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Biomedical subjects

M Lerner

Publications and source records attributed to M Lerner.

At least 19 recordsLinked to original sources
PubMed2004

Cecal volvulus: a report of two cases occurring after the antegrade colonic enema procedure.

BACKGROUND: Many children with chronic constipation and fecal incontinence have benefited from the antegrade colonic enema (ACE) procedure. Routine antegrade colonic lavage often allows such children to avoid daytime soiling. This report describes 2 children in whom the ACE procedure was complicated by a cecal volvulus. METHODS: A retrospective review of 164 children with an ACE procedure was conducted. Two instances of cecal volvulus were identified. RESULTS: The first child presented with abdominal pain and difficulty intubating the ACE site. Over the subsequent day, his pain worsened, and radiographs depicted a colonic obstruction. At laparotomy, a cecal volvulus resulting in bowel necrosis was observed, and resection of the affected bowel and appendix (in the right lower quadrant) and end ileostomy was required. He subsequently had the stoma closed and a new ACE constructed with a colon flap. The second child presented with shock and evidence of an acute abdomen. At laparotomy, a cecal volvulus was noted, and ileocolic resection including the ACE stoma (located at the umbilicus) and an ileostomy and Hartmann pouch was performed. He had a protracted hospital course requiring ventilator and inotropic support. He currently is well and still has an ileostomy stoma. CONCLUSIONS: A high index of suspicion for a potentially life-threatening cecal volvulus should be maintained in children undergoing an ACE procedure who present with abdominal pain, evidence of bowel obstruction, or difficulty in advancing the ACE irrigation catheter.

Anus, Imperforate↗
PubMed2004

Worldwide trends in alcohol and drug impaired driving.

Improved laws, enhanced enforcement, and public awareness brought about by citizens' concern, during the 1980s led to dramatic declines in drinking and driving in the industrialized world. The declines included about 50% in Great Britain, 28% in The Netherlands, 28% in Canada, 32% in Australia, 39% in France, 37% in Germany, and 26% in the United States. Some of these declines may be due in part to lifestyle changes, demographic shifts, and economic conditions. In most countries the declines reversed in the early 1990s and drinking and driving began to increase. By the middle of that decade the increases stabilized and the rates of drinking and driving again began to decline. These decreases were much less dramatic than those in the 1980s. Approaching the end of the 1990s and early in the new century, the record has been mixed. Some countries (France and Germany (until 2002)) continued to reduce drinking and driving while in other countries (Canada, the Netherlands, Great Britain, and the United States), there was stagnation and in some cases small increases or even large increase as was the case in Sweden. Complacency and attention to other issues in recent years have been difficult to overcome in some countries. Harmonization of traffic safety laws in the European Union has strengthened laws in some countries but threatens existing strong policies in others. It may be that the major gains have already been made and that additional progress will require a much greater level of scientific knowledge, use of new and emerging technologies, and political and social commitment to put in place proven countermeasures.

Accidents, Traffic↗
PubMed2002

Stimulation of protein kinase C pathway mediates endocytosis of human nongastric H+-K+-ATPase, ATP1AL1.

The human nongastric H+-K+-ATPase, ATP1AL1, shown to reabsorb K+ in exchange for H+ or Na+, is localized in the luminal plasma membrane of renal epithelial cells. It is presumed that renal H+-K+-ATPases can be regulated by endocytosis. However, little is known about the molecular mechanisms that control plasma membrane expression of renal H+-K+-ATPases. In our study, activation of protein kinase C (PKC) using phorbol esters (phorbol 12-myristate 13-acetate) leads to clathrin-dependent internalization and intracellular accumulation of the ion pump in stably transfected Madin-Darby canine kidney cells. Functional inactivation of the H+-K+-ATPase by PKC activation is shown by intracellular pH measurements. Proton extrusion capacity of ATP1AL1-transfected cells is drastically reduced after phorbol 12-myristate 13-acetate incubation and can be prevented with the PKC blocker bisindolylmaleimide. Ion pump internalization and inactivation are specifically mediated by the PKC pathway, whereas activation of the protein kinase A pathway has no influence. Our results show that the nongastric H+-K+-ATPase is a specific target for the PKC pathway. Therefore, PKC-mediated phosphorylation is a potential regulatory mechanism for apical nongastric H+-K+-ATPase plasma membrane expression.

Animals↗
PubMed2002

The use of a laboratory school protocol to evaluate concepts about efficacy and side effects of new formulations of stimulant medications.

Recently, new long-acting formulations of racemic methylphenidate (MPH: Ritalin LA, Metadate CD and Concerta) and amphetamine (AMP: Adderall XR) were developed and are now approved by the Food and Drug Administration (FDA). In addition, dexmethylphenidate (Focalin), the pharmacologically active d-threo enantiomer of MPH, also was approved by the FDA. In the initial phases of development, prototypes of these five new formulations were evaluated using the University of California, Irvine (UCI) Laboratory School Protocol (LSP), in which surrogate measures of efficacy are collected in highly controlled settings rather than clinical measures of effectiveness in the less-controlled, natural environments of home or school. The LSP studies were followed by large effectiveness and safety studies required for gaining FDA approval. These initial efficacy and side effect studies in the LSP provided missing information about the basic pharmacokinetic (PK) and pharmacodynamic (PD) properties of MPH and AMP and produced some new discoveries (i.e., acute tolerance) that were used to help design the final products. The final once-a-day formulations used different drug delivery systems to achieve long-acting efficacy (Ritalin LA, Metadate CD, Concerta, Adderall XR). All four drug delivery systems were based on two processes: first, a bolus delivery (BD) process to achieve rapid onset of efficacy (mg), and second, a controlled delivery (CD) process to achieve rates of delivery (mg/hr) or a delayed bolus (mg) to maintain efficacy. A theoretical approach was used to compare and contrast the new once-a day formulations of MPH by selecting total daily doses (mg/d) that would equate drug delivery by the first process (mg of the initial bolus) and the second process (mg/hr over specified time period). In addition to efficacy, applications of the LSP to measure common side effects related to eating and sleeping were described and discussed.

Amphetamines↗
PubMed2001

Placebo-controlled, blinded comparison of antenatal betamethasone on mouse liver development.

The objective of this investigation was to evaluate, in a placebo-controlled manner, the developing mouse liver after antenatal exposure either to a single dose or to a multidose of betamethasone. Ninety gravid CD-1 mice were randomly divided into three groups (n = 30/group) to receive either saline (0.25 mL s.c.) or betamethasone (0.10 mg s.c.) as a single dose on gestational day (GD) 14 of a 19-day gestation or as a 0.10 mg dose given twice daily on GD 14 and on GD 15 (4 doses). GD 0 is defined by the presence of a copulatory plug. These exposures of betamethasone cause fetal mouse lung maturation as would be observed in premature humans at 24-34 weeks of gestation. The livers were removed either from the fetuses on GD 16.5 or from the offspring on postnatal day 1, 3, 5, and 120. Special stains were used to evaluate hepatocyte architecture, glycoprotein and glycogen content, extramedullary hematopoiesis and iron storage. Hepatocyte intranuclear DNA content, cell size, and cell shape were measured by image analysis (CAS 200). At GD 16.5, betamethasone produced a significant decrease in the liver/body weight ratio that, when compared with the placebo group, was greater with the multidose (p < 0.01) than with the single dose (p < 0.05). 16.5 GD single dose hepatocytes were smaller in size as compared to placebo without impact on intranuclear DNA (p < 0.01). Single dose PND 1 hepatocytes demonstrated an increase in intranuclear DNA as compared to placebo but without change in cell size (p < 0.001). The prenatal reduced liver weight recovered in the newborn period. No difference in microscopic architecture of the hepatocytes or histologic differences between either of the three treatment groups was found in glycogen deposition, extramedullary hematopoiesis or iron metabolism at GD 16.5 and postnatally. It was concluded antenatal betamethasone can cause a decrease in the liver/body weight ratio in the fetal mouse that recovers eventually without any functional impact as assessed histologically.

Animals↗
PubMed2001

Olanzapine-induced leukopenia with human leukocyte antigen profiling.

Olanzapine is an atypical antipsychotic medication frequently used in the management of psychotic states. While it has proved to be safe compared to clozapine with regard to haematotoxicity, because it has only been available for a few years, full documentation of its haematological side-effects remains incomplete. We report a case of olanzapine-induced leukopenia with associated neutropenia. Since clozapine-induced haematotoxicity has been associated with characteristic human leukocyte antigen (HLA) groups, HLA typing was determined in this patient. Following failure with typical antipsychotic medication, the patient received 10 mg/day of olanzapine. Three weeks later, he developed fever and a significant decrease in leukocyte count. Olanzapine was immediately discontinued. HLA typing was determined. The white cell count returned to normal and the fever, most probably secondary to the low white cell count, subsided with antibiotic treatment. HLA typing results were: A1 24, B7, B35, DRB1*15, DRB1*11, DRB3*01-03, DRB5*01-02. Olanzapine may induce serious leukopenia and neutropenia. HLA typing in this single patient demonstrated a distinct haplotype compared to that previously observed in clozapine-induced haematoxicity.

Clozapine↗
PubMed2000

Homologs of the yeast Sec complex subunits Sec62p and Sec63p are abundant proteins in dog pancreas microsomes.

Cotranslational protein transport into dog pancreas microsomes involves the Sec61p complex plus a luminal heat shock protein 70. Posttranslational protein transport into the yeast endoplasmic reticulum (ER) involves the so-called Sec complex in the membrane, comprising a similar Sec61p subcomplex, the putative signal peptide receptor subcomplex, and the heat shock protein 40-type subunit, Sec63p, plus a luminal heat shock protein 70. Recently, human homologs of yeast proteins Sec62p and Sec63p were discovered. Here we determined the concentrations of these two membrane proteins in dog pancreas microsomes and observed that the canine homologs of yeast proteins Sec62p and Sec63p are abundant proteins, present in almost equimolar concentrations as compared with Sec61alphap monomers. Furthermore, we detected fractions of these two proteins in association with each other as well as with the Sec61p complex. The J domain of the human Sec63p was shown to interact with immunoglobulin heavy chain binding protein. Thus, the membrane of the mammalian ER contains components, known from the posttranslationally operating protein translocase in yeast. We suggest that these components are required for efficient cotranslational protein transport into the mammalian ER as well as for other transport processes.

Amino Acid Sequence↗
PubMed2000

Assembly of heterodimeric luciferase after de novo synthesis of subunits in rabbit reticulocyte lysate involves hsc70 and hsp40 at a post-translational stage.

Heterodimeric luciferase from Vibrio harveyi had been established as a unique model enzyme for direct measurements of the effects of molecular chaperones and folding catalysts on protein folding and subunit assembly after de novo synthesis of subunits in rabbit reticulocyte lysate. It was observed that luciferase assembly can be separated in time from synthesis of the two subunits and that under these post-translational conditions assembly was inhibited by either ATP depletion or inhibition of peptidylprolyl cis/trans isomerases, that is, by addition of cyclosporin A or FK506. Furthermore, it was observed that the inhibitory effect of FK506 on luciferase assembly can be suppressed by addition of purified cyclophilin, thereby providing the first direct evidence for the involvement of peptidylprolyl cis/trans isomerases in protein biogenesis in the eukaryotic cytosol. Here the ATP requirement in luciferase assembly has been characterized. Depletion of either Hsp90 or CCT from reticulocyte lysate did not interfere with luciferase assembly. However, addition of purified Hsc70 stimulated luciferase assembly. While addition of purified Hsp40 did not have any effect on luciferase assembly, the stimulatory effect of Hsc70 was further increased by Hsp40. Thus, after synthesis of the two subunits in reticulocyte lysate assembly of heterodimeric luciferase involves Hsc70 and its co-chaperone Hsp40. Therefore, Hsc70 aids protein biogenesis in the eukaryotic cytosol not only at the levels of nascent polypeptide chains and precursor proteins that have to be kept competent for transport into cell organelles, but also at the level of subunits that have to be kept competent for assembly.

Adenosine Triphosphate↗
PubMed2000

Mind-body health at 25: an assessment.

This is a personal assessment of the past 25 years of the mind-body health movement. It argues that, despite many advances, the movement is notably marred by its unwillingness to confront the economic and environmental determinants of health.

Complementary Therapies↗
PubMed1999

Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children.

OBJECTIVES: To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder. METHODS: Double-blind trials were conducted in a laboratory school setting in which multiple measures of efficacy were obtained frequently in the morning and afternoon across the school day. In study I, relative efficacy was determined for three dosing patterns of methylphenidate: a standard twice-daily profile, a flat profile, and an ascending profile. In study II, tolerance was assessed by comparison of three-times-a-day regimens in which the time of the middle dose varied. RESULTS: In study I, the efficacy of the ascending treatment increased across the day, and in the afternoon it was equal to the efficacy of the twice-daily treatment, indicating that an initial bolus was not required for efficacy. The efficacy of the flat treatment declined across the day, and in the afternoon it was significantly less than in the twice-daily treatment, suggesting that tolerance may be developing. In study II, acute improvements in efficacy were reduced to the second of two closely spaced but not to two widely spaced bolus doses, suggesting that shortly after exposure to high concentrations, efficacy is reduced to given concentrations of methylphenidate. In a concentration-effect model, a tolerance term was needed to account for counterclockwise hysteresis. CONCLUSIONS: Acute tolerance to methylphenidate appears to exist. This should be considered in the design of an optimal dosing regimen for the treatment of children with attention deficit hyperactivity disorder.

Analysis of Variance↗
PubMed1999

Assessment and intervention for attention-deficit/hyperactivity disorder in the schools. Lessons from the MTA study.

The MTA experience provides several lessons that may have clinical relevance. First, the MTA study identified six key instruments (see Table 1) that clinicians may want to use, but even on these instruments discrepancies in parent and teacher sources should be expected. We believe that unnoticed or unresolved discrepancies may be important factors contributing to the "disconnect" identified by the Consensus Conference Panel. Based on the MTA experience, we recommend a telephone call to the child's teacher, specifically to inquire about any discrepancy in the "source by domain" summary, as an efficient way to make a meaningful connection "... between developmental or educational (school-based) assessments and health-related (medical practice-based) services" for children with ADHD. Second, evaluation of pharmacologic intervention in the MTA study confirmed that teachers' reports are crucial for documenting efficacy, whereas parent reports are crucial for documenting side effects. Based on the MTA experience, we recommend frequent telephone contact with the teacher specifically to inquire about the peak effects and dissipation of effects of medication that are expected to occur during the school hours as a way to improve "... communication between diagnosticians and those who implement and monitor treatment in the schools."

Attention Deficit Disorder with Hyperactivity↗
PubMed1999

Experimental cross-validation of DSM-IV types of attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine the discriminant validity of DSM-IV attention-deficit/hyperactivity disorder (ADHD) types by testing the hypothesis that types are associated with specific kinds of functional impairment and to compare overlap of DSM-IV and DSM-III-R ADHD. METHOD: Consecutive referrals (n = 692) to a pediatric subspecialty clinic for ADHD were classified into 1 of each of the 3 DSM-IV types of ADHD using parent and teacher checklist ratings of ADHD symptoms. The resulting types were compared on clinical correlates and on whether the children also met criteria for DSM-III-R ADHD. RESULTS: The validity of DSM-IV types was supported by dimension-specific impairment and other distinct correlates. Academic problems aggregated in the 2 types defined by extreme inattention, and externalizing problems aggregated in the 2 types defined by extreme hyperactivity. CONCLUSION: DSM-IV appeared superior to DSM-III-R in subcategorical homogeneity and in exhaustiveness (ability to classify all apparent cases).

Adolescent↗
PubMed1999

A complementary perspective to primary socialization theory.

Primary socialization theory as formulated by Oetting and his associates emphasizes the transmission of societal norms during childhood and adolescence within society's three major socializing agencies: family, school, and small, intimate peer groups. The norms thus transmitted may be prosocial or deviant, with prosocial norms more likely to be transmitted through strong bonds to healthy families or schools. Personality traits and other personal characteristics influence negative outcomes, such as deviance or drug use, only to the extent that they interfere with socialization to family or school. Our own research does not address primary socialization theory directly in that we have not focused on the transmission of norms per se as central. Nevertheless, we have studied social factors, personality factors, and various psychopathologies as etiological for deviance and substance use. By and large our research has supported the hypotheses of primary socialization theory, even extending them in specific areas, such as the importance of family influences as etiological. Our work has also emphasized the significance of rebelliousness and impulse control in this regard. Like all large-scale theories which necessarily abstract from the totality and diversity of human behavior, primary socialization theory leaves some gaps requiring further elucidation. Among these is its ethnocentric and temporocentric perspective, but even within this perspective it understates the difficulties for adolescents in making a successful transition to adult social roles (Kingley Davis) and in establishing a unique identity independent of parents (Erik H. Erikson). Also, it generally ignores the salience of the youth culture as rebellious against the older generation, a particularly important characteristic of modern society. And finally, it should cover the process of "maturing out" of deviance, which perhaps results in a reaffirmation of the legitimacy of norms transmitted earlier, and it should also cover gender differences in their transmission and legitimization. Nevertheless, despite these caveats and especially because of this theory's insightfulness and path-breaking character, its hypotheses should be tested in carefully designed, large-scale studies. These studies should allow, among other factors, measurement of the effects of genetic factors on the early emergence of deviant personality attributes and of their impact on the transmission of prosocial norms. [Translations are provided in the International Abstracts Section of this issue.]

Adult↗
PubMed1998

Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach.

Previously in this journal, we reported an association of the dopamine D4 receptor gene (DRD4) and attention deficit hyperactivity disorder (ADHD). In a population-association (case-control) study of 39 children with a refined phenotype of ADHD and 39 ethnically matched controls, we observed an increased percentage of the 7 repeat allele (29% vs 12%) and the 7+ genotype (49% vs 21%) in the ADHD group compared to the control group. In a replication and an extension of our initial study, we recruited another sample of ADHD subjects and found percentages of the 7 repeat allele (28%) and the 7+ genotype (48%) consistent with our previous findings. We used a family-based approach to evaluate a predicted association of DRD4 and ADHD based on a test of allele transmission focused on the 7 repeat allele. We identified 52 families based on the diagnosis of the refined phenotype of ADHD in the proband and the availability of DNA from both biological parents as well as the proband. Haplotype relative risk (HRR) analysis was performed to test our a priori hypothesis and produced significant results (chi-square = 4.65, P < 0.035). This provides additional evidence that the DRD4 gene is associated with a refined phenotype of ADHD.

Alleles↗
PubMed1998

Evaluation of individual subjects in the analog classroom setting: I. Examples of graphical and statistical procedures for within-subject ranking of responses to different delivery patterns of methylphenidate.

In this article, we describe graphical and statistical methods developed to evaluate the response patterns of individual children with attention deficit hyperactivity disorder (ADHD) to different conditions of treatment with stimulant medication. We used data from an investigation of drug delivery patterns to demonstrate these methods. Thirty-one children with ADHD participated in a double-blind crossover study of four conditions (three patterns of delivery of methylphenidate and a placebo control). In each condition, the children were evaluated across an 11-hour (7:00 a.m. to 6:00 p.m.) laboratory school day, and ratings of classroom behavior were obtained at regular intervals across the day. Graphical procedures were developed to display, for each individual, time courses of multiple measures of behavior taken across each double-blind test day. Expert clinicians judged these graphs and used this information to rank-order the test days from best to worst. A within-subject variant of Kendall's W was used to evaluate, for each subject, whether the rankings of these multidimensional graphs were reliable (concordant) across judges. A generalized kappa statistic was used to evaluate, for each condition, the reliability of the judges' rankings across subjects. Friedman's analysis of variance of ranks was used to evaluate, for the study, whether the conditions differed in terms of the average (consensus) rank assigned by the judges.

Attention Deficit Disorder with Hyperactivity↗
PubMed1998

Evaluation of individual subjects in the analog classroom setting: II. Effects of dose of amphetamine (Adderall).

Multiple dependent variables were graphed for 29 subjects who participated in a double-blind evaluation of 4 doses of Adderall, plus positive (methylphenidate) and placebo control conditions. Five judges ranked the conditions for each subject, and analyses of individual subjects indicated that these rankings were concordant (reliable) across judges. Consensus rankings were assigned to each subject, and an analysis of these ranks showed that the conditions differed significantly. The choice of best conditions were judged to be across 3 doses of Adderall (10, 15, and 20 mg). This confirms the clinical impression of individual differences in optimal dose of stimulant medication. The methodological, graphical, and statistical methods presented in this article provide a systematic, reliable procedure for evaluating relative response of individuals to different doses of stimulant medication.

Amphetamine↗