cssi/SciSciGPT-SciSciNet huggingface dataset:
Erythema multiforme associated with phenytoin and cranial radiation therapy: a report of three patients and review of the literature.

Background Intracranial malignancies (primary and metastatic) are often complicated by seizure activity. Phenytoin (Dilantin) is typically employed as prophylactic anticonvulsant in this setting. Uncommonly, erythema multiforme (EM) can develop in such patients at the port site during or soon after cranial radiation and can rapidly progress to EM major. Herein, in addition to a comprehensive literature review of this entity, three additional patients are presented. The acronym ‘EMPACT’ is suggested (E: erythema; M: multiforme; associated with P: phenytoin; A: and; C: cranial, radiation; T: therapy) to best describe this disorder. Methods An extensive review of the English medical literature through the National Library of Medicine (PUBMED) was performed to identify patients who had received or continued to receive radiation therapy while on phenytoin. A total of 24 patients were identified and clinical information of varying detail was available in all cases. Clinical and histological information on three additional patients seen at two institutions (Rochester Methodist Hospital, Rochester, MN, and Fairview-University Medical Center, Minneapolis, MN) by the authors were also compiled. Results The mean age was 44 years (range: 23–67) and no sexual predisposition was noted. All patients had taken phenytoin for variable time periods (range 16–80 days; mean: 40) and were on the medication when the skin lesions first appeared. These lesions developed within the port site during the radiation treatments (11 cases) or soon after (nine cases) its completion (mean: 16 days; range: 2–35). Subsequent disease evolution to EM major occurred in all cases (Stevens–Johnsons syndrome developed in 73% of patients). No relationship was identified between the extent and the severity of the skin lesions with the phenytoin and radiation dosages and with the histologic type and origin of the intracranial malignancy. None of the patients demonstrated the requisite features of the ‘Dilantin hypersensitivity syndrome’. Although, a systemic steroid taper was employed in 10 out of the 14 patients before the development of the skin lesions, the subsequent progression of the skin lesions was not influenced by the use of systemic steroid therapy. Complete recovery occurred in all but two patients typically within 1–8 weeks of discontinuation of phenytoin. Conclusions The need for prophylactic anticonvulsant therapy especially utilizing phenytoin in patients undergoing cranial radiation therapy should be assessed on a case by case basis. If anticonvulsants are employed, then they must be administered with caution, and all cutaneous reactions developing subsequently within the radiation site must be promptly evaluated with a high index of suspicion for erythema multiforme.
Neuropsychological correlates of early symptoms of autism.

Both the medial temporal lobe and dorsolateral prefrontal cortex have been implicated in autism. In the present study, performance on two neuropsychological tasks-one tapping the medial temporal lobe and related limbic structures, and another tapping the dorsolateral prefrontal cortex-was examined in relation to performance on tasks assessing autistic symptoms in young children with autism, and developmentally matched groups of children with Down syndrome or typical development. Autistic symptoms included orienting to social stimuli, immediate and deferred motor imitation, shared attention, responses to emotional stimuli, and symbolic play. Compared with children with Down syndrome and typically developing children, children with autism performed significantly worse on both the medial temporal lobe and dorsolateral prefrontal tasks, and on tasks assessing symptoms domains. For children with autism, the severity of autistic symptoms was strongly and consistently correlated with performance on the medial temporal lobe task, but not the dorsolateral prefrontal task. The hypothesis that autism is related to dysfunction of the medial temporal lobe and related limbic structures, such as the orbital prefrontal cortex, is discussed.
Analysis of gene-specific DNA damage and repair using quantitative polymerase chain reaction.

Soon after discovery of the polymerase chain reaction (PCR), various laboratories have attempted to use quantitative PCR (QPCR) to detect DNA damage in specific gene segments. The development of techniques that facilitate long PCR increased the sensitivity of the assay so that biologically relevant doses of DNA-damaging agents could be assessed. QPCR has been used to survey DNA damage induced by different genotoxicants and to establish the repair kinetics of numerous genes. Current work seeks to analyze damage and repair in specific genes from animals exposed to specific DNA-damaging agents such as oxidative stress.
A Probabilistic Approach to Determining the Number of Units to Build in a Yield-Constrained Process

Many cost estimating problems involve determining the number of units to build in a yield-constrained manufacturing process, when it takes, on average, n attempts to produce m successes (m ≤ n). Examples include computer chips, focal plane arrays, circuit boards, field programmable gate arrays, etc. The simplistic approach to this problem is to multiply the number of units needed, m, by the expected number of attempts needed to produce a single success, n. For example, if a contractor reports that it takes, on average, 10 attempts to build one working unit, and if four such units are needed for a space-borne application, then the simplistic approach would be to plan for 4 × 10 = 40 units, and estimate the cost accordingly. However, if the cost analyst uses the simplistic approach, he or she is likely to be disappointed, as the probability that 40 attempts will actually produce four working units is only about 57%. Consequently, there is a 43% probability that 40 attempts will be insufficient. In fact, if ...
USDA regulatory guidelines and practices for veterinary Leptospira vaccine potency testing

Batch-release potency testing of leptospiral vaccines licensed by the United States Department of Agriculture (USDA) historically was conducted through animal vaccination-challenge models. The hamster vaccination-challenge assay was Codified in 1974 for bacterins containing Leptospira pomona, Leptospira icterohaemorrhagiae, and Leptospira canicola, and in 1975 for bacterins containing Leptospira grippotyphosa. In brief, 10 hamsters are vaccinated with a specified dilution of bacterin. After a holding period, the vaccinated hamsters, as well as nonvaccinated controls, are challenged with virulent Leptospira and observed for mortality. Eighty percent of vaccinated hamsters must survive in the face of a valid challenge. The high cost of the Codified tests, in terms of monetary expense and animal welfare, prompted the Center for Veterinary Biologics (CVB) to develop ELISA alternatives for them. Potency tests for other serogroups, such as Leptospira hardjo-bovis, that do not have Codified requirements for potency testing continue to be examined on a case-by-case basis.
Identifying “Worst Case” Persistence Factors for Carbon Monoxide Modeling Near Intersections in Orlando, Florida

At-grade intersections of busy roadways are places where carbon monoxide (CO) concentrations tend to accumulate. Modeling the 8-hour "worst-case" CO concentration (C8WC) often is done by multiplying a worst-case 1-hour CO concentration (C1WC) by a total persistence factor (TPF). The TPF reflects the fact that both emissions and meteorology vary (and result in lower CO concentrations) over an eight-hour period as compared with the peak 1-hour modeled conditions. A computer tape with hourly meteorological observations and stability classes for Orlando, Florida, was obtained from the National Climatic Data Center. The data Were grouped into 18-hour days (6:00 a.m. to midnight) for a ten-year period. Eight-hour turning movement data from several intersections were analyzed and a composite, 18-hour turning movement traffic scenario was developed for this study. The intersection model, TEXIN2, was run with the traffic scenario and historical hourly meteorological data to develop (modeled) daily peak 1-hour CO c...
Extension and Representation of Divergence-free Vector Fields on Bounded Domains

(1.1) gj(x) := x− yj |x− yj |n , x ∈ Rn \ {yj}. Let Hs,p denote the usual scale of Lp-Sobolev spaces, and denote by div and Div the divergence of 1-tensors (i.e., vector fields) and 2-tensors, respectively. Given a divergence-free vector field u on Ω, possessing a certain regularity, e.g., u ∈ Hs,p(Ω), we want to investigate two closely related problems. One is to extend u to a divergence-free vector field ũ defined on a neighborhood of Ω (in fact, defined on Rn \{yj}), such that ũ is as smooth as u. The second is to produce an anti-symmetric 2-tensor field v such that (1.2) u = Div v + ∑
Phenotypic plasticity and the epigenetics of human disease

It is becoming clear that epigenetic changes are involved in human disease as well as during normal development. A unifying theme of disease epigenetics is defects in phenotypic plasticity--cells' ability to change their behaviour in response to internal or external environmental cues. This model proposes that hereditary disorders of the epigenetic apparatus lead to developmental defects, that cancer epigenetics involves disruption of the stem-cell programme, and that common diseases with late-onset phenotypes involve interactions between the epigenome, the genome and the environment. Increased understanding of epigenetic-disease mechanisms could lead to disease-risk stratification for targeted intervention and to targeted therapies.
MARKOV CHAINS, IMPERFECT STATE INFORMATION, AND BAYESIAN LEARNING

Abstract Consider a system whose behavior over time is governed by a Markov chain with unknown transition probabilities. Suppose that a Bayesian investigator attempts to learn about the transition probabilities by observing the system's evolution. However, let the sequence of observations (possibly) convey impefect information about the exact state of the system at each date. Now ask: What implications will this have for Bayesian learning? In addressing this question the present paper focuses on three distinct issues. The first issue concerns the form of the Bayesian posterior distribution. The second issue centers on the computation of the first moment of this distribution. The third issue discusses the asymptotic behavior of the posterior sequence.
Pharmacological specificity of synaptosomal and synaptic membrane γ-aminobutyric acid (GABA) transport processes☆

Abstract Amino cyclopentane and amino cyclohexane carboxylic acids were examined as potential inhibitors of γ-aminobutyric acid (GABA) uptake in brain synaptosomes and in synaptic membrane vesicles. The resealed synaptic plasma membrane vesicle preparation was used extensively in determining the potency inhibition of GABA uptake by these agents and in comparing their activities to the activities of various acyclic GABA analogs and to analogs of piperidyl-3-carboxylic acid (nipecotic acid). A number of the cyclic and acyclic GABA analogs also stimulated the carrier-mediated efflux of [ 3 b]GABA from preloaded synaptic membrane vesicles, whereas nipecotic acid did not increase the efflux of [ 3 H]GABA in a dose-dependent manner. These results suggest that there is a competitive type of interaction of the cyclic and acyclic GABA analogs with membrane uptake carriers and that a more complex type of action of nipecotic acid on these carriers occurs. The order of potency of uptake inhibition by some of these agents was compared with previously published orders of activation of physiologic GABA receptors by these compounds.
SVM Parameter Optimization Based on Immune Memory Clone Strategy and Application in Bus Passenger Flow Counting

The performance of support vector machine (SVM) depends on the selection of model parameters, however, the selection of SVM model parameters more depends on the empirical value. According to the above deficiency, this paper proposed a parameters optimization method of support vector machine based on immune memory clone strategy (IMC). This method can solve the multi-peak model parameters selection problem better which is introduced by n-folded cross-verification. Tests on standard datasets show that this method has higher precision and faster optimization speed compared with other four methods. Then the proposed method was applied to bus passenger flow counting. The experimental results show that the method reposed in this paper obtains higher classification accuracy.
Functioning lipoadenoma of a supernumerary parathyroid gland in the mediastinum

A patient underwent reexploration for a parathyroid adenoma; following identification of four normal glands in the cervical region, the mediastinum was entered, and an intrathymic lipoadenoma was excised. These very rare tumors have been associated with hypercalcemia in approximately half of the previously reported cases; however, none has previously been described as occurring entirely in the mediastinum.
Real-time transient stability assessment of a power system during energy generation shortfall

Real-time transient stability assessment (TSA) in power system is to determine a power system's ability to continue to provide service (electric energy) in case of an unforeseen catastrophic contingency in real-time. During system operation, the online determination of the dynamic security level is fundamental in order to take appropriate countermeasures, with the aim of restoring the system, if necessary, to a more secure operation condition. To assess the level of system strength or weakness relative to the occurrence of an undesired event, a quantitative measure based on transient stability index is often considered. In this paper, a practical generator maintenance scheduling (GMS) which is a reflection of power generation loss due to scheduled shutdown maintenance, load shedding and large unforeseen transient disturbance in form of three-phase fault are the credible contingencies considered. These contingencies are analyzed using prony method, transient energy function (TEF) analysis and real-time transient stability assessment indexes (TSAIs) of Nigerian power system modeled on the real-time digital simulator platform. The contribution of this paper is to implement the TSA in real-time, and investigate the effectiveness of the prony method, TEF analysis and real-time TSAIs as important tools for electric energy management when subjected contingencies.
PULMONARY EMBOLISM COMPLICATED BY PATENT FORAMEN OVALE AND PARADOXICAL EMBOLIZATION

We present the case of a 74-year-old male with chest pain, dyspnea, and syncope secondary to an acute pulmonary embolism complicated by a patent foramen ovale with straddling thrombus and paradoxical embolization. We review the literature with specific focus on the pathogenesis and acute treatment of this life-threatening occurrence.
Growth hormone insensitivity syndromes: lessons learned and opportunities missed.

The concept of growth hormone (GH) insensitivity has evolved since the condition was originally identified in 1966, and we now know that the primary defect involved is in the GH receptor. Cloning of the receptor molecule has led to great progress in our understanding of GH insensitivity (GHI) and its therapy, including the roles of GH and insulin-like growth factor I (IGF-I) in growth and development, and the relationships between height and serum levels of GH, IGF-I and their binding proteins. Despite the success of work on GHI and IGF-I, a number of opportunities have been missed in the past. The differences between the metabolic effects of GH and IGF-I are not fully understood, while measurements of IGF-I and IGF-binding protein 3 are perhaps not the ideal means of diagnosing GHI. Finally, the use of IGF-I to treat GHI has a number of limitations, and work is underway to develop alternative therapies.
Phospholipid metabolism in kidney. II. Potassium uptake, lipid composition, and P32 labelling of the phospholipids in rabbit kidney cortex slices in vitro, and the effects of diphenylhydantoin

Abstract Cold-saline treated slices of rabbit kidney cortex were incubated at 37 ° in Krebs-Ringer medium III. Under these conditions the intracellular potassium concentration increased twofold within 30 min., while the intracellular sodium and chloride concentrations decreased. A rapid uptake of inorganic P 32 into the phospholipids was also observed; lecithin and the inositol phospholipid fraction were labelled most rapidly, while the specific activity of the phosphatidic acid-polyglycerophospholipid fraction remained very low. Diphenylhydantoin increased the rate of uptake of potassium but had no effect on the amount or rate of labelling of any phospholipid. The lack of correlation between lipid phosphorus turnover and ion flux is discussed.
The mechanism of covalent reaction of bromoacetyl-phenylalanyl-transfer RNA with the peptidyl-transfer RNA binding site of the Escherichia coli ribosome

Abstract Results are presented to prove that bromoacetyl-phenylalanyl-transfer RNA reacts covalently with 50 S ribosomal proteins L2 and L27 while it is bound correctly to the peptidyl site on the 70 S ribosome. Attachment of the BrAcPhe moiety to tRNA causes a 100-fold enhancement of its reactivity with ribosomes. This reactivity closely parallels binding of tRNA whether measured by poly(U) stimulation or competition with deacylated tRNA. BrAcPhe-tRNA can bind correctly to the P site as judged by puromycin releasibility and lack of tetracycline inhibition. Little significant reaction of BrAcPhe-tRNA with L2 and L27 occurs during procedures used to purify and analyze ribosomal proteins. If ribosomes are first incubated with BrAcPhe-tRNA and subsequently treated with puromycin before analysis, little inhibition of the covalent reaction with L2 and L27 is observed. In contrast, a few minor reaction products are markedly suppressed. Covalently attached BrAcPhe-tRNA is still capable of accepting an amino acid from Phe-tRNA or puromycin. The products from this reaction are found attached to proteins L2 and L27 and to a lesser extent to L15 and L16. This shows that true affinity labeling of proteins in the peptidyl binding site has been accomplished. Some covalent reaction of BrAcPhe-tRNA with the 30 S protein S18 is also observed. This reaction is not poly(U)-dependent, however, and S18-reacted BrAcPhe-tRNA is not capable of peptide bond formation with Phe-tRNA. It seems likely that reaction with S18 results from a non-functional interaction of the affinity label with the ribosome.
1013-69 Dipyridamole Rb-82 Positron Emission Tomography Has Limitations for Predicting Cardiac Events Peri- and Post-Operatively after Vascular Surgery

Thallium imoying has been used to risk-stratify pts undergoing vascular surgery (VS), though the efficacy of this approach is debated. Positron emission tomography (PET) has the benefit of permitting a true resting scan, measurement of the extent of ischemia, and is highly specific for the diagnosis of coronary disease. We investigated the benefit of more accurate identification of ischemia and a lower frequency of false positives by using PET for risk stratification in 77 pts (68 ± 9 y, 52 males) undergoing VS (including 39 aortic operations — 51%) without recent myocardial revascularization. One or more clinical risk factors (ageg 70, diabetes, angina, prior infarction or heart failure) were present in 63 pts; 32 had g 2 factors. PET followed infusion of 60 mCi of Rb82 at rest and after dipyridamole-handgrip stress. Using a quantitative color scale in a 24 segment model of the left ventricle, scans were reported as normal, fixed defects only (FD) or reversible (deteriorationg 15% with stress) defects (RD). Events included infarction (MI) and unstable angina (UA), perioperatively and at late follow-up (17 ± 6 months) in 74 pts. Fourteen pts (18%) suffered peri-operative events (5 MI, 9 UA, no cardiac deaths) giving PET-RD a sensitivity of 71%. Of 63 pts without events, RD was present in 16 (p = 0.003) giving a specificity of 66%. Seven pts suffered late events ; Rb-PET Perioperative MI Perioperative UA Late events RD (n = 26) 2 8 3 FD (n = 31) 1 0 4 Normal (n = 20) 2 1 0 Among 26 pts with RD (19 of whom were on anti-anginal therapy at the time of surgery), only 10 (38%) had peri operative events. The extent of ischemia in pts with RD having events (9 ± 7 segments) exceeded that in pts with RD not having events (6 ± 4 segments, p = NS). In pts with RD, 7/10 pts with events had extensive ischemia (g 5 segments), compared with 9/16 without events (p = NS). Conclusion Absence of RD by PET confers a low probability of events (especially UA), comparable to conventional imaging. FD by PET are not associated with events. However, RD at PET has a low specificity for peri-operative events (irrespective of extent of RDI; avoidance of events in the absence of myocardial revascularization may be attributable to medical and anesthetic measures.
Ecological correlates of human dispersal in 19th century sweden

Abstract Historic Swedish human demographic data were used to examine ecological correlates of natal dispersal. In addition to sex and age of dispersers, these data contain information on social, spatial and temporal atributes influencing dispersal; information important to delimiting functional advantages of this behaviour. It was predicted that in the monogamous and, apparently, resource defence mating system of 19th century Sweden male competition for resources would result in (1) a female bias in dispersal and that (2) male dispersal would be influenced by the (a) relative local availability of resources and (b) individual ability to gain access to resources. Dispersal hazard, the probability that an individual will disperse over a given time period, rose sharply at the age of reproductive maturity, supporting the concept that dispersal is related to reproductive strategies. Females, throughout life, consistently had a higher probability of leaving their natal parish than did males. Parish resource availability and individual ability to access resources (Birth order and father's socio-economic class) correlated with natal dispersal probability of males. Dispersers, male and female, were predominantly pre-reproductive and may have contributed to inbreeding avoidance. Female dispersal also varied with availability of and individual access to resources, perhaps in response to availability of mates or due to pressures from other residents.
Student learning of thermochemical concepts in the context of solution calorimetry

Student understanding of heat and thermal phenomena has been the subject of considerable investigation in the science education literature. Published studies have reported student conceptions on a variety of advanced topics, but calorimetry - one of the more elementary applications of thermochemical concepts - has apparently received little attention from science education researchers. Here we report a detailed analysis of student performance on solution calorimetry problems in an introductory university chemistry class. We include data both from written classroom exams for 207 students, and from an extensive longitudinal interview series with a single subject who was herself part of that larger class. Our findings reveal a number of learning difficulties, most of which appear to originate from failure to understand that net increases and decreases in bond energies during aqueous chemical reactions result in energy transfers out of and into, respectively, the total mass of the resultant solution.
A Multipole-Based Algorithm for Efficient Calculation of Forces and Potentials in Macroscopic Periodic Assemblies of Particles

A new and efficient algorithm based on multipole techniques is presented which calculates the electrostatic forces and potentials in macroscopic periodic assemblies of particles. The fast multipole algorithm (FMA) can be used to compute forces within then-particle unit cell inO(n) time. For the cubic lattice, forces due to a 3k× 3k× 3klattice of images of the unit cell, containing 33knparticles, can be computed inO(nk2+k3logk) time to arbitrary precision. The algorithm was readily added onto an existing FMA implementation, and computational results are presented. Accurate electrostatic computations were done on a 38× 38× 38region of 100000-particle unit cells, giving a volume of 28 quadrillion particles at less than a twofold cost over computing the forces and potentials in the unit cell alone. In practice, ak= 4?6 simulation approximates the true infinite lattice Ewald sum forces (including the shape-dependent dipole correction) to high accuracy, taking 25?30 % more time to compute than only the unit cell. The method extends to noncubic unit cell shapes, and noncubic macroscopic shapes. Simple code modifications allowed computation of forces within macroscopic spheres and ellipsoids, and within near-infinite square, circular, and elliptical surfaces formed of unit cubes replicated along two of the three axes. In addition to efficient periodic simulations, the method provides a powerful tool to study limiting behavior of various finite crystal shapes, as well as surface phenomena in molecular dynamics simulations.
Effect of stress on cochlear glucocorticoid protein: Acoustic stress

Levels of glucocorticoid (GR) receptor protein were determined by a quantitative enzyme-linked immunosorbent assay (ELISA) technique in inner ear tissue of rats exposed daily to 85 dB SPL white noise for 4 hours on 3 consecutive days. GR levels in spiral ligament and organ of Corti tissues were detected using a monoclonal antibody to the GR receptor, BuGR2. A non-significant 13% decrease in GR levels of spiral ligament tissues was observed in the noise exposed animals relative to untreated animals. A statistically significant decrease of 27% in GR protein levels was seen in the organ of Corti region (P < 0.03), however. There was a concomitant increase of serum corticosterone levels (P < 0.03) in noise exposed animals as opposed to those of controls. These results indicate a tissue specific response of GR receptor to acoustic stress. Inner ear GR protein therefore may be a useful marker in determining the effect of stress on the inner ear. Finally, such data may be applicable to support the hypothesis that stress is an etiological agent in Meniere's disease.
The Hot Gas Content of Low-Luminosity Early-Type Galaxies and the Implications Regarding Supernova Heating and Active Galactic Nucleus Feedback

We have analyzed Chandra observations of 18 low-luminosity early-type galaxies with LB 3 × 1010 L☉B. Thermal emission from hot gas with temperatures between 0.2 and 0.8 keV comprises 5%-70% of the total 0.5-2.0 keV emission from these galaxies. We find that the total X-ray luminosity from LMXBs (resolved plus the power-law component of the unresolved emission) scales roughly linearly with the K-band luminosity of the galaxies with a normalization comparable to that found in more luminous early-type galaxies. All of the galaxies in our sample are gas-poor, with gas masses much less than that expected from the accumulation of stellar mass loss over the lifetime of the galaxies. The average ratio of gas mass to stellar mass in our sample is Mgas/M* = 0.001, compared to more luminous early-type galaxies that typically have Mgas/M* = 0.01. The time required to accumulate the observed gas mass from stellar mass loss in these galaxies is typically 3 × 108 yr. Since the cooling time of the gas is longer than the replenishment time, the gas cannot be condensing out of the hot phase and forming stars, implying that the gas is most likely being expelled from these galaxies in a wind. The one exception to this is NGC 4552, which is the most optically luminous galaxy in our sample and has the highest gas content. Using recent estimates of the Type Ia supernova rate and AGN heating rate in early-type galaxies, we find that, on average, heating by Type Ia supernovae should exceed AGN heating in galaxies with LB 3 × 1010 L☉B. We also find that heating by Type Ia supernovae is energetically sufficient to drive winds in these galaxies, even if the present Type Ia supernova rate is overestimated by a factor of 2 or the present stellar mass-loss rate is underestimated by a factor of 2.
Identical twins with primary pulmonary hypertension: beraprost vs epoprostenol.

Background The course of 12-year-old, homozygotic twins with primary pulmonary hypertension (PPH) treated with different vasoactive agents, beraprost vs epoprostenol, is described. Methods Clinical, exercise, and hemodynamic assessments were made at baseline, and at 9 months and 24 months of treatment. Findings Twin A had a rapid improvement with epoprostenol. In contrast, twin B, initially treated with beraprost, had progressive worsening with subsequent improvement on epoprostenol. Interpretation Epoprostenol was efficacious for identical twins with PPH. A 9-month delay in initiating epoprostenol for twin B did not appear to have irreversible short-term detrimental effects.
Inhibition of steroid 5α-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450

Abstract It has been shown previously that liver microsomal steroid 5α-reductase activity increases with age in female but not male rats, which coincides with a female-specific, age-dependent decline in the cytochrome P-450-dependent oxidation of testosterone to 1β-, 2α-, 2β-, 6α-, 6β-, 7α-, 15β-, 16α-, 16β-, and 18-hydroxytestosterone and androstenedione. To determine whether the increase in steroid 5α-reductase activity is responsible for the decrease in testosterone oxidation, we have examined the effects of the steroid 5α-reductase inhibitor, 4-MA (17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one), on the pathways of testosterone oxidation catalyzed by rat liver microsomes. We have also determined which hydroxytestosterone metabolites are substrates for steroid 5α-reductase. At concentrations of 0.1 to 10 μ m , 4-MA completely inhibited steroid 5α-reductase activity without inhibiting the pathways of testosterone oxidation catalyzed by liver microsomes from rats of different age and sex, and from rats induced with phenobarbital or pregnenolone-16α-carbonitrile. 4-MA (10 μ m ) had little or no effect on the oxidation of testosterone catalyzed by liver microsomes from mature male rats (which have low steroid 5α-reductase activity). In contrast, the hydroxylated testosterone metabolites formed by liver microsomes from mature female rats (which have high steroid 5α-reductase activity) accumulated to a much greater extent in the presence of 4-MA. Evidence is presented that 4-MA increases the accumulation of hydroxytestosterones by two mechanisms. First, 4-MA inhibited the 5α-reduction of those metabolites (such as 6β-hydroxytestosterone) that were found to be excellent substrates for steroid 5α-reductase. In the absence of 4-MA, these metabolites eventually disappeared from incubations containing liver microsomes from mature female rats. Second, 4-MA inhibited the formation of 5α-dihydrotestosterone, which otherwise competed with testosterone for oxidation by cytochrome P-450. This second mechanism explains why 4-MA increased the accumulation of metabolites (such as 7α-hydroxytestosterone) that were found to be poor substrates for steroid 5α-reductase. Despite its marked effect on the accumulation of hydroxylated testosterone metabolites, 4-MA had no effect on their initial rate of formation by liver microsomes from either male or female rats. From this we conclude that age- and sex-dependent differences in testosterone hydroxylation are largely due to age- and sex-dependent differences in the profile of cytochrome P-450 isozymes in liver microsomes, and are not an artifact due to differences in steroid 5α-reductase activity. The lack of effect of 4-MA on the initial rate of testosterone hydroxylation by liver microsomes from mature female rats also suggests that rat liver microsomal steroid 5α-reductase and cytochrome P-450 do not compete with each other for electrons from NADPH-cytochrome P-450 reductase.
Does Presynaptic Regulation of Sympathetic Transmission Occur Within a Limited Range of Neuronal Activity

Recent reports indicate that the presynaptic negative feedback mechanism involved in regulating sympathetic neurotransmission is only functional within a narrow range of neuronal activity. The specific aim of this report is to examine the release of sympathetic transmitter at varying frequencies of stimulation, and the effects of α-adrenoceptor antagonists on the overflow. The experiments were carried out in the3H-noradrenaline-labeled heart of the guinea pig. The overflow of tritium (per pulse) increased from a stimulation frequency of 0.125 to 10 Hz and declined at 30 Hz. Phentolamine or yohimbine produced facilitation of the overflow from 0.125 to 10 Hz; the effect was more pronounced at lower frequencies of stimulation. We conclude that the presynaptic α-adrenoceptor-mediated negative feedback mechanism operates over a wide range of cardiac sympathetic nerve activity.
Crystal Structure of 1:1 Complex of Barbital with 1-Methylimidazole

Abstract The prediction of a strong hydrogen-bonding interaction between barbital and 1-methylimidazole was confirmed. Two crystal complexes were obtained, 1:1 and 2:1, and the X-ray structure was determined for the 1:1 complex, which is monoclinic, space group P2 1 /c, with a = 12.236(3) A, b = 11.332(4) A,c = 12.495(4) A, and d = 120.67(1)°.The structure contains disk-shaped hydrogen-bonded tetramers with two molecules of each kind. There is a short NH—N hydrogen bond (2.82 A) in which barbiturate provides the NH donor.
Localization and Physical Mapping of the Prostate-Specific Membrane Antigen (PSM) Gene to Human Chromosome 11

The prostate-specific membrane antigen (PSM) was identified by the monoclonal antibody 7E11-C5.3, which was raised against the human prostatic carcinoma cell line LNCaP (3). The PSM antigen is expressed by normal, neoplastic, and metastatic prostatic tissues. The 2.65-kb cDNA encoding the 100-kDa PSM glycoprotein was cloned from LNCaP cells (4). Studies have shown that the expression of PSM is tissue-specific (5). In the present study monochromosomal somatic cell hybrids were used to localize the PSM gene to human chromosome 11. Using this information, initial mapping studies identified two potential PSM gene loci at 11p11.1-p13 and 11q14. Further high-stringency analysis using cosmid probes identified the 11q14 region as the location of the PSM gene.
When More of a Good Thing Is Better: Reply to Hayes et al. (1996)

More of a good process component is better when clients are not already getting enough. Process components may be in short supply because of limited resources or ignorance, because they are evaluations themselves, or because they are difficult-to-attain subgoals on the way to valued outcomes. Levels of crucially important process components that are not in short supply (including most commonly used therapeutic interventions) are unlikely to be statistical predictors of outcome. Conversely, then, null correlations with outcome do not impugn a component's therapeutic importance. Many of A.M. Hayes, L.G. Castonguay, and M.R. Goldfried's (1996b) examples of positive correlations usefully illustrated clients' cognitive and emotional processes that were treatment subgoals or evaluative indexes. However, by focusing on the (relatively rare) positive correlations, they overlooked the more common null or inconsistent correlations of theoretically important process components with outcome, which are the central topic of the responsiveness critique.
MALAdaptive: Do We Avoid Metformin Unnecessarily?

Convention holds that the use of metformin is contraindicated in many patients secondary to concerns about lactic acidosis. However, current evidence suggests that metformin-associated lactic acidosis is at most idiosyncratic. Awareness of the current evidence should permit broader use of this valuable medication.
AKT1 E17K in Colorectal Carcinoma Is Associated with BRAF V600E but Not MSI-H Status: A Clinicopathologic Comparison to PIK3CA Helical and Kinase Domain Mutants

The PI3K/AKT/mTOR pathway is activated through multiple mechanisms in colorectal carcinoma. Here, the clinicopathologic and molecular features of AKT1 E17K–mutated colorectal carcinoma in comparison with PIK3CA-mutated colorectal carcinoma are described in detail. Interestingly, in comparison with PIK3CA mutants, AKT1 E17K was significantly associated with mucinous morphology and concurrent BRAF V600E mutation. Among PIK3CA mutants, exon 21 mutations were significantly associated with BRAF V600E mutation, MSI-H status, and poor differentiation, while exon 10 mutations were associated with KRAS/NRAS mutations. Three of four AKT1 mutants with data from both primary and metastatic lesions had concordant AKT1 mutation status in both. Both AKT1- and PIK3CA-mutant colorectal carcinoma demonstrated frequent loss of PTEN expression (38% and 34%, respectively) and similar rates of p-PRAS 40 expression (63% and 50%, respectively). Both patients with AKT1 E17K alone had primary resistance to cetuximab, whereas 7 of 8 patients with PIK3CA mutation alone experienced tumor shrinkage or stability with anti-EGFR therapy. These results demonstrate that AKT1 E17K mutation in advanced colorectal carcinoma is associated with mucinous morphology, PIK3CA wild-type status, and concurrent RAS/RAF mutations with similar pattern to PIK3CA exon 21 mutants. Thus, AKT1 E17K mutations contribute to primary resistance to cetuximab and serve as an actionable alteration. Implications: This first systematic study of AKT1 and PIK3CA hotspot mutations and their association with cetuximab resistance and BRAF V600E mutation has important ramifications for the development of personalized medicine, particularly in identifying patient candidates for PI3K or AKT inhibitors. Mol Cancer Res; 13(6); 1003–8. ©2015 AACR.
Functional analysis of secA homologues from rickettsiae.

The molecular basis of protein secretion that underlines rickettsial pathogenesis remains unknown. This paper reports the molecular and functional analysis of the putative secA gene, an essential component of the Sec-dependent protein secretion pathway, from Rickettsia rickettsii and Rickettsia typhi, the aetiological agents of Rocky Mountain spotted fever and murine typhus, respectively. The sequence analysis of the cloned secA genes from R. rickettsii and R. typhi show ORFs of 2721 and 2718 nt, respectively. Alignment of the deduced amino acid sequences reveals the presence of highly conserved amino acid residues and motifs considered to be essential for the ATPase activity of SecA in preprotein translocation. Transcription analysis indicates that R. rickettsii secA is expressed monocistronically from the canonical prokaryotic promoter, with a transcriptional start point located 32 nt upstream of the secA initiation codon. Complementation analysis shows that the full-length SecA protein from R. rickettsii and R. typhi fails to restore growth of the temperature-sensitive Escherichia coli strain MM52 secA51(ts) at a non-permissive temperature (42 °C), despite the detection of SecA protein expression by Western blotting. However, the chimeric SecA protein carrying the N-terminal 408 aa of R. rickettsii SecA fused with the C-terminal 480 aa of E. coli SecA restores the growth of E. coli strain MM52 secA51(ts) at the non-permissive temperature (42 °C). These results suggest that the N-terminal ATPase domain is highly conserved, whereas the C-terminal domain appears to be species specific.
Inhibition of Neuronal Voltage-Gated Sodium Channels by Brilliant Blue G

Brilliant blue G (BBG), best known as an antagonist of P2X7 receptors, was found to inhibit voltage-gated sodium currents in N1E-115 neuroblastoma cells. Sodium currents elicited from a holding potential of -60 mV were blocked with an IC(50) of 2 μM. Block was enhanced in a use-dependent manner at higher stimulation rates. The voltage-dependence of inactivation was shifted in the hyperpolarizing direction, and recovery from inactivation was slowed by BBG. The most dramatic effect of BBG was to slow recovery from inactivation after long depolarizations, with 3 μM BBG increasing half-time for recovery (measured at -120 mV) from 24 to 854 ms after a 10-s step to 0 mV. These results were mimicked by a kinetic model in which BBG binds weakly to resting channels (K(d) = 170 μM) but tightly to fast-inactivated channels (K(d) = 5 μM) and even more tightly (K(d) = 0.2 μM) to slow-inactivated channels. In contrast to BBG, the structurally related food-coloring dye Brilliant Blue FCF had very little effect at concentrations up to 30 μM. These results show that BBG inhibits voltage-gated sodium channels at micromolar concentrations. Although BBG inhibition of sodium channels is less potent than inhibition of P2X7 receptors, there may be significant inhibition of sodium channels at BBG concentrations achieved in spinal cord or brain during experimental treatment of spinal cord injury or Huntington's disease. Considered as a sodium channel blocker, BBG is remarkably potent, acting with more than 10-fold greater potency than lacosamide, another blocker thought to bind to slow-inactivated channels.
Land-cover change within and around protected areas in a biodiversity hotspot.

The landscape surrounding protected areas influences their ability to maintain ecosystem functions and achieve conservation goals. As anthropogenic intensification continues, it is important to monitor land-use and land-cover change in and around protected areas. We measure land-cover change surrounding protected areas in the Maputaland-Pondoland-Albany Biodiversity hotspot from the 1980s to present. Using Landsat imagery, we classified land cover within and around each protected area. Agricultural land uses were increasing and often directly border protected area boundaries. Human settlements increased around every protected area, potentially increasing human activity along the edges of protected areas and threatening their ecological integrity. Urban expansion around protected areas varied but increased as much as 10%. Woody vegetation cover varied both within and around protected areas with possible evidence of deforestation and shrub encroachment throughout the hotspot. We recommend monitoring land co...
Investment Reversibility and Agency Cost of Debt

Previous research has argued that debt financing affects equity-holders' investment decisions, producing substantial inefficiency. This paper shows that the size of this inefficiency depends on the degree of investment reversibility. In a dynamic model of financing and investment, the paper provides an upper bound for the inefficiency produced by debt financing. The upper bound is decreasing in the degree of investment reversibility and is zero when investment is perfectly reversible.
A prospective study of childhood social hardships and age at menarche.

Abstract Purpose To determine the role of type, timing, and cumulative childhood hardships on age at menarche in a prospective cohort study. Methods A longitudinal analysis was undertaken of 4524 female participants of the National Child Development Study cohort (1958–2003). Six types of childhood hardships were identified with a factor analysis methodology. Paternal absence/low involvement in childhood was an a priori hardship. Retrospective reports of abuse in childhood also were explored in relation to age at menarche. Generalized logit regression analyses explored the impact of type, timing, and cumulative hardships on age at menarche (≤11, 12–13, ≥14 years). Results Cumulative childhood hardships were associated with a graded increase in risk for later menarche with adjusted odds ratio [AOR] of 1.37 (95% confidence interval [95% CI], 1.10–1.70), 1.50 (95% CI, 1.18–1.91), and 1.58 (95% CI, 1.29–1.92) among those with two, three, and four or more adversities, respectively. More than two hardships in early life had the strongest association with late menarche (AOR, 2.32; 95% CI, 1.12–4.80). Sexual abuse was most strongly associated with early menarche (AOR, 2.60; 95% CI, 1.40–4.81). Conclusions Cumulative childhood hardships increased risk for later age at menarche. Child abuse was associated with both early and late menarche, although associations varied by type of abuse.
Feather-Degrading Bacteria: A New Frontier in Avian and Host–Parasite Research?

Birds are important models for the study of host–parasite interactions (Loye and Zuk 1991, Clayton and Moore 1997). Much of this research has focused on arthropod ectoparasites that feed on feathers (e.g., Clayton et al. 2003, Proctor 2003), because feathers are so important to avian life-history traits. Feathers function in thermoregulation (Stettenheim 2000), communication (Andersson 1994, Shuster and Wade 2003), and flight (Rayner 1988). Damaged feathers have reduced abilities to perform these functions (Booth et al. 1993, Swaddle and Witter 1997, Ferns and Lang 2003, Williams and Swaddle 2003), so there are likely fitness consequences for individuals possessing damaged feathers. A subset of plumage bacteria that can degrade feathers has garnered interest, because it may impose significant evolutionary selection pressures on birds, as arthropod ectoparasites do. Aspects of avian morphology, behavior, and life history may be influenced by a coevolutionary battle between birds and feather-degrading bacteria (FDB) that damage their plumage. Research on FDB and birds is in its nascent stages; however, a substantial body of literature has attempted to understand how birds and these microbes interact. Here, I synthesize what we currently know, highlight important gaps in our knowledge, and suggest next steps for the field, while focusing on three fundamental questions: What are FDB and how do they degrade feathers? How prevalent are FDB on birds? And finally, how can FDB and birds influence one another?
Making Medicaid a Block Grant Program: An Analysis of the Implications of Past Proposals

In 2003, President Bush proposed converting Medicaid from an entitlement to a block grant program. Similar ideas from President Reagan in 1981 and Congress in 1995 were introduced but not enacted. Block grants aim to provide greater federal budget certainty and a stronger state incentive to contain program costs. This paper compares the preestablished funding levels proposed in 1981 and 1995 with what actually happened to federal Medicaid spending. Its results show that previous block grant proposals' funding levels at the national and state levels were quite different from what was anticipated and what occurred. As a result, Medicaid probably could not--and cannot--maintain existing health coverage under a block grant financing structure.