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M Smith

Publications and source records attributed to M Smith.

At least 181 records · Page 10Linked to original sources
PubMed2000

Analysis of a 1-megabase deletion in 15q22-q23 in an autistic patient: identification of candidate genes for autism and of homologous DNA segments in 15q22-q23 and 15q11-q13.

We have identified a one megabase deletion in the 15q22-15q23 region in a patient with autism, developmental delay, and mild dysmorphism. Genes that map within the deletion region and genes that are interrupted or rearranged at the deletion breakpoints are candidate genes for autism. Fluroescence in situ hybridization studies in this patient revealed that part or all of the PML gene is absent from one chromosome 15 and a BAC clone containing the D15S124 gene locus hybridizes to only one chromosome 15. BAC clones containing the PTPN9, and SLP-1[hUNC24] genes showed markedly reduced hybridization in the 15q22-q23 region on one chromosome 15 in the patient. These BACs also hybridize to the 15q11-q13 region in close proximity to SNRPN and HERC2, and in this region there is equal intensity of signal on the normal and on the deleted chromosome. There are previous reports of deletions and duplications of the 15q11-q13 region in patients with autism. Our patient represents the first report of a 15q22-q23 deletion. Hybridization of the PTPN9 and Slp-1 Bac clones to the 15q11-q13 and the 15q22-q23 regions of chromosome 15 may be due to the presence of PTPN9 or SLP-1 gene sequences or to the presence of other gene sequences or to non-coding homologous DNA sequences. The PTPN9 gene encodes a non-receptor protein tyrosine phosphatase. The Slp-1 [hUNC24] gene is expressed mainly in the brain. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:765-770, 2000.

Adult↗
PubMed2000

ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999.

P2Y receptors are a class of G protein-coupled receptors activated primarily by ATP, UTP, and UDP. Five mammalian P2Y receptors have been cloned so far including P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11. P2Y1, P2Y2, and P2Y6 couple to the activation of phospholipase C, whereas P2Y4 and P2Y11 couple to the activation of both phospholipase C and the adenylyl cyclase pathways. Additional ADP receptors linked to Galpha(i) have been described but have not yet been cloned. SP1999 is an orphan G protein-coupled receptor, which is highly expressed in brain, spinal cord, and blood platelets. In the present study, we demonstrate that SP1999 is a Galpha(i)-coupled receptor that is potently activated by ADP. In an effort to identify ligands for SP1999, fractionated rat spinal cord extracts were assayed for Ca(2+) mobilization activity against Chinese hamster ovary cells transiently transfected with SP1999 and chimeric Galpha subunits (Galpha(q/i)). A substance that selectively activated SP1999-transfected cells was identified and purified through a series of chromatographic steps. Mass spectral analysis of the purified material definitively identified it as ADP. ADP was subsequently shown to inhibit forskolin-stimulated adenylyl cyclase activity through selective activation of SP1999 with an EC(50) of 60 nM. Other nucleotides were able to activate SP1999 with a rank order of potency 2-MeS-ATP = 2-MeS-ADP > ADP = adenosine 5'-O-2-(thio)diphosphate > 2-Cl-ATP > adenosine 5'-O-(thiotriphosphate). Thus, SP1999 is a novel, Galpha(i)-linked receptor for ADP.

3T3 Cells↗
PubMed2000

The products of the Drosophila stoned locus interact with synaptic vesicles via synaptotagmin.

The stoned locus of Drosophila melanogaster encodes two novel proteins, stonedA (STNA) and stonedB (STNB), both of which are expressed in the nervous system. Flies with defects at the stoned locus have abnormal behavior and altered synaptic transmission. Genetic interactions, in particular with the shibire (dynamin) mutation, indicated a presynaptic function for stoned and suggested an involvement in vesicle cycling. Immunological studies revealed colocalization of the stoned proteins at the neuromuscular junction with the integral synaptic vesicle protein synaptotagmin (SYT). We show here that stoned interacts genetically with synaptotagmin to produce a lethal phenotype. The STNB protein is found by co-immunoprecipitation to be associated with synaptic vesicles, and glutathione S-transferase pull-downs demonstrate an in vitro interaction between the micro2-homology domain of STNB and the C2B domain of the SYTI isoform. The STNA protein is also found in association with vesicles, and it too exhibits an in vitro association with SYTI. However, we find that the bulk of STNA is in a nonmembranous fraction. By using the shibire mutant to block endocytosis, STNB is shown to be present on some synaptic vesicles before exocytosis. However, STNB is not associated with all synaptic vesicles. We hypothesize that STNB specifies a subset of synaptic vesicles with a role in the synaptic vesicle cycle that is yet to be determined.

Animals↗
PubMed2000

Pregnancy outcome following gestational exposure to echinacea: a prospective controlled study.

BACKGROUND: Echinacea products are among the most popular phytomedicines on the North American market. Since at least half of all pregnancies are unplanned, many women inadvertently use echinacea in their first trimester. Presently, there is a paucity of information regarding the gestational safety of this herb. The primary objective of this study was to evaluate the safety of echinacea in pregnancy when used for upper respiratory tract ailments. PATIENTS AND METHODS: The study group consisted of women who were prospectively followed up after contacting the Motherisk Program regarding the gestational use of echinacea. This cohort was disease-matched to women exposed to nonteratogenic agents by maternal age, alcohol, and cigarette use. Rates of major and minor malformations between the groups were compared. RESULTS: A total of 206 women were enrolled in the study group after using echinacea products during pregnancy; 112 women used the herb in the first trimester. There were a total of 195 live births, including 3 sets of twins, 13 spontaneous abortions, and 1 therapeutic abortion. Six major malformations were reported, including 1 chromosomal abnormality, and 4 of these malformations occurred with echinacea exposure in the first trimester. In the control group, there were 206 women with 198 live births, 7 spontaneous abortions, and 1 therapeutic abortion. Seven major malformations were reported. There were no statistical differences between the study and control groups for any of the end points analyzed. CONCLUSIONS: This first prospective study suggests that gestational use of echinacea during organogenesis is not associated with an increased risk for major malformations.

Congenital Abnormalities↗
PubMed2000

Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes. Activation of this receptor in liposarcomas and breast and colon cancer cells also induces cell growth inhibition and differentiation. In the present study, we show that PPARgamma is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPARgamma gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our preclinical data, we conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone, a PPARgamma ligand used for the treatment of type 2 diabetes. Forty-one men with histologically confirmed prostate cancer and no symptomatic metastatic disease were treated orally with troglitazone. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. These data suggest that PPARgamma may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated.

Aged↗
PubMed2000

Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing.

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP.

Amino Acid Sequence↗
PubMed2000

Pancreatic pseudocyst treated by laparoscopic Roux-en-Y cystojejunostomy. Report of a case and review of the literature.

Advances in laparoscopic surgical technique and instrumentation have furthered our ability to perform more complex laparoscopic procedures. We report the case of a 45-year-old man in whom a giant pancreatic pseudocyst developed after biliary pancreatitis. He underwent laparoscopic internal drainage by a Roux-en-Y cyst-jejunal anastomosis after unsuccessful percutaneous drainage. The surgical technique and a review of the current literature is presented. We conclude that although laparoscopic internal drainage technically is feasible in selected cases, additional data are required to define the role of this surgical approach in the treatment of pancreatic pseudocysts.

Anastomosis, Roux-en-Y↗
PubMed2000

Spiritual issues associated with traumatic-onset disability.

PURPOSE: The present study used a qualitative approach to discover the concepts used by people with a sudden-onset disability to express issues of spirituality. Using a cross-sectional time frame, the study sought to understand how spiritual issues were experienced at the onset of a disability from the perspective of the disabled person him or herself. The study also compared the perceptions of brain injury respondents to spinal cord injury respondents. METHOD: The qualitative approach was chosen to capture a detailed understanding of perceptions about spirituality, and the relationship of the disability to the disabled person's spiritual beliefs. The sample consisted of 16 individuals, all of whom had experienced a spinal cord injury or a brain injury. RESULTS: The main findings of the study were as follows: (1) Participants recovering from a disability described spiritual issues relating to five themes which arose directly from the data (awareness, closeness, trust, purpose, vulnerability) and relating to three relationships found throughout the literature on spirituality (intrapersonal, interpersonal and transpersonal). These eight dimensions can be combined to form a matrix, which serves as a framework for considering spiritual issues associated with disability; and (2) There were differences in the spiritual concepts described by the participants with brain injury compared to those with spinal cord injury. In particular, those with brain injuries seemed to place greater emphasis on the importance of their families, and to be more aware of the need for trust in view of their memory deficits. CONCLUSIONS: These results represent one of the earliest attempts to take an empirical approach to the development of theory in the area of spirituality and disability. Building on theory developed in other populations (palliative care and ageing), the study offers a theoretical model for clinicians, educators and researchers to better understand spirituality in the context of disability.

Acute Disease↗
PubMed2000

3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.

Animals↗
PubMed2000

Immunity to murine breast cancer cells modified to express MUC-1, a human breast cancer antigen, in transgenic mice tolerant to human MUC-1.

The high incidence of breast cancer in women and the severity of the disease have stimulated a need for improved and novel forms of therapy. The product of the MUC-1 gene has been identified as a breast cancer-associated antigen in breast cancer patients. The gene has been cloned and sequenced. Transgenic mice were prepared that express human mucin and are naturally tolerant to the molecule, providing a unique opportunity to investigate immunotherapeutic strategies in experimental animals that might eventually be applied to breast cancer patients. A cell line (410.4) derived from a mouse mammary adenocarcinoma that arose in a BALB/c mouse was transduced with a retroviral vector (R1-MUC1-pEMSVscribe) that encoded MUC-1. After confirmation of the expression of human mucin, the cells (E3) were further modified by transduction with retroviral vectors encoding interleukin (IL)-2, IL-4, IL-12, or IFN-gamma to evaluate the effect of cytokine-secretion on the immunogenic properties of the cells in the MUC-1 transgenic mice. The results indicated that modification of the breast cancer cells to secrete IL-12 reduced and at times eliminated the tumorigenic growth properties of the cells. Under similar circumstances, progressively growing tumors formed in MUC-1 transgenic mice that received injections of unmodified E3 cells or with E3 cells modified to secrete IL-2, IL-4, or IFN-gamma. Immunity to breast cancer developed in MUC-1 transgenic mice that had rejected IL-12-secreting E3 cells because the animals were resistant to challenge with (non-cytokine-secreting) E3 cells. In vitro analyses confirmed the presence of T cell-mediated cytotoxicity toward the breast cancer cells in MUC-1 transgenic mice immunized with the IL-12-secreting cells. Our data obtained in a unique animal model system point toward an analogous form of therapy for breast cancer patients.

Adenocarcinoma↗
PubMed2000

Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention.

An association of the dopamine receptor D4 (DRD4) gene located on chromosome 11p15.5 and attention deficit/hyperactivity disorder (ADHD) has been demonstrated and replicated by multiple investigators. A specific allele [the 7-repeat of a 48-bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an etiological factor in attentional deficits manifested in some children diagnosed with this disorder. In the current study, we evaluated ADHD subgroups defined by the presence or absence of the 7-repeat allele of the DRD4 gene, using neuropsychological tests with reaction time measures designed to probe attentional networks with neuroanatomical foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7-present subgroup showed normal speed and variability of response whereas the average reaction times of the 7-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7-present subgroup seemed to be free of some of the neuropsychological abnormalities thought to characterize ADHD.

Alleles↗
PubMed2000

Apo-transferrin is internalized and routed differently from Fe-transferrin by caco-2 cells: a confocal microscopy study of vesicular transport in intestinal cells.

Caco-2 cells grown as monolayers on porous membranes in bicameral chambers have been used to study the transport of Fe from the apical (lumenal) chamber to the basal (serosal) chamber. The transport of Fe is stimulated by the presence of either apo-transferrin (apo-Tf) or ferri-transferrin (Fe-Tf) in the basal chamber with the stimulation occurring at much lower concentrations of apo-Tf than Fe-Tf. To further explore the involvement of Tf in Fe transport across the basal surface, laser scanning confocal microscopy with 3-dimensional reconstruction of the confocal images was used to visualize the internalization of Texas Red-labeled apo-Tf and Bodipy-labeled Fe-Tf from the basal chamber. These studies show that apo-Tf was readily internalized and routed preferentially to a perinuclear region of the Caco-2 cells while internalized Fe-Tf stayed preferentially below the nuclei. These findings suggest that intestinal cells have a specialized mechanism to recognize and sort apo-Tf. (Blood. 2000;95:721-723)

Apoproteins↗
PubMed2000

Somatoform symptoms and treatment nonadherence in depressed family medicine outpatients.

OBJECTIVES: To examine whether somatoform symptoms, specifically symptoms of conversion, somatization, and hypochondriasis, are associated with side-effect reporting and treatment nonadherence in depressed family medicine outpatients, and to measure whether symptoms improve with pharmacotherapy. DESIGN: Inception cohort study with 14-week follow-up. SETTING: Inner-city family medicine residency clinic. PATIENTS: Thirty-nine consecutive adults with major depressive disorder were asked to participate, and 30 consented. INTERVENTION: Antidepressants for 14 weeks. MAIN OUTCOME MEASURES: The Personality Assessment Inventory (PAI) was administered before treatment. The PAI is a self-reported inventory compatible with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, designed to measure a broad range of personality characteristics. After 14 weeks, the side-effect incidence and treatment nonadherence rates were determined, and 12 patients were readministered the PAI. RESULTS: Depressed family medicine patients demonstrated trends toward elevated Somatic Complaints scale and conversion subscale scores and a lower Suicidal Ideation scale score relative to those of a standardized depressed psychiatric patient profile. Conversion and hypochondriacal symptoms were associated with side-effect reporting and treatment nonadherence. Somatization and hypochondriacal symptoms improved clinically and statistically during treatment for depression. CONCLUSIONS: Somatoform distress is a complex, common, and understudied phenomenon in primary care that can adversely affect the treatment of depression. Somatoform symptoms of conversion and hypochondriasis, but not somatization, were found to be risk factors for treatment nonadherence. Somatization and hypochondriacal symptoms may represent personality states that improve with pharmacotherapy, and conversion symptoms may be a personality trait resistant to medical treatment for depression.

Adult↗
PubMed2000

ASW: a gene with conserved avian W-linkage and female specific expression in chick embryonic gonad.

Vertebrates exhibit a variety of sex determining mechanisms which fall broadly into two classes: environmental or genetic. In birds and mammals sex is determined by a genetic mechanism. In mammals males are the heterogametic sex (XY) with the Y chromosome acting as a dominant determiner of sex due to the action of the testis-determining factor, SRY. In birds females are the heterogametic sex (ZW); however, it is not known whether the W chromosome carries a dominant ovary-determining gene, or whether Z chromosome dosage determines sex. Using an experimental approach, which assumes only that the sex-determining event in birds is accompanied by sex-specific changes in gene expression, we have identified a novel gene, ASW (Avian Sex-specific W-linked). The putative protein for ASW is related to the HIT (histidine triad) family of proteins. ASW shows female-specific expression in genital ridges and maps to the chicken W chromosome. In addition, we show that, with the exception of ratites, ASW is linked to the W chromosome in each of 17 bird species from nine different families of the class Aves.

Amino Acid Sequence↗
PubMed2000

Development of a modified picture-sort food frequency questionnaire administered to low-income, overweight, African-American adolescent girls.

There is essentially no ideal method of dietary assessment. Physiologic methods (i.e., doubly labeled water) probably come closest, but high cost, participant burden, and limited information limit their use. Furthermore, most dietary assessment methods have been designed for and tested in white adults. Very few have been designed for and tested in African-American adolescents. This study examined validity and reliability of a modified picture-sort food frequency questionnaire (FFQ) administered to 22 low-income, overweight, African-American adolescent girls, aged 11 to 17 years. The FFQ was administered to subjects twice during a 2-week period, and evaluated using the mean values of three 24-hour recalls. The natural log-transformed energy-adjusted, deattenuated correlation coefficients between the second FFQ and the mean from 3 recalls exceeded 0.50 for most nutrients, ranging from 0.32 (protein) to 0.87 (saturated fat). The energy and nutrient values from the first FFQ were greater than those from the second FFQ. Most correlation coefficients for the test-retest reliability of the FFQ were not significant. We conclude that although larger samples are needed to generalize results, the picture-sort dietary assessment method appears to be promising and merits further research.

Adolescent↗
PubMed2000

Changes in spiritual beliefs after traumatic disability.

OBJECTIVES: To discover the effect of sudden-onset disability on spirituality, specifically, to investigate changes following the onset of disability in spiritual concepts and to outline a theoretical framework consisting of relationships with the self, others, the world, and a supreme power. STUDY DESIGN: The study used a cross-sectional, qualitative approach to understand changes in spirituality from the perspective of the disabled person. Intensive semistructured interviews were conducted with 16 participants, each of whom had either a spinal cord injury or brain injury, within the 2-year period after discharge from rehabilitation. Changes in spiritual concepts were explored in relation to 3 types of relationships (intrapersonal, interpersonal, and transpersonal) and 5 themes (awareness, closeness, trust, purpose, and vulnerability). RESULTS: Specific changes in spirituality described by sample members were: greater awareness of the self; a change in their view of their own independence; a sense of purpose in life that was not present before the onset of the disability; greater awareness of their own mortality and vulnerability; a new understanding of trust, especially when depending on others; loss of some significant relationships; greater appreciation and closeness with others and the world; and greater understanding of other disadvantaged groups. CONCLUSIONS: The interviews portrayed a significant ability to conceptualize issues in a spiritual context in the 2-year period after discharge from rehabilitation. Further, the changes reported suggest a positive effect of spirituality in the adjustment period following onset.

Adult↗