Rehabilitation of the elderly patient on dialysis

Rehabilitation for geriatric patients, as well as rehabilitation for patients with a chronic disease, strives to mobilize individuals' residual capacity for optimal function in their usual environment. It is clear from observational studies that chronic dialysis patients often experience marked limitations in physical functioning, and these limitations tend to increase with patients' age. However, both prospective studies and controlled trials conducted with elderly persons demonstrate that muscle strengthening and cardiovascular exercise are related to improved physical functioning, and there is evidence that dialysis patients can also benefit from many of these interventions. Inpatient rehabilitation in a specialized geriatric unit has been shown to be associated with better functional outcomes and decreased need for institutionalization among elderly persons; the process of comprehensive geriatric assessment may also have beneficial outcomes. More controlled studies are needed in order to better specify the effectiveness of various geriatric interventions, for elderly subjects in general and for elderly dialysis patients specifically.     

Stimulus functions of drugs and the assessment of abuse liability

The development of a unifying framework for conceptualizing the commonalities in various forms of substance abuse must encompass the data base focused upon the stimulus functions of drugs. In the first instance, for example, the research on drug self-administration has provided convincing evidence of a remarkable concordance between laboratory animals and human substance abusers in the reinforcing stimulus functions of a range of chemical agents. The recognition of these cross-species and cross-drug generalities has radically changed conceptualizations of substance abuse from a reactive to a more active process and has encouraged the kind of functional analysis of drug-seeking and drug-taking that has proven productive and useful in the study of other behavioral interactions. In this regard as well, recent refinements in the analysis of the discriminative stimulus functions of drugs have provided a more comprehensive basis for characterizing a chemical agent's spectrum of action and evaluating its abuse liability. While the correlation between the discriminative stimulus functions and the reinforcing stimulus functions is remarkably high for some drug classes, there are notable exceptions. Finally, the assessment of abuse liability requires an analysis of the eliciting stimulus functions of drugs as reflected by the physiological and behavioral changes, both acute and chronic, that follow drug administration. The methods used to evaluate both physiological dependence and behavioral toxicity in relationship to sensory and motor effects for a range of abused drugs have depended heavily upon an assessment of the eliciting stimulus functions of such compounds.     

Patterns of Cocaine Use Among Cocaine-Dependent Outpatients

The authors systematically evaluated the frequency patterns of cocaine use in 85 cocaine-dependent outpatients and found four patterns of use: continuous (27%), intermittent patterned (35%), intermittent nonpatterned (25%), and occasional (13%). Few subjects reported consistent cycling between binges and crashes. There were no significant differences in patterns of use associated with gender, race, educational level, route of administration, or recency of heroin use. Continuous users and occasional users were older than intermittent users. Because different contingencies may control patterned vs. nonpatterned cocaine use, pattern of use may have implications for treatment, even in individuals reporting similar amounts of cocaine use.     

Comparison of the Permeability Characteristics of a Human Colonic Epithelial (Caco-2) Cell Line to Colon of Rabbit,Monkey, and Dog Intestine and Human Drug Absorption

The in vitro permeabilities of Caco-2 monolayers and permeabilities in tissue sections from colon of monkey, rabbit, and dog were compared using a series of compounds. The selected compounds differed in their physicochemical properties, such as octanol/water partition coefficient, water solubility, and molecular weight. Their structure included steroids, carboxylic acids, xanthins, alcohols, and polyethylene glycols. A linear permeability relationship was established between Caco-2 and colon tissue from both rabbit and monkey. The results suggest that Caco-2 is twice as permeable as rabbit and five times as permeable as monkey colon. However, no clear relationship could be established between Caco-2 monolayers and dog colon permeability. A relationship between permeability in Caco-2 monolayers and human absorption was found. The results suggest that within certain limits, permeability of Caco-2 monolayers may be used as a predictive tool to estimate human drug absorption.     

Acute psychoses: A proposed diagnosis for ICD-11 and DSM-V

This paper concerns the diagnostic classification of nonaffective acute remitting psychosis (NARP), which we also term acute brief psychosis. We argue that NARP can be delineated from both schizophrenia and the affective psychoses and considered as a single diagnosis. As indicated by the term NARP, four criteria would be central to the diagnosis: 1. nonaffective, 2. acute onset (over less than two weeks), 3. recovery within a brief duration (less than six months), and 4. psychosis broadly defined. We review the rationale and the empirical evidence for this proposed classification.     

The effect of immigrant generation and duration on self-rated health among US adults 2003–2007

Global self-rated health (SRH) is increasingly a key indicator in the assessment of immigrant health. However, evidence of the impact on SRH of generational status, duration of residence in the US, and socioeconomic status (SES) among immigrants and their offspring is limited and inconsistent. We overcome limitations in existing research on this topic by using a uniquely large and diverse data source, the March Annual Social and Economic Supplement of the Current Population Survey (CPS; 2003–2007) (n = 637,209). As a result, we are able to disaggregate results by race/ethnicity, account for country of origin, and consider the role of multiple dimensions of SES. We find that overall first-generation immigrants in the US have lower odds of poor/fair SRH compared to the third-generation. This association is particularly strong for blacks and Hispanics but not significant for Asians. Among first-generation Asians and Hispanics, longer duration of residence is positively associated with poor/fair SRH. Finally, socioeconomic gradients in SRH tend to be less pronounced among the first-generation (versus the third) and, within the first-generation, among recent arrivals (versus those with longer durations). Our results highlight the importance of explicitly accounting for multiple immigration-related variables and their interactions with race/ethnicity and SES. Otherwise, studies may misestimate SRH differences by race/ethnicity and socioeconomic status. The continued growth of the US immigrant population and the second-generation underscore the need to examine patterns in immigrant health systematically.     

A tumor-targeted and conditionally replicating oncolytic adenovirus vector expressing TRAIL for treatment of liver metastases.

We have constructed a new capsid-modified adenovirus (Ad) vector that specifically replicates in tumor cells and expresses TNF-related apoptosis-inducing ligand (TRAIL). The Ad capsid contains short-shafted fibers derived from Ad serotype 35, which allow for efficient infection of malignant tumor cells, and largely avoids innate toxicity after intravenous application. Replication-dependent homologous recombination in Ad genomes was used to achieve tumor-specific expression of Ad E1a (to mediate viral replication) and TRAIL (to mediate apoptosis and enhance release of progeny virus from infected cells). We demonstrated that our oncolytic vector (Ad5/35.IR-E1A/TRAIL) induced apoptosis in human tumor cell lines derived from colorectal, lung, prostate, and liver cancer. Both in vitro and in vivo tumor models showed efficient intratumoral spread of this vector. In a model for metastatic colon cancer, tail vein infusion of Ad5/35.IR-E1A/TRAIL resulted in elimination of preestablished liver metastases. Intravenous injection of this vector caused a transient elevation of serum glutamic pyruvic transaminase in tumor-bearing mice, which we attributed to factors released from apoptotic tumor cells. Liver histology analyzed at day 14 after virus injection did not show signs of hepatocellular damage. This new oncolytic vector represents a potentially efficient means for gene therapy of metastatic cancer.     

Regulation of COX-2 mediates acid-induced bone calcium efflux in vitro.

Chronic metabolic acidosis induces net Ca efflux from bone; this osteoclastic bone resorption is mediated by increased osteoblastic prostaglandin synthesis. Cyclooxygenase, the rate-limiting enzyme in prostaglandin synthesis, is present in both constitutive (COX-1) and inducible (COX-2) forms. We report here that acidosis increases both osteoblastic RNA and protein levels for COX-2 and that genetic deficiency or pharmacologic inhibition of COX-2 significantly reduces acid-induced Ca efflux from bone. INTRODUCTION: Incubation of neonatal mouse calvariae in medium simulating physiologic metabolic acidosis induces an increase in osteoblastic prostaglandin E2 (PGE2) release and net calcium (Ca) efflux from bone. Increased PGE2 is necessary for acid-induced bone resorption, because inhibition of cyclooxygenase activity with indomethacin significantly decreases not only PGE2 production but also Ca release. Cyclooxygenase is present in both constitutive (COX-1) and inducible (COX-2) forms. Because COX-2 activity has been implicated in several forms of pathological bone resorption, we tested the hypothesis that COX-2 is critical for acid-induced, cell-mediated bone Ca efflux. MATERIALS AND METHODS: To determine the effect of metabolic acidosis on COX-2 RNA and protein, primary cells isolated from neonatal CD-1 mouse calvariae were cultured in neutral (Ntl) or physiologically acidic medium (Met). RNA levels for COX-2 and COX-1 were measured by quantitative real-time PCR. Levels of COX-2 and COX-1 protein were measured by immunoblot analysis. To determine the effect of acidosis on bone Ca efflux in genetically deficient COX-2 mice, mice heterozygous for the COX-2 knockout (strain B6;129S7-Ptgs2(tm1Jed)/J) were used as breeders, and neonatal calvariae were cultured in Ntl or Met. To determine the effects of the specific COX-2 inhibitor, NS398, on acid-induced bone resorption, CD-1 calvariae were incubated in Ntl or Met with or without NS398 (1 microM). Medium PGE2 was assayed by ELISA. RESULTS: Incubation of mouse calvarial cells in Met significantly increased COX-2 RNA and protein levels without a change in COX-1. Increased COX-2 protein levels in response to Met were also observed in cultured calvariae. Acid-induced, cell-mediated Ca efflux from B6;129S7-Ptgs2(tm1Jed)/J calvariae was dependent on genotype. From 0 to 24 h, when physicochemical Ca efflux predominates, Met significantly increased net Ca efflux in all genotypes. After 24 h, when cell-mediated Ca efflux predominates, Met induced greater Ca efflux from (+/+) than from (+/-), and there was no increase from (-/-). In calvariae from CD-1 mice, NS398 significantly inhibited both the acid-induced increase in PGE2 and Ca release. CONCLUSIONS: The specific acid-induced increase in COX-2 RNA and protein levels and the dependency of the increased Ca efflux on COX-2 activity, as determined by both genetic deficiency and pharmacologic inhibition, show that COX-2 is critical for acid-induced, cell-mediated bone resorption.     

Familial stenosis of the pulmonary artery branches with a JAG1 mutation.

Although most congenital heart defects are isolated abnormalities of embryonic development, with little genetic contribution, a small number are components of syndromes. In such cases, an accurate diagnosis has important implications for individual prognosis and familial genetic counseling. Alagille syndrome (AGS) is a dominantly inherited multisystem developmental disorder, which primarily affects the liver, heart, eyes, skeleton, and face. In recent years, the identification of the AGS gene has drawn attention to the existence of subclinical carriers, and broadened the spectrum of phenotypical variation associated with this syndrome. The authors present a case of mother and son with benign stenosis of the pulmonary artery branches. Subtle facial aspects suggested the diagnosis of AGS, which was confirmed by molecular analysis. Relevant clinical investigations and diagnostic implications are discussed.     

Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is established therapy for selected patients with acute leukemia. After transplantation, antileukemic immune responses are believed to eliminate residual leukemia cells and decrease the likelihood of relapse. However, the clinical effect of successful antigen-specific immune reconstitution after HSCT on the likelihood of leukemic relapse and overall survival is not known. Pediatric recipients of unrelated cord blood transplants who underwent transplantation for acute leukemia were sequentially evaluated for their development of antigen-specific T-lymphocyte immunity to herpes viruses. The clinical effect of a positive antigen-specific response on relapse-free survival was determined. The presence of an antigen-specific response resulted in a relapse-free survival advantage (P = .0001), which was primarily due to a decrease in leukemic relapse (P = .003). Proportional hazards modeling for time to relapse and time to relapse or death defined 3 variables that were strongly associated with a poor outcome: female gender, poor remission status before transplantation, and negative antigen-specific T-lymphocyte proliferation. Notably neither acute nor chronic graft-versus-host disease had any effect on the incidence of leukemic relapse. Successful antigen-specific immune reconstitution after unrelated cord blood transplantation results in decreased leukemic relapse and improved overall survival.