baclofen were reduced by a similar extent. 5. Neither forskolin (10 microM) nor the protein kinase A inhibitor, H89 (10 microM), had any effect on Ih or its inhibition by baclofen. 6. These data suggest that the inhibition of Ih by baclofen is secondary to the activation of GIRK, i.e., due directly to alteration of membrane conductance, rather than a distinct effect, and is not mediated by inhibition of adenylyl cyclase.


Anti-reflux mucosectomy for gastroesophageal reflux disease in the absence of hiatus hernia: a pilot study.
In our previous case report of circumferential mucosal resection for short-segment Barrett's esophagus with high-grade dysplasia, symptoms of gastro-esophageal reflux disease (GERD) were significantly improved. This observation suggests that anti-reflux mucosectomy (ARMS) could represent an effective anti-reflux procedure, with the advantage that no artificial devices or prostheses would be left in situ. In this pilot study, 10 patients with treatment-refractory GERD received ARMS, 2 of whom circumferential, and the remaining 8 crescentic. Key symptoms of GERD improved significantly after ARMS. In the DeMeester score, mean heartburn score decreased from 2.7 to 0.3 (P=0.0011), regurgitation score from 2.5 to 0.3 (P=0.0022), and total score from 5.2 to 0.67 (P=0.0011). At endoscopic examination, the flap valve grade decreased from 3.2 to 1.2 (P=0.0152). In 24-h esophageal pH monitoring the fraction of time at pH <4 improved from 29.1% to 3.1% (P=0.1). Fraction time absorbance more than >0.14 of bile reflux was controlled from 52% to 4% (P=0.05). In 2 cases of total circumferential resection, repeat balloon dilation was necessary to control stenosis. In all cases, proton pump inhibitor prescription could be discontinued with no ill effects. This initial case series demonstrated the potential anti-reflux effect of ARMS, with a crescentic mucosal resection appearing adequate. Further longitudinal study of patients without sliding hiatus hernia will be required to establish ARMS as an effective technique to control GERD in this setting.


Effects of differential selection in the sexes on cytonuclear polymorphism and disequilibria.
We develop a series of models that examine the effects of differential selection between the sexes on cytonuclear polymorphism and disequilibria. A detailed analysis is provided for populations under constant fertility or viability selection censused at life stages without frequency differences in the sexes. We show analytically that cytonuclear disequilibria can be generated de novo if the cytoplasmic and nuclear loci each affect female fitness and there is no nonmultiplicative fitness interaction between them. While computer simulations demonstrate that the majority of disequilibria produced by random selection are transient and small in magnitude, measurable permanent disequilibria can result from selective differences both within and between the two sexes. We derive analytic conditions for a protected cytonuclear polymorphism and use numerical simulations to quantitate the likelihood of obtaining permanent nuclear, cytoplasmic, and cytonuclear variation under various patterns of selection. The numerical analysis identifies special selection regimes more likely to generate disequilibria and maintain cytonuclear polymorphism and reveals a direct correlation to the strength of selection. As a byproduct, our models also provide the first decomposition of the different parental contributions to cytonuclear dynamics and the analytic conditions under which selection can cause cytoplasmic frequency changes or a cytonuclear hitchhiking effect.


Granulocyte Macrophage Colony Stimulating Factor Treatment is Associated with Improved Cognition in Cancer Patients.
BACKGROUND: Endogenous Granulocyte Macrophage Colony Stimulating Factor (GMCSF) is released in rheumatoid arthritis patients, who are largely protected from Alzheimer's disease (AD). Introducing exogenous GMCSF into an AD mouse model reduced amyloid deposition by 55% and restored normal cognition. No published studies have examined exogenous GMCSF and cognitive functioning in humans. OBJECTIVES/DESIGN: The goal of the current study was to examine the association between receipt of GMCSF and cognitive functioning in patients receiving colony stimulating factors as part of routine supportive care for hematopoietic cell transplantation (HCT). SETTING AND PARTICIPANTS: Archived neuropsychological data were examined from a longitudinal study of cognitive functioning in 95 patients receiving HCT at the Moffitt Cancer Center. INTERVENTION: Receipt of GMCSF and/or Granulocyte Colony Stimulating Factor (GCSF) was ascertained through patient billing records. MEASUREMENTS: Patients were assessed with a battery of neuropsychological tests prior to transplant and 6 and 12 months post-transplant. RESULTS: Patients treated with GMCSF and GCSF (n=19) showed significantly greater improvement in total neuropsychological functioning (TNP) at 6 months than patients treated with GCSF only (n=76) (p=.04). There was no group difference in TNP at 12 months (p=.24). Improvement in TNP from baseline to 6 months post-HCT was significant in the GMCSF+GCSF group (p=.01) but not the GCSF only group (p=.33). Improvement in TNP from baseline to 12 months post-HCT was significant in both groups (ps<.01). CONCLUSION: Preliminary data from this study of humans receiving colony stimulating factors suggest that receipt of GMCSF+GCSF was associated with greater cognitive improvement than GCSF alone. Randomized controlled trials of the effects of GMCSF on cognitive functioning in humans are warranted and underway to confirm these findings.


Aging and diabetes impair the neovascular potential of adipose-derived stromal cells.
Aging and diabetes are major risk factors for poor wound healing and tissue regeneration that reflect an impaired ability to respond to ischemic insults. The authors explored the intrinsic neovascular potential of adipose-derived stromal cells in the setting of advanced age and in type 1 and type 2 diabetes. Adipose-derived stromal cells isolated from young, aged, streptozotocin-induced, and db/db diabetic mice were exposed to normoxia and hypoxia in vitro. Vascular endothelial growth factor (VEGF) expression, proliferation, and tubulization were measured. Conditioned media harvested from adipose-derived stromal cell cultures were assessed for their ability to stimulate human umbilical vein endothelial cell proliferation (n = 3 and n = 3). Young adipose-derived stromal cells demonstrated significantly higher levels of VEGF production, proliferation, and tubulogenesis than those derived from aged, streptozotocin-induced, and db/db mice in both normoxia and hypoxia. Although aged and diabetic adipose-derived stromal cells retained the ability to up-regulate VEGF secretion, proliferation, and tubulogenesis in response to hypoxia, the response was blunted compared with young controls. Conditioned media derived from these cells cultured in normoxia in vitro also had a significantly greater ability to increase human umbilical vein endothelial cell proliferation compared with media harvested from aged, streptozotocin-induced, and db/db adipose-derived stromal cells. This effect was magnified in conditioned media harvested from hypoxic adipose-derived stromal cell cultures. This study demonstrates that aging and type 1 and type 2 diabetes impair intrinsic adipose-derived stromal cell function; however, these cells may still be a suitable source of angiogenic cells that can potentially improve neovascularization of ischemic tissues.


The warm-up effect protects against ischemic left ventricular dysfunction in patients with angina.
The goal of this study was to investigate whether the "warm-up" effect in angina protects against ischemic left ventricular (LV) dysfunction. After exercise, patients with coronary disease demonstrate persistent myocardial dysfunction, which may represent stunning, as well as warm-up protection against further angina, which may represent ischemic preconditioning. The effect of warm-up exercise on LV function during subsequent exercise has not been investigated. Thirty-two patients with multivessel coronary disease and preserved LV function performed two supine bicycle exercise tests 30 min apart. Equilibrium radionuclide angiography was performed before, during and up to 60 min after each test. Global LV ejection fraction and volume changes and regional ejection fraction for nine LV sectors were calculated for each acquisition. Onset of chest pain or 1 mm ST depression was delayed and occurred at a higher rate-pressure product during the second exercise test. Sectors whose regional ejection fraction fell during the first test showed persistent reduction at 15 min (68 +/- 20 vs. 73 +/- 20%, p < 0.0001). These sectors demonstrated increased function during the second test (71 +/- 20 vs. 63 +/- 20%, p = 0.0005). The reduction at 15 min and the increase during the second test were both in proportion to the reduction during the first test. Effects on global function were only apparent when the initial response to exercise was considered. The warm-up effect is accompanied by protection against ischemic regional LV dysfunction. The degree of stunning and protection after exercise is related to the severity of dysfunction during exercise, consistent with results from experimental models.


Cerebellar cognitive affective syndrome and autosomal recessive spastic ataxia of charlevoix-saguenay: a report of two male sibs.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by mutations in the SACS gene (13q12) encoding the protein sacsin. It is characterized by early-onset cerebellar ataxia, lower limb spasticity, sensorimotor axonal polyneuropathy, and atrophy of the superior cerebellar vermis. Cerebellar disorders in general may be accompanied by the cerebellar cognitive affective syndrome (CCAS) which presents with disturbances of executive functioning, spatial cognition, linguistic capacities, and affect. Two middle-aged brothers with ARSACS, one of whom was referred for behavioral disinhibition, are described. A detailed neuropsychiatric and neuropsychological assessment was performed. Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunctions were present; these were much more pronounced in the older sib. These observations add to the literature which suggests that the cerebellum, apart from its significance for motor behavior, plays a functional role in human cognition and affect. The nonmotor symptoms of ARSACS are discussed in terms of the CCAS.


Evaluation of schistosomicidal activity of myrrh extract: parasitological and histological study.
Ninety mice were divided into three main groups: G. I (non-infected control), G. II (infected non treated control) and G. III (infected treated), which was further subdivided into 4 subgroups: IIIA, IIIB, IIIC & IIID, where the drug was administered in a dose of 500 mg/kg body weight for five days before infection for subgroup IIIA, on the 1st day post infection (PI) for subgroup IIIB, 21 days PI for subgroup IIIC and 45 days post infection for subgroup IIID. All animals were sacrificed 80 days after the start of the experiment. Anti-schistosomal activity was assessed parasitologically by estimating the percentage reducetion of worm burden, egg count/gm tissues (liver & intestine), and the oogram pattern; histologically & histopathologically by examination of jejunum using different stains. The percentage reduction of worm burden was 30.35%, 64.54%, 76.92% and 98.46% respectively when compared to the infected non-treated control G. The maximum effect of the drug was observed in subgroups IIIC & IIID. Also, there was marked reduction in the egg count in tissues (liver & intestine). In addition the oogram pattern showed that myrrh had high antischistosomal activity. The histologically and histopathologically infected untreated (GII), when compared to non-infected non-treated control G. showed apparent shortening and flattening of the jejunal villi with focal loss of the epithelial covering. Loss of PAS positive brush border of many enterocytes with goblet cells hyperplasia was seen. Bilharzial granulomas were frequently encountered in the submucosa and the musculosa with numerous eosinophils content. In subgroups IIIA & IIIB, there was mild amelioration of the mucosal structural abnormalities. The granulomas were less frequently seen with decrease of their eosinophils. In subgroups IIIC & IIID there was restoration of the jejunal mucosal continuity, marked decrease in the granulomas and paucity of eosinophils. The present data proved that myrrh has a valuable schistosomicidal effect against different maturation stages of S. mansoni. The chemotherapeutic effect was more evident when the drug was given to the infected mice on the 21st as well as on the 45th day PI. The drug proved a promising chemoprophylactic agent when used five days before exposure to infection.


Surgical intervention in severe and complicated renal hypertension: Report of the Sydney Renal Hypertension Group (1969-75).
1. A prospective study was undertaken in seventy-eight patients with renal hypertension (fifty-eight with renovascular disease and twenty with renal parenchymal disease), after their presentation to an advisory group as possible candidates for surgical management. 2. Vascular repair and/or nephrectomy were performed in forty-four patients, and the remainder were treated with anti-hypertensive drugs. The control of blood pressure was then assessed over periods of 6-70 months. 3. Of the patients treated surgically, fifteen (34%) were normotensive without medication and fifteen had improved blood pressure control; the morbidity rate was the same as in the medically treated group, but mortality was lower and blood pressure control was better, particularly among patients under 40 years of age. 4. Surgery undertaken primarily to conserve renal function was beneficial in four of nine patients with bilateral renal artery stenosis and severe, progressive uraemia. 5. The blood pressure response to surgical correction of unilateral renal lesions was predicted correctly by the preoperative renal vein renin ratio in fifteen of eighteen cases.


Wind-Mediated Spread of Low-Pathogenic Avian Influenza Virus into the Environment during Outbreaks at Commercial Poultry Farms.
Avian influenza virus-infected poultry can release a large amount of virus-contaminated droppings that serve as sources of infection for susceptible birds. Much research so far has focused on virus spread within flocks. However, as fecal material or manure is a major constituent of airborne poultry dust, virus-contaminated particulate matter from infected flocks may be dispersed into the environment. We collected samples of suspended particulate matter, or the inhalable dust fraction, inside, upwind and downwind of buildings holding poultry infected with low-pathogenic avian influenza virus, and tested them for the presence of endotoxins and influenza virus to characterize the potential impact of airborne influenza virus transmission during outbreaks at commercial poultry farms. Influenza viruses were detected by RT-PCR in filter-rinse fluids collected up to 60 meters downwind from the barns, but virus isolation did not yield any isolates. Viral loads in the air samples were low and beyond the limit of RT-PCR quantification except for one in-barn measurement showing a virus concentration of 8.48 x 10(4) genome copies/m(3). Air samples taken outside poultry barns had endotoxin concentrations of ~50 EU/m(3) that declined with increasing distance from the barn. Atmospheric dispersion modeling of particulate matter, using location-specific meteorological data for the sampling days, demonstrated a positive correlation between endotoxin measurements and modeled particulate matter concentrations, with an R(2) varying from 0.59 to 0.88. Our data suggest that areas at high risk for human or animal exposure to airborne influenza viruses can be modeled during an outbreak to allow directed interventions following targeted surveillance.


Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection.
Recurrent hepatitis C virus (HCV) infection is a major cause of morbidity and mortality after liver transplantation for HCV-related end stage liver disease. Although previous studies have shown a short-term effect of interferon-based treatment on fibrosis progression, it is unclear whether this translates to improved graft survival. We evaluated whether treatment of recurrent HCV leads to an improved graft survival. Cohort study included consecutive HCV patients who underwent liver transplantation between 1 January 1995 and 1 January 2005 in the Mayo Clinic, Rochester, MN. Two hundred and fifteen patients were included in the study. During a median follow-up of 4.4 years (interquartile range 2.2-6.6), 165 patients (77%) had biopsy-proven recurrent HCV infection confirmed by serum HCV RNA testing. Seventy-eight patients were treated. There were no differences in MELD-score, fibrosis stage or time towards HCV recurrence between treated and untreated patients at time of recurrence. There was a trend for greater frequency of acute cellular rejection among untreated patients. The incidence of graft failure was lower for patients treated within 6 months of recurrence compared to patients not treated within this time-period (log rank p = 0.002). Time-dependent multivariate Cox regression analysis showed that treatment of recurrent HCV infection was statistically significantly associated with a decreased risk of overall graft failure (hazard ratio 0.34; CI 0.15-0.77, p = 0.009) and a decreased risk of graft failure due to recurrent HCV (hazard ratio 0.24; CI 0.08-0.69, p = 0.008). In conclusion, although a cause and effect relationship cannot be established, treatment of recurrent HCV infection after liver transplantation is associated with a reduced risk of graft failure.


Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease.
A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not associated with PD. However, more than 20 years exposure to manganese (Odds Ratio [OR] = 10.61, 95% Confidence Interval [CI] = 1.06, 105.83) or copper (OR = 2.49, 95% CI = 1.06,5.89) was associated with PD. Occupational exposure for > 20 years to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07,7.50), and iron-copper (OR = 3.69, 95% CI = 1.40,9.71) was also associated with the disease. No association of occupational exposure to iron, mercury or zinc with PD was found. A lack of statistical power precluded analyses of metal combinations for those with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings suggest that chronic occupational exposure to manganese or copper, individually, or to dual combinations of lead, iron and copper, is associated with PD.


[Electrophysiologic arousal reactions during sufentanil-/isoflurane anesthesia].
There is controversy about relevant EEG signal changes indicating adequate or inadequate anaesthesia. Differences of drug-induced and nociceptive mediated signal changes have not been studied in detail. The present study investigates whether signal changes during decreases of depth of anaesthesia due to surgical stimulation depend on different isoflurane concentrations during sufentanil anaesthesia. Following IRB approval and written informed consent 28 patients (ASA: I; age 43 +/- 11 y) scheduled for elective abdominal surgery were included in the study. Anaesthesia: propofol (2.0 mg/kg) and sufentanil (1.0 micrograms/kg). Following endotracheal intubation (vecuronium 0.1 mg/kg) patients were normoventilated (P(ET)CO2: 36-38 mmHg). Randomly assigned to steady-state anaesthesia (group 1: P(ET)Isoflurane 0.2%, (14n); group 2: P(ET)Isoflurane 0.6%, (14n) during the start of surgery. Monitoring: heart rate (HF), mean arterial blood pressure (MAP), P(ET)CO2, arterial oxygen saturation and rectal temperature. EEG (16 channels referenced to Cz; CATEEM, Medisyst, Linden) recorded 5 min before until 10 min after the start of surgery. EEG-analysis (FFT: 4s, 256/s, 0.45-35.0 Hz): topographical distribution of power spectral densities (delta, theta, alpha 1, and alpha 2). Artifact control: ECG and EOG. Surgical stimulation resulted in increases of MAP in both groups (p < 0.05 vs BL), whereas HR was only slightly affected in group 2 when compared with BL. Other variables except of EEG data did not change over time. In group 1 (0.2% isoflurane) surgical stimulation resulted in decreases of delta over the whole cortex (F2, C3, P3, O1) and in marked increases of alpha predominantly at central leads (C3)(p < 0.05 vs BL). In group 2 (0.6% isoflurane) nociceptive stimulation was associated with decreases of faster waves (alpha: F3)(p < 0.05 vs BL) and increases in delta at fronto-central areas (F3, C3)(p < 0.05 vs BL). EEG recordings are useful in assessing pharmacodynamic drug effects. In contrast, intraoperative EEG recordings have a low correlation to clinical signs of changes in the anaesthetic state. Previous studies demonstrate paradoxical EEG-arousal reactions during isoflurane anaesthesia. The present data suggest that classical or even paradoxical EEG arousal due to nociceptive stimulation may depend on the isoflurane concentration. It seems reasonable that the ascending reticular formation is functionally blocked by isoflurane in a dose-dependent manner.


Momentum space design of high-Q photonic crystal optical cavities.
The design of high quality factor (Q) optical cavities in two dimensional photonic crystal (PC) slab waveguides based upon a momentum space picture is presented. The results of a symmetry analysis of defect modes in hexagonal and square host photonic lattices are used to determine cavity geometries that produce modes which by their very symmetry reduce the vertical radiation loss from the PC slab. Further improvements in the Q are achieved through tailoring of the defect geometry in Fourier space to limit coupling between the dominant momentum components of a given defect mode and those momentum components which are either not reflected by the PC mirror or which lie within the radiation cone of the cladding surrounding the PC slab. Numerical investigations using the finite-difference time-domain (FDTD) method predict that radiation losses can be significantly suppressed through these methods, culminating with a graded square lattice design whose total Q approaches 10;5 with a mode volume of approximately 0.25 cubic half-wavelengths in vacuum.


Pseudodeficiency of glutamine in infant liver disease.
Gamma-glutamyltransferase (gamma-GT) is an early marker for cholestasis and has the capability of glutamine-deamidation. Two infants with elevated serum gamma-GT had a decreased serum glutamine. A time course of glutamine and glutamate concentration changes was performed. This revealed a time dependent decrease of glutamine far below the normal lower limit while glutamate increased above the normal upper limit. In conclusion, increased in vitro gamma-GT can cause pseudodeficiency of glutamine. To avoid pitfalls, physicians should inform the laboratory on accompanying pathologies.


Cationic porphyrins promote the formation of i-motif DNA and bind peripherally by a nonintercalative mechanism.
Telomeric C-rich strands can form a noncanonical intercalated DNA structure known as an i-motif. We have studied the interactions of the cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphine (TMPyP4) with the i-motif forms of several oligonucleotides containing telomeric sequences. TMPyP4 was found to promote the formation of the i-motif DNA structure. On the basis of (1)H NMR studies, we have created a model of the i-motif-TMPyP4 complex that is consistent with all the available experimental data. Two-dimensional NOESY data prompted us to conclude that TMPyP4 binds specifically to the edge of the intercalated DNA core by a nonintercalative mechanism. Since we have shown that TMPyP4 binds to and stabilizes the G-quadruplex form of the complementary G-rich telomeric strand, this study raises the intriguing possibility that TMPyP4 can trigger the formation of unusual DNA structures in both strands of the telomeres, which may in turn explain the recently documented biological effects of TMPyP4 in cancer cells.


Synthesis and evaluation of novel α-fluorinated (E)-3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyl oxime (ABP688) derivatives as metabotropic glutamate receptor subtype 5 PET radiotracers.
In the search for an optimal fluorine-18-labeled positron emission tomography (PET) radiotracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5), we have prepared a series of five α-fluorinated derivatives based on the ABP688 structural manifold by application of a two-step enolization/NFSI α-fluorination method. Their binding affinities were evaluated in vitro, and the most promising candidate (Z)-16 exhibited a K(i) of 5.7 nM and a clogP value of 2.3. The synthesis of the precursor tosylate (E)-22 revealed a preference for the (E)-configurational isomer (K(i) = 31.2 nM), and successful radiosynthesis afforded (E)-[(18)F]-16 which was used as a model PET tracer to establish plasma and PBS stability. (E)-[(18)F]-16 (K(d) = 70 nM) exhibited excellent specificity for mGluR5 in autoradiographic studies on horizontal rat brain slices in vitro.


Effect of two durations of short-term intermittent hypoxia on ventilatory chemosensitivity in humans.
The purpose of this study was to clarify the influence of duration of intermittent hypoxia per day on ventilatory chemosensitivity. Subjects were assigned to three different groups according to the duration of exposure to intermittent hypoxia (12.3 +/- 0.2% O(2)): a first group (H-1, n = 6) was exposed to hypoxia for 1 h per day, the second group (H-2, n = 6) was exposed for 3 h per day, and the third (C, n = 7) was used as control. Hypoxic and hypercapnic ventilatory responses (HVR and HCVR) were determined before and after 1 week of intermittent hypoxia. HVR was increased significantly (P < 0.05) after intermittent hypoxia in both the H-1 and H-2 groups. However, there was no significant difference in magnitude of increased HVR between H-1 and H-2 groups. HCVR did not show any changes in all groups after intermittent hypoxia. These results suggest that 1 h of daily exposure is as equally effective as 3 h of daily exposure to severe hypoxia for a short period for enhancing ventilatory chemosensitivity to hypoxia.


Antenatal thyroid hormone therapy and antithyroid drug use in Norway from 2004 to 2018.
Thyroid disease during pregnancy is associated with adverse pregnancy outcomes and suboptimal fetal development. During the last decades, guidelines for diagnosing thyroid disease during pregnancy have changed considerably and there has been increased awareness. This study aimed to describe the prevalence of thyroid disease treatment over time among pregnant women in Norway. Nationwide register-based study. We combined historical data from the Medical Birth Registry of Norway and the Norwegian Prescription Database, identifying pregnant women using thyroid therapy from 2004 to 2018. A total of 855,067 pregnancies were included in the analyses. The proportion of women using thyroid hormone replacement therapy during pregnancy increased from 1.46% (n = 800) in 2004 to 3.57% (n = 1940) in 2018. The proportion of women using antithyroid medications also increased from 0.04% (n = 20) in 2004 to 0.10% (n = 56). During these 15 years, the mean maternal age increased by 0.9 years. When adjusting for age, the risk for being on thyroid hormone replacement therapy during pregnancy increased by an average of 5% per year (odds ratio: 1.05, 95% CI: 1.05-1.05). During the recent 15 years, there has been a substantial increase in the use of thyroid hormone therapy in Norwegian pregnant women. We speculate that this could be due to an increased awareness in combination with overdiagnosis because of inappropriate diagnostic criteria. To truly understand the possible causes and consequences of this development, further research is warranted.


Review and standard operating procedures for collection of biospecimens and analysis of biomarkers in new onset refractory status epilepticus.
New onset refractory status epilepticus (NORSE), including its subtype with a preceding febrile illness known as febrile infection-related epilepsy syndrome (FIRES), is one of the most severe forms of status epilepticus. The exact causes of NORSE are currently unknown, and there is so far no disease-specific therapy. Identifying the underlying pathophysiology and discovering specific biomarkers, whether immunologic, infectious, genetic, or other, may help physicians in the management of patients with NORSE. A broad spectrum of biomarkers has been proposed for status epilepticus patients, some of which were evaluated for patients with NORSE. Nonetheless, none has been validated, due to significant variabilities in study cohorts, collected biospecimens, applied analytical methods, and defined outcome endpoints, and to small sample sizes. The NORSE Institute established an open NORSE/FIRES biorepository for health-related data and biological samples allowing the collection of biospecimens worldwide, promoting multicenter research and sharing of data and specimens. Here, we suggest standard operating procedures for biospecimen collection and biobanking in this rare condition. We also propose criteria for the appropriate use of previously collected biospecimens. We predict that the widespread use of standardized procedures will reduce heterogeneity, facilitate the future identification of validated biomarkers for NORSE, and provide a better understanding of the pathophysiology and best clinical management for these patients.


Functional Hemispheric (A)symmetries in the Aged Brain-Relevance for Working Memory.
Functional hemispheric asymmetries have been described in different cognitive processes, such as decision-making and motivation. Variations in the pattern of left/right activity have been associated with normal brain functioning, and with neuropsychiatric diseases. Such asymmetries in brain activity evolve throughout life and are thought to decrease with aging, but clear associations with cognitive function have never been established. Herein, we assessed functional laterality during a working memory task (N-Back) in a healthy aging cohort (over 50 years old) and associated these asymmetries with performance in the test. Activity of lobule VI of the cerebellar hemisphere and angular gyrus was found to be lateralized to the right hemisphere, while the precentral gyrus presented left > right activation during this task. Interestingly, 1-Back accuracy was positively correlated with left > right superior parietal lobule activation, which was mostly due to the influence of the left hemisphere. In conclusion, although regions were mostly symmetrically activated during the N-Back task, performance in working memory in aged individuals seems to benefit from lateralized involvement of the superior parietal lobule.


Postural stability using different neck positions in normal subjects and patients with neck trauma.
Subjects with neck problems, such as whiplash injuries, often complain of disturbed equilibrium and, in some instances, provocation of the neck position can elicit such problems. The importance of neck proprioceptors for maintaining balance is gaining increased interest, moreover the function or malfunction of the otoliths may disturb equilibrium in certain head positions. The aim of the study was to create a reference material for postural control and its dependence on head position in healthy subjects and to compare this with a set of patients with known neck problems and associated vertiginous problems. A total of 32 healthy subjects (16 men, 16 women, age range 21-58 years) as well as 10 patients age range 27-62 years (mean 44 years) with neck problems and associated balance problems since a whiplash injury were tested for postural control using the EquiTest dynamic posturographic model. The normal subjects were initially split into four age groups in order to estimate the effects of age on performance. The postural stability was evaluated for dependence of support surface conditions (stable or sway-referenced), visual input (eyes open or closed) and head position (neutral, left rotated, right rotated, extended backwards or flexed forward) using analysis of variance (ANOVA) with Tukey's post hoc test in case of a significant factor effect. As expected, visual cues as well as stable support surface improve postural stability (p < 0.001). Postural stability is statistically different in the head extended backwards condition compared with the other four head positions (p < 0.001 in all cases) in both patients and controls. Eliminating this test condition from the analysis, only a slight (p < 0.05) difference between head forwards and head turned left remained. This pattern of results remained if the normal subjects were only split into two age groups instead of four. Finally, the patient group exhibited significantly lower postural performance than all the groups of normal subjects (p <0.01), but none of the normal groups differed significantly from each other. It is concluded that the postural control system is significantly challenged in the head extended backwards condition in both normal subjects and patients with previous whiplash injury and persistent neck problems. The patient group differed statistically from all groups of normal subjects. This suggests that neck problems impair postural control, and that the head extended position is a more challenging task for the postural system to adapt to. Whether this is due to utricular malpositioning, central integrative functions or cervical proprioceptive afferents is not within the scope of this study to answer.


Polymorphism of FtsZ filaments on lipid surfaces: role of monomer orientation.
FtsZ is a bacterial cytoskeletal protein involved in cell division. It forms a ringlike structure that attaches to the membrane to complete bacterial division. It binds and hydrolyzes GTP, assembling into polymers in a GTP-dependent manner. To test how the orientation of the monomers affects the curvature of the filaments on a surface, we performed site-directed mutagenesis on the E. coli FtsZ protein to insert cysteine residues at lateral locations to orient FtsZ on planar lipid bilayers. The E93C and S255C mutants were overproduced, purified, and found to be functionally active in solution, as well as being capable of sustaining cell division in vivo in complementation assays. Atomic force microscopy was used to observe the shape of the filament fibers formed on the surface. The FtsZ mutants were covalently linked to the lipids and could be polymerized on the bilayer surface in the presence of GTP. Unexpectedly, both mutants assembled into straight structures. E93C formed a well-defined lattice with monomers interacting at 60° and 120° angles, whereas S255C formed a more open array of straight thicker filament aggregates. These results indicate that filament curvature and bending are not fixed and that they can be modulated by the orientation of the monomers with respect to the membrane surface. As filament curvature has been associated with the force generation mechanism, these results point to a possible role of filament membrane attachment in lateral association and curvature, elements currently identified as relevant for force generation.


[Daily eating habits of obese women living in Rocinha Shanytown (Rio de Janeiro, RJ, Brazil)].
This article presents conclusions of research conducted at Ensp/Fiocruz, as part of a master's degree course. One of the objectives of the research to investigate the eating habits of women living in the Rocinha Shantytown (Rio de Janeiro, RJ, Brazil) from a socio-anthropological perspective. The results revealed that the eating habits of the group were repetitive, with few variations in the menu consisting basically of rice, bean, sugars and fats. We further observed the rejection of industrialized and canned products. This food consumption pattern seems to conform to Brazilian food culture revealing the preservation of the national identity based on feeding habits. Consequently, it is necessary to set aside presuppositions regarding the relationship between food consumption and obesity, especially with respect to the predominant idea of changes in diet with the incorporation of a "modern" or "western" diet that prevail in studies in the field of nutrition in Brazil. In this sense, we signaled the need to reassert a multidimensional approach for studies about food and nutrition in the country. This proposal involves overcoming restricted conceptual outlooks and the creation of new avenues of investigation.


On the structural stability of guanosine-based supramolecular hydrogels.
Supramolecular hydrogels formed from the self-assembly of low molecular weight derivatives are very attractive systems, because of their potential applications in nano- and bio-technology. In this paper, the stable and transparent hydrogels observed in binary mixtures of guanosine derivatives (G), namely guanosine 5'-monophosphate (GMP) and guanosine (Gua), dissolved in water (at volume fractions larger than 0.95), were investigated by microscopy techniques and Small Angle X-ray Scattering (SAXS). The results confirm the presence of G-quadruplexes, chiral cylindrical rods obtained by the regular stacking of self-assembled planar cyclic guanosine quartets. However, the addition of Gua determines the formation of very stable hydrogels able to trap large amounts of water (up to a volume fraction of 0.99) and characterised by an unusual anisotropic order. A modified lateral helix-to-helix interaction pattern, tuned by Gua, is suggested to be responsible for the supramolecular gelation and the stability of the hydrogels during swelling.


Transgene expression in the guinea pig cochlea mediated by a lentivirus-derived gene transfer vector.
The utility of lentivirus as a gene delivery vector in the cochlea was evaluated in vitro and in vivo. Lentivirus transduction was assessed through expression analysis of a reporter gene, green fluorescent protein (GFP), integrated within the viral genome. In vitro characterization of lentivirus-GFP was assessed by infection of explants from cochleas of neonatal rat. The lentiviral vector transduced both spiral ganglion neurons (SGNs) and glial cells. In vivo characterization of lentivirus-GFP was assessed by directly infusing the vector into the guinea pig cochlea via an osmotic minipump. Sections of lentivirus-infused cochlea revealed a highly restricted fluorescence pattern limited to the periphery of the perilymphatic space. Transduction of SGNs and glial cells by lentivirus in vitro but not in vivo suggests limited dissemination of the viral vector from the perilymphatic space. The cellular and tissue architecture of the lentivirus-infused cochlea was intact and free of inflammation. Restricted transduction of cell types confined to the periphery of the perilymphatic space by the lentivirus is ideal for stable production of gene products secreted into the perilymph.


Acceptance of Antidepressant Treatment by Patients on Hemodialysis and Their Renal Providers.
Depression is common in patients receiving chronic hemodialysis but seems to be ineffectively treated. We investigated the acceptance of antidepressant treatment by patients on chronic hemodialysis and their renal providers. As part of a clinical trial of symptom management in patients on chronic hemodialysis conducted from 2009 to 2011, we assessed depression monthly using the Patient Health Questionnaire 9. For depressed patients (Patient Health Questionnaire 9 score ≥10), trained nurses generated treatment recommendations and helped implement therapy if patients and providers accepted the recommendations. We assessed patients' acceptance of recommendations, reasons for refusal, and provider willingness to implement antidepressant therapy. We analyzed data at the level of the monthly assessment. Of 101 patients followed for ≤12 months, 39 met criteria for depression (Patient Health Questionnaire 9 score ≥10 on one or more assessments). These 39 patients had depression on 147 of 373 (39%) monthly assessments. At 103 of these 147 (70%) assessments, patients were receiving antidepressant therapy, and at 51 of 70 (70%) assessments, patients did not accept nurses' recommendations to intensify treatment. At 44 assessments, patients with depression were not receiving antidepressant therapy, and in 40 (91%) instances, they did not accept recommendations to start treatment. The primary reason that patients refused the recommendations was attribution of their depression to an acute event, chronic illness, or dialysis (57%). In 11 of 18 (61%) instances in which patients accepted the recommendation, renal providers were unwilling to provide treatment. Patients on chronic hemodialysis with depression are frequently not interested in modifying or initiating antidepressant treatment, commonly attributing their depression to a recent acute event, chronic illness, or dialysis. Renal providers are often unwilling to modify or initiate antidepressant therapy. Future efforts to improve depression management will need to address these patient- and provider-level obstacles to providing such care.


Evaluation of the effect of comorbidity on survival in pancreatic cancer by using "Charlson Comorbidity Index" and "Cumulative Illness Rating Scale".
Effect of comorbidity on the treatments that patients receive is not clear, as healthy elderly patients and the elderly with less comorbid diseases are included in the studies. In the present study, the effect of comorbidity on the survival was evaluated using Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS). The general features and comorbid diseases of the pancreatic cancer patients were retrospectively screened from the patient files using the automated system. CCI and CIRS were used as the comorbidity indices. A total of 106 patients with pancreatic cancer were included in the study. The median overall survival rate was 9.0 [95 % confidence interval (CI): 6.7-11.3] months. The median overall survival rate was found as 9.4 (95 % CI: 6.7-12.1) months in the patients whose CCI score was ≤ 2 and was found as 6.2 (95 % CI: 4.0-8.3) months in the patients with CCI scores ≥ 3 (p = 0.05). The median overall survival rate was calculated as 9.8 (95 % CI: 6.3-13.4) months in the patients with CIRS scores ≤ 2 and was calculated as 8.3 (95 % CI: 6.0-10.6) months in the patients with CIRS scores ≥ 3 (p = 0.51). When surgery, radiotherapy, grading, and CCI score were evaluated using multivariate analysis, it was observed that only the treatment modality had a significant effect on the survival rate. The results on the use of comorbidity indices are contradictory for the cancers with lower survival rates such as pancreatic cancer. New prognostic scales might be developed for this patient group by considering the side effects of chemotherapy.


Interleukin-35 promotes early endothelialization after stent implantation by regulating macrophage activation.
Background: Early strut coverage after sirolimus-eluting stent (SES) implantation is associated with the activation of inflammation, but the underlying mechanisms are not completely understood. The present study aimed to identify the relationship between the anti-inflammatory cytokine interleukin (IL) 35 (IL-35) and early strut coverage in vivo and in vitroMethods: We utilized a retrospective study design to measure IL-35 levels in 68 stents from 68 patients with coronary artery disease and recorded serial optical coherence tomography (OCT) images (0 and 3 months) to assess stent endothelialization. The mechanism underlying the regulatory effects of IL-35 on macrophages and human umbilical vein endothelial cells (HUVECs) was also investigated. SESs were surgically implanted into the right common carotid arteries of 200 male New Zealand White rabbits receiving intravenous injections of IL-35 or a placebo.Results: At the 3-month OCT evaluation, complete endothelium coverage was correlated with IL-35 levels. IL-35 induced the activation of an anti-inflammatory M2-like macrophage phenotype by targeting the signal transducer and activators of transcription (STAT)1/4 signalling pathway, and IL-35-treated macrophages induced endothelial proliferation and alleviated endothelial dysfunction. IL-35-treated New Zealand White rabbits with implanted SESs showed lower percentages of cross-sections with an uncovered strut, elevated mean neointimal hyperplasia (NIH) thickness, and inhibited inflammatory responses.Conclusions: We investigated the effect of IL-35 expression on early stent endothelialization in vivo and in vitro and identified a crucial role for IL-35 in inducing the activation of an anti-inflammatory M2-like macrophage phenotype. The present study highlights a new therapeutic strategy for early stent endothelialization.


Effects of omalizumab therapy on allergic rhinitis: a pilot study.
The use of omalizumab, a humanized monoclonal antibody able to binding Ig-E, is currently authorized only for treatment of severe bronchial asthma. The use of omalizumab in other Ig-E related diseases is off-label, although some studies have provided promising results about it. The aim of this study was to evaluate if therapy with omalizumab in patients affected by asthma and allergic rhinitis has an impact also on allergic rhinitis-related symptoms. A longitudinal study was conducted on 11 patients affected by severe asthma and a periodic allergic rhinitis. Patients were treated with omalizumab for 24 weeks with a monthly subcutaneous administration at the dosage recommended by the current guidelines. We observed at the start and at the end of treatment: rhinitis symptoms using the Visual Analogue Scale (VAS); the state of nasal mucosa with fiberoptic nasal endoscopy; airways inflammation by measuring the Fractional Exhaled Nitric Oxide (FeNO); asthmatic symptomatology by means of the Asthma Control Test; the amount of total Ig-E in a blood sample; and the use of symptomatic drugs before and after treatment. VAS scores to measure general symptomatology and symptoms including nasal obstruction, rhinorrhea, itching and sneezing were significantly reduced. Turbinate hypertrophy was resolved in six of nine patients. Furthermore, eight patients (73%) reduced or eliminated the use of symptomatic drugs. Our data confirm the efficacy of omalizumab in the treatment of allergic rhinitis. Controlled studies will now have to be carried out to confirm these preliminary data and will specify indications for a very efficacious but still significantly expensive therapy.


The pgip family in soybean and three other legume species: evidence for a birth-and-death model of evolution.
Polygalacturonase-inhibiting proteins (PGIPs) are leucine-rich repeat (LRR) plant cell wall glycoproteins involved in plant immunity. They are typically encoded by gene families with a small number of gene copies whose evolutionary origin has been poorly investigated. Here we report the complete characterization of the full complement of the pgip family in soybean (Glycine max [L.] Merr.) and the characterization of the genomic region surrounding the pgip family in four legume species. BAC clone and genome sequence analyses showed that the soybean genome contains two pgip loci. Each locus is composed of three clustered genes that are induced following infection with the fungal pathogen Sclerotinia sclerotiorum (Lib.) de Bary, and remnant sequences of pgip genes. The analyzed homeologous soybean genomic regions (about 126 Kb) that include the pgip loci are strongly conserved and this conservation extends also to the genomes of the legume species Phaseolus vulgaris L., Medicago truncatula Gaertn. and Cicer arietinum L., each containing a single pgip locus. Maximum likelihood-based gene trees suggest that the genes within the pgip clusters have independently undergone tandem duplication in each species. The paleopolyploid soybean genome contains two pgip loci comprised in large and highly conserved duplicated regions, which are also conserved in bean, M. truncatula and C. arietinum. The genomic features of these legume pgip families suggest that the forces driving the evolution of pgip genes follow the birth-and-death model, similar to that proposed for the evolution of resistance (R) genes of NBS-LRR-type.


Cellular membranes and lipid-binding domains as attractive targets for drug development.
Interdisciplinary research focused on biological membranes has revealed them as signaling and trafficking platforms for processes fundamental to life. Biomembranes harbor receptors, ion channels, lipid domains, lipid signals, and scaffolding complexes, which function to maintain cellular growth, metabolism, and homeostasis. Moreover, abnormalities in lipid metabolism attributed to genetic changes among other causes are often associated with diseases such as cancer, arthritis and diabetes. Thus, there is a need to comprehensively understand molecular events occurring within and on membranes as a means of grasping disease etiology and identifying viable targets for drug development. A rapidly expanding field in the last decade has centered on understanding membrane recruitment of peripheral proteins. This class of proteins reversibly interacts with specific lipids in a spatial and temporal fashion in crucial biological processes. Typically, recruitment of peripheral proteins to the different cellular sites is mediated by one or more modular lipid-binding domains through specific lipid recognition. Structural, computational, and experimental studies of these lipid-binding domains have demonstrated how they specifically recognize their cognate lipids and achieve subcellular localization. However, the mechanisms by which these modular domains and their host proteins are recruited to and interact with various cell membranes often vary drastically due to differences in lipid affinity, specificity, penetration as well as protein-protein and intramolecular interactions. As there is still a paucity of predictive data for peripheral protein function, these enzymes are often rigorously studied to characterize their lipid-dependent properties. This review summarizes recent progress in our understanding of how peripheral proteins are recruited to biomembranes and highlights avenues to exploit in drug development targeted at cellular membranes and/or lipid-binding proteins.


Peripheral nerve stimulation in the treatment of intractable pain.
Peripheral nerve stimulating devices were implanted for pain control in 33 patients with a variety of disabling chronic pain conditions, which had persisted despite usual medical and surgical therapy. The implants were placed on major nerves innervating the area of the patient's pain. Records were obtained of each patient's stated relief from pain produced by nerve stimulation, along with assessments of narcotic withdrawal, ability to return to work, sleep pattern, and relief from depression. Based on these five criteria 17 patients were judged to be treatment failures, while eight patients had excellent results, and seven had intermediate results. Twelve of the failures were in patients with either low back pain with sciatica, or pain from metastatic disease. The most dramatic successes occurred in patients with peripheral nerve trauma. The incidence of complications has been low, and two patients have used the stimulator for 5 years without adverse effects. Techniques of peripheral stimulator implantation, possible mechanisms of action, and conclusions regarding peripheral nerve stimulation in the treatment of chronic pain are discussed.


Nonnative forest insects and pathogens in the United States: Impacts and policy options.
We review and synthesize information on invasions of nonnative forest insects and diseases in the United States, including their ecological and economic impacts, pathways of arrival, distribution within the United States, and policy options for reducing future invasions. Nonnative insects have accumulated in United States forests at a rate of ~2.5 per yr over the last 150 yr. Currently the two major pathways of introduction are importation of live plants and wood packing material such as pallets and crates. Introduced insects and diseases occur in forests and cities throughout the United States, and the problem is particularly severe in the Northeast and Upper Midwest. Nonnative forest pests are the only disturbance agent that has effectively eliminated entire tree species or genera from United States forests within decades. The resulting shift in forest structure and species composition alters ecosystem functions such as productivity, nutrient cycling, and wildlife habitat. In urban and suburban areas, loss of trees from streets, yards, and parks affects aesthetics, property values, shading, stormwater runoff, and human health. The economic damage from nonnative pests is not yet fully known, but is likely in the billions of dollars per year, with the majority of this economic burden borne by municipalities and residential property owners. Current policies for preventing introductions are having positive effects but are insufficient to reduce the influx of pests in the face of burgeoning global trade. Options are available to strengthen the defenses against pest arrival and establishment, including measures taken in the exporting country prior to shipment, measures to ensure clean shipments of plants and wood products, inspections at ports of entry, and post-entry measures such as quarantines, surveillance, and eradication programs. Improved data collection procedures for inspections, greater data accessibility, and better reporting would support better evaluation of policy effectiveness. Lack of additional action places the nation, local municipalities, and property owners at high risk of further damaging and costly invasions. Adopting stronger policies to reduce establishments of new forest insects and diseases would shift the major costs of control to the source and alleviate the economic burden now borne by homeowners and municipalities.


[Development of the Japanese version of the Thought Control Ability Questionnaire and evaluation of its reliability and validity].
Intrusive thoughts and difficulty in controlling thoughts are common, not only for people with psychological disorders, but also for healthy people. Individual differences in thought control ability may underlie such problems. The Thought Control Ability Questionnaire (TCAQ), which consists of 25 items, was developed by Luciano et al. (2005) in order to measure individual differences in the perceived ability to control unwanted intrusive thoughts. The purpose of the present study was to develop the Japanese version of the TCAQ and evaluate its reliability and validity. We translated the English version of the TCAQ into Japanese. We also conducted confirmatory factor analysis with a one factor solution, similar to the previous study. Based on the analysis, we excluded items whose factor loadings were lower than .30, resulting in 22 items for the Japanese version of the TCAQ. The model exhibited acceptable goodness-of-fit. The Japanese version of the TCAQ also demonstrated good reliability as well as evidence of construct validity. Thus, the development of the Japanese version of the TCAQ was successful.


Development of a cancer pain self-management resource to address patient, provider, and health system barriers to care.
The majority of self-management interventions are designed with a narrow focus on patient skills and fail to consider their potential as "catalysts" for improving care delivery. A project was undertaken to develop a patient self-management resource to support evidence-based, person-centered care for cancer pain and overcome barriers at the levels of the patient, provider, and health system. The project used a mixed-method design with concurrent triangulation, including the following: a national online survey of current practice; two systematic reviews of cancer pain needs and education; a desktop review of online patient pain diaries and other related resources; consultation with stakeholders; and interviews with patients regarding acceptability and usefulness of a draft resource. Findings suggested that an optimal self-management resource should encourage pain reporting, build patients' sense of control, and support communication with providers and coordination between services. Each of these characteristics was identified as important in overcoming established barriers to cancer pain care. A pain self-management resource was developed to include: (1) a template for setting specific, measureable, achievable, relevant and time-bound goals of care, as well as identifying potential obstacles and ways to overcome these; and (2) a pain management plan detailing exacerbating and alleviating factors, current strategies for management, and contacts for support. Self-management resources have the potential for addressing barriers not only at the patient level, but also at provider and health system levels. A cluster randomized controlled trial is under way to test effectiveness of the resource designed in this project in combination with pain screening, audit and feedback, and provider education. More research of this kind is needed to understand how interventions at different levels can be optimally combined to overcome barriers and improve care.


Comparison of the microbiome, metabolome, and lipidome of obese and non-obese horses.
Metabolic diseases such as obesity and type 2 diabetes in humans have been linked to alterations in the gastrointestinal microbiota and metabolome. Knowledge of these associations has improved our understanding of the pathophysiology of these diseases and guided development of diagnostic biomarkers and therapeutic interventions. The cellular and molecular pathophysiology of equine metabolic syndrome (EMS) and obesity in horses, however, remain ill-defined. Thus, the objectives of this study were to characterize the fecal microbiome, fecal metabolome, and circulating lipidome in obese and non-obese horses. The fecal microbiota, fecal metabolome, and serum lipidome were evaluated in obese (case) horses (n = 20) and non-obese (control) horses (n = 20) matched by farm of origin (n = 7). Significant differences in metabolites of the mitochondrial tricarboxylic acid cycle and circulating free fatty acids were identified in the obese horses compared to the non-obese horses. These results indicate that the host and bacterial metabolism should be considered important in obese horses. Further studies to determine whether these associations are causal and the mechanistic basis of the association are warranted because they might reveal diagnostic biomarkers and therapeutic interventions to mitigate obesity, EMS, and sequelae including laminitis.


Predicting Risk of Infection in Infants with Congenital Diaphragmatic Hernia.
To predict incident bloodstream infection and urinary tract infection (UTI) in infants with congenital diaphragmatic hernia (CDH). We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010-2016. Infants with CDH admitted at 22 participating regional neonatal intensive care units were included; patients repaired or discharged to home prior to admission/referral were excluded. The primary outcome was death or the occurrence of bloodstream infection or UTI prior to discharge. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants. Median gestation and postnatal age at referral in this cohort (n = 1085) were 38 weeks and 3.1 hours, respectively. The primary outcome occurred in 395 patients (36%); and was associated with low birth weight, low Apgar, low admission pH, renal and associated anomalies, patch repair, and extracorporeal membrane oxygenation (P < .001 for all; area under receiver operating curve = 0.824; goodness of fit χ2 = 0.52). After omitting death from the outcome measure, admission pH, patch repair of CDH, and duration of central line placement were significantly associated with incident bloodstream infection or UTI. Infants with CDH are at high risk of infection which was predicted by clinical factors. Early identification and low threshold for sepsis evaluations in high-risk infants may attenuate acquisition and the consequences of these infections.


Personality judgments based on physical appearance.
Despite the crucial role of physical appearance in forming first impressions, little research has examined the accuracy of personality impressions based on appearance alone. This study examined the accuracy of observers' impressions on 10 personality traits based on full-body photographs using criterion measures based on self and peer reports. When targets' posture and expression were constrained (standardized condition), observers' judgments were accurate for extraversion, self-esteem, and religiosity. When targets were photographed with a spontaneous pose and facial expression (spontaneous condition), observers' judgments were accurate for almost all of the traits examined. Lens model analyses demonstrated that both static cues (e.g., clothing style) and dynamic cues (e.g., facial expression, posture) offered valuable personality-relevant information. These results suggest that personality is manifested through both static and expressive channels of appearance, and observers use this information to form accurate judgments for a variety of traits.


MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers.
Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs and through selective activation of these enhancers to regulate tissue-specific genes.


Hyperlipidemia in glycogen storage disease type III: effect of age and metabolic control.
While the presence of hyperlipidaemia in glycogen storage disease (GSD) type Ia and Ib is generally accepted, few investigators have adequately assessed lipid profiles of GSD III in children, in whom the presence of hyperlipidaemia may be most prominent. We analysed the lipid profiles in 44 GSD III patients from 6 months to 30 years of age. Hypertriglyceridaemia and hypercholesterolaemia were common in children younger than 3 years of age. Hypertriglyceridaemia correlated negatively with age, and may reflect increased severity of hypoglycaemia in this younger population. The presence of hyperlipidaemia during childhood in these patients identifies another GSD population that could be at risk for early cardiovascular disease (CVD). Consequently, the outcome of clinical trials investigating the vascular effect of hyperlipidaemia in GSD applies to types other than GSD I.


Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial.
Parkinson's disease (PD) has a progressive course and is characterized by the degeneration of dopaminergic neurons. Although no neuroprotective treatments for PD have been found to date, the endocannabinoid system has emerged as a promising target. From a sample of 119 patients consecutively evaluated in a specialized movement disorders outpatient clinic, we selected 21 PD patients without dementia or comorbid psychiatric conditions. Participants were assigned to three groups of seven subjects each who were treated with placebo, cannabidiol (CBD) 75 mg/day or CBD 300 mg/day. One week before the trial and in the last week of treatment participants were assessed in respect to (i) motor and general symptoms score (UPDRS); (ii) well-being and quality of life (PDQ-39); and (iii) possible neuroprotective effects (BDNF and H(1)-MRS). We found no statistically significant differences in UPDRS scores, plasma BDNF levels or H(1)-MRS measures. However, the groups treated with placebo and CBD 300 mg/day had significantly different mean total scores in the PDQ-39 (p = 0.05). Our findings point to a possible effect of CBD in improving quality of life measures in PD patients with no psychiatric comorbidities; however, studies with larger samples and specific objectives are required before definitive conclusions can be drawn.


Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.


Sub-optimal allocation of time in sequential movements.
The allocation of limited resources such as time or energy is a core problem that organisms face when planning complex actions. Most previous research concerning planning of movement has focused on the planning of single, isolated movements. Here we investigated the allocation of time in a pointing task where human subjects attempted to touch two targets in a specified order to earn monetary rewards. Subjects were required to complete both movements within a limited time but could freely allocate the available time between the movements. The time constraint presents an allocation problem to the subjects: the more time spent on one movement, the less time is available for the other. In different conditions we assigned different rewards to the two tokens. How the subject allocated time between movements affected their expected gain on each trial. We also varied the angle between the first and second movements and the length of the second movement. Based on our results, we developed and tested a model of speed-accuracy tradeoff for sequential movements. Using this model we could predict the time allocation that would maximize the expected gain of each subject in each experimental condition. We compared human performance with predicted optimal performance. We found that all subjects allocated time sub-optimally, spending more time than they should on the first movement even when the reward of the second target was five times larger than the first. We conclude that the movement planning system fails to maximize expected reward in planning sequences of as few as two movements and discuss possible interpretations drawn from economic theory.


Dermoscopy of pigmented lesions of the mucosa and the mucocutaneous junction: results of a multicenter study by the International Dermoscopy Society (IDS).
To better characterize the dermoscopic patterns of mucosal lesions in relation to the histopathologic characteristics. Retrospective and observational study. Fourteen referral pigmented lesion clinics in 10 countries. A total of 140 pigmented mucosal lesions (126 benign lesions, 11 melanomas, 2 Bowen disease lesions, and 1 metastasis) from 92 females (66%) and 48 males (34%) were collected from October 2007 through November 2008. Scoring the dermoscopic patterns (dots, globules, or clods, circles, lines, or structureless) and colors (brown, black, blue, gray, red, purple, and white) and correlation with the histopathologic characteristics. Based on univariate analysis and 2 diagnostic models, the presence of structureless zones inside the lesions with blue, gray, or white color (the first model) had a 100% sensitivity for melanoma and 92.9% sensitivity for any malignant lesion, and 82.2% and 83.3% specificity for benign lesions in the group with melanoma lesions and the group with malignant lesions, respectively. Based on the colors (blue, gray, or white) only (the second model), the sensitivity for the group with melanoma was 100% and for the group with any malignant lesion was 92.9%, and the specificity was 64.3% and 65.1%, respectively. Patients with malignant lesions were significantly older than patients with benign lesions (mean [SD] ages, 60.1 [22.8] years vs 43.2 [17.3] years, respectively). The combination of blue, gray, or white color with structureless zones are the strongest indicators when differentiating between benign and malignant mucosal lesions in dermoscopy.


Psychosocial correlates of healthful diets among male auto workers.
A better understanding of factors associated with healthful eating practices can improve the design and evaluation of dietary intervention programs. Up to now, little information has been available about these factors in high-risk but healthy populations. This article presents findings of a study of psychosocial factors, including stage of change, and their relationship to patterns of consumption of dietary fat, fiber, and fruits and vegetables in a population of males at increased risk of colorectal cancer. Data are from the baseline survey for the Next Step Trial, a randomized, controlled trial of worksite nutrition and colorectal cancer screening promotion interventions. The respondents (n = 2764) were actively employed or retired auto workers at increased colorectal cancer risk. The psychosocial constructs measured were predisposing factors (benefits, motivation, knowledge; eight items; Cronbach alpha = 0.50), enabling factors (barriers, norms, social support; six items; Cronbach alpha = 0.55), and stages of change for adopting diets lower in fat and higher in fiber/fruits and vegetables. The measures of diet, assessed with a food frequency questionnaire, were intakes of fat, fiber, and servings of fruits and vegetables. There were strong and statistically significant positive associations between both predisposing and enabling scale scores and stages of change for fat and fiber. The percentage of respondents in maintenance stage ranged from 4-80% for fat and 11-81% for fiber, across low to high predisposing scale scores; for enabling scale scores, ranges were 11-71% for fat and 22-81% for fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, with the greatest change observed between action and maintenance. Correlations with dietary outcomes were significantly greater for predisposing factors (r = -0.30 for fat and 0.36 for fiber) than for enabling factors (r = -0.23 for fat and 0.28 for fiber). Multiple regression models, which included the predisposing and enabling factor scales, stage of change, and covariates related to diet, explained a total of between 16 and 27% of the variance in diet. Predisposing and enabling factors are significantly associated with of stage of change and current diet in this high-risk sample of male auto workers. Stage of change is the strongest correlate examined and seems to serve as a mediating factor for dietary change. Results from the Next Step Trial will provide additional data on whether and how health promotion interventions influence these factors, and whether such changes are associated with dietary change.


TorsinA protects against oxidative stress in COS-1 and PC12 cells.
Dystonia is a highly frequent movement disorder, the pathogenesis of which remains unclear. The cloning of TorsinA, the gene responsible for early-onset dystonia, was a major breakthrough. However, the function of this protein remains unclear. By sequence homology, TorsinA belongs to the ATPases associated with diverse cellular activities-family, many of whose members are chaperones and/or proteases. We report here that in an in vitro model for oxidative stress, H2O2 treatment, overexpression of TorsinA was protective against cell death. COS-1 cells overexpressing TorsinA demonstrated drastically reduced terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-staining following exposure to H2O2. Furthermore, transfection with TorsinA significantly increased survival of PC12 after H2O2 treatment. To our knowledge, this is the first demonstration that TorsinA protects against oxidative stress. We speculate that a loss of this cellular function in mutant TorsinA may be linked to the pathogenesis of early-onset dystonia.


Research Gaps in Gestational Diabetes Mellitus: Executive Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.
The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and treatment and 2) pharmacologic treatment strategies. This article summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children.


Continental configuration controls ocean oxygenation during the Phanerozoic.
The early evolutionary and much of the extinction history of marine animals is thought to be driven by changes in dissolved oxygen concentrations ([O2]) in the ocean1-3. In turn, [O2] is widely assumed to be dominated by the geological history of atmospheric oxygen (pO2)4,5. Here, by contrast, we show by means of a series of Earth system model experiments how continental rearrangement during the Phanerozoic Eon drives profound variations in ocean oxygenation and induces a fundamental decoupling in time between upper-ocean and benthic [O2]. We further identify the presence of state transitions in the global ocean circulation, which lead to extensive deep-ocean anoxia developing in the early Phanerozoic even under modern pO2. Our finding that ocean oxygenation oscillates over stable thousand-year (kyr) periods also provides a causal mechanism that might explain elevated rates of metazoan radiation and extinction during the early Palaeozoic Era6. The absence, in our modelling, of any simple correlation between global climate and ocean ventilation, and the occurrence of profound variations in ocean oxygenation independent of atmospheric pO2, presents a challenge to the interpretation of marine redox proxies, but also points to a hitherto unrecognized role for continental configuration in the evolution of the biosphere.


Patient and Provider Perspectives on Acceptability, Access, and Adherence to 17-Alpha-Hydroxyprogesterone Caproate for Preterm Birth Prevention.
Background: Preterm birth (PTB) is a pressing maternal and child health issue with long-standing racial inequities in outcomes and care provision. 17-Alpha-hydroxyprogesterone caproate (17OHPC) has been one of few clinical interventions for recurrent PTB prevention. Little is known about the factors influencing successful administration and receipt of 17OHPC among mothers in the Medicaid program. Materials and Methods: We conducted individual semistructured interviews with 17OHPC-eligible pregnant women and obstetric providers from two academic medical centers in Philadelphia, PA. Patient participants were publicly insured, eligible for 17OHPC treatment, and purposively sampled as either (1) actively receiving treatment or (2) declining/discontinuing treatment. Providers had experience providing care to Medicaid-enrolled patients. Interview transcripts were coded and analyzed to identify themes related to treatment acceptability, access, and adherence. Results: Of the 17 patient participants, the mean age was 30 years. Ten providers (MDs, nurse practitioners, and registered nurses) were also interviewed. Factors facilitating 17OHPC uptake and adherence among patients included severity of prior PTB, provider counseling, and coordination among the clinic, pharmacy, and insurance. Pain was cited as the most significant barrier to 17OHPC for patients, while providers perceived social adversity and beliefs about patients' commitment to treatment to be primary patient barriers. For providers, clinical experience and practice guidelines contributed to their use of 17OHPC. Administrative complexity and coordination of services were the primary provider barrier to 17OHPC administration. Conclusions: Patient-provider communication is a primary driver of 17OHPC acceptability and adherence. Comprehensive patient-centered consultation may improve uptake of clinical therapies among pregnant women at high risk for PTB.


Squeezing terahertz light into nanovolumes: nanoantenna enhanced terahertz spectroscopy (NETS) of semiconductor quantum dots.
Terahertz spectroscopy has vast potentialities in sensing a broad range of elementary excitations (e.g., collective vibrations of molecules, phonons, excitons, etc.). However, the large wavelength associated with terahertz radiation (about 300 μm at 1 THz) severely hinders its interaction with nano-objects, such as nanoparticles, nanorods, nanotubes, and large molecules of biological relevance, practically limiting terahertz studies to macroscopic ensembles of these compounds, in the form of thick pellets of crystallized molecules or highly concentrated solutions of nanomaterials. Here we show that chains of terahertz dipole nanoantennas spaced by nanogaps of 20 nm allow retrieving the spectroscopic signature of a monolayer of cadmium selenide quantum dots, a significant portion of the signal arising from the dots located within the antenna nanocavities. A Fano-like interference between the fundamental antenna mode and the phonon resonance of the quantum dots is observed, accompanied by an absorption enhancement factor greater than one million. NETS can find immediate applications in terahertz spectroscopic studies of nanocrystals and molecules at extremely low concentrations. Furthermore, it shows a practicable route toward the characterization of individual nano-objects at these frequencies.


Surface characteristics of isopod digestive gland epithelium studied by SEM.
The structure of the digestive gland epithelium of a terrestrial isopod Porcellio scaber has been investigated by conventional scanning electron microscopy (SEM), focused ion beam-scanning electron microscopy (FIB/SEM), and light microscopy in order to provide evidence on morphology of the gland epithelial surface in animals from a stock culture. We investigated the shape of cells, extrusion of lipid droplets, shape and distribution of microvilli, and the presence of bacteria on the cell surface. A total of 22 animals were investigated and we found some variability in the appearance of the gland epithelial surface. Seventeen of the animals had dome-shaped digestive gland "normal" epithelial cells, which were densely and homogeneously covered by microvilli and varying proportions of which extruded lipid droplets. On the surface of microvilli we routinely observed sparsely distributed bacteria of different shapes. Five of the 22 animals had "abnormal" epithelial cells with a significantly altered shape. In three of these animals, the cells were much smaller, partly or completely flat or sometimes pyramid-like. A thick layer of bacteria was detected on the microvillous border, and in places, the shape and size of microvilli were altered. In two animals, hypertrophic cells containing large vacuoles were observed indicating a characteristic intracellular infection. The potential of SEM in morphological investigations of epithelial surfaces is discussed.


Transphyseal Humeral Separations: What Can We Learn? A Retrospective, Multicenter Review of Surgically Treated Patients Over a 25-Year Period.
Transphyseal humeral separations (TPHS) are rare injuries with only case reports and small series reported in the literature. This multicenter study aimed to assess the various patient characteristics, injury patterns, treatments, outcomes, and complications in a large series of these injuries. A retrospective review was conducted at 5 pediatric institutions to identify TPHS that were treated surgically in patients 0 to 3 years of age over a 25-year period. Patient demographics, mechanisms of injury, Child Protective Services involvement, diagnostic modalities, time to surgery, pin size and configuration, time to fracture union, and complications were recorded. A total of 79 patients aged 0 to 46 months, with a mean of 17.6 months, were identified and followed for a median of 57 days postoperatively. The most common mechanism of injury was accidental trauma (n=49), followed by nonaccidental trauma (n=21), cesarean section (n=6), and vaginal delivery (n=3). Child Protective Services were involved in 30 cases (38%). Additional injuries were reported in 19 of the patients; most commonly additional fractures including the humerus, rib, and skull fractures. All patients had elbow radiographs, whereas 4 patients had an elbow ultrasound and/or a magnetic resonance imaging. Time to surgery was greater than 24 hours in 62% of patients (n=49). Intraoperatively, 87% of patients underwent an arthrogram (n=69), 78% of patients had lateral pins only (n=62), averaging utilization of 2.2 pins, and 2 patients underwent an open reduction. In total, 11 complications (14%) were noted, including decreased range of motion (n=4), cubitus varus/valgus (n=6), and need for additional surgery (n=1). No cases of avascular necrosis or physeal arrest were found. No losses of reduction were noted. This multicenter review provides the largest known demographic and outcomes data on TPHS. TPHS have excellent outcomes in the vast majority of patients when treated surgically. Nonaccidental trauma accounted for 27% of these injuries so it needs to remain high on the differential diagnosis. Level III-retrospective cohort study.


Improving access to high-quality primary care for socioeconomically disadvantaged older people in rural areas: a mixed method study protocol.
The UK has an ageing population, especially in rural areas, where deprivation is high among older people. Previous research has identified this group as at high risk of poor access to healthcare. The aim of this study is to generate a theory of how socioeconomically disadvantaged older people from rural areas access primary care, to develop an intervention based on this theory and test it in a feasibility trial. On the basis of the MRC Framework for Developing and Evaluating Complex Interventions, three methods will be used to generate the theory. First, a realist review will elucidate the patient pathway based on existing literature. Second, an analysis of the English Longitudinal Study of Ageing will be completed using structural equation modelling. Third, 15 semistructured interviews will be undertaken with patients and four focus groups with health professionals. A triangulation protocol will be used to allow each of these methods to inform and be informed by each other, and to integrate data into one overall realist theory. Based on this theory, an intervention will be developed in discussion with stakeholders to ensure that the intervention is feasible and practical. The intervention will be tested within a feasibility trial, the design of which will depend on the intervention. Lessons from the feasibility trial will be used to refine the intervention and gather the information needed for a definitive trial. Ethics approval from the regional ethics committee has been granted for the focus groups with health professionals and interviews with patients. Ethics approval will be sought for the feasibility trial after the intervention has been designed. Findings will be disseminated to the key stakeholders involved in intervention development, to researchers, clinicians and health planners through peer-reviewed journal articles and conference publications, and locally through a dissemination event.


Angptl4 does not control hyperglucagonemia or α-cell hyperplasia following glucagon receptor inhibition.
Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498-15503]. Angptl4 is a secreted protein and inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. We report that Angptl4-/- mice treated with an anti-glucagon receptor monoclonal antibody undergo elevation of plasma glucagon levels and α-cell expansion similar to wild-type mice. Overexpression of Angptl4 in liver of mice caused a 8.6-fold elevation in plasma triglyceride levels, but did not alter plasma glucagon levels or α-cell mass. Furthermore, administration of glucagon receptor-blocking antibody to healthy individuals increased plasma glucagon and amino acid levels, but did not change circulating Angptl4 concentration. These data show that Angptl4 does not link glucagon receptor inhibition to compensatory hyperglucagonemia or expansion of α-cell mass, and that it cannot be given to induce such secretion and growth. The reduction of plasma triglyceride levels in Angptl4-/- mice and increase following Angptl4 overexpression suggest that changes in plasma triglyceride metabolism do not regulate α-cells in the pancreas. Our findings corroborate recent data showing that increased plasma amino acids and their transport into α-cells link glucagon receptor blockage to α-cell hyperplasia.


Acute antimanic efficacy and safety of oxcarbazepine in an open trial with an on-off-on design.
Carbamazepine has shown reasonable antimanic properties, but its use has been limited because of enzyme-inducing effects. The keto-derivative oxcarbazepine (OXC) is very similar to carbamazepine, however, the metabolic pathway is different. OXC is not metabolized to the 10, 11-epoxide, which seems to be responsible for several undesirable side-effects of carbamazepine and furthermore OXC has less enzyme-inducing properties. In this non-random open label study, patients were treated with OXC for 14 days, crossed over to no OXC for 7 days, and then crossed back over to OXC for the remaining 14 days. OXC was titrated to a final dose in a range of 900-2100 mg due to individual response. Treatment success was defined as a reduction of the original Young Mania Rating Scale (YMRS) score of more than 50% at the end of study period. Four of the 12 included patients (33%) met defined response criteria at the end of study period. Fifty percentage of the patients had to be prematurely excluded from the trial. The mean YMRS scores of the on-periods were obviously different from the off-period. Forty-two percentage of the patients experienced side-effects leading to premature discontinuation in two of 12 patients. Antimanic activity of OXC was demonstrated in this pilot study only for patients with mild or moderate manic symptoms. Further studies are encouraged to clarify OXC's role as mood-stabilizer and assess whether it has a profile similar to that of carbamazepine.


Characterization of Ca2+ and phosphocholine interactions with C-reactive protein using a surface plasmon resonance biosensor.
The interactions between Ca2+ and C-reactive protein (CRP) have been characterized using a surface plasmon resonance (SPR) biosensor. The protein was immobilized on a sensor chip, and increasing concentrations of Ca2+ or phosphocholine were injected. Binding of Ca2+ induced a 10-fold higher signal than expected from the molecular weight of Ca2+. It was interpreted to result from the conformational change that occurs on binding of Ca2+. Two sites with different characteristics were distinguished: a high-affinity site with K(D)=0.03 mM and a low-affinity site with K(D)=5.45 mM. The pH dependencies of the two Ca2+ interactions were different and enabled the assignment of the different sites in the three-dimensional structure of CRP. There was no evidence for cooperativity in the phosphocholine interaction, which had K(D)=5 microM at 10 mM Ca2+. SPR biosensors can clearly detect and quantify the binding of very small molecules or ions to immobilized proteins despite the theoretically very low signals expected on binding, provided that significant conformational changes are involved. Both the interactions and the conformational changes can be characterized. The data have important implications for the understanding of the function of CRP and suggest that Ca2+ is an efficient regulator under physiological conditions.


Fear of hypoglycaemia: defining a minimum clinically important difference in patients with type 2 diabetes.
To explore the concept of the Minimum Clinically Important Difference (MID) of the Worry Scale of the Hypoglycaemia Fear Survey (HFS-II) and to quantify the clinical importance of different types of patient-reported hypoglycaemia. An observational study was conducted in Germany with 392 patients with type 2 diabetes mellitus treated with combinations of oral anti-hyperglycaemic agents. Patients completed the HFS-II, the Treatment Satisfaction Questionnaire for Medication (TSQM), and reported on severity of hypoglycaemia. Distribution- and anchor-based methods were used to determine MID. In turn, MID was used to determine if hypoglycaemia with or without need for assistance was clinically meaningful compared to having had no hypoglycaemia. 112 patients (28.6%) reported hypoglycaemic episodes, with 15 patients (3.8%) reporting episodes that required assistance from others. Distribution- and anchor-based methods resulted in MID between 2.0 and 5.8 and 3.6 and 3.9 for the HFS-II, respectively. Patients who reported hypoglycaemia with (21.6) and without (12.1) need for assistance scored higher on the HFS-II (range 0 to 72) than patients who did not report hypoglycaemia (6.0). We provide MID for HFS-II. Our findings indicate that the differences between having reported no hypoglycaemia, hypoglycaemia without need for assistance, and hypoglycaemia with need for assistance appear to be clinically important in patients with type 2 diabetes mellitus treated with oral anti-hyperglycaemic agents.


Real-Time Observation of Reconstruction Dynamics on TiO2(001) Surface under Oxygen via an Environmental Transmission Electron Microscope.
The surface atomic structure has a remarkable impact on the physical and chemical properties of metal oxides and has been studied extensively by scanning tunneling microscopy. However, acquiring real-time information on the formation and evolution of the surface structure remains a great challenge. Here we use environmental transmission electron microscopy to directly observe the stress-induced reconstruction dynamics on the (001) surface of anatase TiO2. Our in situ results unravel for the first time how the (1 × 4) reconstruction forms and how the metastable (1 × 3) and (1 × 5) patterns transform into the (1 × 4) surface stable structure. With the support of first-principles calculations, we find that the surface evolution is driven by both low coordinated atoms and surface stress. This work provides a complete picture of the structural evolution of TiO2(001) under oxygen atmosphere and paves the way for future studies of the reconstruction dynamics of other solid surfaces.


[Dyslipidemia in diabetes mellitus: significance, diagnosis and treatment].
Dyslipidemias are frequent in diabetic subjects: they increase the risk for atherosclerosis, in addition to the risk of diabetes mellitus per se. The pathogenesis of dyslipidemias differs between type I and type II diabetes: untreated type I diabetic subjects demonstrate frequently increased triglyceride concentrations due to diminished removal of triglyceride-containing particles, as a result of diminished activity of lipoprotein lipase. In addition, more triglycerides are produced due to increased lipolysis and increased free fatty acid supply to the liver. Type II diabetic subjects demonstrate very low density lipoprotein (VLDL) over-production due to obesity, insulin resistance and caloric overconsumption. In addition, triglyceride removal may be diminished due to diminished lipoprotein lipase activity when diabetes mellitus is poorly controlled. In addition, high density lipoprotein (HDL) is frequently lowered. During decompensation low density lipoprotein (LDL) concentrations may also increase. LDL particle composition is frequently abnormal. A severe dyslipidemia in diabetes mellitus is frequently a combined effect of diabetes mellitus and a congenital lipoprotein abnormality. The evaluation and treatment of dyslipidemias in diabetic subjects should be performed similarly to non-diabetics according to the guidelines published recently by the Working Group 'Lipids' of the Swiss Foundation of Cardiology. Additional accents in diabetic subjects are necessary. It is recommended that serum cholesterol, triglycerides and HDL are determined in every patient when diabetes mellitus is diagnosed. If serum cholesterol is greater than 6.5 mmol/l and the cholesterol/HDL-ratio is greater 6.5, dietary treatment should be reinforced; if its effect is insufficient, drug therapy should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)