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To develop age- and BMI-adjusted alignment targets to improve patient-specific management and operative treatment outcomes.Retrospective review of a single-center stereographic database. ASD patients receiving operative or non-operative treatment, ≥ 18y/o with complete baseline (BL) ODI scores and radiographic parameters (PT, SVA, PILL, TPA) were included. Patients were stratified by age consistent with US-Normative values (norms) of SF-36( 35, 35-55, 45-54, 55-64, 65-74, ≥ 75y/o), and dichotomized by BMI (Non-Obese 30; Obese ≥ 30). Linear regression analysis established normative age- and BMI-specific radiographic thresholds, utilizing previously published age-specific US-Normative ODI values converted from SF-36 PCS (Lafage et al.), in conjunction with BL age and BMI means.486 patients were included (Age: 52.5, Gender: 68.7%F, mean BMI: 26.2, mean ODI: 32.7), 135 of which were obese. Linear regression analysis developed age- and BMI-specific alignment thresholds, indicating PT, SVA, PILL, and TPA to increase with both increased age and increased BMI (all R 0.5, p 0.001). For non-obese patients, PT, SVA, PILL, and TPA ranged from 10.0, - 25.8, - 9.0, 3.1 in patients 35y/o to 27.8, 53.4, 17.7, 25.8 in patients ≥ 75 y/o. Obese patients' PT, SVA, PILL, and TPA ranged from 10.5, - 7.6, - 7.1, 5.8 in patients 35 y/o to 28.3, 67.0, 19.15, 27.7 in patients ≥ 75y/o. Normative SVA values in obese patients were consistently ≥ 10 mm greater compared to non-obese values, at all ages.Significant associations exist between age, BMI, and sagittal alignment. While BMI influenced age-adjusted alignment norms for PT, SVA, PILL, and TPA at all ages, obesity most greatly influenced SVA, with normative values similar to non-obese patients who were 10 years older. Age-adjusted alignment thresholds should take BMI into account, calling for less rigorous alignment objectives in older and obese patients.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Drug interactions involving benzodiazepines and related drugs (BZDs) are increasingly recognized as a contributor to increased risk of unintentional traumatic injury. Yet, it remains unknown to what extent drug interaction triads (3DIs) may amplify BZDs’ inherent injury risk. We identified BZD 3DI signals associated with increased injury rates by conducting high-throughput pharmacoepidemiologic screening of 2000–2019 Optum’s health insurance data. Using self-controlled case series design, we included patients aged ≥ 16 years with an injury while using a BZD + co-dispensed medication (i.e., base pair). During base pair-exposed observation time, we identified other co-dispensed medications as candidate interacting precipitants. Within each patient, we compared injury rates during time exposed to the drug triad versus to the base pair only using conditional Poisson regression, adjusting for time-varying covariates. We calculated rate ratios (RRs) with 95% confidence intervals (CIs) and accounted for multiple estimation via semi-Bayes shrinkage. Among the 65,123 BZD triads examined, 79 (0.1%) were associated with increased injury rates and considered 3DI signals. Adjusted RRs for signals ranged from 3.01 (95% CI = 1.53–5.94) for clonazepam + atorvastatin with cefuroxime to 1.42 (95% CI = 1.00–2.02, p = 0.049) for alprazolam + hydrocodone with tizanidine. These signals may help researchers prioritize future etiologic studies to investigate higher-order BZD interactions.

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N=21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β]=2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β=0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β=0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs=-2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

INTRODUCTION: Colchicine is currently approved for the treatment of gout and familial Mediterranean fever, among other conditions. Clarithromycin, a strong inhibitor of CYP3A4 and P-glycoprotein, dramatically increases colchicine’s half-life, augmenting the risk of a life-threatening adverse reaction when used inadvertently with colchicine. OBJECTIVES: The aim of this study was to examine the evidence and clinical implications of concomitant use of colchicine and clarithromycin. METHODS: Case reports of colchicine–clarithromycin co-administration were searched using the FDA’s Adverse Event Reporting System (FAERS) database. PubMed, EMBASE, and Web of Science electronic databases were also searched from January 2005 through November 2019 for articles reporting colchicine–clarithromycin concomitant use. Individual reports were reviewed to identify consequences of coadministration, dose, days to onset of interaction, symptoms, evidence of renal disease, time to resolution of symptoms, and Drug Interaction Probability Scale (DIPS) rating. RESULTS: The FAERS search identified 58 reported cases, nearly 53% of which were from patients aged between 65 and 85 years. Of 30 reported deaths, 11 occurred in males, and 19 in females. Other frequent complications reported in FAERS included diarrhea (31%), pancytopenia (22%), bone marrow failure (14%), and vomiting (14%). From published literature, we identified 20 case reports of concomitant exposure, 19 of which were rated ‘probable’ and one ‘possible’ according to DIPS rating. Of these cases, four ‘probable’ patients expired. The documented onset of colchicine toxicity occurred within 5 days of starting clarithromycin, and death within 2 weeks of concomitant exposure. CONCLUSION: Clinical manifestations of colchicine–clarithromycin interaction may resemble other systemic diseases and may be life threatening. Understanding this clinically meaningful interaction can help clinicians avoid unsafe medication combinations.

The AHRQ (Agency for Healthcare Research and Quality) has requested the correction of the result Tables 1–3 of this study: All stated numbers below 10 shall be modified to read “

This paper presents a new approach towards the design of paper based autonomous microfluidic devices. Autonomy in the device operation is achieved through the incorporation of mechanically actuated microfluidic switches that are versatile in their design and may be configured to be simple time triggered ON or OFF switches or more complex switches that can be timed to be in multiple states (timed ON, followed by timed OFF). These switches are self-contained and require no external power for their operation, deriving their functionality solely through stored elastic energy. This paper presents the design and fabrication of these switches as fluidic analogs of electronic transistors, and their integration into microfluidic paper based circuit demonstrating their operation as a programmable paper-based microfluidic device.

Cardiac anomalies are prevalent in patients with bony spinal anomalies. Prior studies evaluating incidences of bony congenital anomalies of the spine are limited. The Kids’ Inpatient Database (KID) yields national discharge estimates of rare pediatric conditions like congenital disorders. This study utilized cluster analysis to study patterns of concurrent vertebral anomalies, anal atresia, cardiac malformations, trachea-esophageal fistula, renal dysplasia, and limb anomalies (VACTERL anomalies) co-occurring in patients with spinal congenital anomalies. Retrospective review of KID 2003–2012. KID-supplied hospital- and year-adjusted weights allowed for incidence assessment of bony spinal anomalies and cardiac, gastrointestinal, urinary anomalies of VACTERL. K-means clustering assessed relationships between most frequent anomalies within bony spinal anomaly discharges; k set to n − 1(n = first incidence of significant drop/little gain in sum of square errors within clusters). There were 12,039,432 KID patients 0–20 years. Incidence per 100,000 discharges: 2.5 congenital fusion of spine, 10.4 hemivertebra, 7.0 missing vertebra. The most common anomalies co-occurring with bony vertebral malformations were atrial septal defect (ASD 12.3%), large intestinal atresia (LIA 11.8%), and patent ductus arteriosus (PDA 10.4%). Top congenital cardiac anomalies in vertebral anomaly patients were ASD, PDA, and ventricular septal defect (VSD); all three anomalies co-occur at 6.6% rate in this vertebral anomaly population. Cluster analysis revealed that of bony anomaly discharges, 55.9% of those with PDA had ASD, 34.2% with VSD had PDA, 22.9% with LIA had ASD, 37.2% with ureter obstruction had LIA, and 35.5% with renal dysplasia had LIA. In vertebral anomaly patients, the most common co-occurring congenital anomalies were cardiac, renal, and gastrointestinal. Top congenital cardiac anomalies in vertebral anomaly patients were ASD, PDA, and VSD. VACTERL patients with vertebral anomalies commonly presented alongside cardiac and renal anomalies.

The BURDEN IBS-C study was conducted to better understand the experiences, attitudes, and unmet needs of sufferers of irritable bowel syndrome with constipation (IBS-C) in comparison to the perceptions and challenges of healthcare providers (HCPs) who treat IBS-C patients. This was an author-developed, online questionnaire using KnowledgePanel® to survey individuals with IBS-C (N = 1311). HCPs participated in a complementary online questionnaire and were recruited separately (N = 331). The study was fielded from June 29, 2016, to January 30, 2017. Most patients had used (86%) and/or were using (76%) over-the-counter treatments for their IBS-C, with 12% currently on prescription therapy. At the time this study was conducted, 66% and 63% were not satisfied/completely satisfied with over-the-counter or prescription treatment, respectively, citing inadequate efficacy (55%) and side effects (39%), most commonly diarrhea, as common reasons for dissatisfaction. IBS-C respondents most commonly reported feeling frustrated (43%) and stressed (28%) regarding IBS-C, though 39% were accepting of IBS-C as part of daily life. HCPs were aligned with patients in thinking that patients were frustrated (76%) and stressed (65%) but HCPs were less likely to recognize that patients had become accepting of their IBS-C (13%). Most HCPs (79%) were not satisfied/completely satisfied with the prescription treatments available at the time this study was conducted. Inadequate response rates to current therapies (55%) and treatment adherence/compliance issues (58%) were the most frequent challenges encountered by HCPs. IBS-C respondents reported that their symptoms impacted productivity and personal activity, on average, 4 and 3 days/month, respectively. These results suggest that current management pathways may not be adequately addressing the symptoms and needs of individuals with IBS-C, most notably side effects and lack of efficacy. Patients and HCPs expressed dissatisfaction with over-the-counter and prescription treatments available at the time this study was conducted. Additional treatment options and improved dialogue would be beneficial to HCPs and patients. Synergy Pharmaceuticals Inc.

Litotes, “a figure of speech in which an affirmative is expressed by the negative of the contrary” (OED) has had some tough reviews. For Pope and Swift (“Scriblerus” 1727), litotes—stock examples include “no mean feat”, “no small problem”, and “not bad at all”—is “the peculiar talent of Ladies, Whisperers, and Backbiters”; for Orwell (1946), it is a means to affect “an appearance of profundity” that we can deport from English “by memorizing this sentence: A not unblack dog was chasing a not unsmall rabbit across a not ungreen field.” But such ridicule is not without equivocation, given that litotes, or “logical” (non-concordial) double negation, may or may not be semantically redundant. When the negation of a logical contrary yields an unexcluded middle, it contributes to expressive power: someone who is not unhappy may not be happy either, and an occurrence may not be infrequent without being frequent. But if something is not possible, what can it be but possible? Why does Crashaw’s “not impossible she” survive rhetorically while Orwell’s “not unsmall rabbit” is doomed? How is Robbie being “not not friends” with Mary on 7th Heaven distinct from being friends with her, if not not-p reduces to p? The key is recognizing in litotes a corollary of MaxContrary, the tendency for contradictory (wide-scope) sentential negation ¬p to strengthen (at least) pragmatically to a contrary ©p, as when the formal contradictory Fr. “Il ne faut pas partir” (lit. ‘It is not necessary to leave’) is reinterpreted as expressing a contrary (‘one must not-leave’). Just as the Law of Excluded Middle can apply where it “shouldn’t”, resulting in pragmatically presupposed disjunctions between semantic contraries, so that “p v ©p” amounts to an instance of “p v ¬p”, the Law of Double Negation can fail to apply where it “should”. When not not-p conveys ¬©p, the negation of a virtual contrary, the middle between p and not-p is no longer excluded, rendering the Fregean dictum that “Wrapping up a thought in double negation does not alter its truth value” not unproblematic.

Anxiety disorders are prevalent and represent an important focus of treatment within the field of psychiatry as well as within medicine more broadly. First-line pharmacotherapy treatment for anxiety disorders is serotonin selective reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). For patients who do not responsd to an initial first-line treatment, clinicians should ensure that there has been adequate exposure to the medication by assessing compliance and optimizing the prescribed dose. Non-response to a treatment trial should also prompt a re-evaluation of the diagnosis and a search for occult psychiatric, substance, or general medical disorders. Laboratory tests and other components of a diagnostic work-up should be considered if they have not already been completed. Following confirmation of the diagnosis, the clinician should consider a switch to an agent from a different class, for example a tricyclic antidepressant or monoamine oxidase inhibitor. Combination treatments with an antidepressant plus a benzodiazepine, second-generation antipsychotic, anticonvulsant, β-blocker, or other medication may be considered but data is limited. Psychotherapy is an important treatment component for anxiety disorders and should be implemented whenever feasible. Variants of cognitive behavioral therapy (CBT) in particular are effective in reducing anxiety symptoms, and data suggest that the combination for CBT plus medication may be particularly beneficial for patients. Obsessive-compulsive disorder (OCD), while sharing many clinical features with anxiety disorders, represents its own unique clinical challenge and has been removed from the category of anxiety disorders in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). SSRIs are first-line therapy for OCD and higher doses are often required compared with anxiety disorders or major depressive disorder. Exposure and response prevention may be a particularly helpful form of psychotherapy for this patient population. For severe, intractable OCD, deep brain stimulation may be an appropriate therapeutic option.

In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or γ-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die.

Previous studies in rodents show that early exposure to methylphenidate alters later responsiveness to drugs of abuse. An interesting feature of these studies is that early methylphenidate treatment decreases the rewarding value of cocaine when measured by conditioned place preference (CPP), but the same treatment increases cocaine self-administration.The goal of the present study was to examine the effects of early methylphenidate exposure on cocaine-induced responding using both reward paradigms.Rats were treated with methylphenidate (0, 2, or 5 mg/kg) from postnatal days (PDs) 11 to 20, and then cocaine-induced CPP or cocaine self-administration was measured in separate groups of rats in adulthood. The CPP procedure included 8 days of acquisition training, 8 days of extinction training, and a reinstatement test. Rats were conditioned with 0, 10, or 20 mg/kg cocaine. Reinstatement was assessed after a priming dose of cocaine (10 mg/kg). For the self-administration experiment, a jugular catheter was implanted and rats were trained to press a lever reinforced with cocaine (0.25 or 0.75 mg/kg/infusion) on a fixed ratio (FR) one schedule. Rats were gradually moved from an FR1 to an FR10 schedule and, after criterion was reached, rats were placed on a progressive ratio schedule for 5 days.Cocaine produced robust rewarding effects as determined by both the CPP and self-administration experiments; however, early methylphenidate exposure only enhanced the reinforcing effects of cocaine on the self-administration paradigm. Interestingly, this methylphenidate enhancement was only seen in male rats.These data suggest that in males, methylphenidate enhances the reinforcing value of cocaine, but not cocaine-associated cues.

Peer tutoring is an evidence-based procedure for improving academic performance for a variety of skill areas. The current study evaluated the feasibility and impact of a peer tutoring package for reading fluency with 4 middle school students receiving Tier II remedial supports. This study used a multiple baseline design across participants to evaluate impact of the peer tutoring procedure on students’ oral reading rate on instructional passages. Results indicated that students’ oral reading rate on instructional probes increased following implementation of the peer tutoring procedure. Moreover, peer tutors implemented most steps of the procedure with a high degree of integrity. Results are discussed in terms of contributions to the peer tutoring and Response to Intervention literatures, as well as application to applied practice.

For the investigation of the atomic level structure of heavy elements which can only be produced at on-line facilities such as GSI, a novel experimental procedure has been developed. It is based on Radiation Detected Resonance Ionization Spectroscopy (RADRIS) and can be applied to elements like nobelium produced at rates of a few ions per second. Fusion reaction products are separated from the primary beam by the velocity filter SHIP at GSI, stopped in a buffer gas cell, collected on a tantalum filament and then re-evaporated as atoms. The ions produced by resonance ionization with tunable laser beams are detected via their characteristic α decay. First on-line experiments on α-active 155 Yb, which is supposed to have an atomic level structure similar to nobelium, were performed. These test experiments focused on the optimization of the collection and re-evaporation process of the radioactive ions, the laser ionization efficiency and the detection via α decay. An overall efficiency for RADRIS of 0.8% with respect to the target production rate was measured. While further improvements of this efficiency are in progress it should already be sufficient for the search for atomic levels in nobelium.

Methods are presented to measure axial species and temperature profiles within catalytic partial oxidation foam monoliths at atmospheric pressure with 0.3 mm spatial resolution using a capillary sampling technique with a quadrupole mass spectrometer. The system allows sampling within the catalyst with negligible interference in flow or temperature by using a 0.6 mm quartz capillary containing a thermocouple and possessing a 0.3 mm side orifice. The capillary tightly fills a concentric channel drilled within the 10 mm long ceramic foam minimizing gas bypass. This technique has been used to measure axial catalyst species profiles at temperatures up to 1300 °C for catalytic partial oxidation of methane and ethane to synthesis gas and ethylene, respectively. CH4 and O2 conversion are approximately twice as fast on Rh than on Pt. For C2H6 the reaction products at the catalyst entrance are H2, H2O, CO, and CO2. Ethylene production begins only after ~4 mm into the catalyst after most of the O2 has reacted. Transient operation where the feed composition is varied stepwise between different C/O ratios has also been used to characterize these systems. The capillary sampler has a time resolution of ~0.05 s, and C/O step changes within 0.5 s have been achieved using mass flow controllers. For switches from C/O = 0.6 to 1.4, sharp overshoots are observed for syngas (H2 and CO) and similar undershoots for combustion products (H2O and CO2). By placing the sampling orifice at different positions and stepping the C/O ratio, spatio-temporal profiles can be obtained. Spatio-temporal profiles are extremely important in validating detailed reaction mechanisms because their information content is much higher compared to integral steady state measurements at the reactor outlet. The spatial profiles show where and how quickly different species are formed or consumed along the catalyst axis. Transient profiles provide additional diagnostics of mechanisms and surface coverages because they show how temperature and species concentrations follow a perturbation from steady state.

Drift time measurements of ions in a buffer gas cell filled with argon have been performed from which changes of the ion mobility and ionic radii for various heavy elements and their compounds were determined. The ionic radius of americium shrinks by (3.1 ± 1.3)% with respect to that of plutonium, and an increase of the radius by (28 ± 2)% of plutonium oxide with respect to plutonium was found. Ion chemical reactions of erbium ions were studied online in an argon buffer gas cell to which the reaction gases oxygen (O2) and methane (CH4) were added. The erbium ions were implanted into the buffer gas cell with an energy of 50 MeV. The online measured reaction constant k Er+O2 = (3.2 ± 0.4) · 10−10 cm3/(molecule · s) for the reaction Er+ + O2 → ErO+ + O agrees with a reference measurement kskEr+O2/FT = (3.6 ± 0.4) ·10−10 cm3/(molecule · s), performed with a Fourier-Transform-Mass-Spectrometer.

We present comparative Mossbauer investigations of nanosized FeOOH and FeOOD biomineral phases nucleated within the 7-nm diameter cavity of horse-spleen apoferritin in order to assess deuterium isotopic effects on nanoscale, bioinorganic lattice structures with extended hydrogen bond networks. Differences in magnetic anisotropy energy, packing density and degree of crystallinity in the resulting iron oxo-hydroxide nanophases obtained via D2O (heavy water) vs. H2O (light water) solution chemistry are noted. These observations point to the possibility of stabilizing new thermodynamic states in the solid-state by utilizing isotope effects, with important implications for new synthetic pathways to novel nano materials.

Superconducting transition-edge sensors have been used extensively in cryogenic particle detectors, either as thermometers for microcalorimetry or as bolometers for the detection of the prompt phonons resulting from a particle decay in a single crystal absorber. Bolometer action depends upon the energy coupling of the prompt phonons to the bolometer electrons. A study has been made of the electron-phonon coupling for a series of Au-Ti bolometers on a Si substrate and of the use of these bolometers for prompt phonon detection below 1 K. The electron-phonon coupling was found to be proportional to the normalized resistance (R/Rn) of the bolometer; R is the bolometer resistance and Rn is the normal resistance. When extrapolated to R/Rn = 1, this coupling was consistent with κ/VT3 = 3 × 109 W⋅m−3⋅K−4 where κ is the thermal conductance from the bolometer electrons to the Si phonons and V and T are the volume and transition temperature of the bolometer. The response of the bolometers to heat pulses generated by a thin film heater on the opposite face of a Si single crystal were similar to that generally seen above 1 K, apart from a delay time constant that varied from ∼0.5 to ∼1.3 µs as the transition temperature decreased from 600 to 200 mK. This delay time constant is attributed to the thermal equilibrium time of normal regions of the bolometer.

Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H(+)/K(+)-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H(+)/K(+)-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property. Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them - even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk.Thus, whereas all PPIs have been shown to be generally effective and safely used for the treatment of acid-mediated disorders, there are chemical, pharmacodynamic and pharmacokinetic differences among these drugs that may make certain ones more, or less, suitable for treating different patient subgroups. Of course, the absolute magnitude of risk from any PPI in terms of drug-drug interactions is probably low - excepting interactions occurring as class effects related to acid suppression (e.g. increased digoxin absorption or inability to absorb ketoconazole).

A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg−1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.

Resonance Ionization Mass Spectrometry (RIMS) has nowadays reached the status of a routine method for sensitive and selective ultratrace determination of long-lived radioactive isotopes in environmental, biomedical and technical samples. It provides high isobaric suppression, high to ultra-high isotopic selectivity and good overall efficiency. Experimental detection limits are as low as 106 atoms per sample and permit the fast and sensitive determination of ultratrace amounts of radiotoxic contaminations. Experimental arrangements for the detection of different radiotoxic isotopes, e.g. 236–244Pu, 89,90Sr and 99Tc in environmental samples are described, and the application of RIMS to the ultrarare long-lived radioisotope 41Ca for cosmochemical, radiodating and medical purposes are presented.

The diagnostic potential of technetium-99m hexamethylpropylene amine oxime (HMPAO) following systemic administration of the cerebral vasodilator acetazolamide (acetazolamide test) was evaluated by regional cerebral blood flow (rCBF) single-photon emission tomography (SPET) in patients with Alzheimer’s disease (AD) or vascular dementia (VD). An initial, high-resolution SPET study was performed with 99mTc-HMPAO, and after 2 days the patients were re-evaluated with 99mTc-HMPAO following systemic administration of acetazolamide. Reconstructed SPET slices were evaluated visually and semiquantitatively by a semi-automatic rCBF map method. When 99mTc-HMPAO alone was used, bilateral hypoperfusion was found in the temporal and/or parietal regions in 33% (6/18) of the VD patients and in 70% (23/33) of the AD patients. The corresponding data obtained by quantitative evaluation were 41% (7/17) and 71% (15/21), respectively. The vascular reserve capacity, as determined with the acetazolamide test, was preserved visually in 22% (4/18) and quantitatively in 29% (5/17) of the VD patients, but in 73% (24/33) and 76% (16/21) of the AD patients. The differences in the perfusion patterns between the VD and AD patients were statistically significant (P

Glucagon-like peptide 1 [7-36 amide] (GLP-1) and the obese gene product (leptin) are thought to be involved in the central regulation of feeding. Both may act from the peripheral circulation to influence brain function. To study potential interactions, GLP-1 ([7-36 amide]: 0.4, 0.8 pmol kg-1 min-1 or placebo on separate occasions) was infused intravenously (from -30 to 240 min) into nine healthy volunteers [age 26 +/- 3 years, body mass index: 22.9 +/- 1.6 kg/m2, glycated haemoglobin HbA1c: 5.0% +/- 0.2% (normal: 4.0%-6.2%), creatinine: 1.1 +/- 0.1 mg/dl], and (at 0 min) a liquid test meal (50 g sucrose in 400 ml 8% amino acid, total amino acids 80 g/l) was administered via a nasogastric tube. Plasma leptin (radioimmunoassay, RIA), glucose, insulin (microparticle enzyme immunoassay), C-peptide (enzyme-linked immunosorbent assay) and GLP-1 (RIA) were measured, and statistical analysis was done with repeated-measures ANOVA and Student's t-test. Plasma leptin concentrations were 31 +/- 6 pmol/l in the basal state. They did not change within 240 min after meal ingestion nor in response to the infusion of exogenous GLP-1 [7-36 amide] (P = 0.99 for the interaction of experiment and time) leading to GLP-1 mean plasma levels of 25 +/- 2 and 36 +/- 3 (basal 6 +/- 1) pmol/l. On the other hand, glucose (from basal 4.7 +/- 0.1 to 6.0 +/- 0.2 mmol/l at 15 min, P0.05) and insulin (from basal 28 +/- 2 to 325 +/- 78 pmol/l at 45 min, P0.05) increased clearly after the meal with placebo. In conclusion, (1) plasma leptin levels in normal human subjects show no short-term changes after feeding a liquid mixed meal and (2) do not appear to be directly influenced by physiological and pharmacological elevations in plasma GLP-1 [7-36 amide] concentrations. This does not exclude interactions at the cerebral (hypothalamic) level or on more long-term temporal scales.

The glycoconjugates of hamster epididymis were investigated with conventional and lectin histochemistry. A zone of the caput epididymis, with particular histochemical characteristics, has been differentiated. beta-Elimination in combination with lectins was used to establish the presence and distribution of N- and O-linked glycoconjugates. The epithelium, spermatozoa and the intertubular matrix were rich in glycoconjugates. The Golgi apparatus and stereocilia of the principal cells were intensely positive with HPA, PNA and SBA lectins. beta-Elimination indicated that these cells contained abundant O-linked glycoconjugates. Apical and clear cells presented a common lectin affinity; their reactivities towards WGA and UEA-I were very positive. These cells probably contain abundant N-glycoconjugates. The spermatozoa were stained by periodic acid-Schiff (PAS) and by all the lectins (especially in the acrosome), except by those with an affinity for alpha-L-fucosyl residues; the most intense reaction was found with HPA, WGA, PNA and SBA. Changes in the sperm lectin binding along the ductus were observed: sperm flagellum abruptly acquired WGA and PNA labelling from the posterior caput, and HPA reactivity was negative only in the zone between the caput and the corpus.

The X-ray interference patterns obtained by the divergent beam transmission technique (pseudo Kossel technique in transmission mode) permit an evaluation of high precision. Especially the low resolution triple intersections appearing in the pattern can be utilized for precise determination of lattice constants. For cubic crystals the parameters can be calculated directly using analytical methods. The computer graphics method is also applicable for crystal systems with low symmetry. It is shown on patterns from LiF obtained with Fe-K and Cu-K radiation that the computer graphics method provides a fast way for the precise determination of lattice constants.

The possible increase in total and low-density lipoprotein cholesterol following severe restriction of dietary NaCl was reported in 1990 and and 1991 from three experiments, one in the United States and two in Germany. Each of these experiments lasted only 1 week. To evaluate the clinical side effects we analyzed data collected from patients who completed a course of NaCl-restricted weight reduction at the Duke Diet and Fitness Center. Observations of lipid changes are not available for periods of less than 3 weeks; however, we were able to collect data on lipid and lipoprotein changes from 556 participants 25 days after they were referred for weight reduction. Total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels returned to normal in the majority of obese patients. In our slightly longer observation period in patients on a 1000 mg NaCl restricted diet we found no evidence of hyperlipidemic side effects. We believe that the hyperlipidemia resulting from severe sodium restriction in non-hypertensive, normal-weight individuals is not relevant to the problem of nonpharmacological and diuretic treatment of obese hypertensive patients. In clinically healthy, normal-weight, normotensive individuals severe salt restriction serves no practical or therapeutic purpose.

New polymers with exceptional properties are needed for applications in high-performance structures, novel electrical, optical and electro-optical devices, and for multi-functional smart materials. Concurrently, new computational capabilities and methods for properties prediction and analysis have enabled the study of a variety of polymer chain architectures to examine the principles that govern their high-performance properties. By semi-empirical and ab initio computational methods, flexible, stiff-chain, rigid-rod, and biological structures could be analyzed. Single chain molecular stress-strain curves for axial tension and compression were calculated, and the strain dependence of the molecular modulus and vibrational frequencies were compared to measurements of molecular deformation, such as IR and Raman spectroscopy. However, of special interest is the distinctly different response of alpha-helical biopolymer chains to strain. Indeed, in this study we compare on a theoretical basis the ‘spring-like’ microscopic mechanical response of alpha-helical biopolymers having a reinforcing intra-molecular hydrogen bonding network to analogous synthetic extended chain polymers, especially poly(para-phenylene terephthalamide) (PPTA) [KEVLARTM]. The theoretical verification of the absence of compressive buckling in alpha-helical biopolymer chains rationalizes the molecular elasticity and resistance to ‘kinking’ of those strands, manifested by the prevalence in Nature for coiled coils. The understanding of the structure-tofunction relationship in biopolymers explaining the role of the alpha-helix in these systems as a requirement for superior compressive mechanical properties, may enable new guidance for the synthesis of motifs consistent with molecular frameworks optimized by Nature.

A patient with positive serological HIV-II reactions is presented, who lived for many years in North and West Africa and on the Arabian peninsula, and who developed asthenica, incontinence, gait disturbances, impaired mental function, personality changes and finally spastic paraplegia and peripheral neuropathy. He was shown to have a chronic inflammatory process of the central nervous system with cerebral atrophy.

The oxydation-reduction potential of the feces of nurslings decreases in the first hours of life from a high positive (+ 139 mV) to a low negative level (-152 mV). Under the influence of breast feeding the values decrease to a low positive level (+ 12 mV), with great individual differences. Adding cow-milk-formulas to the breast feeding the potential was further lovered to moderate negative values (-35 mV). With a gradual change of the diet to a mixed one, the potential fell progressively to levels of-300 mV and less. The contents of 6 free amino acids in the aqueous extracts of the feces increased with the beginning of breast feeding (from 256 mg-% dried meconium to 909 mg-% dried feces). They decreased when vegetables were incorporated in the diet (365 mg-%) and then progressively to the level of the feces of adults (152 mg-%). The amino-nitrogen levels behaved similarly. The levels of total-nitrogen decreased from 3% in the meconium to 0.57% with normal mixed diet or in adults. No influence of the different diets was perceptible.

DURING the second cruise of the Atlantic Seal, the Texas Instruments, Inc., contract oceanographic research vessel, a Palaeocene core was taken from the Norwegian basin at 66° 21′ N. and 00° 18′ E. (Fig. 1). The collection and analysis of the core were part of the US Naval Oceanographic Office, Marine Geophysical Survey Project. The occurrence of this core is important for several reasons: it provides knowledge of the diversity of Palaeocene planktonic organisms in a high latitude; and it establishes the existence of a seaway in this part of the North Atlantic in Palaeocene times.

The effect of 4 different flavonoids on the respiratory activity of cytochrome oxidase in rat liver homogenate was measured in vitro using the Warburg apparatus. The results show that 3 compounds of the catechin group are especially active.

The (+)-catechin stimulates the multiplication and the protidic biosynthesis ofP. fluorescens. Its effect seems related to a modification of the terminal respiratory pathway.

Glycosylated hemoglobin (gly-hgb) is widely used as a marker of long term diabetic control (2-3 months), while glycosylated albumin (half-life 14 days) is a marker of short term control (2-4 weeks). We separated glycosylated and non-glycosylated proteins by an affinity column method (Glyc-Affin™, Isolab) and determined levels of albumin (colorimetrically) and transferrin (radial immunodiffusion). Serum was collected from children with type I diabetes before and 10 days after attending a camp session in which blood glucose levels were carefully controlled. Gly-hgb in these subjects ranged from 4.6 to 14.6% (mean ± SEM= 8.1 ± 0.2%). Mean pre-camp gly-alb in 73 subjects was 16.4 ± 0.6% (SEM), which was elevated compared to the mean of levels in 20 non-diabetic control subjects (8.7 ± 0.3% SEM), and correlated well with levels of gly-hgb (r=0.71). After 10 days mean gly-alb fell to 14.6 ± 0.5% (SEM) (p

The dependence of the helix-coil transition on the irradiation time was investigated on desoxyribonucleic acids of varying composition and heterogeneity. The fall of the T/sub m/ value with increasing irradiation time is shown graphically. In heterogeneous DNA types (calf thymus and herring sperm) and in DNA with high GC concentration (Streptomyces chrysomallus), significant anomalies were observed in the T/sub m/ decrease. The heterogeneity of the DNA increases after irradiation, corresponding to a broadening of the thermal transition. (J.S.R.)