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Biomedical subjects

D Greenstein

Publications and source records attributed to D Greenstein.

At least 19 recordsLinked to original sources
PubMed2007

Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update.

Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125; Faraone et al., 2005; Biol Psychiatry 57:1313-1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow-up (n = 107, baseline mean age n = 9, follow-up mean age of n = 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P = 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder.

Adolescent↗
PubMed2006

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories.

Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P=0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

Adolescent↗
PubMed2006

Intellectual ability and cortical development in children and adolescents.

Children who are adept at any one of the three academic 'R's (reading, writing and arithmetic) tend to be good at the others, and grow into adults who are similarly skilled at diverse intellectually demanding activities. Determining the neuroanatomical correlates of this relatively stable individual trait of general intelligence has proved difficult, particularly in the rapidly developing brains of children and adolescents. Here we demonstrate that the trajectory of change in the thickness of the cerebral cortex, rather than cortical thickness itself, is most closely related to level of intelligence. Using a longitudinal design, we find a marked developmental shift from a predominantly negative correlation between intelligence and cortical thickness in early childhood to a positive correlation in late childhood and beyond. Additionally, level of intelligence is associated with the trajectory of cortical development, primarily in frontal regions implicated in the maturation of intelligent activity. More intelligent children demonstrate a particularly plastic cortex, with an initial accelerated and prolonged phase of cortical increase, which yields to equally vigorous cortical thinning by early adolescence. This study indicates that the neuroanatomical expression of intelligence in children is dynamic.

Adolescent↗
PubMed2005

Dysbindin (DTNBP1, 6p22.3) is associated with childhood-onset psychosis and endophenotypes measured by the Premorbid Adjustment Scale (PAS).

Straub et al. (2002) recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid dysfunction and clinical follow-up were obtained. Fourteen SNPs were genotyped in the gene DTNBP1. Family-based pairwise and haplotype transmission disequilibrium test (TDT) analysis with the clinical phenotype, and quantitative transmission disequilibrium test (QTDT) explored endophenotype relationships. One SNP was associated with diagnosis (TDT p=.01). The QTDT analyses showed several significant relationships. Four adjacent SNPs were associated (p values=.0009-.003) with poor premorbid functioning. These findings support the hypothesis that this and other schizophrenia susceptibility genes contribute to early neurodevelopmental impairment.

Adolescent↗
PubMed2005

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss.

Postmortem brain studies have shown deficits in the cortical gamma-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5' upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

5' Flanking Region↗
PubMed2004

Toxicity of parking lot runoff after application of simulated rainfall.

Stormwater runoff is an important source of toxic substances to the marine environment, but the effects of antecedent dry period, rainfall intensity, and duration on the toxicity of runoff are not well understood. In this study, simulated rainfall was applied to parking lots to examine the toxicity of runoff while controlling for antecedent period, intensity, and duration of rainfall. Parking areas were divided into high and low use and maintained and unmaintained treatments. The parking stalls were cleaned by pressure washing at time zero. Simulated rainfall was then applied to subplots of the parking lots so that antecedent periods of 1, 2, and 3 months were achieved, and all of the runoff was collected for analysis. On a separate parking lot, rainfall was applied at a variety of intensities and durations after a 3-month antecedent period. Runoff samples were tested for toxicity using the purple sea urchin fertilization test. Every runoff sample tested was found to be toxic. Mean toxicity for the sea urchin fertilization test ranged from 2.0 to 12.1 acute toxic units. The toxicity increased rapidly during the first month but then decreased approximately to precleaning levels and remained there. No difference in toxicity was found between the different levels of use or maintenance treatments. The intensity and duration of rainfall were inversely related to degree of toxicity. For all intensities tested, toxicity was always greatest in the first sampling time interval. Dissolved zinc was most likely the primary cause of toxicity based on toxicant characterization of selected runoff samples.

Animals↗
PubMed2002

Acute superficial venous thrombophlebitis: does emergency surgery have a role?

BACKGROUND: Superficial venous thrombophlebitis (SVT) of the long saphenous vein (LSV) has been shown to be associated with thrombus propagation into the common femoral vein in up to 44% of cases. Conservative management can thus result in deep vein thrombosis (DVT), deep vein insufficiency or fatal pulmonary embolism (PE). To examine the effects of emergency division of the sapheno-femoral junction (SFJ) on the deep venous system in SVT of the LSV we used pre- and postoperative venous duplex ultrasound. METHODS: Emergency division of the SFJ was performed in 17 patients presenting with acute superficial venous thrombophlebitis. All patients had duplex ultrasound, which demonstrated thrombus of the above knee long saphenous vein together with a normal deep venous system. A follow-up duplex ultrasound scan was arranged on discharge and at 2 months. RESULTS: No patient had propagation of thrombus into the deep venous system or a PE. One patient developed a non-occlusive clot in the popliteal vein at 2 months follow-up. All patients were discharged at 48 hours. CONCLUSIONS: Using duplex ultrasound it has been shown that emergency division of the SFJ is a safe and effective way of preventing serious complications caused by thrombus in above knee LSV SVT.

Acute Disease↗
PubMed2001

A sperm cytoskeletal protein that signals oocyte meiotic maturation and ovulation.

Caenorhabditis elegans oocytes, like those of most animals, arrest during meiotic prophase. Sperm promote the resumption of meiosis (maturation) and contraction of smooth muscle-like gonadal sheath cells, which are required for ovulation. We show that the major sperm cytoskeletal protein (MSP) is a bipartite signal for oocyte maturation and sheath contraction. MSP also functions in sperm locomotion, playing a role analogous to actin. Thus, during evolution, MSP has acquired extracellular signaling and intracellular cytoskeletal functions for reproduction. Proteins with MSP-like domains are found in plants, fungi, and other animals, suggesting that related signaling functions may exist in other phyla.

Amino Acid Sequence↗
PubMed2001

CLH-3, a ClC-2 anion channel ortholog activated during meiotic maturation in C. elegans oocytes.

BACKGROUND: ClC anion channels are ubiquitous and have been identified in organisms as diverse as bacteria and humans. Despite their widespread expression and likely physiological importance, the function and regulation of most ClCs are obscure. The nematode Caenorhabditis elegans offers significant experimental advantages for defining ClC biology. These advantages include a fully sequenced genome, cellular and molecular manipulability, and genetic tractability. RESULTS: We show by patch clamp electrophysiology that C. elegans oocytes express a hyperpolarization- and swelling-activated Cl(-) current with biophysical characteristics strongly resembling those of mammalian ClC-2. Double-stranded RNA-mediated gene interference (RNAi) and single-oocyte RT-PCR demonstrated that the channel is encoded by clh-3, one of six C. elegans ClC genes. CLH-3 is inactive in immature oocytes but can be triggered by cell swelling. However, CLH-3 plays no apparent role in oocyte volume homeostasis. The physiological signal for channel activation is the induction of oocyte meiotic maturation. During meiotic maturation, the contractile activity of gonadal sheath cells, which surround oocytes and are coupled to them via gap junctions, increases dramatically. These ovulatory sheath cell contractions are initiated prematurely in animals in which CLH-3 expression is disrupted by RNAi. CONCLUSIONS: The inwardly rectifying Cl(-) current in C. elegans oocytes is due to the activity of a ClC channel encoded by clh-3. Functional and structural similarities suggest that CLH-3 and mammalian ClC-2 are orthologs. CLH-3 is activated during oocyte meiotic maturation and functions in part to modulate ovulatory contractions of gap junction-coupled gonadal sheath cells.

Animals↗
PubMed2000

The Caenorhabditis elegans gonad: a test tube for cell and developmental biology.

Sexual reproduction of multicellular organisms depends critically on the coordinate development of the germ line and somatic gonad, a process known as gonadogenesis. Together these tissues ensure the formation of functional gametes and, in the female of many species, create a context for production and further development of the zygote. Since the future of the species hangs in the balance, it is not surprising that gonadogenesis is a complex process involving conserved and multi-faceted developmental mechanisms. Genetic, anatomical, cell biological, and molecular experiments have established the nematode Caenorhabditis elegans as a paradigm for studying gonadogenesis. Furthermore, these studies demonstrate the utility of C. elegans gonadogenesis for exploring broad issues in cell and developmental biology, such as cell fate specification, morphogenesis, cell signaling, cell cycle control, and programmed cell death. The synergy of molecular genetics and cell biology conducted at single-cell resolution in real time permits an extraordinary depth of analysis in this organism. In this review, we first describe the embryonic and post-embryonic development and morphology of the C. elegans gonad. Next we recount seminal experiments that established the field, highlight recent results that provide insight into conserved developmental mechanisms, and present future prospects for the field.

Animals↗
PubMed2000

EMB-30: an APC4 homologue required for metaphase-to-anaphase transitions during meiosis and mitosis in Caenorhabditis elegans.

Here we show that emb-30 is required for metaphase-to-anaphase transitions during meiosis and mitosis in Caenorhabditis elegans. Germline-specific emb-30 mutant alleles block the meiotic divisions. Mutant oocytes, fertilized by wild-type sperm, set up a meiotic spindle but do not progress to anaphase I. As a result, polar bodies are not produced, pronuclei fail to form, and cytokinesis does not occur. Severe-reduction-of-function emb-30 alleles (class I alleles) result in zygotic sterility and lead to germline and somatic defects that are consistent with an essential role in promoting the metaphase-to-anaphase transition during mitosis. Analysis of the vulval cell lineages in these emb-30(class I) mutant animals suggests that mitosis is lengthened and eventually arrested when maternally contributed emb-30 becomes limiting. By further reducing maternal emb-30 function contributed to class I mutant animals, we show that emb-30 is required for the metaphase-to-anaphase transition in many, if not all, cells. Metaphase arrest in emb-30 mutants is not due to activation of the spindle assembly checkpoint but rather reflects an essential emb-30 requirement for M-phase progression. A reduction in emb-30 activity can suppress the lethality and sterility caused by a null mutation in mdf-1, a component of the spindle assembly checkpoint machinery. This result suggests that delaying anaphase onset can bypass the spindle checkpoint requirement for normal development. Positional cloning established that emb-30 encodes the likely C. elegans orthologue of APC4/Lid1, a component of the anaphase-promoting complex/cyclosome, required for the metaphase-to-anaphase transition. Thus, the anaphase-promoting complex/cyclosome is likely to be required for all metaphase-to-anaphase transitions in a multicellular organism.

Alleles↗
PubMed1999

Ultrastructural features of the adult hermaphrodite gonad of Caenorhabditis elegans: relations between the germ line and soma.

Genetic and embryological experiments have established the Caenorhabditis elegans adult hermaphrodite gonad as a paradigm for studying the control of germline development and the role of soma-germline interactions. We describe ultrastructural features relating to essential germline events and the soma-germline interactions upon which they depend, as revealed by electron and fluorescence microscopy. Gap junctions were observed between oocytes and proximal gonadal sheath cells that contract to ovulate the oocyte. These gap junctions must be evanescent since individual oocytes lose contact with sheath cells when they are ovulated. In addition, proximal sheath cells are coupled to each other by gap junctions. Within proximal sheath cells, actin/myosin bundles are anchored to the plasma membrane at plaque-like structures we have termed hemi-adherens junctions, which in turn are closely associated with the gonadal basal lamina. Gap junctions and hemi-adherens junctions are likely to function in the coordinated series of contractions required to ovulate the mature oocyte. Proximal sheath cells are fenestrated with multiple small pores forming conduits from the gonadal basal lamina to the surface of the oocyte, passing through the sheath cell. In most instances where pores occur, extracellular yolk particles penetrate the gonadal basal lamina to directly touch the underlying oocytes. Membrane-bounded yolk granules were generally not found in the sheath cytoplasm by either electron microscopy or fluorescence microscopy. Electron microscopic immunocytochemistry was used to confirm and characterize the appearance of yolk protein in cytoplasmic organelles within the oocyte and in free particles in the pseudocoelom. The primary route of yolk transport apparently proceeds from the intestine into the pseudocoelom, then through sheath pores to the surface of the oocyte, where endocytosis occurs. Scanning electron microscopy was used to directly visualize the distal tip cell which extends tentacle-like processes that directly contact distal germ cells. These distal tip cell processes are likely to play a critical role in promoting germline mitosis. Scanning electron microscopy also revealed thin filopodia extending from the distal sheath cells. Distal sheath filopodia were also visualized using a green fluorescent protein reporter gene fusion and confocal microscopy. Distal sheath filopodia may function to stretch the sheath over the distal arm.

Animals↗
PubMed1998

Regulated nuclear entry of the C. elegans Pax-6 transcription factor.

It is shown that the C. elegans Pax-6 locus encodes two protein isoforms. One contains a Paired DNA binding domain as well as a homeodomain; the other consists only of the carboxy-terminal portion of the locus encoding the homeodomain. These two isoforms are expressed in a variety of postembryonic cell lineages. In one set of lineages, nuclear localization of a homeodomain-only form (MAB-18 isoform) appears to be under temporal and spatial control. Nuclear localization of MAB-18 is correlated with the genetic requirement for mab-18 and with activation of a reporter gene driven by a mab-18 promoter. Reporter gene expression is dependent on mab-18 gene activity. It is hypothesized that a positive feedback loop is activated by regulated nuclear entry.

Animals↗
PubMed1998

The role of leukocytes in the pathogenesis of vibration-induced white finger.

Vibration white finger (VWF) is an occupational disorder associated with long-term exposure to hand-transmitted vibration. The condition exhibits features of secondary Raynaud's phenomenon. The etiology is unknown. The aim of this study was to examine the role of leukocyte rheology in the pathogenesis of VWF. Fifty-two male subjects divided into two groups were exposed to controlled acute hand-transmitted vibration. One group consisted of 29 workers who have all had occupational exposure to handheld vibration and all suffered from VWF (mean age 46.9 years, range 22-66). The second group consisted of 23 controls. Venous blood was analyzed from the dorsum of the hand before and after vibration to determine granulocyte deformability, granulocyte morphology, and white blood cell count with differential. There was a subpopulation of hard and poorly deformable granulocytes in the VWF group when compared with controls (p < 0.05). Acute hand-transmitted vibration had no in vitro effect on leukocyte rheology in either group. Leukocyte rheology may play a role in the pathogenesis of microvascular disease and tissue ischemia in VWF, although whether this is a cause or an effect of the disorder is not clear.

Adult↗
PubMed1997

The POU gene ceh-18 promotes gonadal sheath cell differentiation and function required for meiotic maturation and ovulation in Caenorhabditis elegans.

In Caenorhabditis elegans, specialized contractile myoepithelial cells of the somatic gonad, the gonadal sheath cells, are closely apposed to oocytes and are required for normal meiotic maturation and ovulation. Previously we found that mutations in the ceh-18 gene, which encodes a POU-class homeoprotein expressed in sheath cells, result in oocyte defects. To determine the basis for these oocyte defects, we have used time-lapse video Nomarski microscopy to observe meiotic maturation, ovulation, and early embryogenesis in ceh-18 mutants. In ceh-18 mutants sheath cell contractions are weaker, less frequent, and uncoordinated throughout the sequence of ovulation events, and ovulation is defective. Defective ovulation can result in the formation of endomitotic oocytes in the gonad, the formation of haploid embryos, and reversals in embryonic polarity. ceh-18 mutant oocytes exhibit defects prior to nuclear envelope breakdown, suggesting that they are physiologically different from the wild type. We observed delays in meiotic maturation, as well as maturation out of the normal spatial and temporal sequence, suggesting that proximal sheath cells directly or indirectly promote and spatially restrict meiotic maturation. Analysis of sheath cell differentiation in ceh-18 mutants using antibodies to proteins of the contractile apparatus reveals that although contractile proteins are expressed, the sheath cells appear disorganized. Transmission electron microscopy reveals that ceh-18 mutant sheath cells are morphologically irregular and only loosely cover oocytes. Taken together, these observations indicate that ceh-18 is a crucial determinant of sheath cell differentiation, a function required for normal meiotic maturation and ovulation.

Animals↗
PubMed1997

The hemorheologic effects of hand-transmitted vibration.

Vibration white finger (VWF) is an ischemic condition of the hands that is associated with long-term exposure to hand-held vibration tools. The pathophysiology of VWF remains unknown. The aim of this study was to assess the hemorheologic effect of acute hand-transmitted vibration. This study investigated 52 men divided into two groups: VWF = 29, mean age 46.9 years (range twenty-two to sixty-six); Controls = 23, mean age 42.8 years (range twenty to sixty-four). Each subject gripped a vibrating handle for seven minutes thirty seconds at a vibration frequency of 120 Hz with an amplitude of displacement of 0.25 mm. Venous blood was analyzed before and after acute vibration to determine the hematocrit, the plasma hemoglobin concentration, plasma viscosity, and red cell deformability, expressed as red cell transit time (RCTT). At rest, there was no significant difference in RCTT, plasma viscosity, hematocrit, and plasma hemoglobin concentration between the VWF group and controls. Acute vibration did, however, significantly increase the red cell transit time in the VWF group but not in the control group. In both groups vibration resulted in a significant increase in plasma viscosity, hematocrit, and plasma hemoglobin concentration in hand venous blood. Moreover, in each group there was a highly significant correlation between the change in plasma viscosity and the change in the hemoglobin concentration and the hematocrit. The authors conclude that hand-transmitted vibration is associated with hemoconcentration.

Adult↗
PubMed1996

The menstrual cycle and Raynaud's phenomenon.

Fluctuations in female sex hormones may be responsible for the high prevalence of Raynaud's phenomenon (RP) observed in premenopausal women. These hormones are known to act on central and peripheral thermoreceptors. In an attempt to establish whether cold sensitivity is altered during the menstrual cycle 50 premenopausal women were investigated. Of these, 26 had primary RP and 24 acted as controls. Each subject was exposed to environmental heating and cooling at three stages of the menstrual cycle to coincide with peaks and troughs in hormone levels. These stages were menstruation, periovulation, and during the midluteal phase. Finger hemodynamics was assessed by means of venous occlusion strain gauge plethysmography and fingertip temperature. Core temperature was assessed with an oral thermocouple. The results show that cold sensitivity was altered during the menstrual cycle in both groups with the fastest finger rewarming pattern during menstruation. Moreover, a significant difference was observed in core temperature between the two groups during the midluteal phase. As a group, subjects with RP failed to show a significant rise in core temperature following ovulation. The authors conclude that the menstrual cycle is associated with changes in the effect of cold on digital blood flow.

Adolescent↗