Search PubMed⌕ Search

Biomedical subjects

R Gardner

Publications and source records attributed to R Gardner.

At least 37 records · Page 2Linked to original sources
PubMed1999

RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast.

Eukaryotic checkpoint genes regulate multiple cellular responses to DNA damage. In this report, we examine the roles of budding yeast genes involved in G2/M arrest and tolerance to UV exposure. A current model posits three gene classes: those encoding proteins acting on damaged DNA (e.g. RAD9 and RAD24), those transducing a signal (MEC1, RAD53 and DUN1) or those participating more directly in arrest (PDS1). Here, we define important features of the pathways subserved by those genes. MEC1, which we find is required for both establishment and maintenance of G2/M arrest, mediates this arrest through two parallel pathways. One pathway requires RAD53 and DUN1 (the 'RAD53 pathway'); the other pathway requires PDS1. Each pathway independently contributes approximately 50% to G2/M arrest, effects demonstrable after cdc13-induced damage or a double-stranded break inflicted by the HO endonuclease. Similarly, both pathways contribute independently to tolerance of UV irradiation. How the parallel pathways might interact ultimately to achieve arrest is not yet understood, but we do provide evidence that neither the RAD53 nor the PDS1 pathway appears to maintain arrest by inhibiting adaptation. Instead, we think it likely that both pathways contribute to establishing and maintaining arrest.

Alleles↗
PubMed1998

Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.

Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies, which suggested LD might be a generalized storage disease. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.

Alternative Splicing↗
PubMed1998

Sequence determinants for regulated degradation of yeast 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.

The degradation rate of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-R), a key enzyme of the mevalonate pathway, is regulated through a feedback mechanism by the mevalonate pathway. To discover the intrinsic determinants involved in the regulated degradation of the yeast HMG-R isozyme Hmg2p, we replaced small regions of the Hmg2p transmembrane domain with the corresponding regions from the other, stable yeast HMG-R isozyme Hmg1p. When the first 26 amino acids of Hmg2p were replaced with the same region from Hmg1p, Hmg2p was stabilized. The stability of this mutant was not due to mislocalization, but rather to an inability to be recognized for degradation. When amino acid residues 27-54 of Hmg2p were replaced with those from Hmg1p, the mutant was still degraded, but its degradation rate was poorly regulated. The degradation of this mutant was still dependent on the first 26 amino acid residues and on the function of the HRD genes. These mutants showed altered ubiquitination levels that were well correlated with their degradative phenotypes. Neither determinant was sufficient to impart regulated degradation to Hmg1p. These studies provide evidence that there are sequence determinants in Hmg2p necessary for degradation and optimal regulation, and that independent processes may be involved in Hmg2p degradation and its regulation.

Amino Acid Sequence↗
PubMed1998

The brain and communication are basic for clinical human sciences.

This article focuses on basic concepts modelled on medical science for the human sciences. This reformulates problems experienced by people who consult counsellors, psychologists, psychiatrists, social workers and other human science clinicians as located in the brain. These troubles can be described as difficulties in social life and human communication, on the one hand, and as varied brain physiology, on the other. These problems and their solutions are not traditionally biological but restrictive views of biology need modification as the brain is obviously the central organ for not only the medical specialities of neurology and psychiatry but for all professionals concerned with social interactions. The human genome determines the brain of each person: each such brain constitutes the latest iteration of ancestral genomes that include species precursor to humans and primates, extending back to unicellular life forms. The genome that determines the human brain confers remarkable flexibility or learning potential. Yet many factors influence what is learned and experienced. Understanding this entails comparing and contrasting humans and non-humans. The genomes of chimpanzees and gorillas differ little from that of humans so most basic plans determining behaviour must be shared. Yet contrasted to these animals, the human brain is three times greater in mass and the human cerebral cortex has four times more area. This increased brain correlated with more social interaction; humans are the story-telling animal, producing, consuming and otherwise using small and large tales intensely and incessantly. But do communicational features resemble each other across species? Commnunicational propensity states in humans compare to those of non-humans. So do those of normal people and psychiatric patients. Psychiatry's efforts at systematic description and nosology provided guidelines to the ethology of ancient but still active communicational propensity states called PSALICs (Gardner, 1988). This double acronym refers to their normal function and prehuman origins; they are defined from a three-legged base in that each exists in psychiatric patients, normal people and non-human animals. This article describes the following psalics: alpha, audience, in-group omega, mating, nurturant, nurturance-eliciting, out-group omega and spacing-avoidant. The article describes psalics' varied expression in people. This basic science formulation and an across-species comparisons approach has implications for treating patients and clients.

Animals↗
PubMed1998

Increased circulating levels of soluble HLA class I heterodimers in patients with sickle cell disease.

This study examined the presence of a persistent state of low-grade inflammation in sickle cell anemia patients by measuring circulating sHLA-I heterodimers and C-reactive protein during the steady state and after recent crises. Thirty-nine pediatric sickle hemoglobinopathy patients were studied during the steady state and 11 patients were evaluated within 1 month of a painful crisis. A disease severity score was generated for each patient, and soluble HLA-I (sHLA-I) and C-reactive protein levels were determined. Soluble HLA-I was significantly elevated in 55% of the steady-state group and in 36% of the recent-crisis group. The percentage of patients with elevated sHLA-I differed in the various disease subgroups in the steady state: 46% of Hb SS patients, 70% of Hb SC patients, 75% of Hb S beta-thal patients, and 20% of Hb SSF patients. Steady-state and recent-crisis sHLA-I levels were not significantly different. C-reactive protein levels were elevated in 11% of steady-state patients and in 9% of recent-crisis patients. Soluble HLA-I levels did not correlate with C-reactive protein levels or disease severity score, age, hemoglobin, reticulocyte count, platelet count, or white cell count. These results show that the majority of sickle hemoglobinopathy patients have elevated sHLA-I levels during the steady state and after recent crisis, suggesting the presence of chronic inflammation during the steady state.

Anemia, Sickle Cell↗
PubMed1997

Sociophysiology as the basic science of psychiatry.

The medical specialty of psychiatry should possess a basic science in which pathologies are considered deviations from normal brain physiology. Historically, psychoanalytic pathogenesis was considered separately from brain physiology. It was not scientific because observations could not be refuted. Countering this, Eli Robins's legacy stemmed partly from his having been damaged by a psychoanalyst. It eschewed pathogenesis. Attempting to integrate psychiatry with medicine more generally, Robins and colleagues refocused on empiricism, although they acknowledged the brain's centrality. Here I hold that the term biology used in the context of psychiatry should broadly encompass social facets of organismal function. The term "sociophysiology" may best describe the central basic science of psychiatry because it alludes to brain functions used for the person's social realm. Disruptions of such functions result in deviant behaviors and unpleasant feelings which psychiatrists diagnose and treat. Future study encompassing top-down and bottom-up research should include genome-neural-behavioral analyses.

History, 17th Century↗
PubMed1997

Tumor necrosis factor alpha in children with sickle cell disease in stable condition.

Tumor necrosis factor alpha (TNF-alpha) is known to induce wasting in humans and animals. This study was undertaken to determine TNF-alpha concentrations in children with sickle cell disease (SCD) and whether high TNF-alpha levels are more likely to be present in children with growth deficits, infection, or pain crisis. Tumor necrosis factor alpha was measured using enzyme immunoassay in 143 blood samples obtained from 101 children. Mean TNF-alpha levels were higher in patients (50 pg/mL) than in 21 control children (19 pg/mL) and in 26 laboratory employees (20 pg/mL). During the follow-up period, 35%, 38%, and 28% of children with SCD had infection, pain crisis, or a blood transfusion, respectively. Mean TNF-alpha concentrations were higher in children who had an infection than in those who did not. No significant effect of pain crisis or blood transfusion was observed. Tumor necrosis factor alpha concentrations were above normal (> 40 pg/mL) in 15% of controls, 34% of children with SCD, and 52% of children with SCD who had an infection and 33% of those who did not. A higher percentage of children who had elevated TNF-alpha levels had weight (46% versus 31%) or height (50% versus 28.6%) deficits than children who had normal TNF-alpha levels. These results indicate that most children with SCD in stable condition have normal TNF-alpha concentrations and that those with high TNF-alpha levels are more likely to have growth deficits.

Adolescent↗
PubMed1996

A statistical analysis of data on exposure to xylene at selected workplaces in the U.K.

The results of sampling surveys carried out by the Health and Safety Executive (HSE) during 1987-1988 at a random selection of 49 premises, where xylene was used, are reported. A total of 465 personal exposure samples were collected, from which 369 8-h time weighted average (TWA) exposures were calculated. These had a geometric mean (GM) of 2.2 ppm (GSD, +/- 2.9; range, < 1-202 ppm). At that time HSE already had data for personal exposure to xylene in 122 premises collected between 1980 and 1987. These data yielded 511 8-h TWA personal exposures to xylene with a GM of 7.5 ppm (GSD, +/- 4.3; range, < 1-610 ppm). These GMs are significantly different (P < 0.01), suggesting that the pre-existing data were somewhat biased. This is discussed in the context of the use of these data in setting the Occupational Exposure Limits for xylene and the significance to standard setting of any bias in HSE data.

Air Pollutants, Occupational↗
PubMed1995

The impact of extreme prematurity and congenital anomalies on the interpretation of international comparisons of infant mortality.

OBJECTIVE: To identify the potential impact that different definitions of live births and practice patterns have on infant mortality rates in England and Wales, France, Japan, and the United States. METHODS: United States data were obtained from the 1986 linked national birth-infant death cohort, and those for the other countries came from either published sources or directly from the Ministries of Health. RESULTS: In 1986 in the United States, infants weighing less than 1 kg accounted for 36% of deaths (32% white and 46% black); 32% resulted from fatal congenital anomalies. These rates were much higher in both categories than in England and Wales in 1990 (24 and 22%, respectively), France in 1990 (15 and 25%, respectively), and Japan in 1991 (9% for infants weighing less than 1 kg, percentage of fatal congenital anomalies unknown). These cases are more likely to be excluded from infant mortality statistics in their countries than in the United States. CONCLUSIONS: In 1990, the United States infant mortality rate was 9.2 per 1000 live births, ranking the United States 19th internationally. However, infant mortality provides a poor comparative measure of reproductive outcome because there are enormous regional and international differences in clinical practices and in the way live births are classified. Future international and state comparisons of reproductive health should standardize the definition of a live birth and fatal congenital anomaly, and use weight-specific fetal-infant mortality ratios and perinatal statistics.

Birth Weight↗
PubMed1995

The paradoxical power of the depressed patient: a problem for the ranking theory of depression.

The social ranking (or social competition) theory of depression suggests that the capacity for episodes of depressed mood evolved as a mechanism for inhibiting challenge. Depressed mood induces the sufferer to accommodate to low social rank, or to losing in social competition, or to adopting the one-down position in a complementary relationship (Price, 1991; Price, Sloman, Gardner, Gilbert & Rohde, 1994; Sloman, Price, Gilbert & Gardner, 1994). Thus depressed patients should be observed to forego the privileges of high rank and of winning, such as exercising social power and getting their own way. However, several commentators have noted that depressed patients often seem to be very powerful, and even appear to use their depression to manipulate others. This paper attempts to reconcile the theory to such observations.

Animals↗
PubMed1994

Adaptive function of depression: psychotherapeutic implications.

Using the frameworks of attachment and social hierarchy theories, strategies seen in depression and in normal life are better understood. A hierarchial encounter elicits the "Involuntary Subordinate Strategy" ("ISS") in the loser, which terminates the "ISS" and brings the encounter to an end. These are psychophysiological mechanisms deeply rooted in our phylogenetic ancestry. Loss of a love object also elicits ineffective anger or rage which may, in turn, trigger the ISS. A prolonged intense ISS manifests in depression. Factors are examined that prevent "acceptance" of losing, thereby contributing to an escalation of the ISS and culminating in depressive illness. Psychotherapeutic implications include cognitive restructuring to enable the patient to explore options that might turn off the ISS such as "acceptance" (without making negative self-evaluations), changing unrealistic ideals and aspirations, leaving the scene, or becoming more self-assertive. Case examples are given to illustrate these interventions.

Adult↗
PubMed1994

The social competition hypothesis of depression.

Depressive personality and depressive illness are examined from an evolutionary adaptationist standpoint. It is postulated that the depressive state evolved in relation to social competition, as an unconscious, involuntary losing strategy, enabling the individual to accept defeat in ritual agonistic encounters and to accommodate to what would otherwise be unacceptably low social rank.

Cognitive Behavioral Therapy↗
PubMed1994

Effects of active student response during error correction on the acquisition, maintenance, and generalization of science vocabulary by elementary students: A systematic replication.

We compared active student response (ASR) error correction and no-response (NR) error correction while teaching science terms to 5 elementary students. When a student erred on ASR terms, the teacher modeled the definition and the student repeated it. When a student erred on NR terms, the teacher modeled the definition while the student looked at the vocabulary card. ASR error correction was superior on each of the study's seven dependent variables.

Journal Article↗