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Biomedical subjects

K Lloyd

Publications and source records attributed to K Lloyd.

At least 19 recordsLinked to original sources
PubMed1996

A subpopulation of human urothelial cells is stimulated to proliferate by treatment in vitro with lipoteichoic acid, a cell wall component of Streptococcus faecalis.

Urinary tract infection with gram-positive bacteria is common. Avenues for ingress of bacteria into the bladder include luminal and suburothelial infection. Terminally differentiated superficial urothelial cells lining the lumen of the bladder are often shed in response to infection. In contrast, infection-induced altered function of progenitors of urothelial cells residing in the basal layer of the urothelium is likely to have long lasting effects on the structure and function of the urothelium. The main objective of the present studies was to investigate in vitro the possibility that exposure to lipoteichoic acid, a cell wall component of the gram-positive Streptococcus faecalis (LT-2), stimulates basal urothelial cells to proliferate. To simulate conditions that restrict proliferation and inhibit terminal differentiation of urothelial cells in the basal layer, secondary cultures of urothelial cells (UT) were grown on collagen or fibronectin coated substrate in medium containing low levels of Ca2+ (0.2 mM) and growth factors (0.005% bovine pituitary extract [BPE]). Under these conditions, UT cultures displayed a highly reproducible colony size distribution, possibly due to the fact that colonies were progeny of basal cells with various proliferative potentials, retained in vitro. In cultures grown under growth-restricting conditions the majority of progenitors appeared to be quiescent, just like stem cells in the basal layer of the urothelium. Thus, the population of large colonies (more than six cells/colony), was small when a steady state of growth was achieved, 3-7 days after seeding. Growth factors (0.005-0.5% BPE) caused a dose-dependent increase in this population of large colonies. Moreover, treatment of UT grown under growth-restricting conditions (0.005% BPE) with LT-2 increased steady-state levels of the population of large colonies to levels obtained in cultures growing under optimal conditions with respect to growth factors. These results indicated that the subpopulation of progenitors, quiescent under normal conditions, could be stimulated to proliferate. Two lines of evidence were consistent with the possibility that treatment with LT-2 stimulated proliferation of the subpopulation of progenitors and that large colonies were the progeny of this subpopulation of single cells: (1) treatment with LT-2 increased the percentage of single cells that incorporated bromodeoxyuridine (i.e., proliferated) in a time-dependent manner. (2) An increase in the percentage of large colonies was found following LT-2-triggered proliferation of single cells. We propose that, under normal conditions, cells produced in response to LT-2-triggered proliferation of stem cells are removed from the system due to an increased rate of differentiation followed by apoptosis. Recurrent infection and inflammation may not allow these processes to proceed effectively, resulting in chronic injury to the bladder. Moreover, under conditions in which stem cells accumulate mutations that incapacitate their progeny to undergo apoptosis, LT-triggered proliferation could be a contributing factor to tumorigenesis.

Animals↗
PubMed1996

Long-term treatment with lipoteichoic acid from Streptococcus faecalis affects differentiation and expression and cellular distribution of beta 1 integrins in human urothelial cells.

Gram-positive bacteria are recognized pathogens in urinary tract infections. Cellular mechanisms triggered by lipoteichoic acids (LTs), cell well components of gram-positive bacteria, have not been completely defined. We have postulated that infection-induced altered function of progenitors of urothelial cells residing in the basal layer is likely to have long lasting effects on the architecture and function of the urothelium. Our recent studies in vitro showed that treatment of poorly differentiated urothelial cells of basal type with LT from Streptococcus faecalis (LT-2) stimulated rapid proliferation of a subpopulation of progenitors of urothelial cells, supporting this possibility (Elgavish et al., 1996, J. Cell. Physiol., 169:42-51). The hypothesis underlying the present studies was that, following LT-triggered increase in proliferation of progenitors, the rate of differentiation of the resulting progeny was also stimulated. We proposed that this mechanism may allow rapid removal of cells from the injured area and replacement by cells that have not been exposed to infection. To simulate in vitro conditions in the basal layer that inhibit terminal differentiation, cells grew on fibronectin or collagen-coated substrate, in medium containing low Ca2+ (0.2 mM) and low levels of growth factors (0.005% bovine pituitary extract [BPE]). During the last 3 days in culture, cells grew in the same low Ca2+ (0.2 mM) medium, but without BPE, with or without LT-2. In a positive control group, cells grew during their last 3 days in culture in medium without BPE and LT-2 but in which levels levels of Ca2+ were higher (2 mM), a condition known to stimulate differentiation in other cell types. Several lines of evidence supported the possibility that long-term treatment with LT-2 stimulated progression of large colonies (i.e., the progeny resulting from LT-triggered proliferation) to a more differentiated state: (1) the rate of their differentiation, determined by criterion of intense cytokeratin 8 expression, was increased; (2) steady-state level of beta mRNA and expression of beta 1 subunit of integrins at the protein level were inhibited; (3) in contrast to large colonies in control cultures, the entire population of LT-2-treated large colonies contained beta 1 integrins distributed at cell-cell contacts. Raising extracellular Ca2+ concentration to 2 mM induced similar effects, suggesting that LT-2 may act by stimulating an increase in intracellular levels of Ca2+. However, further studies will be needed to elucidate the molecular mechanisms underlying the stimulatory effect of LT-2 on proliferation of progenitors of urothelial cells in the basal layer of the urothelium and subsequent differentiation of their progeny. We propose that these processes may have a causative role in the pathological changes that occur in the aftermath of chronic or recurrent suburothelial infection in the urinary bladder.

Cell Differentiation↗
PubMed1996

Nitric oxide mediates the action of lipoteichoic acid on the function of human urothelial cells.

Gram-positive bacteria are recognized pathogens in urinary tract infections. Lipoteichoic acids, major components of the cell wall of gram-positive bacteria, are important virulence attributes, but their mechanism of action is not well understood. We have postulated that infection-induced altered function of progenitors of urothelial cells (UT) residing in the basal layer is likely to have long-lasting effects on the architecture and function of the urothelium. Our earlier in vitro studies in UT of basal type, grown under growth restricting conditions, have shown that 1) treatment with lipoteichoic acid from Streptococcus faecalis (LT-2) stimulates a subpopulation of progenitors of urothelial cells to proliferate, and 2) resulting large colonies differentiated at an increased rate under conditions simulating those in the basal layer of the urothelium. The hypothesis underlying the present studies was that nitric oxide (NO) mediated LT-2 action on these functions of UT. Immunocytochemical studies using an antibody against inducible nitric oxide synthase (iNOS) confirmed expression of iNOS in LT-2-treated UT. Our hypothesis was tested by treating UT grown under growth restricting conditions (0.005% bovine pituitary extract) with LT-2 (25 micrograms/ml), in the presence or absence of inhibitors of NOS (1 mM NG-nitro-L-arginine methyl ester [L-NAME]; 1 microM dexamethasone [DEXA]) or 25 microM hemoglobin, a potent inactivator of NO. Treatment with LT-2 in the presence of these agents prevented the following effects of LT-2 alone: 1) the stimulatory effect on proliferation of single cells, as well as within the resulting large colonies; 2) the subsequent differentiation of large colonies resulting from this proliferative activity, as indicated by distribution of beta 1 subunit-containing integrins to cell-cell contacts; 3) the inhibitory effect on the subsequent ability of LT-2-treated UT to attach to extracellular matrix proteins. These studies suggest that induction of NOS by LT-2, initially aimed at restricting the replication of infectious agents, may have potential cost of damage to the host bladder by interfering with urothelial differentiation.

Animals↗
PubMed1996

Epidemiology of current treatment for sexual dysfunction in spinal cord injured men in the USA model spinal cord injury centers.

This study is a prospective multicenter cooperative survey of the evaluation and treatment of erectile dysfunction in men with spinal cord injury (SCI). Uniform database questionnaires were completed prospectively by patients seeking therapy for erectile dysfunction. Eighty-five SCI men aged 17-68 years (mean age = 26 +/- 17) were enrolled. Mean duration of traumatic SCI was 3 +/- 3.2 years (Range = 0.3-18 years). The level of injury was cervical in 20 patients, thoracic in 31, lumbar in 29 and sacral in five. Patients were fully evaluated and then counseled as to their therapeutic options. Twenty-eight chose to use a vacuum erection device (VED), 26 preferred pharmacological penile injection and five used both intracorporeal therapy and VED. The remainder were managed with marriage and sexual counseling in 10 patients, three underwent penile prosthesis placement and two used topical pharmacotherapy. Four patients used other forms of treatment and in nine no therapy was recommended. Of the patients that used pharmacologic injection only, 74 percent used papaverine as a single agent, 20 percent used papaverine with phentolamine, five percent used prostaglandin E (PGE1) alone and one percent used a mixture. Patients using injection therapy report sexual intercourse a mean of 3 +/- 3.4 times per month as compared with 5 +/- 3.2 times per month in those using VED. Five intracorporeal injection patients developed priapism while two patients using the VED developed subcutaneous bleeding and one developed penile ischemia. We conclude that although a spectrum of erectile dysfunction treatment is present among SCI centers, VED and pharmacological penile injection are by far the two most popular methods of treatment and papaverine is the most common drug. The incidence of complications is small in the model centers.

Adolescent↗
PubMed1996

Monoclonal antibody to VIP: production, characterization, immunoneutralizing activity, and usefulness in cytochemical staining.

A very stable cell line has been generated that produces monoclonal antibody to VIP designated as CURE.V55. This hybridoma was produced by fusion of spleen cells from an immunized Robertsonian mouse containing the translocated 8.12 chromosome with FOX-NY myeloma cells that are APRT deficient. VIP monoclonal antibody producing cell line #55 was selected by limiting dilutions using thymocytes as feeder layers. Ascites fluid containing high concentration of VIP monoclonal antibody was produced from pristane-primed BALB/c mice. Ascites fluid contained approximately 20 mg/ml IgG and bound 50% of 2 fmol 125I-VIP at a final dilution of 1:50,000. Binding of this IgG1 antibody was inhibited by 50% at 5 nM concentration of either VIP 1-28 or VIP 7-28. Protein-A purified IgG of this antibody, used in a concentration of 30 mg/kg per rat (IV), completely reversed the inhibitory effect of gastric corpus contractions induced by intravenous injection of VIP (10 nmol/kg) in sodium pentothal-anesthetized rats. A control anti-keyhole limpet hemocyanin monoclonal antibody did not alter the stimulatory effect of VIP on gastric corpus contractions. Immunohistochemistry showed that this VIP monoclonal antibody stains neurons, and nerve fibers in human and rat gallbladder and the sphincter of Oddi as previously described with our polyclonal antiserum.

Animals↗
PubMed1995

Somatostatin inhibits B-cell secretion via a subtype-2 somatostatin receptor in the isolated perfused human pancreas.

Recently five somatostatin receptor subtypes (SSTR) have been cloned, allowing the development of highly specific selective agonists for these SSTR. The present study was undertaken to determine which SSTR is responsible for the inhibitory effect of somatostatin on islet hormone secretion. Single-pass perfusion of four agonists was performed in pancreata obtained from four cadaveric organ donors using a modified Krebs-media with 3.9 mM glucose. Sequential 10-min specific receptor agonist infusions (5 ng/ml) of DC32-87 (SSTR2), DC25-12 (SSTR3), DC32-97 (SSTR3), or DC32-92 (SSTR5) were performed in random order separated by 10-min basal periods. Infusion of SSTR2 agonist into the isolated perfused human pancreas resulted in a significant inhibition of insulin and C-peptide secretion (insulin = -1468 +/- 480 pM, P < 0.05, and C-peptide = -2328 +/- 437 pM, P < 0.05) but not islet amyloid polypeptide or somatostatin. These results suggest that the inhibitory effect of somatostatin on B-cell secretion is mediated through the subtype-2 receptor within the human islet.

Adolescent↗
PubMed1995

The phenomenology and explanatory models of common mental disorder: a study in primary care in Harare, Zimbabwe.

In order to describe the explanatory models and the etic and emic phenomena of common mental disorder in Harare, Zimbabwe, 110 subjects were selected by general nurses in three clinics and by four traditional healers from their current clients. The subjects were interviewed using the Explanatory Model Interview and the Revised Clinical Interview Schedule. Mental disorder most commonly presented with somatic symptoms, but few patients denied that their mind or soul was the source of illness. Spiritual factors were frequently cited as causes of mental illness. Subjects who were selected by traditional healer, reported a greater duration of illness and were more likely to provide a spiritual explanation for their illness. The majority of subjects were classified as 'cases' by the etic criteria of the CISR. Most patients, however, showed a mixture of psychiatric symptoms that did not fall clearly into a single diagnostic group. Patients from a subgroup with a spiritual model of illness were less likely to conform to etic criteria of 'caseness' and they may represent a unique category of psychological distress in Zimbabwe. A wide variety of emic phenomena were elicited that have been incorporated in an indigenous measure of non-psychotic mental disorder. Kufungisisa, or thinking too much, seemed to be the Shona term closest to the Euro-American concept of neurotic illness.

Adolescent↗
PubMed1995

The economics of depression in primary care. Department of Health initiatives.

BACKGROUND: Most mental illness is treated in primary and not secondary care settings, with depression and anxiety the commonest conditions encountered. METHOD: The paper describes on-going Department of Health initiatives to optimise the primary care of common mental illnesses such as depression. DISCUSSION: Primary care attenders with depression are often higher consumers of general health care than non-depressed attenders. Further data will become available soon from these ongoing studies to inform the debate on the optimal use of available resources in primary care. There is a particular need to evaluate non-pharmacological interventions in primary care.

Adult↗
PubMed1994

Use of the Fab fragment for immunoneutralization of somatostatin in the isolated perfused human pancreas.

The role of the somatostatin-secreting D cell in the islet remains controversial. The present study was undertaken to determine whether infusion of the Fab fragment of a highly sensitive somatostatin monoclonal antibody into the isolated, perfused human pancreas would influence insulin secretion. Single-pass perfusion was performed in pancreata obtained from cadaveric organ donors using a modified Krebs-media with 3.9 mM glucose. Sequential test periods separated by basal periods were performed with either somatostatin monoclonal antibody Fab fragment (SFab), somatostatin-14 (SS-14), or a combined infusion. Immunoneutralization of intraislet somatostatin with SFab resulted in a significant increase in both immunoreactive insulin (IRI) (1,122 +/- 497 pM) (p < 0.05) and immunoreactive C-peptide (IRC-P) secretion (146 +/- 53 pM) (p < 0.05). Infusion of SS-14 resulted in inhibition of both IRI secretion (-3,372 +/- 1,360 pM) (p < 0.05) and IRC-P secretion (-708 +/- 220 pM) (p < 0.05). Combined infusion of SFab and SS-14 reversed the inhibitory effect of exogenous SS-14 on IRI and IRC-P secretion. The data suggest that intraislet somatostatin has an inhibitory role in the regulation of B-cell secretion in the human islet and demonstrates that the Fab fragment of the somatostatin monoclonal antibody is an effective tool for immunoneutralization studies in the human pancreas. In addition, immunostaining of the donor pancreata demonstrated the presence of somatostatin-immunoreactive endocrine cells interspersed throughout the islet core and mantle. The demonstrated proximity of somatostatin-immunoreactive endocrine cells to B cells lends anatomic support to the concept that intraislet somatostatin influences insulin secretion in the human islet.

Adult↗
PubMed1994

Integrin-mediated adhesive properties of uroepithelial cells are inhibited by treatment with bacterial toxins.

Gram-negative bacteria are a dominant cause of urinary tract infection, and their ability to produce toxins is an important virulence attribute. Cellular mechanisms triggered by the production of toxins in the lower urinary tract have not been completely defined. Ureteral epithelial cells (UT; A. Elgavish, Infect. Immun. 61: 3304-3312, 1993) have served as an in vitro model to explore the possibility that bacterial toxins act on UT by affecting integrin-mediated adhesive properties. The effect of treatment with lipopolysaccharides (LPS) from three strains of the gram-negative Escherichia coli [055:B5 (LPS-1), 0111:B4 (LPS-4), and 0127:B8 (LPS-5)] and lipoteichoic acids from two gram-positive bacteria, Streptococcus faecalis (LT-2) and Bacillus subtilis (LT-3), were examined. LPS-5 inhibited markedly UT attachment to collagen and fibronectin. LPS-4 had no effect, whereas LPS-1 inhibited UT attachment to collagen but not to fibronectin. The fact that LPS-5 and LT-2 inhibited an Arg-Gly-Asp sequence-sensitive component of UT attachment to fibronectin is consistent with the possibility that these toxins acted via a mechanism involving typical fibronectin receptors. UT spreading was inhibited markedly by LPS-1, LT-2, and LT-3, whereas LPS-4 and LPS-5 had no effect. Because clustering of integrins is a crucial step in integrin-mediated signal transduction, the possibility that toxins inhibited spreading by affecting clustering was tested. Treatment with LT-2, which inhibited spreading dramatically, abolished completely a UT cell population containing more than five to eight beta 1- or beta 4-subunit-containing integrin clusters.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

The clinical profile of sumatriptan: safety and tolerability.

The safety and tolerability of sumatriptan have been extensively studied. The majority of adverse events (defined as any medical event irrespective of possible causal relationship to treatment) were mild to moderate in intensity, transient and resolved spontaneously. In short-term studies, the most frequently reported adverse events were nausea, vomiting, dizziness, vertigo, malaise, fatigue, injection-site reactions, heaviness, pressure, feelings of warmth and headache. The adverse event profile was unchanged during long-term open treatment and was unaffected by frequency of treatment with sumatriptan. In 3-5% of patients, the symptoms of pressure and warmth were experienced in the chest, but extensive investigations, including ECG monitoring, have indicated that these symptoms are not normally associated with cardiac dysfunction.

Administration, Oral↗
PubMed1993

Sumatriptan in the acute treatment of migraine.

Sumatriptan is a selective 5-HT1-like agonist, which is effective in the treatment of migraine and cluster headache. It has been rigorously assessed in clinical trials involving over 7000 patients who have treated over 35,000 migraine attacks. Both subcutaneous and oral sumatriptan provide a high level of efficacy with 86% of patients obtaining relief after a single 6 mg injection (at 2 h) and 75% after 100 mg oral sumatriptan (4 h), compared with up to 37% in the placebo-treated group (P < 0.001). The onset of effect is rapid, occurring 10 min after injection and 30 min after the tablet. Oral sumatriptan (100 mg) has been evaluated against ergotamine, 2 mg, plus caffeine, 200 mg (as Cafergot); and against aspirin, 900 mg, plus metoclopramide, 10 mg. Headache relief was superior in sumatriptan-treated patients; 66% obtaining relief at 2 h, compared with 48% on Cafergot (P < 0.001). The percentage of patients obtaining complete relief of headache (Grade 0, no pain) was significantly higher with sumatriptan (40%) than with Cafergot (14%) at 2 h. Associated symptoms such as nausea, vomiting and photophobia are effectively relieved by sumatriptan, whereas Cafergot provoked nausea and vomiting in a proportion of patients. Headache relief with sumatriptan was also superior to that seen with aspirin plus metoclopramide. Sumatriptan was as effective in the relief of accompanying nausea and vomiting as aspirin plus metoclopramide. The efficacy of sumatriptan is maintained after repeated long-term use; over a six-month period efficacy was comparable in the first and last attacks, regardless of how many attacks were treated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Depression and anxiety among Afro-Caribbean general practice attenders in Britain.

Schizophrenia is diagnosed more frequently among Afro-Caribbeans in Britain than among white British controls. Studies among the general population indicate that non-psychotic disorders such as anxiety, depression and functional somatic symptoms are the commonest expression of psychiatric morbidity. Yet, among Afro-Caribbean primary care attenders, rates of anxiety and depression appear lower than in the general population. This finding is at odds with the reportedly higher rates of schizophrenia among this group. The majority of authors favour socio-cultural explanations to account for the higher rates of schizophrenia. Yet many of the factors that are evoked to account for the greater incidence of schizophrenia would be expected to lead to higher rates of non-psychotic disorders in primary care settings. Possible explanations for these apparently contradictory findings are discussed.

Anxiety Disorders↗
PubMed1992

Psychotropic medication and ethnicity: an inpatient survey.

A survey of the catchment area psychiatric inpatient population of the Bethlem and Maudsley Hospitals showed that more black (Afro Caribbean) than non-black (white British) patients received anti-psychotic medication. This finding ceased to be significant after adjustment for diagnosis because a larger proportion of black than non black patients received a diagnosis of schizophrenia. However, after adjustment for diagnosis, black patients were significantly more likely to be receiving depot anti-psychotic medication, to be detained under a section and to have been involved in a violent incident during the present admission. There were no significant ethnic differences in total dose equivalents of anti-psychotic medication but doses of the depot form were significantly higher for black patients.

Adolescent↗