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P Kelly

Publications and source records attributed to P Kelly.

At least 37 records · Page 2Linked to original sources
PubMed2001

Calcium-calmodulin signalling pathway up-regulates glutamatergic synaptic function in non-pyramidal, fast spiking rat hippocampal CA1 neurons.

1. The role of Ca(2+)-calmodulin (CaM) signalling cascades in modulating glutamatergic synaptic transmission on CA1 non-pyramidal fast-spiking neurons was investigated using whole-cell recording and perfusion in rat hippocampal slices. 2. Paired stimuli (PS), consisting of postsynaptic depolarization to 0 mV and presynaptic stimulation at 1 Hz for 30 s, enhanced excitatory postsynaptic currents (EPSCs) on non-pyramidal neurons in the stratum pyramidale (SP). The potentiation was reduced by the extracellular application of D-amino-5-phosphonovaleric acid (DAP-5, 40 microM), and blocked by the postsynaptic perfusion of 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA, 10 mM), a CaM-binding peptide (100 microM) or CaMKII (281-301) (an autoinhibitory peptide of CaM-dependent protein kinases, 100 microM). 3. The application of adenophostin, an agonist of inositol trisphosphate receptors (IP(3)Rs) that evokes Ca(2+) release, into SP non-pyramidal neurons via the patch pipette (1 microM) enhanced EPSCs and occluded PS-induced synaptic potentiation. The co-application of BAPTA (10 mM) with adenophostin blocked synaptic potentiation. In addition, Ca(2+)-CaM (40:10 microM) induced synaptic potentiation, which occluded PS-induced potentiation and was attenuated by introducing CaMKII (281-301) (100 microM). EPSCs were sensitive to an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). 4. Application of Ca(2+)-CaM into SP non-pyramidal neurons induced the emergence of AMPAR-mediated EPSCs that were not evoked by low stimulus intensity before perfusion. Ca(2+)-CaM also increased the amplitude and frequency of spontaneous EPSCs. A scavenger of nitric oxide, carboxy-PTIO (30 microM in slice-perfusion solution), did not affect these increases in sEPSCs. 5. The magnitude of PS-, adenophostin- or Ca(2+)-CaM-induced synaptic potentiation in SP non-pyramidal neurons increased during postnatal development. 6. These results indicate that Ca(2+)-CaM signalling pathways in CA1 SP non-pyramidal neurons up-regulate glutamatergic synaptic transmission probably through the conversion of inactive-to-active synapses.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2001

Functional requirements for phenotypic correction of murine beta-thalassemia: implications for human gene therapy.

As initial human gene therapy trials for beta-thalassemia are contemplated, 2 critical questions important to trial design and planning have emerged. First, what proportion of genetically corrected hematopoietic stem cells (HSCs) will be needed to achieve a therapeutic benefit? Second, what level of expression of a transferred globin gene will be required to improve beta-thalassemic erythropoiesis? These questions were directly addressed by means of a murine model of severe beta-thalassemia. Generation of beta-thalassemic mice chimeric for a minority proportion of genetically normal HSCs demonstrated that normal HSC chimerism levels as low as 10% to 20% resulted in significant increases in hemoglobin (Hb) level and diminished extramedullary erythropoiesis. A large majority of the peripheral red cells in these mice were derived from the small minority of normal HSCs. In a separate set of independent experiments, beta-thalassemic mice were bred with transgenic mice that expressed different levels of human globins. Human gamma-globin messenger RNA (mRNA) expression at 7% of the level of total endogenous alpha-globin mRNA in thalassemic erythroid cells resulted in improved red cell morphology, a greater than 2-g/dL increase in Hb, and diminished reticulocytosis and extramedullary erythropoiesis. Furthermore, gamma-globin mRNA expression at 13% resulted in a 3-g/dL increase in Hb and nearly complete correction of red cell morphology and other indices of inefficient erythropoiesis. These data indicate that a significant therapeutic benefit could be achieved with expression of a transferred globin gene at about 15% of the level of total alpha-globin mRNA in patients with severe beta-thalassemia in whom 20% of erythroid precursors express the vector genome.

Animals↗
PubMed2001

Lack of evidence for small intestinal mucosal T-cell activation as a pathogenic mechanism in African HIV-associated enteropathy.

The role of mucosal T-cell activation in HIV-associated enteropathy is uncertain. Twenty Zambian patients with AIDS and chronic diarrhea were studied, as were nine controls. Distal duodenal biopsies were taken at endoscopy. Morphometric analysis and dual color immunofluorescence staining were performed. Villous height was reduced [177 (118-228) vs 305 (244-358) microm P = 0.002] and crypt depth increased [220 (164-202) vs 194 (164-202) microm P = 0.008] in AIDS patients compared to controls. CD3+CD4+ T cells were reduced in AIDS patients compared to controls [12.9 (5.7-25.2) vs 47.6 (33.4-65.5)% P = 0.04]. There was no significant difference in expression of CD8, CD25, CD69, HML-1, or HLA-DR on T cells between the AIDS patients and controls, with the exception of CD3+HML-1+ cells, which were increased in AIDS patients (P = 0.05). Small intestinal T-cell activation was similar between AIDS patients and controls. We conclude, therefore, that this mechanism is not likely to be important in the pathogenesis of HIV-associated enteropathy.

Adult↗
PubMed2001

Self-rated psychosocial consequences and quality of life in the acute porphyrias.

A battery of self-report psychosocial measures was mailed to 116 patients who had been referred for clinical management (clinic attenders) or laboratory diagnosis (non-clinic attenders) to the London Supraregional Assay Service Centre for Porphyria over the past decade and who tested positive for porphyria. Usable replies were received from 81 (70%) patients. Our interest focused on the prevalence of psychosocial symptoms in acute porphyrias and the perceived effects of porphyria on quality of life and patient experience. Research questions examined included (i), lifestyle factors; (ii) life events; (iii) mental health; (iv) general health; and (v) perceptions of illness of patients receiving specialist clinical management compared to respondents referred for diagnostic investigations, between patients with latent or manifest symptomology and between patients with different types of porphyria. Patients with porphyria have an impaired quality of life, particularly manifest cases, compared to controls and to diabetic patients. Depression, and particularly anxiety, is more common than in the general population or general medical outpatient attenders. Quality oflife is lower in acute intermittent porphyria (AIP) than in other forms of porphyria and a significant number of patients had major life event consequences, e.g. failure to secure, or loss of, employment, limitation of family size. Patients attending a clinic providing specialist porphyria advice, management and counselling received some perceived lifestyle benefits.

Acute Disease↗
PubMed2001

Impaired bioavailability of vitamin A in adults and children with persistent diarrhoea in Zambia.

BACKGROUND: We have previously demonstrated a strong relationship between low serum retinol concentration and mortality in Zambian AIDS patients with diarrhoea, but were unable to detect any benefit from oral micronutrient supplementation. AIM: To test the hypothesis that this is related to impaired availability of vitamin A, we analysed serum retinol concentration changes over 6 h following oral mega-dose therapy (60, 120 or 180 mg retinol). METHODS: Twenty-four men without diarrhoea, 15 adults with persistent diarrhoea and 11 children (six girls, five boys) with persistent diarrhoea were studied. RESULTS: Men with persistent diarrhoea had lower baseline serum retinol concentrations (median 0.39 micromol/L, interquartile range 0.21-0.56) than controls (median 1.16 micromol/L, interquartile range 0.84-1.47; P=0.0003). After 60 mg retinol, the rise in serum retinol in HIV seropositive controls (median 0.63 micromol/L, interquartile range 0.35-0.77) did not differ significantly from that observed in HIV seronegative controls (median 0.35 micromol/L, interquartile range - 0.04-0.56; P=0.20). Increasing the dose to 120 mg or 180 mg retinol did not enhance the increase in serum retinol concentration. The increase in serum retinol was less in adults with persistent diarrhoea (median 0.25 micromol/L, interquartile range 0.04-0.35) and in children (median 0.11 micromol/L, interquartile range 0.04-0.46) than in men without diarrhoea (median 0.44 micromol/L, interquartile range 0.26-0.74; P=0.03). Adults and children with diarrhoea had greater losses of retinol in urine over a 24-h period than controls, but less than 1% of the ingested dose was excreted. CONCLUSIONS: These results suggest that persistent diarrhoea in this population is associated with reduced bioavailability of retinol. Further work is required to determine the metabolic fate of therapeutic doses of retinol and to determine appropriate replacement strategies for HIV infected individuals.

Administration, Oral↗
PubMed2001

A pilot study of treatment of herpes labialis with 1072 nm narrow waveband light.

A randomized prospective double-blind study was performed to compare the efficacy of a single 5 min 1072 nm narrow waveband light application against topical aciclovir applied five times daily in the treatment of herpes labialis. Treatment was initiated within 36 h of the onset of symptoms and the end point was defined as the day that the crust was discarded leaving an uninterrupted underlying skin at the site of the cold sore. The results demonstrated that a single 5 min light treatment significantly reduced cold sore healing time by 4 days; 1072 nm light healed cold sores in 4.3 +/- 1.8 days (mean +/- SD) as compared with aciclovir applied five times daily, 8.5 +/- 3.0 days (P < 0.0001).

Acyclovir↗
PubMed2001

Factors associated with tolerance to, and discomfort with, unsedated diagnostic gastroscopy.

BACKGROUND: Identification of patients likely to experience high levels of discomfort during unsedated gastroscopy would be useful as these patients could be prospectively targeted for sedation. We prospectively assessed patient and endoscopic variables in subjects attending for endoscopy in order to identify factors associated with patients' experience of the unsedated examination. METHODS: We studied 508 patients attending for routine diagnostic gastroscopy. Clinical and endoscopic data were collected and patients completed a two-part questionnaire assessing their anxiety with, and experience of, the procedure. RESULTS: Thirty-nine subjects failed to complete the initial unsedated endoscopy. Failure to tolerate endoscopy was associated with younger age (P = 0.002) and examination with a standard-bore (> or = 9.0 mm) endoscope (P = 0.004). High levels of patient discomfort during the procedure were associated with younger age (P < 0.001), high levels of pre-endoscopic anxiety (P < 0.001), high levels of pre-endoscopic discomfort due to throat spray (P = 0.02) and examination with a standard-bore endoscope (P < 0.001). Preference for sedation during future examinations was related to female gender (P = 0.02), young age (P = 0.02), high levels of apprehension (P < 0.001), the examining doctor (P = 0.002) and use of a standard-bore endoscope (P < 0.001). CONCLUSIONS: Discrete clinical characteristics and endoscopic variables are associated with patients' experience of unsedated endoscopy. Further work might result in an algorithm for identifying patients who would benefit from sedation prior to gastroscopy.

Age Factors↗
PubMed2001

Effects of follicle-stimulating hormone with and without luteinizing hormone on serum hormone concentrations, follicle growth, and intrafollicular estradiol and aromatase activity in gonadotropin-releasing hormone-immunized heifers.

To evaluate the roles of FSH and LH in follicular growth, GnRH-immunized anestrous heifers (n = 17) were randomly assigned (Day 0) to one of three groups (n = 5 or 6). Group 1 received i.m. injections of 1.5 mg porcine FSH (pFSH) 4 times/day for 2 days; group 2 received i.v. injections of 150 microg pLH 6 times/day for 6 days; group 3 received both pFSH and pLH as described for groups 1 and 2. After slaughter on Day 6, measurements were made of follicle number and size, and follicular fluid concentrations of progesterone (P(4)), estradiol (E(2)), and aromatase activity. Injection of pFSH increased (P: < 0.01) the serum concentrations of FSH between 12 and 54 h. Infusion of pLH increased (P: < 0.05) mean and basal concentrations of LH and LH pulse frequency. Serum E(2) concentrations were higher (P: < 0.05) for heifers given pFSH + pLH than those given either pFSH or pLH alone. There was no difference (P: > or = 0.24) between treatments in the number of small follicles (<5 mm). Heifers given pFSH or pFSH + pLH had more (P: < or = 0.02) medium follicles (5.0-9.5 mm) than those that were given pLH alone (none present). Heifers given pFSH + pLH had more (P: = 0.04) large follicles (> or =10 mm) than those given either pLH or pFSH alone (none present). Overall, only 1 of 35 small follicles and 2 of 96 medium follicles were E(2)-active (i.e., E(2):P(4) >1.0), whereas 18 of 21 large follicles (all in the pFSH + pLH treatment) were E(2)-active; of these, 8 of 18 had aromatase activity. Concentrations of E(2) and E(2) activity in follicular fluid were correlated (r > or = 0.57; P: < 0.0001) with aromatase activity in heifers given pLH + pFSH. In conclusion, pLH failed to stimulate follicle growth greater than 5 mm; pFSH stimulated growth of medium follicles that were E(2)-inactive at slaughter and failed to increase serum E(2) concentrations; whereas pFSH + pLH stimulated growth of medium follicles and E(2)-active large follicles, and a 10- to 14-fold increase in serum E(2) concentrations.

Animals↗
PubMed2001

What did we learn about interdisciplinary collaboration in institutions?

The Interdisciplinary Generalist Curriculum (IGC) Project significantly advanced collaboration in the development of medical school curricula. As primary care faculty began to work together they encountered and overcame many challenges inherent in this new process. Inclusion of other faculty and departments, as well as dedicated support from the deans' offices, became necessary to the success of the projects. The continuation of successful collaborative projects in the medical school environment requires a common commitment of faculty, students, department chairs, and the dean's office; protected time; and involvement of faculty from other disciplines. This article outlines initial models of collaboration implemented in the IGC Project, followed by a description of the expected and unexpected outcomes of these collaborative efforts, and a discussion of the emergence of new ways of collaborating, with recommendations for successful collaborative efforts.

Communication↗
PubMed2001

What did we learn about the impact on university-based faculty?

Meeting the objectives and requirements of the Interdisciplinary Generalist Curriculum (IGC) Project had positive and negative effects on the university-based basic science and clinical faculty, which have been divided into four categories: boundary issues, collaboration, teaching, and development. The specific experiences of two schools, the University of California, San Francisco, School of Medicine and the Joan C. Edwards School of Medicine at Marshall University, are compared against the experiences of the ten schools as documented in the IGC Project external evaluation team's final report. Boundary issues regarded as negative effects of the IGC Project included perceived encroachment on the time devoted to basic science education, loss of the unique identity of the university-based faculty as academicians, and reduced prominence of subspecialist clinical faculty. Effects of the IGC Project in the other areas were, for the most part, positive. The increased collaboration yielded a net benefit to the university-based faculty at large. The clinical faculty experienced more opportunities to teach. Introduction of teacher development programs were of benefit to both clinical and basic science faculty. The other arm of development, professional development, was evidenced by increased stature and promotions of IGC faculty directors. In conclusion, changes within the university-based faculty occurred in stages as faculty realized that the design of the IGC Project enhanced the educational experience of the students.

Cooperative Behavior↗
PubMed2001

The Interdisciplinary Generalist Curriculum Project at Joan C. Edwards School of Medicine at Marshall University.

The Interdisciplinary Generalist Curriculum (IGC) Project was designed to enhance interest in and support of generalism during the first two years of medical education. The original goals at Joan C. Edwards School of Medicine at Marshall University included the design and implementation of a core curriculum, Introduction to Patient Care (IPC), and enhancement of teaching excellence through faculty development. The core curriculum facilitated integration with the basic sciences and early introduction of physical examination skills, which were further developed in longitudinal clinical experiences with mentors. Although it was not originally intended to include basic scientists in the preceptor groups, they became important additions and created additional opportunities for interdisciplinary teaching and reciprocal learning. The mentor program, another well-received and intended curriculum change, evolved from a structured experience to a more flexible component of the curriculum. The program met the requirements of the IGC Project but 53% of the originally intended mentor time was achievable, due to curriculum constraints. Faculty development, another success, was originally intended to target IPC faculty but ultimately became a university-wide effort. The changes implemented as a result of the IGC Project continue to flourish beyond the funding period and have become integral aspects of the curriculum and the medical school.

Curriculum↗
PubMed2001

Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition.

BACKGROUND: Persistent diarrhea-malnutrition syndrome is a complex of infection and immune failure that involves protein, calorie and micronutrient depletion, and metabolic disturbances. We report an analysis of the impact of HIV infection on infectious disease, clinical presentation, and mortality in Zambian children with persistent diarrhea and malnutrition. METHODS: Two hundred children (94 boys and 106 girls, 6-24 months old) were examined on admission to the malnutrition ward of University Teaching Hospital in Lusaka, Zambia. There was then 1 month of follow-up. RESULTS: Antibodies to HIV were found in 108 of the children (54%). The common intestinal infections (Cryptosporidium parvum [26%] and nontyphoid Salmonella spp [18%]), septicemia (17%), and pulmonary tuberculosis confirmed by gastric lavage (13.5%) were not significantly more common in HIV-seropositive than in HIV-seronegative children. HIV-seropositive children were more likely to have marasmus whereas HIV-seronegative children were more likely to have kwashiorkor. Weight-for-age z scores at nadir (postedema) were lower in HIV-seropositive children (median, -4.4; interquartile range [IQR], -5.0 to -3.8) than in HIV-seronegative children (median, -3.7; IQR, -4.2 to -3.1; P < 0.0001). Height-for-age and weight-for-height z scores and mid-upper arm circumference showed a similar difference. Of the 200 children, 39 (19.5%) died within 28 days; cryptosporidiosis and marasmus were the only independent predictors of death. CONCLUSIONS: Although intestinal and systemic infections did not differ for HIV-seropositive and HIV-seronegative children, HIV influenced nutritional states of all children. Cryptosporidiosis and marasmus were associated with higher mortality.

AIDS-Related Opportunistic Infections↗
PubMed2001

The clinical features of functional dysphonia.

OBJECTIVE: This report aims to study the prevalence of features of laryngeal muscle tension in a population of patients with functional dysphonia (FD) and nondysphonic control subjects. STUDY DESIGN: Prospective control-blinded, cross-sectional study. METHODS: We reported on a prospective control-blinded, cross-sectional study of the prevalence of the six features described by Van Lawrence and the six features incorporated in the Morrison-Rammage classification. A senior laryngologist and senior speech pathologist independently rated sound-free, random-sequence video laryngoscopies of 51 patients with FD and 52 nondysphonic control subjects. Assessments were made of the presence or absence of the 12 laryngoscopic features of laryngeal dysfunction, and an overall rating made of the vocal technique as "normal" or "abnormal." RESULTS: More than 60% of the control population demonstrated 1 or more of the 12 features of hyperfunction. There was no significant difference in the prevalence of the six Van Lawrence features, the six Morrison-Rammage features, or the total number of abnormal features between patients with FD and control subjects. On overall assessment, both assessors noted a high prevalence (50% and 36%, respectively) of abnormal vocal technique in the control population. There was no statistical difference in the total number of abnormal features observed between patients with FD and control subjects. Positive predictive value calculations showed that the presence of a clinical feature, at best, presented a 75% chance of correctly identifying a patient with FD and, at worst, a 50% chance. CONCLUSION: The laryngoscopy features commonly associated with FD are frequently prevalent in the nondysphonic population and fail to distinguish patients with FD from normal subjects.

Adolescent↗
PubMed2001

Tropical enteropathy: a T-cell-mediated crypt hyperplastic enteropathy.

OBJECTIVE: Tropical enteropathy is widespread throughout the tropics, but its pathogenesis is unknown. T-cell activation has been demonstrated to result in enteropathy in vitro and in animal models, and occurs in untreated patients with coeliac disease. We have therefore examined the hypothesis that T-cell activation is important in the pathogenesis of tropical enteropathy. PATIENTS AND METHODS: Healthy black Zambian subjects were compared with black and white South Africans. Quantitative microscopy was conducted on distal duodenal biopsies. Mucosal T-cell activation was quantitated by dual colour immunofluorescence staining for CD3 plus CD69 or HLA-DR. Crypt proliferation was measured by direct counting of Feulgen-stained mitotic figures, and systemic immune activation by assay of serum tumour necrosis factor alpha (TNF-alpha). RESULTS: Villous height was reduced (P = 0.0004), crypt depth increased (P < 0.0001), and mitoses per crypt increased (P = 0.014) in black Zambians compared with black and white South Africans. Mucosal thickness was similar. Intraepithelial lymphocyte count was increased in the black groups compared with whites (P = 0.03). CD3+CD69+ (P = 0.0007) and CD3+HLA-DR+ (P < 0.0001) expression was increased in black Zambians compared with black and white South Africans. Serum TNF-alpha was similar in all groups. CONCLUSIONS: Tropical enteropathy is associated with mucosal T-cell activation and crypt hyperplasia. Tropical enteropathy occurs in the absence of malnutrition, diarrhoea or systemic illness.

Adult↗
PubMed2001

GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis.

GT160-246, a high-molecular-weight soluble anionic polymer, was tested in vitro and in vivo for neutralization of Clostridium difficile toxin A and B activities. Five milligrams of GT160-246 per ml neutralized toxin-mediated inhibition of protein synthesis in Vero cells induced by 5 ng of toxin A per ml or 1.25 ng of toxin B per ml. In ligated rat ileal loops, 1 mg of GT160-246 neutralized fluid accumulation caused by 5 microg of toxin A. At doses as high as 80 mg/loop, cholestyramine provided incomplete neutralization of fluid accumulation caused by 5 microg of toxin A. GT160-246 protected 80% of the hamsters from mortality caused by infection with C. difficile, whereas cholestyramine protected only 10% of animals. Treatment of C. difficile-infected hamsters with metronidazole initially protected 100% of the hamsters from mortality, but upon removal of treatment, 80% of the hamsters had relapses and died. In contrast, removal of GT160-246 treatment did not result in disease relapse in the hamsters. GT160-246 showed no antimicrobial activity in tests with a panel of 16 aerobic bacteria and yeast and 22 anaerobic bacteria and did not interfere with the in vitro activities of most antibiotics. GT160-246 offers a novel, nonantimicrobial treatment of C. difficile disease in humans.

Animals↗
PubMed2001

Helicobacter pylori infection in an urban African population.

We have studied 221 adults drawn from an impoverished urban population with high human immunodeficiency virus (HIV) seroprevalence (35%) to determine the prevalence of gastroduodenal pathology and its relationship to serological markers of Helicobacter pylori virulence proteins and other potential environmental and immunological determinants of disease including HIV infection. Eighty-one percent were H. pylori seropositive, and 35% were HIV seropositive. Urban upbringing and low CD4 count were associated with a reduced likelihood of H. pylori seropositivity, as was current Ascaris infection, in keeping with recent evidence from an animal model. One hundred ninety-one adults underwent gastroduodenoscopy, and 14 had gastroduodenal pathology. Mucosal lesions were a major cause of abdominal pain in this population. While the majority of patients with gastroduodenal pathology (12 of 14) were seropositive for H. pylori, none were seropositive for HIV. Smoking was associated with increased risk of macroscopic pathology, and a history of Mycobacterium bovis BCG immunization was associated with reduced risk. Antibodies to H. pylori lipopolysaccharide were associated with pathology. HIV infection was associated with protection against mucosal lesions, suggesting that fully functional CD4 lymphocytes may be required for the genesis of gastroduodenal pathology.

Adolescent↗
PubMed2001

Body weight and fat deposition in prolactin receptor-deficient mice.

To explore the roles of the lactogens in adipose tissue development and function, we measured body weight, abdominal fat content, and plasma leptin concentrations in a unique model of lactogen resistance: the PRL receptor (PRLR)-deficient mouse. The absence of PRLRs in knockout mice was accompanied by a small (5-12%), but progressive, reduction in body weight after 16 weeks of age. Females were affected to a greater degree than males. The reduction in weight in female PRLR-deficient mice (age 8-9 months) was associated with a 49% reduction in total abdominal fat mass and a 29% reduction in fat mass expressed as a percentage of body weight. Lesser reductions were noted in male mice. Plasma leptin concentrations were reduced in females but not in males. That the reductions in abdominal fat may reflect in part the absence of lactogen action in the adipocyte is suggested by the demonstration of PRLR messenger RNA in normal mouse white adipose tissue. Nevertheless, steady state levels of PRLR messenger RNA in mature adipocytes are very low, suggesting that the effects of lactogens might be mediated by other hormones or cellular growth factors. Our observations suggest roles for the lactogens in adipose tissue growth and metabolism in pregnancy and postnatal life.

Abdomen↗