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Biomedical subjects

S Martin

Publications and source records attributed to S Martin.

At least 343 records · Page 19Linked to original sources
PubMed1996

Inflammatory myopathy causing pharyngeal dysphagia: a new entity.

Seven patients presented to our swallowing center with solid food dysphagia. The age range at presentation was 69 to 90 years. All patients had normal findings on neurologic evaluation, and in those patients undergoing electromyography and nerve conduction studies, results of all such tests were also normal. Pooling of saliva in the pharyngeal recesses was noted on fiberoptic laryngoscopy in most cases. The swallowing videofluoroscopy findings were strikingly similar. All patients had a prominent cricopharyngeus muscle, and some had a prominence in a more proximal portion of the inferior constrictor muscle. All patients had decreased epiglottic tilt and moderate or severe residue in the pharyngeal recesses. Three patients underwent pharyngoesophageal sphincter myotomy. Biopsies of the omohyoid and cricopharyngeus muscles showed inflammatory myopathy with no evidence of inclusion bodies. This is a distinct clinical entity defined by isolated pharyngeal dysphagia in elderly patients with a unique videofluoroscopic appearance and pharyngeal myopathy.

Aged↗
PubMed1996

An index of need for psychiatric services based on in-patient utilisation.

BACKGROUND: The paper describes the development of an index of the relative need for psychiatric services for the purposes of distributing NHS funds in England. METHOD: The study is based on an empirical analysis of all psychiatric in-patient completed episodes in England in 1991/92. Any index of need should be independent of the effect of variations in health care supply on the use of psychiatric services. In order to disentangle the influences of supply from social and clinical determinants of utilisation, two stage least squares regression and multilevel modelling techniques were used. RESULTS: The outcome was an index comprising six health and socio-economic variables. This is now being used by the NHS Executive to distribute about pound 2.2 billion of annual NHS expenditure for psychiatric services between English health authorities. CONCLUSION: It is shown that the index is much more sensitive to needs and therefore more redistributive than the previous index of need used in the NHS.

Adolescent↗
PubMed1996

Relationships between FSH and ovarian follicular waves during the last six months of pregnancy in cattle.

Follicles were monitored daily by ultrasound and blood samples for FSH assay were collected daily from eight heifers from day 90 of pregnancy to the emergence of the first postpartum follicular wave. Follicles > or = 6 mm in diameter emerged in groups or waves in each heifer (P < 0.005). Follicular waves developed rhythmically throughout pregnancy, except that follicles > or = 6 mm were not detected during the last 21.6 +/- 2.4 (mean +/- SEM) days of pregnancy. The characteristics of the first follicular wave after day 90 were similar to previous reports for days 10-100. However, between months 4 (days 90-119) and 5, there was a decrease (P < 0.05) in monthly means for maximum diameter (mm) of largest (21.1 +/- 0.5 versus 9.5 +/- 0.5) and second largest (8.0 +/- 0.3 versus 6.9 +/- 0.2) follicles, duration of the interwave interval (8.1 +/- 0.4 versus 6.6 +/- 0.3 days), and number of follicles per wave (3.7 +/- 0.4 versus 2.5 +/- 0.4). Averaged over all follicular waves during months 4-9, the concentrations of FSH normalized to the emergence of a follicular wave increased (P < 0.05) over the 3 days before emergence, reached peak values on the day of emergence of the future dominant follicle at 4 mm, and decreased (P < 0.05) over the 3 days following emergence. Surges in FSH concentrations occurred throughout pregnancy, but during the last 30 days of pregnancy the number of surges was reduced and each heifer had one or two ineffective surges (no follicular wave detected). The temporal relationship between FSH surges and emergence of waves was closer (P < 0.01) than would be expected if the two events were independent. Surges of FSH occurred rhythmically even when there was no follicular response (no follicle > 5 mm). In association with waves in which the largest follicle reached > or = 10 mm compared with 6-9 mm, there was greater depression in the FSH nadir, longer intervals from FSH peak to nadir, and longer intervals between adjacent FSH peaks and adjacent waves.

Animals↗
PubMed1996

Elevated levels of circulating intercellular adhesion molecule-3 (cICAM-3) in Psoriasis.

Intercellular adhesion molecule (ICAM)-3 is important in regulating leukocyte function and T-lymphocyte-antigen presenting cell interactions. Soluble, circulating forms of ICAM-3 and ICAM-1 (cICAM-3, cICAM-1) exist in serum, and levels are elevated in a variety of autoimmune diseases. Two types of soluble circulating tumour necrosis factor receptor (cTNF-R1, cTNF-R2) are found in the sera of healthy people. cTNF-R1 binds TNF-alpha and is important in regulating TNF-alpha-mediated inflammation. Psoriasis is a T-lymphocyte-mediated disease, characterized by cutaneous expression of ICAM-1, ICAM-3 and TNF-alpha. As it is unknown whether cICAM-3 is increased in sera of patients with psoriasis, we measured serum levels of cICAM-3 and compared them to levels of cICAM-1, cTNF-R1 and clinical severity of psoriasis. Sera was taken from 112 healthy controls and 32 patients with psoriasis. Clinical severity of psoriasis was assessed using the psoriasis area severity index (PASI). cICAM-1, cICAM-3 and cTNF-R1 in serum were quantitated using a dual antibody, solid phase ELISA, Levels of cICAM-3, cICAM-1 and cTNF-R1 were significantly increased in sera of patients with psoriasis as compared with controls, and these elevated levels correlated with clinical severity of psoriasis as assessed by the PASI. Also, there were good correlations between serum levels of cICAM-3, cICAM-1 and cTNF-R1 in psoriasis. These results demonstrate, for the first time, that circulating levels of cICAM-3 are increased in psoriasis and that these levels correlate both with disease severity and with elevated levels of cICAM-1 and cTNF-R1. The exact physiologic roles of circulating, soluble adhesion molecules and cTNF-R1 are unknown, but it is hypothesised that elevation of their circulating levels, as observed in psoriasis, may play a role in modulating the inflammatory reactions occurring in this disease.

Adolescent↗
PubMed1996

The role of prohormone convertases in insulin biosynthesis: evidence for inherited defects in their action in man and experimental animals.

The hormone insulin remains the cornerstone of diabetic therapy since it is required for almost all cases of Type 1 and many cases of Type 2 diabetes. Since the discovery of insulin in 1921, much has been learned about its chemistry, structure and action as well as its production in the beta cell. Insulin is formed through a series of precursors, beginning with preproinsulin, the protein encoded in the insulin gene. These precursors direct the prohormone into the secretory pathway and ultimately into the secretory granules where it is converted into insulin and C-peptide. These products are stored and secreted together in a highly regulated manner in response to glucose and other stimuli. This review focuses on the recently discovered prohormone convertases, PC2 and PC3 (PC1), the enzymes responsible for the endoproteolytic processing of proinsulin to insulin and C-peptide in the beta cell as well as for the selective processing of proglucagon to glucagon in the alpha cell or GLP1 in intestinal L-cells. PC2 and PC3 are calcium-dependent serine proteases related to the bacterial enzyme subtilisin. They cleave selectively at Lys-Arg or Arg-Arg sites in precursors, generating products with C-terminal basic residues that are then removed by carboxypeptidase E, an exopeptidase. All 3 enzymes are expressed mainly in secretory granules of neuroendocrine cells throughout the body and in the brain. Inherited defects affecting the prohormone-processing enzymes have recently been found in association with unusual syndromes of obesity and other metabolic disorders.

Animals↗
PubMed1996

Implementation and evaluation of a liberalized visiting policy.

BACKGROUND: Visiting policies have been liberalized in ICUs, but the process and outcome of policy modifications have not been well described. OBJECTIVES: To describe the process by which nurses in one critical care unit modified visiting from a restricted to a liberalized (i.e., modified open) policy, and to evaluate the nurses' perceptions about visiting before and after the policy was liberalized. METHODS: A group of ICU/coronary care unit nurses met to discuss changes in their unit's visiting policy. Before the change was initiated, nurses (N = 36) in the unit were informally surveyed regarding their perceptions and attitudes about visiting. After a 3-month trial of liberalized visiting, in which visiting hours were increased at the discretion of the nursing staff, nurses (N = 32) were surveyed using a questionnaire about their beliefs, attitudes, level of satisfaction, and perceptions of their actual visiting policy. RESULTS: Nurses confirmed that the visiting policy had become liberalized, and they believed that liberalized visiting had positive effects on patients' emotional well-being. Nurses had more positive attitudes about the effects of liberalized visiting on families than on patients and unit function. Most nurses were satisfied with liberalized visiting. However, attitudes differed about how liberalized visiting affected patients' physiological responses or the unit function. CONCLUSIONS: Effective implementation of liberalized visiting depends on assessment of the following: nurses' beliefs, attitudes, and satisfaction about a change toward a more open visiting policy; staff involvement in determining the policy; and nurse manager and clinical nurse specialist support.

Attitude of Health Personnel↗
PubMed1995

Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide.

Proglucagon is processed differently in the islet alpha cells and the intestinal endocrine L cells to release either glucagon or glucagon-like peptide 1-(7-37) (GLP1-(7-37)), peptide hormones with opposing actions in vivo. In previous studies with a transformed alpha cell line (alpha TC1-6) we demonstrated that the kexin/subtilisin-like prohormone convertase, PC2 (SPC2), is responsible for generating the typical alpha cell pattern of proglucagon processing, giving rise to glucagon and leaving unprocessed the entire C-terminal half-molecule known as major proglucagon fragment or MPGF (Rouillé, Y., Westermark, G., Martin, S. K., Steiner. D. F. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 3242-3246). Here we present evidence, using mouse pituitary AtT-20 cells infected with a vaccinia viral vector encoding proglucagon, that PC3 (SPC3), the major neuroendocrine prohormone convertase in these cells, reproduces the intestinal L cell processing phenotype, in which MPGF is processed to release two glucagon-related peptides, GLP1 and GLP2, while the glucagon-containing N-terminal half-molecule (glicentin) is only partially processed to oxyntomodulin and small amounts of glucagon. Moreover, in AtT-20 cells stably transfected with PC2 (AtT-20/PC2 cells), glicentin was efficiently processed to glucagon, providing further support for the conclusion that PC2 is the enzyme responsible for the alpha cell processing phenotype. In other cell lines expressing both PC2 and PC3 (STC-1 and beta TC-3), proglucagon was also processed extensively to both glucagon and GLP1-(7-37), although STC-1 cells express lower levels of PC2 and processed the N-terminal domain to glucagon less efficiently. In contrast, GH4C1 and COS 7 cells, which express very little or no PC2 or PC3, failed to process proglucagon, aside from a low level of interdomain cleavage which occurred only in the GH4C1 cells. In vitro PC3 did not cleave at the single Arg residue in GLP1 to generate GLP1-(7-37), its truncated biologically active form, indicating the likelihood that another convertase is required for this cleavage.

Amino Acid Sequence↗
PubMed1995

High-performance liquid chromatography-electrochemical determination of salicylate hydroxylation products as an in vivo marker of oxidative stress.

The in vivo measurement of highly reactive free radicals, such as hydroxyl radical (.OH), in humans is very difficult if not impossible. Specific markers are currently under investigation (amino acid hydroxylatin, protein, DNA adducts, and aromatic probes). They are based on the ability of .OH to attack aromatic molecules to produce hydroxylated compounds that can be measured directly. In vivo, radical metabolism of salicylic acid produces two main hydroxylated derivatives, i.e., 2,3- and 2,5-dihydroxybenzoic acid (2,3- and 2,5-DHBA). The measurement of 2,3-DHBA, following oral administration of salicylate or its acetylated form (aspirin), has been proposed for assessment of in vivo oxidative stress. In this work, a sensitive method for the detection of in vivo .OH generation is presented. The methodology employs a high-pressure liquid chromatography with electrochemical detection for the identification and quantification of the hydroxylation products from the reaction of .OH with salicylate. A detection limit of less than 0.1 pmol for the hydroxylation products has been achieved with electrochemical detector responses which were linear over at least five orders of magnitude. Using this technique, we measured plasma levels of 2,3- and 2,5-DHBA and dihydroxylated derivatives/salicylic acid ratios following the administration of 1000 mg aspirin in 20 healthy subjects. In the same individuals, plasma levels of thiobarbituric acid reactants (TBARs), a major index of lipid peroxidation, were also measured and correlation with hydroxylated products was sought. The plasma level of TBARs was positively correlated with the 2,5-DHBA/salicylic acid ratio, but not with the absolute plasma level of 2,3-DHBA.

Adult↗
PubMed1995

The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML.

Acute promyelocytic leukaemia (APL) has been ascribed to a chromosomal translocation event which results in a fusion protein comprising the PML protein and the retinoic acid receptor alpha. PML is normally a component of a nuclear multiprotein complex (termed ND10, Kr bodies, nuclear bodies, PML oncogenic domains or PODs) which is disrupted in the APL disease state. PML contains a number of characterized motifs including a Zn2+ binding domain called the RING or C3HC4 finger. Here we describe the solution structure of the PML RING finger as solved by 1H NMR methods at physiological pH with r.m.s. deviations for backbone atoms of 0.88 and 1.39 A for all atoms. Additional biophysical studies including CD and optical spectroscopy, show that the PML RING finger requires Zn2+ for autonomous folding and that cysteines are used in metal ligation. A comparison of the structure with the previously solved equine herpes virus IE110 RING finger, shows significant differences suggesting that the RING motif is structurally diverse. The role of the RING domain in PML nuclear body formation was tested in vivo, by using site-directed mutagenesis and immunofluorescence on transiently transfected NIH 3T3 cells. Independently mutating two pairs of cysteines in each of the Zn2+ binding sites prevents PML nuclear body formation, suggesting that a fully folded RING domain is necessary for this process. These results suggest that the PML RING domain is probably involved in protein-protein interactions, a feature which may be common to other RING finger domains.

Amino Acid Sequence↗
PubMed1995

Expression and characterization of maize ZBP14, a member of a new family of zinc-binding proteins.

A maize gene (Mz2-12), with a deduced amino acid sequence similar to that of a protein kinase C (PKC) inhibitor from bovine brain, has been expressed in Escherichia coli and the protein (ZBP14) purified to homogeneity. The bovine protein was originally identified by Walsh's group and named PKC inhibitor-1 (PKCI-1). The recombinant maize protein (ZBP14) shares characteristics of bovine PKCI-1: it has similar secondary structure, is dimeric, and has a similar affinity for zinc. However, the maize ZBP14 had very little activity as an inhibitor of mammalian brain PKC, thus precluding zinc sequestration as the mechanism of inhibition. The biological role for the maize protein in plant kinase regulation is therefore unclear. In the presence of both maize ZBP14 and 14-3-3 protein (which inhibits PKC in the absence of diacylglycerol), the effects on PKC appeared to be synergistic.

Animals↗
PubMed1995

Circulating forms of ICAM-3 (cICAM-3). Elevated levels in autoimmune diseases and lack of association with cICAM-1.

The intercellular adhesion molecule-3 (ICAM-3) has been identified as the third LFA-1 ligand in addition to ICAM-1 and ICAM-2. In this report we have identified circulating forms of ICAM-3 (cICAM-3) in human serum. Using a sandwich ELISA with two monoclonal anti-ICAM-3 Abs, we detected cICAM-3 in concentrations between 40 and 360 ng/ml in all of 112 healthy controls. An analysis of patient sera from 10 different immune-mediated diseases revealed a distinct pattern of expression. Significantly elevated cICAM-3 levels were found in rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barré syndrome, and multiple sclerosis, but not in type I diabetes, Grave's disease, chronic autoimmune thyroiditis, ulcerative colitis, or Crohn's disease. cICAM-3 levels were significantly higher in systemic lupus erythematosus patients with active compared with nonactive disease. Despite their binding to the same integrin receptor, serum levels of cICAM-3 did not correlate with cICAM-1 concentrations in either normal persons or in patients. The majority of patients had either elevated cICAM-3 or cICAM-1 levels but not both. In conclusion, a circulating form of ICAM-3 is present in human sera. cICAM-3 expression is elevated in certain immune-mediated diseases but occurs independently of cICAM-1.

Adolescent↗
PubMed1995

Cross-reactive trinitrophenylated peptides as antigens for class II major histocompatibility complex-restricted T cells and inducers of contact sensitivity in mice. Limited T cell receptor repertoire.

The induction of contact sensitivity in mice by hapten reagents such as trinitrochlorobenzene (TNCB) involves the activation of class II major histocompatibility complex (MHC)-restricted, hapten-specific, CD4+ T cells. Reports from different laboratories have indicated that the relevant antigenic epitopes in such reactions might include hapten-conjugated, MHC class II-associated peptides. This study for the first time directly demonstrates that hapten-peptides account for the majority of determinants recognized by trinitrophenyl (TNP)-specific CD4+ T lymphocytes. The sequences of those TNP carrier peptides do not have to be related to mouse proteins. Thus, we show that TNP-modified peptides derived from mouse IgG, pigeon cytochrome c or staphylococcal nuclease known to bind to I-Ab or from lambda repressor with specificity to I-Ad as well as TNP-proteins such as bovine serum albumin, ovalbumin or keyhole limpet hemocyanin all create class II-restricted hapten determinants for a number of TNP-specific T cell clones and hybridomas. All of these cells were induced with cells modified by trinitrobenzene sulfonic acid (TNBS). In addition, we present arguments indicating that individual TNP-specific helper T cells may cross-react with different TNP-peptides bound to identical class II molecules. Chemical treatment of antigen-presenting cells with TNCB or TNBS may thus result in a limited number of particularly repetitive immunodominant hapten epitopes. Immunodominant epitopes were also indicated by an overrepresentation of the TCR elements V beta 2 and V alpha 10 in I-Ab/TNP-specific T cells. Most importantly, however, we demonstrate that TNP attached to lysine 97 in the staphylococcal nuclease peptide 93-105 (i.e. a clearly "non-self" sequence) is able to prime mice for subsequent elicitation of contact sensitivity by TNCB in the absence of foreign protein. We take this to indicate that those TNP-peptide determinants defined by us as immuno-dominant are responsible for the induction of contact sensitivity to haptens.

Amino Acid Sequence↗
PubMed1995

Carrier-reactive hapten-specific cytotoxic T lymphocyte clones originate from a highly preselected T cell repertoire: implications for chemical-induced self-reactivity.

We have recently described trinitrophenyl (TNP)-specific cytotoxic T lymphocyte (CTL) clones from C57BL/6 mice specific for hapten-modified peptides bearing a TNP-lysine in a peripheral position, i.e. in position 7 of H-2Kb-bound octapeptides. CTL recognition of such determinants is always sequence-dependent due to co-recognition of TNP as well as amino acid side chains of the carrier peptide. By the use of glycine-based designer peptides for primary induction of CTL in vitro, we have identified two sub-epitopes on individual position 7-haptenated peptides that form two TcR contact points and which can be independently recognized by cloned CTL. One of these sub-epitopes is represented by the hapten itself, the other by the amino acids tyrosine and lysine in positions 3 and 4 of the carrier peptide, respectively. Immunization with such TNP-modified peptides frequently results in the specific induction of CTL also reacting with the unmodified carrier peptides. DNA sequence analyses of the TcR revealed an extraordinary similarity of several independent TcR of CTL from individual mice and induced with different TNP-peptides. These receptor similarities clearly correlate with structural elements common to the immunizing peptides and suggest their origin from positive thymic selection of TcR on Kb-associated associated self-peptides bearing Tyr in position 3. Our data provide additional information concerning the topology of TcR binding to peptide/MHC complexes with, but also without, TNP. They also indicate a mechanism which might explain the potential of chemicals or drugs to induce autoimmune phenomena.

Amino Acid Sequence↗