cssi/SciSciGPT-SciSciNet huggingface dataset:
Chapter 1.6 Quantitative aspects of brain microdialysis: insights from voltammetric measurements of dopamine next to microdialysis probes

Abstract Microdialysis offers many attributes that make it extremely popular as a technique for sampling the extracellular space in the brain of living animals. Correlating the chemical composition of the extracellular space with behavioral events, pharmacological responses, and brain pathophysiology is a central objective in the field of neurochemistry. Microdialysis has evolved to a position of prominence in efforts to achieve this objective. Nonetheless, questions remain unanswered about the relationship between concentrations as measured by microdialysis and the actual in vivo concentration of target substances in the extracellular space of brain tissue. These questions remain open because it is the case that methods for the in vivo calibration of microdialysis probes are not available and are difficult to envision. Although a technique called quantitative microdialysis, based on the determination of no-net-flux concentrations, has been developed, it actually only provides quantitative information when two key parameters, the extraction fraction and relative recovery, of the target substance are the same during the microdialysis procedure. Although quantitative microdialysis has been applied to dopamine, voltammetric recordings of extracellular dopamine in the tissue adjacent to microdialysis probes caste doubt on the idea that the dopamine extraction fraction and relative recovery are equal to each other. This chapter reviews the quantitative basis of in vivo microdialysis, describes the evidence that suggests a difference between the in vivo extraction fraction and relative recovery of dopamine, and considers the consequences of that difference in terms of the nature of the relationship between dopamine as measured by microdialysis and the actual in vivo concentration of dopamine in the brain extracellular space.
Variational Monte Carlo Calculations of Finite Nuclei

A major goal in nuclear physics is to understand how nuclear structure comes about from the underlying interactions between nucleons. This requires modelling nuclei as collections of strongly interacting particles. Using realistic nucleon-nucleon potentials, supplemented with consistent three-nucleon potentials and two-body electroweak current operators, we calculate nuclear ground-state properties, such as the binding energy, electromagnetic form factors, and momentum distributions. Other properties such as excited states and low-energy reactions are also calculable in this framework.
Eating Fire: My Life as a Lesbian Avenger by Kelly Cogswell

In the process of researching her book Eating Fire: My Life as a Lesbian Avenger, Kelly Cogswell made a trip to the Lesbian Herstory Archives in Brooklyn, New York, to review the Lesbian Avengers’ ...
Anesthetic and perioperative risk in the patient with Ataxia-Telangiectasia.

Summary Objectives/Aim: To report our relatively large experience with perioperative care for patients with Ataxia-Telangiectasia (A-T) and to identify the nature and frequency of complications. Background: Ataxia-Telangiectasia is a rare autosomal recessive genetic disorder resulting in progressive multisystem degeneration and characteristic findings including complex neurodegeneration, immunodeficiency, increased risk of malignancy, and lung disease. Anecdotal reports have suggested high perioperative morbidity in patients with A-T, but few data exist. Methods/Materials: The Ataxia-Telangiectasia Clinical Center database was cross-referenced with operative records between 1995 and 2009 to identify patients with perioperative A-T, and medical records were reviewed for preoperative history, management techniques, and complications. Results: Twenty-one patients with A-T underwent 34 anesthetics during the study period. The median age was 12.5 years (range 6–33 years). Common comorbidities included neurologic (100%), pulmonary (68%), immunologic (50%), oncologic (47%), and gastroenterologic (35%) disorders. Supplemental oxygen was required on postanesthesia care unit discharge for 24% of patients with a maximal duration of 24 h. Although mild postoperative hypothermia was relatively common (44% of anesthetics), there were no major complications, no unplanned admissions, and no mortality in this series. Conclusions: Although limited by its retrospective nature, this is the first series describing perioperative risk for patients with A-T. Our results indicate that general anesthesia, airway manipulation, and perioperative mechanical ventilation may be tolerated with only minor postoperative anesthetic concerns. Perioperative providers should be aware of the complex multisystem medical concerns that may arise in these patients.
FORGIVENESS, COMMEMORATION, AND RESTORATIVE JUSTICE: THE ROLE OF MORAL EMOTIONS

Abstract: Forgiveness of wrongdoing in response to public apology and amends making seems, on the face of it, to leave little room for the continued commemoration of wrongdoing. This rests on a misunderstanding of forgiveness, however, and we can explain why there need be no incompatibility between them. To do this, I emphasize the role of what I call nonangry negative moral emotions in constituting memories of wrongdoing. Memories so constituted can persist after forgiveness and have important moral functions, and commemorations can elicit these emotions to preserve memories of this sort. Moreover, commemorations can be a restorative justice practice that promotes reconciliation, but only on condition that the memories they preserve are constituted by nonangry negative, not retributive, emotions.
Rapid Radioimmunoassay of Triiodothyronine

The method used in this report is based on the immunological production of a specific antisera to triiodothyronine (T3) in rabbits. Conducted at 4 °C, the radioimmunoassay requires three to five days to complete. Hoping to speed this assay, we investigated the influence of time, temperature, and pH. Incubation at 37 °C and pH 8.0 for 30 min did not deleteriously affect either precision, specificity, reproducibility, or accuracy. Bound and unbound T3 were separated in 10 min by adding polyethylene glycol ("Carbowax 6000") at 0-4 °C. T3 was prevented from binding to thyroxine-binding globulin by the addition of 8-anilino-1-naphthalene sulfonic acid. To minimize the differences in protein concentration between standards and unknowns, we added T3-free serum to all standards. Thus, a simplified and convenient method is described for measurement of T3 that is suitable for clinical use because it is simpler and faster than previously reported methods.
The Role of LAT-PLCγ1 Interaction in γδ T cell Development and Homeostasis

LAT is a transmembrane adaptor protein that is vital for integrating TCR-mediated signals to modulate T cell development, activation, and proliferation. Upon T cell activation, LAT is phosphorylated and associates with Grb2, Gads, and PLCγ1 through its four distal tyrosine residues. Mutation of one of these tyrosines, Y136, abolishes LAT binding to PLCγ1. This results in impaired TCR-mediated calcium mobilization and Erk activation. CD4 αβ T cells in LATY136F knock-in mice undergo uncontrolled expansion, resulting in a severe autoimmune syndrome. In this study, we investigated the importance of the LAT-PLCγ1 interaction in γδ T cells by crossing LATY136F mice with TCRβ(-/-) mice. Our data showed that the LATY136F mutation had no major effect on homeostasis of epithelial γδ T cells, which could be found in the skin and small intestine. Interestingly, a population of CD4(+) γδ T cells in the spleen and lymph nodes underwent continuous expansion and produced elevated amounts of IL-4, resulting in an autoimmune syndrome similar to that caused by αβ T cells in LATY136F mice. Development of these hyperproliferative γδ T cells was not dependent on MHC class II expression or CD4, and their proliferation could be suppressed, in part, by regulatory T cells. Our data indicated that a unique subset of CD4 γδ T cells can hyperproliferate in LATY136F mice and suggested that LAT-PLCγ1 signaling may function differently in various subsets of γδ T cells.
Influence of Polydimethylsiloxane on the Oxygen Concentration of Oils at Various Temperatures

The effect of temperature on the oil oxygen concentration, tested in both soybean and olive oils with no added polydimethylsiloxane (PDMS), showed that the oxygen concentration increased with temperature to approximately 100 °C. Above 100 °C, the oxygen concentration abruptly decreased. This change was attributed to the balance between the rates of oxygen uptake and consumption by oil oxidation, which favored oxygen consumption over uptake at temperatures above 100 °C. The addition of 100 ppb PDMS to soybean oil, enough to form a continuous layer over the surface of the oil, reduced the oxygen concentration when compared to a soybean oil control containing no added PDMS at temperatures ranging from 93 to 180 °C; thus suggesting an oxygen barrier effect of PDMS. The accumulation of PDMS at the air–oil interface in soybean oil held at 180 °C was determined by comparing the oil’s internal temperature and the apparent surface temperature. A decrease in the apparent surface temperature while the oil was held at a constant internal temperature was attributed to a change in the emissivity of the surface as a consequence of the accumulation of PDMS in the air–oil interface. The presence of PDMS at the air–oil interface was confirmed for 100 ppm of PDMS, a concentration greater than the concentration necessary to form a monolayer of PDMS on the oil surface.
Use of mossbauer spectroscopy to determine the effect of salinity on the speciation of triorganotins in anacostia river sediments

The speciation of several tributyltin and triphenyltin compounds under varying salinity conditions (0, 20, 40 and 60%) was studied by Mossbauer spectroscopy in both anaerobic and aerobic Anacostia River sediments. The Mossbauer spectral parameters of the spiked sediments indicated that changes in the salinity did not affect the speciation of the tin compounds in either aerobic or anaerobic sediments.
A preliminary note on Phellinus noxius root rot of Cordia alliodora plantings in Vanuatu

The results of a preliminary survey to evaluate the impact and distribution of root disease caused by Phellinus noxius (Corner) G. H. Cunn. in enrichment plantings of the introduced tree Cordia alliodora (Ruiz. and Pav.) Oken in the natural forest of Vanuatu show that the overall impact of the disease is light with some slight increase with increase in age of crop. On Pentecost Island losses are much more severe, increasing rapidly in older plantings. The high level is thought to be due to the interaction of relatively high rainfall and high inoculum level in the natural forest. Further studies and surveys of the disease are planned.
Substrate specificity of the oncoprotein v-Fps: site-specific mutagenesis of the putative P+1 pocket.

Based on the X-ray structure of the insulin receptor kinase [Hubbard, S. R. (1997) EMBO J. 16, 5572−5581], Arg-1130 in the oncoprotein v-Fps, a nonreceptor tyrosine protein kinase, is predicted to ...
Overview of pharmacologic treatment of obesity : Past experiences, present options, and future directions

Objective: To review the literature regarding the past, present, and future pharmacologic agents used in the treatment of obesity. Data Sources: Articles were identified by searching MEDLINE (1966-April 2005) and International Pharmaceutical Abstracts (1970-April 2005) using the key words obesity, antiobesity agents, sibutramine, orlistat, phentermine, and leptin. Additional resources were identified by examining the references of the articles cited. Searches were limited by human subject and English language, but were not limited by time of publication. Study Selection and Data Extraction: Large-scale clinical studies of pharmacologic agents used to treat obesity were selected for this review including agents that were previously available, currently available, and those currently undergoing clinical trials. Data Synthesis: Thyroid hormone was the first antiobesity agent used. Several other agents have been withdrawn from the market due to adverse effects. Current therapies indicated for obesity management include orlistat, sibutramine, and noradrenergic agents. Future therapies include both newer agents and existing agents that are principally used for other indications, mainly diabetes, depression, and seizure disorders. Conclusions: Obesity is a major epidemic in the US, affecting over half of the population. Past experiences with the pharmacologic treatment of obesity have been disappointing and, in some cases, harmful to patients. Current options are available that include noradrenergic agents, orlistat, and sibutramine. However, these agents still have only demonstrated limited efficacy for short-term use plus some undesirable adverse effects. Newer treatment options are being evaluated as new pathways are being identified and other related factors are being discovered.
Forward‐ and reverse‐bias tunneling effects in N+P silicon solar cells

Excess currents due to field-assisted tunneling in both forward and reverse bias directions have been observed in n(+)-p silicon solar cells. These currents arise from the effect of conducting paths produced in the depletion layer by n(+) diffusion and cell processing. Forward-bias data indicate a small potential barrier with height of 0.04 eV at the n(+) end of conducting paths. Under reverse bias, excess tunneling currents involve a potential barrier at the p end of the conducting paths, the longer paths being associated with smaller barrier heights and dominating at the lower temperatures. Low-reverse-bias data give energy levels of 0.11 eV for lower temperatures (253-293 K) and 0.35 eV for higher temperatures (293-380 K). A model is suggested to explain the results.
Critical Issues in the Transition From the Defined Benefit to the Defined Contribution Pension Model Perceptions From Florida Municipal Finance and Human Resource Directors

The dramatically increased costs of maintaining many public pension systems after the recent economic downturn have spurred a number of state and local governments to reassess the sustainability of...
Children With Heart Murmurs: Can Ventricular Septal Defect Be Diagnosed Reliably Without an Echocardiogram?

Abstract Objectives. This study was undertaken to determine the accuracy of expert examination for ventricular septal defect (VSD) among children with a heart murmur. Background. Because the frequency and nature of errors that might be made by reliance solely on expert examination for diagnosis of VSD are speculative, the role of echocardiography in such diagnosis is controversial. Methods. Two hundred eighty-seven consecutive previously unevaluated pediatric subjects were enrolled in the study. For each child, the pediatric cardiologists prospectively recorded a working diagnosis and their level of confidence in the diagnosis, categorizing any VSD diagnosed as small or moderate to large. After echocardiography, VSDs were subcategorized by location and requirement for treatment as minor, intermediate or major. Receiver-operating characteristic (ROC) curves described the accuracy of the clinical examination. Results. Seventy-three subjects had a VSD (minor in 52, intermediate in 10 and major in 11). ROC areas (1.0 = perfect discrimination, 0.5 = indiscriminate) were minor VSD 0.92 ± 0.02 and major/intermediate VSD 0.69 ± 0.07 (p = 0.0016). Four of 52 minor VSDs were not identified at any level of suspicion; the clinical diagnoses were moderate to large VSD in two patients and atrial septal defect and unlimited differential diagnosis in one patient each. Fourteen of 235 patients without a minor VSD were believed with confidence to have a small VSD, but the final diagnosis was intermediate VSD in 4, innocent murmur in 3, major VSD in 2, pulmonary stenosis in 2 and subaortic membrane, atrial septal defect and mitral regurgitation in 1 patient each. Conclusions. Almost all minor VSDs are recognized without echocardiography; however, errors can occur even when an expert examiner is confident. Clinical recognition of an intermediate or major VSD is less accurate than clinical recognition of a minor VSD. Failure to distinguish VSDs of major or intermediate importance from minor VSDs is a weakness of the expert clinical examination. (J Am Coll Cardiol 1997;30:243–6)
Sequential transition of mid-basilar variant to apical form of Takotsubo syndrome.

Takotsubo syndrome, also called apical ballooning syndrome, is a clinical entity characterized by transient hypokinesis, akinesis, or dyskinesis of the left ventricular mid and apical segments without flow limiting obstructive coronary lesions. There have been many reported morphologic variants of apical ballooning syndrome based upon distribution of segment involvement including traditional apical, midventricular, and basilar. We present a patient who demonstrated sequential transition of mid-basilar type to classical apical ballooning type. .
Social support and adjustment in chronically ill and handicapped children

The relationship between social support and adjustment was investigated in children with a chronic physical illness or handicap. Mothers of 153 children with juvenile diabetes, juvenile rheumatoid arthritis, chronic obesity, spina bifida, or cerebral palsy reported on these children's family support, peer support, externalizing behavior problems, and internalizing behavior problems. Children reported as having high social support from both family and peers showed a significantly better adjustment than those with high social support from only one of these sources. Chronically ill or physically handicapped children without high support from both family and peers were reported to have significantly more behavior problems than children in general. Both family and peer support contributed negatively and independently to the variance in externalizing behavior problems, whereas only peer support did so for internalizing behavior problems. There were no interactions between type of support and either sex or age in predicting adjustment.
Non-uniqueness in the integral equation formulation of the biharmonic equation in multiply connected domains

Abstract In the boundary integral equation method, the biharmonic equation is converted to a pair of integral equations by using Green's third identity. In multiply connected domains, for a particular exceptional geometry the integral equations do not have a unique solution. Additional constraint equations are derived to enforce uniqueness in such situations. Two example problems are solved to demonstrate the effectiveness of the constraints.
The pattern of failure after reirradiation of recurrent squamous cell head and neck cancer: implications for defining the targets.

Purpose Reirradiation (re-RT) of recurrent head and neck cancer (HNC) may achieve long-term disease control in some patients, at the expense of high rates of late sequelae. Limiting the re-RT targets to the recurrent gross tumor volume (rGTV) would reduce the volumes of reirradiated tissues; however, its effect on tumor recurrence pattern is unknown. Methods and Materials This is a retrospective review of 66 patients who underwent curative-intent re-RT for nonresectable recurrent or second primary mucosal squamous cell HNC. Treatment was delivered with three-dimensional conformal (3D) RT or intensity-modulated RT (IMRT). The targets in all patients consisted of the rGTVs with tight (0.5-cm) margins, with no intent to treat prophylactically lymph nodes or subclinical disease in the vicinity of the rGTVs. The sites of locoregional failures (LRFs) were determined using imaging at the time of failure and were compared with the rGTVs. Results Median re-RT dose was 68 Gy. Forty-seven patients (71%) received concomitant chemotherapy, and 31 (47%) received hyperfractionated, accelerated RT. At a median follow-up of 42 months, 16 (23%) were alive and disease-free. Fifty patients (77%) had a third recurrence or persistent disease, including 47 LRFs. All LRFs occurred within the rGTVs except for two (4%) (95% confidence interval, 0–11%). Nineteen patients (29%) had Grade ≥ 3 late complications, mostly dysphagia (12 patients). Conclusions Almost all LRFs occurred within the reirradiated rGTVs despite avoiding prophylactic RT of tissue at risk of subclinical disease. These results support confining the re-RT targets to the rGTVs to reduce reirradiated tissue volumes.
ARITHMETIC SPACE–TIME GEOMETRY FROM STRING THEORY

An arithmetic framework for string compactification is described. The approach is exemplified by formulating a strategy that allows to construct geometric compactifications from exactly solvable theories at c = 3. It is shown that the conformal field theoretic characters can be derived from the geometry of space–time, and that the geometry is uniquely determined by the two-dimensional field theory on the worldsheet. The modular forms that appear in these constructions admit complex multiplication, and allow an interpretation as generalized McKay–Thompson series associated to the Mathieu and Conway groups. This leads to a string motivated notion of arithmetic moonshine.
Effects of diet and dietary experience on body weight regulation in rats with septal lesions

A series of three experiments was conducted to assess whether septal lesions would affect the capacity of female rats to respond to changes in diet palatability. It was found that septal lesions produced overeating in rats shifted from an unpalatable powdered diet to a highly palatable mixture of Crisco and powdered food. However, overeating of the Crisco diet only occurred if septal-lesioned rats were first exposed to the powdered diet following surgery. Surprisingly, septal lesions did not affect responsivity to a shift from the Crisco to the powdered diet. The results indicate that, while septal damage appeared to alter responsivity to a change in diet, relative palatability factors alone are not the cause. Rather, septal lesions may produce permanent changes in the pattern of ingestive behavior when lesioned rats are exposed to certain diets following surgery.
Nonlinear nature of gravitation and gravitational-wave experiments.

It is shown that gravitational waves from astronomical sources have a nonlinear effect on laser interferometer detectors on Earth, an effect which has hitherto been neglected, but which is of the same order of magnitude as the linear effects. The signature of the nonlinear effect is a permanent displacement of test mases after the passage of a wave train.
Methods for numerical conformal mapping

Abstract Nonlinear integral equations for the boundary functions which determine conformal transformations in two dimensions are developed and analyzed. One of these equations has a nonsingular logarithmic kernel and is especially well suited for numerical computations of conformal maps including those which deal with regions having highly distorted boundaries. Numerical procedures based on interspersed Gaussian quadrature for approximating the integrals and a Newton-Raphson technique to solve the resulting nonlinear algebraic equations are described. The Newton-Raphson iteration converges reliably with very crude initial approximations. Numerical examples are given for the mapping of a half-infinite region with periodic boundary onto a half plane, with up to nine-figure accuracy for values of the map function on the boundary and for its first derivatives. The examples include regions bounded by “spike” curves characteristic of Rayleigh-Taylor instability phenomena. A differential equation is derived which relates changes in the map function to changes of the boundary. This is relevant to potential problems for regions with time-dependent boundaries. Further nonsingular integral formulas are derived for conformal mapping in a variety of geometries and for application to the boundary-value problems of potential theory.
New porphyrin glyco-conjugates

Porphyrins bearing sugars and other motifs are proposed for a variety of therapeutic applications. Non-hydrolysable glyco conjugates of porphyrins can be formed in rapid, room temperature reacting in greater than 90% yields from tetraperfluorophenyporphyrin. Additional functional groups can be appended using the same chemistry but different stoichiometries of the reagents. Thus sugars, amines, peptides, and cationic moieties designed to target cancer cells or other diseased or disease-causing cells are made rapidly and cleanly. These compounds can then be rapidly screened for cell uptake, or selected from combinatorial libraries by cell uptake assays using a combination of fluorescence microscopy and mass spectrometry. Modifications of the macrocycle allow fine-tuning of the photonic properties for specific medical, imaging, or biochemical applications.
Local similarity matching algorithm for determining SPR angle in surface plasmon resonance sensors

Abstract Surface plasmon resonance (SPR) sensors can detect the presence of molecules of interest at their surface, and can be used to determine their concentration, by comparing the SPR angle (or wavelength) for different samples before and after the reaction event. The degree of usefulness of such devices depends on the stability and sensitivity of the SPR angle determination. The stability means that the determined SPR angle is a function only of controllable parameters and the molecules of interest. The sensitivity means that determined SPR angles are distinct for measurements of distinct concentrations of the molecules of interest. We propose a new method, called “local similarity matching” (LSM), for a determination of the SPR angle that is stable. LSM is sufficiently immune to the uncontrollable fluctuations of input power and sensor noise to allow reliable discrimination of SPR angles differing by 0.01°. Experimental comparison shows that LSM is more stable than existing methods such as centroid, constant-reflectance, polynomial fit, and zero-point-derivative methods.
A sequential phase II/III trial for binary outcomes

This paper describes a simple two-stage design for randomized clinical trials with a binary outcome. An early stopping criterion applies to results in the experimental arm only and seeks to evaluate that arm with respect to some external standard of efficacy. Stopping rules are similar to those commonly used in phase II designs. This design has no adverse impact on the overall type I error rate, though one must increase sample size to accommodate a modest loss in power.
Facile synthesis of stacked, heteronuclear porphyrin arrays with varied architectures.

Utilizing trans-bis(8-carboxynaphthyl) functionalized Cu-porphyrins, a synthetic pathway for the preparation of stacked, heteronuclear cofacial single-stranded porphyrin arrays with the composition [Cu(porphyrinCOO)]2-[K2(MeOH)8]2+ (1) and [Cu(porphyrinCOO)]2-[M(MeOH)6]2+ (M = Mn, Co, Ni, Zn; 3-7) has been detailed, and this approach allows for the assembly of the individual components in several different orientations. Depending on the bridging metal complexes and the meso-aryl substituents (R), solid-state porphyrin architectures with a slipped (R = mesityl, M = K; 1), a twisted (R = mesityl, M = Mn, Co, Ni; 3−5), and an axial symmetric arrangement (R = 3,4,5-trimethoxyphenyl, M = Mn, Zn; 6, 7) of the porphyrin building blocks have been prepared.
Decision support tools for proton therapy ePR: intelligent treatment planning navigator and radiation toxicity tool for evaluating of prostate cancer treatment

The electronic patient record (ePR) has been developed for prostate cancer patients treated with proton therapy. The ePR has functionality to accept digital input from patient data, perform outcome analysis and patient and physician profiling, provide clinical decision support and suggest courses of treatment, and distribute information across different platforms and health information systems. In previous years, we have presented the infrastructure of a medical imaging informatics based ePR for PT with functionality to accept digital patient information and distribute this information across geographical location using Internet protocol. In this paper, we present the ePR decision support tools which utilize the imaging processing tools and data collected in the ePR. The two decision support tools including the treatment plan navigator and radiation toxicity tool are presented to evaluate prostate cancer treatment to improve proton therapy operation and improve treatment outcomes analysis.
Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice

The multifunctional cytokine transforming growth factor (TGF) β1 is secreted in a latent complex with its processed propeptide (latency-associated peptide [LAP]). TGFβ1 must be functionally released from this complex before it can engage TGFβ receptors. One mechanism of latent TGFβ1 activation involves interaction of the integrins αvβ6 and αvβ8 with an RGD sequence in LAP; other putative latent TGFβ1 activators include thrombospondin-1, oxidants, and various proteases. To assess the contribution of RGD-binding integrins to TGFβ1 activation in vivo, we created a mutation in Tgfb1 encoding a nonfunctional variant of the RGD sequence (RGE). Mice with this mutation (Tgfb1RGE/RGE) display the major features of Tgfb1−/− mice (vasculogenesis defects, multiorgan inflammation, and lack of Langerhans cells) despite production of normal levels of latent TGFβ1. These findings indicate that RGD-binding integrins are requisite latent TGFβ1 activators during development and in the immune system.
Pioglitazone in the management of diabetes mellitus after transplantation.

Type 2 diabetes mellitus is a common problem in patients after solid organ transplantation. We studied the safety and efficiacy of pioglitazone therapy in this setting. Ten patients with diabetes mellitus treated with insulin or glyburide after transplantation were studied after the addition of the thiazolidinedione pioglitazone. Serum creatinine, HBA1C, total daily insulin dose, tacrolimus dose, tacrolimus level and prednisone dose were followed for a mean of 242 days and compared to the corresponding values measured before the initiation of pioglitazone. The addition of pioglitazone caused no significant changes in serum creatinine or mean tacrolimus dose, and caused decreases in HBA1C (8.36%± 1.5% pre-pioglitazone, 7.08%± 1.5% post-pioglitazone, p = 0.018) and total daily insulin dose (125.1 ± 28.1 units pre-pioglitazone, 80.6 ± 22.8 units post-pioglitazone, p = 0.002). Our preliminary study suggests that pioglitazone is a safe and effective oral agent for the management of diabetes mellitus after transplantation.
Morphine modulation of the contact hypersensitivity response: characterization of immunological changes.

Previous investigations in our laboratory showed that systemic morphine administration 1 h prior to elicitation of the in vivo contact hypersensitivity (CHS) response produced a robust increase in inflammation at the site of antigen reexposure. The present study extended those findings by characterizing the effect of morphine on immunological processes important in the development of the CHS response. To induce contact hypersensitivity, the antigen 2,4-dinitrofluorobenzene was applied to the pinnae of previously sensitized rats. Morphine administration produced an increase in inducible nitric oxide synthase mRNA and the proinflammatory cytokine interleukin-6, at the site of antigen reexposure. In contrast, morphine did not alter expression of the anti-inflammatory cytokine interleukin-10. Morphine also produced an increase in the proliferation of lymphocytes from the peripheral (i.e., cervical) lymph nodes when assessed 72 h following challenge. These studies show that the morphine-induced increase in the in vivo CHS response involves immunologically specific alterations.
Functional and Psychosocial Outcomes of Older Adults After Burn Injury: Results From a Multicenter Database of Severe Burn Injury

A number of factors increase the susceptibility of older adults to burn injury. The majority of studies of older adults have focused on patient and injury factors related to mortality risk. However, little is known about the long-term functional and psychological outcomes of older adults after severe burn. The purpose of this study is to examine the long-term outcomes of older adults after burn injury. The authors performed an analysis of the outcomes of older adults (age 55 years or older) enrolled in a prospective study of burn injury outcomes. Change in living situation as well as distress, functional impairment, and quality of life were examined at discharge and at 6, 12, and 24 months after hospital discharge. Mixed effects modeling was performed to compare differences across age groups and time as well as to account for missing data. A total of 737 patients aged 55 years or older were enrolled and followed in the National Institute on Disability and Rehabilitation Research burn program. Patients in all age groups had significant deficits in Short Form-36, Functional Independence Measure, and Brief Symptom Inventory scores at time of discharge. Recovery of physical and psychosocial functioning was greatest from discharge to 6 months in patients aged 55 to 74 years and greatest at 1 year for patients aged 75 years or older. This study confirms that severe burn injury significantly impacts both functional outcome and psychosocial quality of life in older adults. However, the impact seems to be age related as are recovery trajectories. Rehabilitation programs lasting up to 1 year after injury could be of tremendous benefit in helping older adults achieve maximal potential recovery.
The 21st Century Board: Structure, Responsibility, Assessment

Redefinition of how a board of directors fulfills its duties to make informed decisions and to monitor and oversee management is a primary focus of corporate governance reform. In a three pronged a...
Stable depression of potentiated synaptic responses in the hippocampus with 1-5 Hz stimulation.

Abstract Adult rats with two chronic stimulating electrodes in the Schaffer collateral/commissural system of the hippocampus and one recording electrode in the stratum radiatum (apical dendrites) of field CA1 were administered high-frequency stimulation (10 brief bursts at theta frequency) to produce long-term potentiation (LTP). ‘Low frequency’ stimulation (100 pulses at 1 Hz alone or followed by 250 pulses at 5 Hz) delivered 5–15 min later had no effect on LTP in 18% of the rats, caused a transient reversal in 18% of the group, but produced an apparent reversal of LTP for the remainder of a 1 h test session in 64% of the animals. LTP did not recover in animals tested 24 h later, at which point a second episode of high-frequency stimulation but without subsequent low-frequency stimulation was administered. This produced an LTP effect that persisted for a 1 h test session in 94% of the cases and that was still present in 86% of the animals tested 24 h later. Low-frequency stimulation applied prior to induction of LTP had no lasting effects on evoked responses not did it affect responses to a control stimulating electrode in those cases in which it reversed LTP. Possible implications of these results for hypotheses concerning the substrates of LTP and mechanisms of forgetting are discussed.
Mapping Dynamic Protein Interactions to Insulin Secretory Granule Behavior with TIRF-FRET

Biological processes are governed by extensive networks of dynamic molecular interactions. Yet, establishing a spatial and temporal map of these interactions and their direct relationship to specific cell functions has remained a challenge. Here, we implement sensitized emission Forster resonance energy transfer (FRET) stoichiometry under total internal reflection fluorescence (TIRF) microscopy. We demonstrate through quantitative analysis and modeling that evanescent fields must be precisely matched between FRET excitation wavelengths to isolate dynamic interactions between bimolecular FRET pairs that are not entirely membrane-delimited. We then use TIRF-FRET to monitor the behavior of individual insulin-containing secretory granules at the plasma membrane of living cells, while simultaneously tracking the dynamic interaction between the GTPase Rab27A and its effector Slp4A, on those same granules. Notably, insulin granules that underwent exocytosis demonstrated a specific increase in Rab27A-GTP/Slp4A FRET in the 5 s before membrane fusion, which coincided temporally with an increase in granule displacement and mobility. These results demonstrate an initial spatiotemporal mapping of a dynamic protein-protein interaction on individual secretory granules that is linked to a specific granule behavior in living cells.
Adaptation to undernutrition: how much food does man need?

Abstract Although many authors have postulated a direct correlation between “widespread chronic undernutrition” and “low levels of physical capacity and labour productivity” in the developing world, in studying East Javanese peasant farmers there was little evidence of undernutrition and it was found that workers with low energy intakes were as productive as those with high intakes. Early measurements indicated that external work produced from a given energy intake varied considerably in relation to the individual consumer and that the work efficiency of the consumer varied inversely in relation to the degree of undernutrition or energy stress. Later studies showed that the average Basal Metabolic Rate (B.M.R.) of a selected high energy intake group was twice that of a comparable low intake group and high intake subjects also used more food energy per unit ergonometric work output. Examination of available data indicates that some forms of both genotypic and phenotypic metabolic adaptation occur in peoples with low intakes enabling them to utilize food energy more efficiently than those with high intakes, and an adaptive change in B.M.R. may play a major role in facilitating higher levels of metabolic efficiency in populations that are labelled “undernourished”. Variations in human metabolic efficiency make it extremely difficult to define clearly either the optimal level of food intake needed to maximize human productivity or the minimal quantity of energy needed to maintain human health. Nevertheless, minimum requirements are clearly well below present recommendations, and field observations show many populations living healthful and productive lives on energy intakes about 60% of present standards. Until these facts are recognized we will continue to be exposed to common misinterpretations of the physiologic and economic significance of available energy data stating that a large proportion of the world's population is “starving” or “weak from hunger”.
A case of proved adrenocorticotropin deficiency.

Summary A case is presented of proved deficiency of pituitary adrenocorticotropin with apparently adequate elaboration of pituitary thyrotropic and gonadotropic hormones. In the absence of a method for specific testing, the status of growth hormone elaboration remains obscure.
THE DETERMINANTS OF PRIVATE DEBT HOLDINGS: EVIDENCE FROM THE LIFE INSURANCE INDUSTRY

Life insurers hold the majority of private debt. Lenders in the private debt market must have the ability to evaluate the credit quality of borrowers and to perform ongoing risk monitoring. The purpose of this study is to examine the determinants of private debt holdings in the life insurance industry. The results suggest that larger insurers, insurers with higher financial quality, mutual insurers, publicly traded insurers, insurers facing stringent regulation, and insurers with greater cash holdings are more prevalent lenders in the private debt market.
Generation of novel reporter stem cells and their application for molecular imaging of cardiac-differentiated stem cells in vivo.

Stem cell therapies offer the potential for repair and regeneration of cardiac tissue. To facilitate evaluation of stem cell activity in vivo, we created novel dual-reporter mouse embryonic stem (mES) cell lines that express the firefly luciferase (LUC) reporter gene under the control of the cardiac sodium–calcium exchanger-1 (Ncx-1) promoter in the background of the 7AC5-EYFP mES cell line that constitutively expresses the enhanced yellow fluorescent protein (EYFP). We compared the ability of recombinant clonal cell lines to express LUC before and after induction of cardiac differentiation in vitro. In particular, one of the clonal cell lines (Ncx-1-43LUC mES cells) showed markedly enhanced LUC expression (45-fold increase) upon induction of cardiac differentiation in vitro. Further, cardiac differentiation in these cells was perpetuated over a period of 2–4 weeks after transplantation in a neonatal mouse heart model, as monitored by noninvasive bioluminescence imaging (BLI) and confirmed via postmortem immunofluorescence and histological assessments. In contrast, transplantation of undifferentiated pluripotent Ncx-1-43LUC mES cells in neonatal hearts did not result in detectable levels of cardiac differentiation in these cells in vivo. These results suggest that prior induction of cardiac differentiation in vitro enhances development and maintenance of a cardiomyocyte-like phenotype for mES cells following transplantation into neonatal mouse hearts in vivo. We conclude that the Ncx-1-43LUC mES cell line is a novel tool for monitoring early cardiac differentiation in vivo using noninvasive BLI.
On the interplay of singular perturbations and wide-band stochastic fluctuations

A class of nonlinear singularly perturbed systems driven by wide-band noise is considered. The asymptotic behavior of the slow variables is studied when the fast variables are sufficiently fast (represented by $\mu \to 0$) and the wide-band noise is sufficiently wide (represented by $\varepsilon \to 0$). A reduced-order Markov model which represents the behavior of the slow variables is derived. It is shown that the slow variables converge weakly to the solution of this reduced-order model as $\varepsilon $ and $\mu $ tend to zero. The coefficients of this reduced-order model depend, in general, on the speeds of $\varepsilon $ and $\mu $ as they approach zero. The implication of such dependence on the engineering practice of neglecting parasitic elements is discussed. Special cases where the model is independent of the speeds of $\varepsilon $ and $\mu $ are explored.
Diethylstilbestrol and Circulating Lipids in Women with Metastatic Breast Cancer: Lack of Dose Response over Three Log Units

Thirty-five women with progressive metastatic breast cancer were treated in a double blind study with diethylstilbestrol in doses of 1.5, 15, 150, or 1500 mg daily. Plasma lipids and lipoproteins were measured serially in samples obtained from fasting patients. The pretreatment value for each variable was paired with the arithmetic mean of all values obtained during treatment. Plasma triglycerides increased 88% and plasma phospholipids rose 15% with therapy. There was no significant difference in mean responses of patients among the 4-dose levels, with increases apparent by 2 weeks of treatment, and stable as long as 2 yr. Plasma total cholesterol was unchanged with the estrogen therapy, although high-density liproprotein cholesterol increased. Serum immunoreactive insulin and plasma free fatty acids and glycerol did not change significantly. These data indicate that estrogen effects on circulating lipids accompanying pharmacologic doses of the hormone are independent of dosage.
Intracellular Mechanisms Responsible for PKG Stimulation of ATP-Sensitive Potassium Channels

The activity of the ATP-sensitive potassium (KATP) channel, a high-fidelity metabolic sensor that couples cellular metabolic status to membrane excitability, is modulated by a variety of post-translational mechanisms. Findings obtained from our recent studies suggest that activation of cGMP-dependent protein kinase (PKG) enhances the function of neuronal KATP channels via intracellular signaling and that generation of reactive oxygen species (ROS) is required for PKG stimulation of the channel. In the present study we further investigated the potential role of intracellular calcium and camodulin in mediating the modulatory effect of PKG and ROS. By performing single-channel recordings in transfected human embryonic kidney (HEK) 293 cells, we found that the increase in the single-channel activity of Kir6.2/SUR1 channels (a neuronal/pancreatic KATP channel isoform) by activation of PKG in cell-attached patches was abrogated by BAPTA-AM, a membrane-permeable calcium chelator and SKF-7171A, a membrane-permeable calmodulin antagonist. Activation of PKG was achieved by bath application of zaprinast, a cGMP-dependent phosphodiesterase inhibitor, and the specificity of PKG activation was verified by selective blockade by PKG- but not PKA-specific inhibitors. Moreover, bath application of H2O2 dose-dependently increased the activity of Kir6.2/SUR1 channels in cell-attached but not inside-out patches, and the stimulatory effect was attenuated by suppression of calmosulin. Altogether, our findings suggest that PKG stimulates neuronal KATP channels via ROS generation and subsequent activation of calmodulin. The cGMP/PKG/ROS/calmodulin signaling cascade may play an important role in controlling neuronal excitability, neurotransmitter release and neuroprotection against ischemic injury, by modulating the function of plasma-membrane KATP channels.
The inflammatory response in myocardial infarction

One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-α release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction.