Search

Eczema (atopic dermatitis, AD) is a skin disease characterized by skin barrier dysfunction due to various factors, including genetics, immune system abnormalities, and environmental triggers. Application of emollients and topical drugs such as corticosteroids and calcineurin inhibitors form the mainstay of treatments for this challenging condition. This review aims to summarize the recent advances made in phytochemical-based topical applications to treat AD and the different carriers that are being used. In this review, the clinical efficacy of several plant extracts and bioactive phytochemical compounds in treating AD are discussed. The anti-atopic effects of the herbs are evident through improvements in the Scoring Atopic Dermatitis (SCORAD) index, reduced epidermal thickness, decreased transepidermal water loss, and alleviated itching and dryness in individuals affected by AD as well as in AD mouse models. Histopathological studies and serum analyses conducted in AD mouse models demonstrated a reduction in key inflammatory factors, including thymic stromal lymphopoietin (TSLP), serum immunoglobulin E (IgE), and interleukins (IL). Additionally, there was an observed upregulation of the filaggrin (FLG) gene, which regulates the proteins constituting the stratum corneum, the outermost layer of the epidermis. Carriers play a crucial role in topical drug applications, influencing dose delivery, retention, and bioavailability. This discussion delves into the efficacy of various nanocarriers, including liposomes, ethosomes, nanoemulsions, micelles, nanocrystals, solid-lipid nanoparticles, and polymeric nanoparticles. Consequently, the potential long-term side effects such as atrophy, eruptions, lymphoma, pain, and allergic reactions that are associated with current topical treatments, including emollients, topical corticosteroids, topical calcineurin inhibitors, and crisaborole, can potentially be mitigated through the use of phytochemical-based natural topical treatments. [ABSTRACT FROM AUTHOR]

Aims: The gut microbiota modulates dopamine levels in vivo, but the bacteria and biochemical processes responsible remain incompletely characterized. A potential precursor of bacterial dopamine production is 3‐methoxytyramine (3MT); 3MT is produced when dopamine is O‐methylated by host catechol O‐methyltransferase (COMT), thereby attenuating dopamine levels. This study aimed to identify whether gut bacteria are capable of reverting 3MT to dopamine. Methods and Results: Human faecal bacterial communities O‐demethylated 3MT and yielded dopamine. Gut bacteria that mediate this transformation were identified as acetogens Eubacterium limosum and Blautia producta. Upon exposing these acetogens to propyl iodide, a known inhibitor of cobalamin‐dependent O‐demethylases, 3MT O‐demethylation was inhibited. Culturing E. limosum and B. producta with 3MT afforded increased acetate levels as compared with vehicle controls. Conclusions: Gut bacterial acetogens E. limosum and B. producta synthesized dopamine from 3MT. This O‐demethylation of 3MT was likely performed by cobalamin‐dependent O‐demethylases implicated in reductive acetogenesis. Significance and Impact of the Study: This is the first report that gut bacteria can synthesize dopamine by O‐demethylation of 3MT. Owing to 3MT being the product of host COMT attenuating dopamine levels, gut bacteria that reverse this transformation—converting 3MT to dopamine—may act as a counterbalance for dopamine regulation by COMT. [ABSTRACT FROM AUTHOR]

This American Epilepsy Society (AES) official statement provides information and preliminary guidance to Society members related to the U.S. Food & Drug Administration (FDA) December 22, 2021 Emergency Use Authorization for Paxlovid™ for the oral treatment of mild to moderate COVID-19 in adults and children (≥12 years and weighing ≥40 kg). Paxlovid is likely to be widely prescribed, and important considerations for patients on antiseizure medications (ASMs) include key contraindications and potential toxicity or dose adjustments while taking Paxlovid. This statement highlights concerns and provides information about their pharmacologic basis. Of particular concern, concomitant use of Paxlovid with the ASMs carbamazepine, phenobarbital, phenytoin, and primidone is contraindicated, because they are strong inducers of the CYP3A4 isozyme that metabolizes Paxlovid and thereby could cause loss of virologic response and development of resistance. Alternate oral or intravenous COVID-19 treatments should be considered. A second concern is that Paxlovid may increase the plasma concentrations of many ASMs, because it inhibits the CYP3A4 isozyme. ASMs that are metabolized, at least in part, by CYP3A4 include cannabidiol, carbamazepine, clobazam, clonazepam, diazepam, ethosuximide, everolimus, felbamate, lacosamide, midazolam, oxcarbazepine, perampanel, stiripentol, tiagabine, and zonisamide. Patients receiving these medications may warrant closer monitoring while being treated with Paxlovid. [ABSTRACT FROM AUTHOR]

CRX and NRL are retina-specific transcription factors that control rod photoreceptor differentiation and synergistically activate rod phototransduction gene expression. Previous experiments showed they interact in vitro and in yeast two-hybrid assays. Here, we examined CRX-NRL interaction in live HEK293T cells using two fluorescence resonance energy transfer (FRET) approaches: confocal microscopy and flow cytometry (FC-FRET). FC-FRET can provide measurements from many cells having wide donor–acceptor expression ranges. FRET efficiencies were calibrated with a series of donor (EGFP)-acceptor (mCherry) fusion proteins separated with linkers between 6–45 amino acids. CRX and NRL were fused at either terminus with EGFP or mCherry to create fluorescent proteins, and all combinations were tested in transiently transfected cells. FRET signals between CRX or NRL homo-pairs were highest with both fluorophores fused to the DNA binding domains (DBD), lower with both fused to the activation domains (AD), and not significant when fused on opposite termini. NRL had stronger FRET signals than CRX. A significant FRET signal between CRX and NRL hetero-pairs was detected when donor was fused to the CRX DNA binding domain and the acceptor fused to the NRL activation domain. FRET signals increased with CRX or NRL expression levels at a rate much higher than expected for collisional FRET alone. Together, our results show the formation of CRX-NRL complexes in live HEK293T cells that are close enough for FRET. [ABSTRACT FROM AUTHOR]

The brain enhances its perceptual and behavioral decisions by integrating information from its multiple senses in what are believed to be optimal ways. This phenomenon of "multisensory integration" appears to be pre‐conscious, effortless, and highly efficient. The present experiments examined whether experience could modify this seemingly automatic process. Cats were trained in a localization task in which congruent pairs of auditory‐visual stimuli are normally integrated to enhance detection and orientation/approach performance. Consistent with the results of previous studies, animals more reliably detected and approached cross‐modal pairs than their modality‐specific component stimuli, regardless of whether the pairings were novel or familiar. However, when provided evidence that one of the modality‐specific component stimuli had no value (it was not rewarded) animals ceased integrating it with other cues, and it lost its previous ability to enhance approach behaviors. Cross‐modal pairings involving that stimulus failed to elicit enhanced responses even when the paired stimuli were congruent and mutually informative. However, the stimulus regained its ability to enhance responses when it was associated with reward. This suggests that experience can selectively block access of stimuli (i.e., filter inputs) to the multisensory computation. Because this filtering process results in the loss of useful information, its operation and behavioral consequences are not optimal. Nevertheless, the process can be of substantial value in natural environments, rich in dynamic stimuli, by using experience to minimize the impact of stimuli unlikely to be of biological significance, and reducing the complexity of the problem of matching signals across the senses. [ABSTRACT FROM AUTHOR]

• Disability as defined by progressive chronic graft-versus-host disease (GVHD) impairments are associated with decline in human activity profile scores and performance status at 18 months. • Worse oral scores and patient-reported eye and skin scores are significantly associated with progressive chronic GVHD impairment at 18 months. Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome. [ABSTRACT FROM AUTHOR]

Objective: The study assesses the bioavailability of diazepam after intranasal administration (diazepam nasal spray) in healthy volunteers. Comparative agents were diazepam rectal gel, which served as the regulatory reference product; and oral diazepam, a product with decades of clinical use. Tolerability of diazepam nasal spray was also assessed. Methods: This was a phase 1, open‐label, randomized, single‐dose, three‐treatment, three‐period, six‐sequence crossover study in 48 healthy adult subjects that consisted of a screening period, a baseline period, and an open‐label treatment period. Interperiod intervals were at least 28 days. Results: Forty‐eight healthy volunteer subjects were enrolled, two of whom discontinued before receiving study medication. For all routes of administration, the onset of diazepam absorption was rapid, with measurable concentrations of drug present by the first sample time point. The tmax (time to reach maximum plasma concentration) was similar for diazepam nasal spray and diazepam rectal gel, both of which were slower than oral diazepam in fasted individuals. Variability (as defined by % coefficient of variation of geometric mean) in peak plasma concentration and area under the curve0‐∞ was lowest with oral diazepam, followed by diazepam nasal spray, with diazepam rectal gel showing the greatest variability. Overall, 131 treatment‐emergent adverse events (TEAEs) were considered mild (42 subjects, 91.3%), four TEAEs were considered moderate (four subjects, 8.3%), and no TEAEs were considered severe. The most commonly reported TEAE was somnolence at 56.5% (26/46) during diazepam nasal spray treatment, 89.1% (41/46) with the rectal diazepam gel treatment, and 82.6% (38/46) with oral diazepam treatment. No nasal irritation was observed for the majority of the subjects at any time point after administration, with no score higher than 2 ("minor bleeding that stops within 1 minute"). Significance: Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures). [ABSTRACT FROM AUTHOR]

The operation of our multiple and distinct sensory systems has long captured the interest of researchers from multiple disciplines. When the Society was founded 50 years ago to bring neuroscience research under a common banner, sensory research was largely divided along modalityspecific lines. At the time, there were only a few physiological and anatomical observations of the multisensory interactions that powerfully influence our everyday perception. Since then, the neuroscientific study of multisensory integration has increased exponentially in both volume and diversity. From initial studies identifying the overlapping receptive fields of multisensory neurons, to subsequent studies of the spatial and temporal principles that govern the integration of multiple sensory cues, our understanding of this phenomenon at the single-neuron level has expanded to include a variety of dimensions. We now can appreciate how multisensory integration can alter patterns of neural activity in time, and even coordinate activity among populations of neurons across different brain areas. There is now a growing battery of sophisticated empirical and computational techniques that are being used to study this process in a number of models. These advancements have not only enhanced our understanding of this remarkable process in the normal adult brain, but also its underlying circuitry, requirements for development, susceptibility to malfunction, and how its principles may be used to mitigate malfunction. [ABSTRACT FROM AUTHOR]

The article focuses on the diagnostic images of various activity related to sports injuries. It states that athletic trainers and therapists are not well-informed about the theories to support the principle in choosing specific imaging techniques. It mentions that imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT) scan and ultrasound are excellent diagnostic tools in the assessment of musculoskeletal injury.

• Outpatient allogeneic hematopoietic cell transplantation (HCT) in older or infirm patients is feasible and safe. • Nearly half of the recipients remained outpatients throughout the HCT course. • Events leading to hospitalization after HCT increased the risk of nonrelapse mortality (NRM). • Five-year NRM (20%) compared favorably to results reported in the literature. Conditioning with fludarabine and low-dose total-body irradiation before allogeneic hematopoietic cell transplantation (HCT) enabled treating older or medically infirm patients with advanced hematologic malignancies in the outpatient setting. Between December 1997 and June 2017, 1037 patients with hematologic malignancies received peripheral blood stem cell (PBSC) grafts from HLA-matched or 1 HLA antigen/allele-mismatched related or unrelated donors. Median age was 58 (range, 18 to 80) years. Serious comorbidities with Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) scores ≥3 were present in 52% of patients. We found that 47% of patients were either never hospitalized or only had an overnight hospital stay for infusion of late-arriving PBSCs while 53% were admitted for a median of 6 days. Main reasons for admission were infection, fever, graft-versus-host disease, and regimen-related toxicity. Two thirds of admissions occurred within 3 weeks of HCT. The 5-year risk of nonrelapse mortality (NRM) was 26% among hospitalized patients and 13% among nonhospitalized patients. Significant risk factors for hospitalization included unrelated transplants, 1 HLA antigen-mismatched transplant, high HCT-CI scores, and diagnosis of nonmyeloma malignancies. Significant risk factors for NRM were hospitalization, older age, unrelated transplants, and high HCT-CI scores. Ambulatory allogeneic HCT is feasible and safe. [ABSTRACT FROM AUTHOR]

• Data came from 488 patients enrolled in prospective observational studies. • Some objective change measures were associated with overall response assessments. • The sensitivity and specificity parameters of this association need improvement. Assessments of overall improvement and worsening of chronic graft-versus-host disease (GVHD) manifestations by the algorithm recommended by National Institutes of Health (NIH) response criteria do not align closely with those reported by providers, particularly when patients have mixed responses with improvement in some manifestations but worsening in others. To elucidate the changes that influence provider assessment of response, we used logistic regression to generate an overall change index based on specific manifestations of chronic GVHD measured at baseline and 6 months later. We hypothesized that this overall change index would correlate strongly with overall improvement as determined by providers. The analysis included 488 patients from 2 prospective observational studies who were randomly assigned in a 3:2 ratio to discovery and replication cohorts. Changes in bilirubin and scores of the lower gastrointestinal tract, mouth, joint/fascia, lung, and skin were correlated with provider-assessed improvement, suggesting that the main NIH response measures capture relevant information. Conversely, changes in the eye, esophagus, and upper gastrointestinal tract did not correlate with provider-assessed response, suggesting that these scales could be modified or dropped from the NIH response assessment. The area under the receiver operator characteristic curve in the replication cohort was 0.72, indicating that the scoring algorithm for overall change based on NIH response measures is not well calibrated with provider-assessed response. [ABSTRACT FROM AUTHOR]

• An augmented comorbidity/age index comprising the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), age, and serum values of albumin, ferritin, and platelets has a higher predictive power for hematopoietic cell transplantation outcomes among recipients of alternative donor grafts compared with the HCT-CI alone. • There were no significant differences in outcomes among the 3 graft sources in either the low-risk or high-risk groups according to the augmented comorbidity/age index, suggesting the suitability of the current practice of using any available alternative donor graft. The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplantation comorbidities and estimate their impact on post-transplantation risks of nonrelapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and the values of 3 markers: ferritin, albumin, and platelet count. So far, research involving The HCT-CI has been limited almost exclusively to recipients of allogeneic hematopoietic cell transplantation (HCT) from HLA-matched grafts. To this end, we sought to investigate the discriminative capacity of an augmented comorbidity/age index among 724 recipients of allogeneic HCT from HLA-mismatched (n = 345), haploidentical (n = 117), and umbilical cord blood (UCB; n = 262) grafts between 2000 and 2013. In the overall cohort, the augmented comorbidity/age index had a higher c-statistic estimate for prediction of NRM compared with the original HCT-CI (.63 versus.59). Findings were similar for recipients of HLA-mismatched (.62 versus.59), haploidentical (.60 versus.54), or UCB grafts (.65 versus.61). Compared with patients with an HCT-CI score ≥4, those with a score <4 had a higher survival rate among recipients of HLA-mismatched (55% versus 39%; P <.0008), HLA-haploidentical (58% versus 38%; P =.01), or UCB (67% versus 48%; P =.004) grafts. Our results demonstrate the utility of the augmented comorbidity/age index as a valid prognostic tool among recipients of allogeneic HCT from alternative graft sources. [ABSTRACT FROM AUTHOR]

Objective: To determine factors that lead to significant discrepancies in second-opinion consultation of orthopedic oncology patients, and particularly if musculoskeletal fellowship training can decrease clinically significant discrepancies.Methods: A PACS database was queried for secondary reads on outside cross-sectional imaging studies, as requested by orthopedic oncology from 2014 to 2017. Comparison of original and secondary reports was performed using a published seven-point scale that defines clinically significant discrepancies. An online search was performed for each original radiologist to record if a fellowship in musculoskeletal imaging was completed. Additionally, years of post-residency experience, number of Medicare part B patients billed per year (marker of practice volume), and average hierarchical condition category for each radiologist (marker of practice complexity) was recorded.Results: A total of 571 patients met the inclusion criteria, with 184 cases initially interpreted by an outside fellowship trained musculoskeletal (MSK) radiologist and 387 cases initially interpreted by a non-MSK trained radiologist. The rate of clinically significant discrepancy was 9.2% when initially interpreted by MSK radiologists compared with 27.9% when initially performed by non-MSK radiologists (p < 0.05). After adjustment by both patient characteristics and radiologist characteristics, the likelihood of clinically significant discrepancies was greater for initial interpretations by non-MSK radiologists compared with MSK radiologists (OR = 1.36; 95% CI = 1.23-2.49).Conclusion: In orthopedic oncology patients, the rate of clinically significant discrepancies was significantly higher when initially interpreted by non-MSK radiologists compared with MSK radiologists. The lower rate of clinically significant discrepancies demonstrates that subspecialty training may direct more appropriate diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Highlights • Drug–drug interactions (DDIs) may confound the management of patients with epilepsy. • Protein binding displacement often underlies DDIs. • Perampanel is highly protein-bound so it is important to assess any potential DDIs. • Perampanel did not displace phenytoin, valproate, or warfarin, or vice versa. • Perampanel has a low potential for DDIs due to protein binding displacement. Abstract Plasma protein binding and effects on volume of distribution and pharmacologically active, circulating-drug concentrations are complex issues. Protein-binding displacement often underlies drug–drug interactions. Perampanel is a once-daily oral anti-seizure drug for focal seizures and primary generalized tonic-clonic seizures. Perampanel is also indicated for monotherapy use for focal seizures in the United States. Perampanel is extensively but slowly metabolized via CYP3A4. Its elimination t ½ is about 100 h, and it displays substantial plasma protein binding (>95%). Here, we examine perampanel's potential to displace highly bound anti-seizure drugs and the ability of warfarin, a standard highly protein-bound drug, to displace perampanel. Protein binding of perampanel, phenytoin, valproate, and warfarin was assessed using equilibrium dialysis. Plasma samples containing each compound were dialyzed against phosphate buffered saline. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of perampanel. After 24 h equilibrium dialysis, amounts of test compounds were analyzed to calculate plasma protein binding. At clinically relevant concentrations, perampanel did not displace other highly bound drugs or vice versa. Protein-binding displacement may confound therapeutic drug monitoring of extensively protein-bound medications. Without empirical data, clinicians might be concerned that addition of perampanel could alter unbound concentrations of other medications, resulting in adverse effects. Our data indicate perampanel has low potential for drug interactions resulting from protein-binding displacement. [ABSTRACT FROM AUTHOR]

The article focuses on lenders might forgo collectivization and debtors would insist on interest rates possible only if the debtor obtained funds within a capital structure designed to throw the firm to the creditor. It mentions developments in bankruptcy practice and creditor activism and capital market creditors are mere stakeholders to pay for any privilege in the form of lower interest rates. It also mentions collective action problem for individual creditor remedies.

Purpose: To determine the effect of ruptured ectopic pregnancies on the rate of future intrauterine pregnancies.Materials and Methods: This was a retrospective study of patients at a University-affiliated hospital with a history of an ectopic pregnancy between January 1991 to December 2016. All patients that underwent a salpingectomy for a tubal ectopic pregnancy were considered for this study. Intrauterine pregnancy rates for patients with a history of a ruptured ectopic pregnancy were compared to those with non-ruptured ectopic pregnancies. Fisher's exact test was used for analysis.Results: During the study period, 77 patients met the inclusion criteria. In this cohort, 14 patients with a history of a tubal ruptured ectopic pregnancy had achieved pregnancy within 12 months, compared to 24 patients in the non-ruptured group (52% vs 48%, p = 0.81). The rate of intrauterine pregnancies, compared to repeat ectopic pregnancy, in both the ruptured and non-ruptured group, was 71% (p > 0.99).Conclusion(s): Ruptured ectopic pregnancies did not adversely affect the rate of intrauterine pregnancy within 12 months of rupture when compared to non-ruptured ectopic pregnancies. [ABSTRACT FROM AUTHOR]

The conditions for terahertz power generation are investigated theoretically in a nanoscale GaN-based diode coupled to an external resonant circuit for operation in the limited space-charge accumulation (LSA) mode under the high-field transport regime. The generation criteria are revisited in terms of a phase plane analysis of the diode high-field transport and circuit equations. Based on a Fourier series analysis, the waveforms of the diode voltage and current are examined and the generated power and conversion efficiencies are estimated at the fundamental and lowest harmonic frequencies. The advantages of group-III nitride LSA diodes are elucidated including their ability to simultaneously achieve large output powers (>10 mW) and high dc-to-rf conversion efficiencies (>1%) over a wide range of frequencies near 1 THz. [ABSTRACT FROM AUTHOR]

This instalment provides an overview of the modern trends and best practices in mobile-phase selection for reversed-phase liquid chromatography (LC). In particular, we focus on selection criteria and rationales for enhancing analytical performance and ease of preparation. [ABSTRACT FROM AUTHOR]

To compare community diagnoses of Autism Spectrum Disorder (ASD) reported by parents to consensus diagnoses made using standardized tools plus clinical observation. 87 participants (85% male, average age 7.4 years), with reported community diagnosis of ASD were evaluated using the Autism Diagnostic Observation Schedule) (ADOS-2), Differential Ability Scale (DAS-II), and Vineland Adaptive Behavior Scales (VABS-II). Detailed developmental and medical history was obtained from all participants. Diagnosis was based on clinical consensus of at least two expert clinicians, using test results, clinical observations, and parent report. 23% of participants with a reported community diagnosis of ASD were classified as non-spectrum based on our consensus diagnosis. ASD and non-spectrum participants did not differ on age at evaluation and age of first community diagnosis. Non-verbal IQ scores and Adaptive Behavior Composite scores were significantly higher in the non-spectrum group compared to the ASD group (104.5 ± 21.7 vs. 80.1 ± 21.6, p < .01; 71.1 ± 15 versus 79.5 ± 17.6, p < .05, respectively). Participants enrolled with community diagnosis of PDD-NOS were significantly more likely to be classified as non-spectrum on the study consensus diagnosis than Participants with Autism or Asperger (36% versus 9.5%, Odds Ratio = 5.4, p < .05). This study shows suboptimal agreement between community diagnoses of ASD and consensus diagnosis using standardized instruments. These findings are based on limited data, and should be further studied, taking into consideration the influence of DSM 5 diagnostic criteria on ASD prevalence. [ABSTRACT FROM AUTHOR]

The antitrust world before 1890 looks barren when compared with today’s global antitrust industry. The most common antitrust laws in pre-modern societies condemned practices that had the perceived tendency to raise prices: forestalling, hoarding and price fixing. Enforcement was focused on retail markets and trade in essential foodstuffs, like grain. Laws intended to ensure fair prices are common throughout history. Rules prohibiting unfair or excessive prices raise the more general question of price controls in pre-industrial societies. The historical evidence is ambiguous. Laws prohibiting monopolistic or abusive conduct are less clearly evident than anti-cartel laws in pre-industrial societies, although a few references exist. Before the 20th century, courts and authorities lacked the tools of modern economic analysis, like mathematics-based theories of harm. This absence of modern economics meant that there was no clear distinction among “economic,” “social,” “moral” and “political” policy objectives. Laws concerning product quality, consumer fraud and misrepresentations are commonly found in pre-modern societies. Although consumer protection rules were based on notions of fair dealing and justice, the rules were consistent with modern economic notions of transaction cost efficiencies, asymmetric market information and imperfect market information. [ABSTRACT FROM AUTHOR]

English competition law before 1900 developed over many centuries and reflected changes in political conditions, economic theories and social values. It mirrored the historical movements in England, from the medieval ideal of fair prices and just wages to 16th and 17th century nation-state mercantilism to the 18th and 19th century Industrial Revolution and notions of laissez faire capitalism and freedom of contract. English competition law at varying times articulated three fundamental principles: monopolies were disfavored; freedom to trade was emphasized; and fair or reasonable prices were sought. The Sherman Act truly was a watershed that significantly took a different path from English law as it had evolved. In England, legal challenges to monopolization were limited to the royal creation of monopolies and were concentrated in the 17th and early 18th centuries. A prominent element of English competition law—bans on forestalling—was repealed in the first half of the 19th century. Enforcement of English law against cartels was largely emasculated by the end of the 19th century with the ascendancy of freedom of contract and laissez faire political theory. [ABSTRACT FROM AUTHOR]

Summary: Background: Aspirin may reduce the risk of several types of cancer. Objectives: To evaluate if folic acid is associated with risk of basal cell carcinoma (BCC). Methods: BCC incidence was evaluated in a randomized, double‐blind, placebo‐controlled clinical trial of aspirin (81 mg daily or 325 mg daily for ~3 years) and/or folic acid (1 mg daily for ~6 years) for the prevention of colorectal adenomas among 1121 participants with a previous adenoma. BCC was confirmed by blinded review of pathology reports. Results: One hundred and four of 958 non‐Hispanic white participants were diagnosed with BCC over a median follow‐up of 13·5 years. Cumulative incidence of BCC was 12% [95% confidence interval (CI) 7–17] for placebo, 16% (95% CI 11–21) for 81 mg aspirin daily and 15% (95% CI 10–20) for 325 mg aspirin daily [hazard ratio (HR) for any aspirin 1·45 (95% CI 0·93–2·26); HR for 81 mg daily 1·57 (95% CI 0·96–2·56); HR for 325 mg daily 1·33 (95% CI 0·80–2·20)]. BCC risk was higher with aspirin use in those without previous skin cancer but lower with aspirin use in those with previous skin cancer (Pinteraction = 0·02 for 81 mg aspirin daily; Pinteraction = 0·03 for 325 mg aspirin daily). Folic acid supplementation was unrelated to BCC incidence (HR 0·85; 95% CI 0·57–1·27). Conclusions: Neither aspirin nor folic acid treatment had a statistically significant effect on risk of BCC. Subgroup analysis suggested that chemopreventive effects of nonsteroidal anti‐inflammatory drugs may be specific to those at high risk for BCC. [ABSTRACT FROM AUTHOR]

The ability to integrate information across multiple senses enhances the brain’s ability to detect, localize, and identify external events. This process has been well documented in single neurons in the superior colliculus (SC), which synthesize concordant combinations of visual, auditory, and/or somatosensory signals to enhance the vigor of their responses. This increases the physiological salience of crossmodal events and, in turn, the speed and accuracy of SC-mediated behavioral responses to them. However, this capability is not an innate feature of the circuit and only develops postnatally alter the animal acquires sufficient experience with covariant crossmodal events to form links between their modality-specific components. Of critical importance in this process are tectopetal influences from association cortex. Recent findings suggest that, despite its intuitive appeal, a simple generic associative rule cannot explain how this circuit develops its ability to integrate those crossmodal inputs to produce enhanced multisensory responses. The present neurocomputational model explains how this development can be understood as a transition from a default state in which crossmodal SC inputs interact competitively to one in which they interact cooperatively. Crucial to this transition is the operation of a learning rule requiring coactivation among tectopetal afferents for engagement. The model successfully replicates findings of multisensory development in normal cats and cats of either sex reared with special experience. In doing so, it explains how the cortico-SC projections can use crossmodal experience to craft the multisensory integration capabilities of the SC and adapt them to the environment in which they will be used. [ABSTRACT FROM AUTHOR]

A lack of effective treatment is one of the main factors contributing to gastric cancer--related death. Discovering effective targets and understanding their underlying anti-cancer mechanism are key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis.Wealso observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagy- and mitophagy-associated proteins (i.e. ATGs, LC3A/B II, and BNIP3). Moreover, we found that TRPM2 modulates autophagy through a c-Jun N-terminal kinase (JNK)-dependent and mechanistic target of rapamycin-independent pathway.Weconclude that in the absence of TRPM2, down-regulation of the JNK-signaling pathway impairs autophagy, ultimately causing the accumulation of damaged mitochondria and death of gastric cancer cells. Of note, by inhibiting cell proliferation and promoting apoptosis, the TRPM2 down-regulation enhanced the efficacy of paclitaxel and doxorubicin in gastric cancer cells. Collectively, we provide compelling evidence that TRPM2 inhibition may benefit therapeutic approaches for managing gastric cancer. [ABSTRACT FROM AUTHOR]

Given the complexities managing Lennox–Gastaut syndrome (LGS)—comorbid conditions, multiple associated seizure types that tend to be refractory to treatment—dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal clobazam lead-in studies. During the lead-in studies, patients received either placebo or clobazam (0.25, 0.50, or 1.0 mg/kg/d) (maximum 40 mg/d); during OLE, patients received clobazam up to 2.0 mg/kg/d (maximum 80 mg/d). The post hoc analysis population comprised patients who had ≥ 25%, ≥ 50%, or ≥ 75% seizure reduction from baseline during lead-in clobazam treatment and ≥ 12 months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥ 20% clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or > 50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in clobazam dosage received. The findings of the analysis indicated that clobazam dosage increases of ≥ 20% during long-term treatment improved seizure control > 80% of patients with LGS who responded to clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥ 75%) lead-in response. [ABSTRACT FROM AUTHOR]

There has been growing recognition of the possible abuse potential of newer generation antiepileptic drugs, and several of these agents have been categorized as controlled substances in the United States. To properly schedule a new medication, the abuse potential, or the potential for a drug to be used for its nonmedical positive subjective effects, must be determined. Performing a human abuse potential study is one step in the overall abuse potential assessment. These studies analyze the abuse potential of a new drug in a very specific population of known recreational drug users. Studying the test drug in this population enables a more meaningful assessment of abuse, and likely represents the population most probable to abuse. In these double-blind, single-dose, active and placebo controlled studies subjects may report their subjective liking, estimated street value, and rate euphoric or depressive sensations of the test drug compared with placebo and scheduled active comparators with a known abuse potential. In order to provide an enhanced understanding of the abuse potential assessment and how it relates to controlled substance scheduling, this review will examine the human abuse potential studies of perampanel, eslicarbazepine, lacosamide, and brivaracetam. [ABSTRACT FROM AUTHOR]

We have measured the activity patterns of wintering Green Sandpipers before and after they were fitted with geolocators attached using leg loop harnesses and compared these with a control group of untagged birds. The geolocators and harnesses represented 1.4-1.6% of the body mass of the birds. Although the proportion of time the birds spent feeding increased over the course of the winter, we found no significant effect of tagging. Tagged birds spent significantly more time preening than untagged birds (6.3% overall compared with 4.6% for untagged birds) but the effect decreased with days after tagging. There was no evidence that this small increase in preening activity led to lower survival of the birds or changes in their migration timetable. [ABSTRACT FROM AUTHOR]

Laws, like gardens, need occasional pruning to remove doctrinal clutter and costly weeds. The attempt to monopolize provision of Section 2 of the Sherman Act is a prime candidate for pruning and should be repealed. The decriminalization of Section 2 makes the attempt to monopolize provision no longer appropriate. The attempt provision fills no important gap in antitrust enforcement and generates unnecessary and significant costs and doctrinal complexities that burden litigation. So long as the attempt to monopolize provision remains in place, courts should discard specific intent as an element of the claim. "Specific intent" is incoherent, confusing, potentially prejudicial, and an unnecessary legal fiction. It erroneously suggests to the factfinder that an intention to gain monopoly power itself makes the challenged conduct an unlawful attempt to monopolize. Evidence of subjective intention (state of mind) should be admissible only as relevant to a specific material issue such as the legitimacy of asserted business justifications or competitive effects. The probative weight of evidence of intent or state of mind should be limited to the issue for which it was admitted. [ABSTRACT FROM AUTHOR]

• Concurrent use of both antidepressants and atypical antipsychotic drugs is common in veterans with epilepsy. • Use of enzyme-inducing ASMs poses a theoretical risk of pharmacokinetic interactions that may complicate therapy. • A surrogate marker for diminished treatment response could be increased psychotropic drug doses, or increased use of augmentation. • Contrary to our hypotheses, patients receiving enzyme-inducing ASMs did not appear to receive either increased psychiatric medication daily doses, or polytherapy with antidepressants and atypical antipsychotic medications. • These findings call into question the clinical relevance of these pharmacokinetic interactions. Patients with epilepsy are likely to suffer from psychiatric comorbidities, including depression and anxiety. They often require treatment with multiple psychotropic drugs (PDs). While it is clear that CYP-inducing ASMs (EIASMs) can increase the oral clearance of multiple medications (thus lowering systemic exposure), it is less clear that all PK interactions are clinically meaningful (e.g. lower efficacy). As a first step in addressing this issue, this study sought to quantify the potential impact of ASM choice, whether EIASM or non-inducer (NIASM), on surrogate markers of suggestive of clinical use, including resultant antidepressant (AD) or antipsychotic (AP) dose, frequency of combination use of AD & AP, and number of multiple drug switches of PDs. Our hypothesis is that because of PK interactions, EIAED treatment would be associated with higher psychotropic drug doses, more frequent Rx adjustments and poly psychotropic comedication, all in order to optimize therapeutic response. Using VA pharmacy and national encounter databases, veterans with epilepsy were identified based on having a seizure diagnosis and being prescribed concomitantly an ASM and a psychotropic drug for at least 365 days between 10/1/2010 and 9/30/2014. Patients for whom psychotropic drugs were prescribed any time between beginning and end prescriptions dates of ASMs were considered. Among those, patients receiving both an EIASM + NEIASM concomitantly were categorized with the EIASM group. Patients were evaluated for AD only, AP only and both (AD & AP). To compute average drug doses per day, averages for each patient were computed and averaged again. Multiple drug switches were defined to be for patients who had been prescribed more than three psychotropic drugs during the observation period. Pearson's Chi-Square test was used to compare relative proportions of AD, AP and AD + AP in both groups. In all, 16,188 patients were identified (57.0% on EIASM, 43.0% on NIASM) with a mean age of 58.7 years (91.2% male). A larger proportion of patients on EIASM received mono treatment with any psychotropic drug, as compared to NIASM (42.0% vs 36.1%). Among all, 59.6% received AD only, 6.5% received AP only, and 33.8% received both concurrently. Of EIASM, 62.5% were on AD, 5.9% on AP, and 31.7% on both AP & AD. For NIASM, 55.9% received AD, 7.4% AP, and 36.7% on AD & AP. Chi-square showed that the distribution of PD was statistically different between EIASM and NIASM groups. Z tests showed that each difference (AD, AP and both) in proportions was statistically significant (p values (4 tests, one Chi-square, 3 Z tests <0.001) between EIASM vs NIASM. Interestingly, mean doses of AD or AP did not appear to differ between ASM groups. Concurrent psychotropic drug use is quite common in the VA population with epilepsy, and a large number of patients still receive enzyme-inducing ASMs that may complicate other medical therapies. Interestingly, in seeming contradiction to our hypothesis, mean daily doses of either AD or AP did not appear to differ between inducers vs non-inducers. Similarly, use of polytherapy, and/or multiple trials of various psychotropic drugs did not appear increased in the CYP-induced group. In fact, combination therapy of AD + AP was higher in NIASM than EIASM. These data suggest that perhaps these types of PK interactions may not in fact result in meaningful clinical differences. Since the present analyses did not include clinical psychiatric measures, future analyses examining direct clinical outcomes are clearly warranted. [ABSTRACT FROM AUTHOR]

Introduction Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects. Methods This was a Phase I, single-center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40 mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1–4); treatment B: titration of ESL (400–800 mg once daily) on Days 5–18, followed by ESL 1200 mg once daily on Days 19–35, with a single dose of rosuvastatin (40 mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study. Results Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t 1/2 was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3] h, and 22.4 [9.5] h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: C max , 64.0% (55.9–73.3%); AUC (0–∞) , 63.0% (57.1–69.4%); and AUC (0–last) , 60.9% (55.2–67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated. Conclusions Rosuvastatin exposure was 36–39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted. [ABSTRACT FROM AUTHOR]

Objectives Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12 years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t 1/2 ) averaging approximately 105 h. Understanding of pharmacokinetic (PK) interactions—enzyme inhibition or induction—and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. Methods A Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of perampanel (Day 1); in the other period, subjects received ketoconazole 400 mg once daily for 10 days with a single 1-mg perampanel dose while fasting (Day 3). Blood samples were drawn at multiple time points up to 288 h after the perampanel dose. Pharmacokinetic parameters of perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp ® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of perampanel in the presence or absence of concomitant ketoconazole. Results Single oral doses of 1 mg perampanel and once-daily oral doses of ketoconazole 400 mg were safe and well tolerated. Maximum perampanel plasma concentration (C max ) and time to C max showed no apparent differences when perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in perampanel AUC ( P < 0.001). This increase, although statistically significant, was a < 2.0-fold AUC change and alone would suggest a modest effect of ketoconazole. To further explore these results, DDI simulations were performed to query the findings and test additional study conditions. Using the actual trial conditions of Study 005, the simulations also predicted an AUC ratio increase <2-fold, providing verification of the simulation assumptions and the modest effect of ketoconazole for 10 days. Simulations further suggested that an interaction effect of ketoconazole on perampanel exposure (>2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200 mg every 6 h) coadministered for a greater time period (e.g., 30 days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. Conclusions Selecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as perampanel that have a long t 1/2 . Although a negligible effect on perampanel PK was observed following co-administration of ketoconazole 400 mg/day for 10 days, this is likely due in part to the relatively brief co-administration period of ketoconazole and perampanel (<3 times the t 1/2 of perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor. [ABSTRACT FROM AUTHOR]

No gold standard has been established as a primary endpoint in trials of initial treatment of chronic graft-versus-host disease (GVHD), and evidence showing the association of any proposed primary endpoint with clinical benefit has not been conclusively demonstrated. To address this gap, we analyzed outcomes in a cohort of 328 patients enrolled in a prospective, multicenter, observational study within 3 months after diagnosis of chronic GVHD. Complete and partial response, stable disease, and progressive disease were defined according to the 2014 National Institutes of Health Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease. Success was defined as complete or partial response with no secondary systemic treatment or recurrent malignancy at 1 year after enrollment. Success was observed in fewer than 20% of the patients. The burden of disease manifestations at 1 year was lower for patients in this category than for those with stable or progressive disease. Systemic treatment ended earlier, and subsequent mortality was lower among patients with complete or partial response than among those with stable or progressive disease and those who had received secondary systemic treatment. We conclude that survival with a complete or partial response and no previous secondary systemic treatment or recurrent malignancy at 1 year after initial systemic therapy is associated with clinical benefit, a critical characteristic for consideration as a primary endpoint in a pivotal clinical trial. This prospective observational study was registered at www.clinicaltrials.gov as #NCT00637689. [ABSTRACT FROM AUTHOR]

It was a great and humbling honor to receive the 2016 Distinguished Career Award from my SSIB colleagues. This paper summarizes the major points of my DCA talk at the 2016 annual meeting. It is a reflection on my 50 year medical and research career and 10 lessons I have learned over those years which might be of help to young investigators near the beginning of their own research careers. These lessons include: the value of being receptive to the opportunities provided you; how clinician-scientists can serve as critical role models for young investigators like me and a history of how my career developed as a result of their influence; the importance of carefully examining your own data, particularly when it doesn't agree with your preconceived ideas; the critical role that students, postdocs and PhD (and even veterinarian) colleagues can play in developing one's career; the likelihood that your career path will have many interesting twists and turns determined by changes in your own scientific interests and how rewarding various areas of research focus are to you; the importance of building a close-knit laboratory staff family; the fact that science and romance can mix. Finally, I offer 3 somewhat self-evident free pieces of advice for building and maintaining a rewarding career. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of β2-adrenoceptor-mediated vasodilation in smokers and never smokers.Methods: In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 μg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived.Results: Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02).Conclusions: These results are consistent with a dysfunction in a β2-adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium. [ABSTRACT FROM AUTHOR]

While the regulation of energy homeostasis by amylin is already well-characterized, emerging data suggest that amylin is also crucial for the development of neural pathways in the hypothalamus and caudal hindbrain (area postrema, AP; nucleus tractus solitarius, NTS). Exciting new findings demonstrate crucial amylin–leptin interactions in altering the activity of specific hypothalamic and AP neurons, and a role for amylin as a novel class of ‘leptin sensitizers’ which enhance leptin signaling in both leptin-sensitive and -resistant individuals, in part by stimulating IL-6 production by hypothalamic microglia. This review summarizes these findings and provides a hypothetical framework for future studies to elucidate the mechanisms by which amylin and leptin act individually and as co-conspirators to alter energy homeostasis and neuronal development. [ABSTRACT FROM AUTHOR]

Objective For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t 1/2eff ) may be a more clinically relevant parameter than elimination half-life (t 1/2z ). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate- and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations. Methods The t 1/2z and t 1/2eff for USL255 and TPM-IR were compared using data from a phase I study (N = 36) of 200 mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t 1/2z was investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR. Results As previously reported, mean t 1/2z was similar between USL255 (80.2 h) and TPM-IR (82.8 h); TPM-IR t 1/2z was ∼4 times longer than reported in the Topamax label (21 h). In contrast, USL255 displayed a 1.5 fold longer t 1/2eff (55.7 vs 37.1 h for TPM-IR). When t 1/2z was calculated from 48 to 336 h, values ranged from 28.8 to 82.8 h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID. Significance As expected for the same moiety, t 1/2z of USL255 and TPM-IR were similar; however, the longer t 1/2eff for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t 1/2z , diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t 1/2z discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t 1/2z , taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t 1/2z may be less clinically meaningful than t 1/2eff, and using t 1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD + ) is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, cell growth, and cell death. Many of these pathways are typically dysregulated in cancer cells, making NAD + an intriguing target for cancer therapeutics. NAD + is mainly synthesized by the NAD + salvage pathway in cancer cells, and not surprisingly, the pharmacological targeting of the NAD + salvage pathway causes cancer cell cytotoxicity in vitro and in vivo . Several studies have described the precise consequences of NAD + depletion on cancer biology, and have demonstrated that NAD+ depletion results in depletion of energy levels through lowered rates of glycolysis, reduced citric acid cycle activity, and decreased oxidative phosphorylation. Additionally, depletion of NAD + causes sensitization of cancer cells to oxidative damage by disruption of the anti-oxidant defense system, decreased cell proliferation, and initiation of cell death through manipulation of cell signaling pathways (e.g., SIRT1 and p53). Recently, studies have explored the effect of well-known cancer therapeutics in combination with pharmacological depletion of NAD + levels, and found in many cases a synergistic effect on cancer cell cytotoxicity. In this context, we will discuss the effects of NAD + salvage pathway inhibition on cancer cell biology and provide insight on this pathway as a novel anti-cancer therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) has a high risk of recurrence after initial surgical therapy. Adjuvant radiation therapy (RT) and chemotherapy may be used to reduce the risk of locoregional and systemic recurrence, respectively, but there are conflicting data regarding their impact on survival. We performed a retrospective analysis of MCC cases from the National Cancer Data Base (NCDB) to assess whether adjuvant therapy was associated with differences in survival.Methods: Six thousand nine hundred and eight MCC patients with staging, treatment, and survival data were included. Multivariable analyses were conducted for overall survival (OS) with various treatment modalities while adjusting for prognostic variables including age, sex, comorbidities (Charlson/Deyo score), margin status, primary tumor site and size, and lymph node status. All statistical tests were two-sided.Results: For localized MCC (stage I: n = 3369, stage II: n = 1474 ), surgery plus adjuvant RT was associated with statistically significantly better OS than with surgery alone in multivariable analyses (stage I: hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.80, P < .001; stage II: HR = 0.77, 95% CI = 0.66 to 0.89, P < .001). In patients with regional nodal metastases (stage III: n = 2065 ), neither adjuvant RT nor chemotherapy was associated with statistically significantly improved or worsened OS.Conclusions: In this study of the largest MCC cohort reported to date, adjuvant RT was associated with improved OS in stages I-II MCC. Neither adjuvant RT nor chemotherapy was associated with improved OS in stage III MCC. These results, with the limitations of retrospective analyses, are consistent with earlier studies suggesting benefit with adjuvant RT but do not support the routine use of adjuvant chemotherapy in MCC. [ABSTRACT FROM AUTHOR]

Obesity and Type 2 diabetes are major worldwide public health issues today. A relationship between total fat intake and obesity has been found. In addition, the mechanisms of long-term and excessive high-fat diet (HFD) intake in the development of obesity still need to be elucidated. The ventromedial hypothalamus (VMH) is a major site involved in the regulation of glucose and energy homeostasis where "metabolic sensing neurons" integrate metabolic signals from the periphery. Among these signals, fatty acids (FA) modulate the activity of VMH neurons using the FA translocator/CD36, which plays a critical role in the regulation of energy and glucose homeostasis. During low-fat diet (LFD) intake, FA are oxidized by VMH astrocytes to fuel their ongoing metabolic needs. However, HFD intake causes VMH astrocytes to use FA to generate ketone bodies. We postulate that these astrocyte-derived ketone bodies are exported to neurons where they produce excess ATP and reactive oxygen species, which override CD36-mediated FA sensing and act as a signal to decrease short-term food intake. On a HFD, VMH astrocyte-produced ketones reduce elevated caloric intake to LFD levels after 3 days in rats genetically predisposed to resist (DR) diet-induced obesity (DIO), but not leptin-resistant DIO rats. This suggests that, while VMH ketone production on a HFD can contribute to protection from obesity, the inherent leptin resistance overrides this inhibitory action of ketone bodies on food intake. Thus, astrocytes and neurons form a tight metabolic unit that is able to monitor circulating nutrients to alter food intake and energy homeostasis. [ABSTRACT FROM AUTHOR]

Fatty acid (FA) -sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy and glucose homeostasis including feeding behavior, secretion insulin and action. Subpopulations of neurons in the arcuate and ventromedial hypothalamic nuclei are selectively either activated or inhibited by FA. Molecular effectors of these FA effects include ion channels such as chloride, potassium or calcium. In addition, at least half of the responses in the hypothalamic ventromedial FA neurons are mediated through interaction with the FA translocator/receptor, FAT/CD36, that does not require metabolism to activate intracellular signaling downstream. Recently, an important role of lipoprotein lipase in FA detection has also been demonstrated not only in the hypothalamus, but also in the hippocampus and striatum. Finally, FA could overload energy homeostasis via increased hypothalamic ceramide synthesis which could, in turn, contribute to the pathogenesis of diabetes of obesity and/or type 2 in predisposed individuals by disrupting the endocrine signaling pathways of insulin and/or leptin. [ABSTRACT FROM AUTHOR]

Rats selectively bred to develop diet-induced obesity (DIO) were compared with those bred to be diet resistant (DR) on a 31% fat high-energy diet with regard to their central leptin signaling and blood-brain barrier (BBB) transport. Peripheral leptin injection (15mg/kg ip) into lean 4 to 5-wk-old rats produced 54% less anorexia in DIO than DR rats. DIO rats also had 21, 63, and 64% less leptin-induced immunoreactive phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expression in the hypothalamic arcuate, ventromedial, and dorsomedial nuclei, respectively. However, hindbrain leptin-induced nucleus tractus solitarius pSTAT3 and generalized sympathetic (24-h urine norepinephrine) activation were comparable. Reduced central leptin signaling was not due to defective BBB transport since transport did not differ between lean 4- to 5-wk-old DIO and DR rats. Conversely, DIO leptin BBB transport was reduced when they became obese at 23 wk of age on low-fat chow or after 6 wk on high-energy diet. In addition, leptin receptor mRNA expression was 23% lower in the arcuate nuclei of 4- to 5-wk-old DIO compared with DR rats. Thus a preexisting reduction in hypothalamic but not brain stem leptin signaling might contribute to the development of DIO when dietary fat and caloric density are increased. Defects in leptin transport appear to be an acquired defect associated with the development of obesity and possibly age. [ABSTRACT FROM AUTHOR]

The article discusses information about the activities of the Agency for Toxic Substances and Disease Registry at the U.S. Centers for Disease Control and Prevention (CDC) to further understand the ties between exposure to hazardous substances in the environment, its impact on human health, and how to protect public health. Topics mentioned include the Pandemic and All-Hazards Preparedness Act of 2006, CDC's Social Vulnerability Index database tool, and U.S. vulnerability at county level.

The haematopoietic cell transplantation-specific comorbidity index ( HCT- CI) was developed in a single centre as a weighted scoring system to predict risks of non-relapse mortality ( NRM) following allogeneic haematopoietic cell transplantation. Information on the performance of the HCT- CI in multi-centre studies is lacking in the literature. To that end, a collaborative multicentre retrospective study was initiated. Comorbidity data from 2523 consecutive recipients of human leucocyte antigen-matched grafts from five different US institutions were analysed. Among all patients, HCT- CI scores of 0 vs. 1-2 vs. ≥3 were associated with 2-year NRM rates of 14%, 23% and 39% ( P < 0·0001), respectively, and 2-year overall survival ( OS) rates of 74%, 61% and 39%, respectively ( P < 0·0001). Using regression models, increasing HCT- CI scores were independently associated with increases in hazard ratios for NRM and worse survival within individual institutions. The HCT- CI retained independent capacity for association with outcomes within different age as well as conditioning intensity groups. C-statistic estimates for the prognostic power of the HCT- CI for NRM and OS were 0·66 and 0·64, respectively. The estimates within each institution were overall similar. The HCT- CI is a valid tool for capturing comorbidities and predicting mortality after haematopoietic cell transplantation across different institutions. [ABSTRACT FROM AUTHOR]