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Nonhuman primates used in biomedical research may experience clinically significant weight loss for a variety of reasons. Episodes of anorexia (complete loss of appetite) or hyporexia (decreased appetite) can result in significant weight loss, potentially altering animal welfare and scientific studies. The FDA has approved several appetite stimulants for use in domestic species, but currently none are approved for use in NHP. Treatment of inappetence and weight loss in NHP often relies on the extralabel use of these compounds. Capromorelin is a ghrelin receptor agonist. As a growth hormone secretagogue, capromorelin increases appetite, leading to weight gain. Studies in several species have shown a positive correlation between capromorelin administration and weight gain; in 2017, an oral solution of capromorelin received FDA approval for use in dogs. We tested this solution in healthy adult rhesus macaques (n = 3 males and 3 females) for its effects on body weight and insulin like growth factor-1 (IGF-1). A control group (n = 2 males and 2 females) was used for comparison. Treated macaques received a 3mg/kg oral dose daily for 7 d. Clinical signs were observed daily. Weights were collected before, during and at the end of treatment. Blood was drawn before, during and after treatment for measurement of IGF-1 levels and standard hematology and biochemistry parameters. Baseline-adjusted mean body weights and IGF-1 levels were significantly higher in treated as compared with control monkeys after 7 d of beginning treatment (body weight of 10.5±0.1kg (mean ± SEM) and 10.1±0.1kg, respectively; IGF-1 of 758±43ng/mL and 639±22ng/mL, respectively). Capromorelin administration was not associated with appreciable changes in hematologic and biochemical values in treated macaques. These findings suggest that capromorelin may be useful for treating inappetence and weight loss in NHP, and based on blood analysis, a 7-d course of treatment does not appear to cause acute toxicity.

In addition to food and protection, altricial young in many species are ectothermic and require that endothermic parents provide warmth to foster growth, yet only one parent-typically the female-broods these young to keep them warm. When this occurs, reduced provisioning by males obliges females to forage instead of providing warmth for offspring, favoring the temporal mapping of male activities. We assessed this in a wild house wren population while experimentally feeding nestlings to control offspring satiety. While brooding, females look out from the nest to inspect their surroundings, and we hypothesized that this helps to determine if their mate is nearby and likely to deliver food to the brood (males pass food to brooding females, which pass the food to nestlings). Females looked out from the nest less often when their partner was singing nearby and when his singing and provisioning were temporally linked, signaling his impending food delivery. Females also left to forage less often when their mate was nearby and likely to deliver food. Nestling begging did not affect these behaviors. Females looking out from the nest more often also provisioned at a higher rate and were more likely to divorce and find a new mate prior to nesting again within seasons, as expected if females switch mates when a male fails to meet expectations. Our results suggest anticipatory effects generated by male behavior and that brooding females temporally map male activity to inform decisions about whether to continue brooding or to leave the nest to forage.

Background: Critical care nurses routinely care for dying patients. Research on obstacles in providing end-of-life care has been conducted for more than 20 years, but change in such obstacles over time has not been examined., Objective: To determine whether the magnitude scores of obstacles and helpful behaviors regarding end-of-life care have changed over time., Methods: In this cross-sectional survey study, questionnaires were sent to 2000 randomly selected members of the American Association of Critical-Care Nurses. Obstacle and helpful behavior items were analyzed using mean magnitude scores. Current data were compared with data gathered in 1999., Results: Of the 2000 questionnaires mailed, 509 usable responses were received. Six obstacle magnitude scores increased significantly over time, of which 4 were related to family issues (not accepting the poor prognosis, intrafamily fighting, overriding the patient's end-of-life wishes, and not understanding the meaning of the term lifesaving measures). Two were related to nurse issues. Seven obstacles decreased in magnitude, including poor design of units, overly restrictive visiting hours, and physicians avoiding conversations with families. Four helpful behavior magnitude scores increased significantly over time, including physician agreement on patient care and family access to the patient. Three helpful behavior items decreased in magnitude, including intensive care unit design., Conclusions: The same end-of-life care obstacles that were reported in 1999 are still present. Obstacles related to family behaviors increased significantly, whereas obstacles related to intensive care unit environment or physician behaviors decreased significantly. These results indicate a need for better end-of-life education for families and health care providers., (© 2020 American Association of Critical-Care Nurses.)

Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The coevolution of parental supply and offspring demand has long been thought to involve offspring need driving begging and parental care, leaving other hypotheses underexplored. In a population of wild birds, we experimentally tested whether begging serves as a negatively condition-dependent signal of need or a positively condition-dependent signal of quality. Across multiple years, we supplemented nestling house wrens with food shortly after hatching and simultaneously manipulated corticosterone levels to simulate the hunger-induced increase in glucocorticoids thought to mediate begging. This allowed us to also test whether begging is simply a proximate signal of hunger. Days after supplementation ended, food-supplemented nestlings were in better condition than nonsupplemented nestlings and begged for food at an increased rate; their parents, in turn, increased provisioning to a greater extent than parents of nonsupplemented young, as begging positively predicted provisioning. Food-supplemented nestlings therefore attained above-average condition, which predicted their recruitment as breeding adults in the local population. Glucocorticoids increased begging in the short term, but this transient effect depended on satiety. Thus, glucocorticoids promoted begging as a proximate response to hunger, whereas the longer-term changes in nestling condition, begging, and food provisioning suggest that begging ultimately signals offspring quality to elicit increased investment, thereby enhancing offspring survival.

Background: Patient satisfaction scores in the vascular interventional radiology department were low, especially related to wait times in registration and for tests/treatments, with low scores for intentions to recommend., Purpose: The purpose of our quality improvement project was to decrease wait times and improve patient satisfaction using Lean Six Sigma's define, measure, analyze, improve, and control (DMAIC) framework with a pre-/postintervention design., Results: There was a statistically significant decrease in wait times (P < .0019) and an increase in patient satisfaction scores in 3 areas: registration wait times (from 17 to 99 percentiles), test/treatment (from 19 to 60 percentiles), and likelihood to recommend (from 6 to 97 percentiles)., Conclusions: Lean Six Sigma was an effective framework for use in decreasing wait times and improving patient satisfaction.

Recently, newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28-CD80/86 specific reagent, is associated with superior patient survival and graft function compared with traditional therapy, but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely used. To that end, we designed a study in a nonhuman primate kidney transplant model where animals were treated with either a belatacept- or a tacrolimus-based immunosuppressive regimen. Interestingly, we found that elevated pretransplant frequencies of CD28 + CD8 + T EMRA cells are associated with rejection on belatacept but not tacrolimus treatment. Further analysis showed that the CD28 + CD8 + T EMRA cells rapidly lose CD28 expression after transplant in those animals that go on to reject with the allograft infiltrate being predominantly CD28 - . These data suggest that CD28 + memory T cells may be resistant to belatacept, capable of further differentiation including loss of CD28 expression while maintaining effector function. The unique signaling requirements of CD28 + memory T cells provide opportunities for the development of targeted therapies, which may synergize with belatacept to prevent costimulation-independent rejection., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

As the predominant aetiological agent of the common cold, human rhinovirus (HRV) is the leading cause of human infectious disease. Early studies showed that a monovalent formalin-inactivated HRV vaccine can be protective, and virus-neutralizing antibodies (nAb) correlated with protection. However, co-circulation of many HRV types discouraged further vaccine efforts. Here, we test the hypothesis that increasing virus input titres in polyvalent inactivated HRV vaccine may result in broad nAb responses. We show that serum nAb against many rhinovirus types can be induced by polyvalent, inactivated HRVs plus alhydrogel (alum) adjuvant. Using formulations up to 25-valent in mice and 50-valent in rhesus macaques, HRV vaccine immunogenicity was related to sufficient quantity of input antigens, and valency was not a major factor for potency or breadth of the response. Thus, we have generated a vaccine capable of inducing nAb responses to numerous and diverse HRV types., Competing Interests: M.L.M. co-founded and serves as Chief Scientific Officer for Meissa Vaccines, Inc. S.L., M.T.N. and M.L.M are co-inventors in a patent application (PCT/US2016/037658) describing the rhinovirus vaccine reported in this paper. The vaccine technology has been optioned to Meissa Vaccines, Inc. by Emory University. The remaining authors declare no competing financial interests.

Costimulation blockade with the fusion protein belatacept provides a desirable side effect profile and improvement in renal function compared with calcineurin inhibition in renal transplantation. This comes at the cost of increased rates of early acute rejection. Blockade of the integrin molecule leukocyte function-associated antigen 1 (LFA-1) has been shown to be an effective adjuvant to costimulation blockade in a rigorous nonhuman primate (NHP) model of islet transplantation; therefore, we sought to test this combination in an NHP renal transplant model. Rhesus macaques received belatacept maintenance therapy with or without the addition of LFA-1 blockade, which was achieved using a murine-derived LFA-1-specific antibody TS1/22. Additional experiments were performed using chimeric rhesus IgG1 (TS1/22R1) or IgG4 (TS1/22R4) variants, each engineered to limit antibody clearance. Despite evidence of proper binding to the target molecule and impaired cellular egress from the intravascular space indicative of a therapeutic effect similar to prior islet studies, LFA-1 blockade failed to significantly prolong graft survival. Furthermore, evidence of impaired protective immunity against cytomegalovirus was observed. These data highlight the difficulties in translating treatment regimens between organ models and suggest that the primarily vascularized renal model is more robust with regard to belatacept-resistant rejection than the islet model., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood-mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. WT and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets were studied in nonimmunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at 1 and 24 h after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages and platelets. Insulin, complement, antibody, neutrophils, macrophages and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 h in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: One in two people may develop symptomatic knee osteoarthritis (OA) in their lifetime. Many OA sufferers have multiple symptoms, including pain, fatigue, and depressive symptoms. Determining whether symptom clusters exist among these older adults and what their effects are on outcomes such as quality of life (QOL) and functional status is essential to provide evidence-based geriatric healthcare., Purpose: The purposes of the secondary analyses were to explore symptoms that form clusters in older adults with OA of the knee and the effects of symptom clusters on their QOL and functional status., Method: A cross-sectional, methodological exploration of existing data from a convenience sample (N = 75) of adults aged 50 years and older with OA of the knee was used. Hierarchical and k-means cluster analyses were used to identify symptom clusters. MANOVA was performed to test for joint differences in QOL and functional status., Results: Two large clusters of pain, fatigue, and depressive symptoms were identified from the cluster, and significant relationships were found between symptom clusters and both QOL (p = .008) and functional status (p < .001). Conclusions about QOL or functional status differences were similar for alternative clustering strategies or numbers of symptom clusters in sensitivity analyses., Conclusion: The findings of this study provide a foundation for targeted interventions to improve QOL and functional status of older adults with OA of the knee.

Background: Research has suggested that dancers may be more at risk of injury when they excessively utilise non-hip components of turnout to compensate for deficits in hip external rotation when trying to achieve maximal total turnout. However, recently different measures of turnout have been cited in the literature as well as suggestions for derived variables to account for shortfalls in particular components of turnout. This study aimed to assess whether measurements of turnout can predict the number of injuries (0 or 1 injury, or 2+ injuries) over a 10-month period., Methods: At the beginning of the academic year, 47 female, full-time, contemporary dance students (mean age 19.9 ± 2.51 yrs; height 1.65 ± 0.05 cm; weight 56.23 ± 6.51 kg) were screened as part of a biannual screening process. Measurements, summed of both legs, were obtained for passive hip external rotation (pER), total passive turnout (TPT), and total active turnout (TAT). From these, three further variables were derived: compensated turnout, muscular turnout, and active ER lag. At the end of 10 months, the dancers' physiotherapist-reported and self-reported injuries were obtained., Results: Binary regression analyses for the six turnout variables identified compensated and muscular values as having significant positive effects. For every 1% increase in compensated and muscular values, there was a corresponding 9% or 8.4% increase in the odds that the dancer would sustain 2 or more injuries compared to 0 or 1 injury., Conclusion: Screening compensated and muscular values may be useful to address shortfalls to prevent injuries in the future.

Human post-transplant lymphoproliferative disorder (PTLD) is an abnormal lymphoid proliferation that arises in 1-12% of transplant recipients as a consequence of prolonged immunosuppression and Epstein-Barr viral infection (EBV). Nonhuman primates, primarily rhesus macaques (Macaca mulatta), have been used extensively in research models of solid organ transplantation, as the nonhuman primate immune system closely resembles that of the human. Lymphocryptovirus of rhesus monkeys has been characterized and shown to be very similar to EBV in humans in regards to its cellular tropism, host immune response, and ability to stimulate B lymphocyte proliferation and lymphomagenesis. Thus, it appears that the NHP may be an appropriate animal model for EBV-associated lymphoma development in humans. The clinical management of post-transplant nonhuman primates that are receiving multiple immunosuppressive agents can be complicated by the risk of PTLD and other opportunistic infections. We report 3 cases of PTLD in rhesus macaques that illustrate this risk potential in the setting of potent immunosuppressive therapies for solid organ transplantation., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Surgical site infections (SSIs) are the most common type of health care-associated infection in surgical patients. We wanted to identify which intraoperative prep solution used in our health network for adult open abdominal surgical procedures resulted in the lowest incidence of SSI 30 days after surgery. In addition, we wanted to know specifically how parachoroxylenol compared with chlorhexidine gluconate, povidone-iodine, and 0.7% iodine and 74% isopropyl alcohol as an intraoperative prep solution. We conducted a retrospective medical record review of 162 consecutive patients ages 18 years and older who had undergone elective open abdominal procedures from December 2008 to December 2010 at four acute care community hospitals within an integrated, tertiary health network in the southeastern United States. No SSIs occurred after procedures in which parachoroxylenol intraoperative prep solution was used (n = 71), whereas five SSIs occurred after procedures in which other prep solutions (ie, chlorhexidine gluconate [no SSIs], povidone-iodine [two SSIs], and 0.7% iodine and 74% isopropyl alcohol [three SSIs]) were used (n = 91). A chi-square test indicated a significant difference in the incidence of SSIs among patients prepped with parachoroxylenol intraoperative prep solution compared to patients prepped with the other solutions., (Copyright © 2013 AORN, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

For health care institutions, intraoperative prep agents are a critical link in combating surgical site infections and the associated economic burden. The question remains, is there an intraoperative prep agent that is truly superior to the others? We conducted a literature review to examine available empirical evidence related to intraoperative prep agents used in our health system for open abdominal, general surgery procedures: povidone-iodine, chlorhexidine gluconate, parachoroxylenol, and iodine povacrylex in 74% isopropyl alcohol. Intraoperative surgical skin prep studies were limited in providing empirical evidence to support one superior prep agent. Each prep agent has a specific mechanism of action along with specific advantages and disadvantages. We concluded that no one perioperative skin prep agent is superior in all clinical situations. Factors to consider when choosing an appropriate intraoperative skin prep agent include contraindications, environmental risks, the patient's allergies and skin condition, the surgical site, the manufacturer recommendations for the prep agent, and surgeon preference., (Published by Elsevier Inc. All rights reserved.)

Accurate assessment of species identity is fundamental for conservation biology. Using molecular markers from the mitochondrial and nuclear genomes, we discovered that many putatively native populations of greenback cutthroat trout (Oncorhynchus clarkii stomias) comprised another subspecies of cutthroat trout, Colorado River cutthroat trout (Oncorhynchus clarkii pleuriticus). The error can be explained by the introduction of Colorado River cutthroat trout throughout the native range of greenback cutthroat trout in the late 19th and early 20th centuries by fish stocking activities. Our results suggest greenback cutthroat trout within its native range is at a higher risk of extinction than ever before despite conservation activities spanning more than two decades.

Excessive daytime sleepiness has been associated with obesity in humans. However, experimental studies on sleep in obese animals are scarce and the results are not consistent. To test the hypothesis that obesity is associated with increased sleep, we examined the effects of obesity, induced by high-fat food, on sleep in mice. We first determined baseline sleep in adult C57BL/6 mice (6 months of age). In the following 6 weeks, the experimental mice (n = 12) were switched to high-fat food, in which fat provided 59% of calories, and the control mice (n = 11) were continuously fed with regular lab chows, in which fat provided 16% of calories. The body weights increased steadily in the high-fat group, but maintained constant in the controls. Wakefulness was reduced when assessed after 2, 4, and 6 weeks of high-fat feeding. Concurrently, there were large increases (about 80-100 min/day) in non-rapid eye movement sleep (NREMS). Rapid eye movement sleep (REMS) was not altered. The numbers of NREMS and REMS episodes were increased, whereas the duration of waking episodes was reduced, mainly during the dark period. These alterations in sleep were not observed in the controls. In the high-fat group, the increases of body weight, but not the amounts of energy intake, were negatively correlated with the change in the amounts of wakefulness and positively correlated with the change in the amounts of NREMS. These results indicate that the obese animals have increased sleep pressure and difficulties in maintaining wakefulness during the active phase.

Ulcers and erosions of the corneal epithelium, as well as delays in resurfacing of the cornea after wounding, are major causes of ocular morbidity and visual loss in diabetes. To study whether intervention by the opioid antagonist naltrexone (NTX; 30 mg/kg, twice daily) can restore reepithelialization in diabetic cornea, we induced diabetes in rats by intravenous injection of 65 mg/kg streptozotocin. After confirmation of diabetes, 5-mm-diameter epithelial defects that did not include the limbus were created by mechanical scraping of the cornea. At 4 and 8 weeks, corneal reepithelialization was markedly subnormal, with delays ranging from 11% to 17-fold in the diabetic animals compared with control counterparts. Rats that were diabetic for 8 weeks also had a significant decrease in the incidence of complete wound closure. At 4 and 8 weeks, diabetic animals that were receiving NTX had an acceleration in reepithelialization compared with diabetic animals that were receiving vehicle and even surpassed controls. DNA synthesis in the corneal epithelium of diabetic rats was decreased up to 90% of control levels, and NTX exposure of diabetic subjects elevated the labeling index by up to eightfold from diabetic animals that were receiving vehicle. Opioid growth factor and opioid growth factor receptor distribution were comparable in diabetic and control animals. These results indicate a delay in reepithelialization that is dependent on the duration of diabetes and that intervention of endogenous opioid-receptor interfacing with an opioid antagonist can facilitate the process of wound healing.

The aims of this study were to determine whether long-term oral administration of the opiate antagonist nalmefene is associated with any beneficial effects in patients with pruritus secondary to cholestatic liver disease and to assess the safety of long-term administration of this drug to these patients. Fourteen patients with unrelieved chronic pruritus of cholestasis were studied. Scratching activity, independent of limb movements, was recorded continuously for 24-hour periods before and during treatment with an initial ameliorating dose of nalmefene. Simultaneously, during these periods, visual analogue scores (VASs) of pruritus were recorded every 4 hours while patients were awake. The dose of nalmefene, which initially was 2 mg orally twice daily, was increased during the study, usually until a satisfactory clinical response was achieved. Five patients experienced a transient opioid withdrawal-like reaction that did not preclude continuing with nalmefene therapy. Serum biochemical indices of cholestasis did not change appreciably during treatment. Thirteen patients reported amelioration of the perception of pruritus on nalmefene. In 5 patients, exacerbations of pruritus occurred approximately 4 weeks after an initial ameliorating dose had been reached; these exacerbations were managed by increasing the dose. Baseline mean values for VAS and scratching activity were higher than corresponding means during nalmefene therapy in 13 (P = .002) and 12 (P = .013) patients, respectively. Possible tolerance to nalmefene occurred in 3 patients. Three patients experienced marked exacerbation of pruritus after nalmefene therapy was suddenly discontinued. Blood levels of nalmefene were consistent with normal pharmacokinetics of the drug. These results suggest that nalmefene may have a favorable risk-to-benefit ratio when it is administered orally long-term to patients with the pruritus of cholestasis.

Bupropion (BUP) may be less likely than other antidepressants to cause switches into mania and rapid cycling, suggesting utility in bipolar disorder. The combination of BUP with the mood-stabilizing anticonvulsants carbamazepine (CBZ) or valproate (VPA) is a strategy that might further lessen the risk of mania. CBZ induces, and to a lesser extent VPA inhibits the hepatic metabolism of various medications, but their effects on BUP have not been previously studied. Inpatients with mood disorders had pharmacokinetic profiles of BUP and metabolites assessed after single, oral, 150-mg doses of BUP while receiving placebo (N = 17) or during chronic blind CBZ (N = 12) or VPA (N = 5) monotherapy. CBZ but not VPA therapy decreased BUP peak concentrations (Cmax) by 87% (p < 0.0001) and 24-h area under the curve (AUC) by 90% (p < 0.0001), threohydrobupropion Cmax by 81% (p <0.0009) and AUC by 86% (p < 0.002), and erythropydrobupropion Cmax by 86% (p < 0.05) and AUC by 96% (p < 0.05). CBZ increased hydroxybupropion (H-BUP) Cmax by 71% (p < 0.007) and AUC by 50% (p < 0.09) and H-BUP AUC by 94% (p < 0.02). Thus, CBZ markedly decreased BUP and increased H-BUP concentrations, whereas VPA did not affect BUP but increased H-BUP concentrations. Further studies are required to determine how these differential effects of CBZ and VPA on BUP pharmacokinetics influence the tolerability and efficacy of combination therapies with these agents.

I recall it as vividly as though it had occurred but yesterday. It made a most enduring impression upon my boyish mind which was my very first impulse to choosing chorea as my virgin contribution to medical lore. Driving with my father through a wooded road leading from East Hampton to Amagansett we suddenly came upon two women, mother and daughter, both tall and thin, almost cadaverous, both bowing, twisting, grimacing. I stared in wonderment, almost in fear. What could it mean? My father paused to speak with them and we passed on. Then my Gamaliel-like instruction began; my medical education had its inception. From this point on, my interest in the disease has never wholly ceased. [George Huntington, at 59, recalling how at the age of 8 years he first saw Huntington disease while traveling with his physician father on his professional rounds in 1858].