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Biomedical subjects

J Kelly

Publications and source records attributed to J Kelly.

At least 181 records · Page 10Linked to original sources
PubMed1999

Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer.

BACKGROUND: Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. AIM: To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. SPECIMENS: Thirty paraffin wax embedded human gastric adenocarcinomas. METHODS: FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. CONCLUSIONS: Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.

Adenocarcinoma↗
PubMed1999

An outpatient psychiatry program for offenders with mental disorders found not guilty by reason of insanity.

OBJECTIVE: Rehospitalization and criminal recidivism were examined among a group of offenders with mental disorders adjudicated as not guilty by reason of insanity and mandated to receive treatment in a forensic psychiatric outpatient program as a condition of release. METHODS: A retrospective chart review was conducted for 43 offenders with mental disorders who were acquitted as being not guilty by reason of insanity for the index offense and were active in the outpatient treatment program in 1996. Data were abstracted on sociodemographic, psychiatric, and criminal characteristics predating the index offense; rehospitalizations and new crimes and rearrests after the offense; and clinical and psychosocial functional outcomes after enrollment in the outpatient program. RESULTS: For the 43 patients, the mean length of stay in the program was 68 months, with a range of 4.9 months to 18.4 years. Almost two-thirds of the patients were diagnosed as having schizophrenia, schizoaffective disorder, or a nonaffective psychotic disorder; 58 percent had a comorbid substance use disorder, and 63 percent had an axis II diagnosis. Since program enrollment, 20 patients (47 percent) were rehospitalized at least once, and eight (19 percent) were rearrested or had committed a new crime. At the end of 1996, only nine (24 percent) were in full remission, and 26 (68 percent) showed at least one indicator of difficulty reintegrating into the community. CONCLUSIONS: Even after treatment in a specialized forensic program, this sample of offenders with serious mental disorders remained impaired symptomatically and functionally. Although avoidance of rehospitalization is considered a successful outcome, rehospitalization is preferable to rearrest for this forensic population.

Adult↗
PubMed1999

Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia.

Leptin acts on specific populations of hypothalamic neurons to regulate feeding behavior, energy expenditure, and neuroendocrine function. It is not known, however, whether the same neural circuits mediate leptin action across its full biologic dose-response curve, which extends over a broad range, from low levels seen during starvation to high levels characteristic of obesity. Here, we show that the characteristic fall in leptin with fasting causes a rise in neuropeptide Y (NPY) messenger RNA (mRNA), as well as a fall in POMC and cocaine and amphetamine-regulated transcript (CART) mRNAs. Sc infusion of leptin sufficient to maintain plasma levels within the physiologic range during the fast prevents changes in the expression of these peptides, as well as changes in neuroendocrine function, demonstrating that multiple neural circuits are highly sensitive to small changes in leptin within its low physiologic range. In contrast, a modest elevation of plasma leptin above the normal fed range by constant sc infusion, which produced marked reduction in food intake and body weight, decreased NPY mRNA in the arcuate hypothalamic nucleus but did not affect the levels of mRNAs encoding the anorexigenic peptides alpha-MSH, CART or CRH. These results suggest that the dose response characteristics of leptin on hypothalamic target neurons at the level of mRNA expression are variable, with some neurons (e.g. NPY) responding across a broad dose range and others (e.g. POMC and CART) showing a limited response within the low range. These results further suggest that the central targets of leptin that mediate the transition from starvation to the fed state may be distinct from those that mediate the response to overfeeding and obesity.

Animals↗
PubMed1999

Activation of SOCS-3 messenger ribonucleic acid in the hypothalamus by ciliary neurotrophic factor.

Ciliary neurotrophic factor (CNTF) is a neurocytokine expressed in glial cells that acts on brain cells to promote gene expression, survival, and differentiation. When administered systemically, CNTF reduces food intake and body weight in rodents. Genes encoding suppressors of cytokine signaling (SOCS) are induced by cytokines that activate membrane receptors in the same class as those that are activated by CNTF. We therefore examined the ability of CNTF to induce expression of socs genes in brain and peripheral tissues of rats and mice. Peripheral CNTF administration to ob/ob mice rapidly induced SOCS-3 messenger RNA (mRNA) in hypothalamus, as determined by Northern blotting and quantitative RT-PCR, but had no effect on cytokine-inducible sequence (CIS), SOCS-1, or SOCS-2 mRNA. In situ hybridization histochemistry of hypothalamus from ob/ob mice and normal rats demonstrated that CNTF induced SOCS-3 mRNA in the arcuate nucleus (Arc). Strong hybridization signals were also detected in the ependymal lining of the ventricles and the subfornical organ. This hybridization pattern was distinct from that resulting from peripheral leptin treatment with overlapping hybridization patterns only in the Arc. CNTF also induced expression of CIS, SOCS-1, SOCS-2, and SOCS-3 mRNA in the liver, and SOCS-2 and SOCS-3 mRNA in the kidney. CNTF induced SOCS-3 mRNA and SOCS-3 protein levels in an astrocyte cell line. Transient expression of SOCS-3, but not CIS or SOCS-2, inhibited CNTF-induced signal transduction in astrocytes. In conclusion, SOCS-3 mRNA is specifically induced by CNTF in regions of the hypothalamus that are both overlapping and distinct from that induced by leptin. Similar to leptin, the Arc is likely to be a direct target of CNTF, and this region may play a role in the body weight-reducing effects of CNTF. SOCS-3 is a negative regulator of CNTF signal transduction, and inhibitors of SOCS-3 function may enhance endogenous CNTF signaling after neuronal injury or enhance the body weight-reducing effect of CNTF after peripheral administration.

Animals↗
PubMed1999

Development of a lacticin 3147-enriched whey powder with inhibitory activity against foodborne pathogens.

The broad-spectrum bacteriocin lacticin 3147, produced by Lactococcus lactis DPC3147, is inhibitory to a wide range of gram-positive food spoilage and pathogenic organisms. A 10% solution of demineralized whey powder was fermented with DPC3147 at a constant pH of 6.5. The fermentate was spray dried, and the resulting powder exhibited inhibitory activity. The ability of the lacticin 3147-enriched powder to inhibit Listeria monocytogenes Scott A and Staphylococcus aureus 10 was assessed in buffer at both acidic (pH 5) and neutral (pH 7) pH. In addition, the ability of the powder to inhibit L. monocytogenes Scott A in an infant milk formulation was assessed. Resuspension of approximately 10(8) midexponential phase L. monocytogenes Scott A cells in a 10% solution of the lacticin 3147-enriched powder resulted in a 1,000-fold reduction in viable cells at pH 5 and pH 7 after 3 h at 30 degrees C. In the case of S. aureus 10, resuspension of 2.5 x 10(7) midexponential phase cells in a 15% solution of the lacticin 3147-enriched powder at pH 5 resulted in only a 10-fold reduction in viable cell counts, compared with a 1,000-fold reduction at pH 7, following incubation for 3 h at 30 degrees C. The use of the lacticin 3147 powder in an infant milk formulation resulted in greater than a 99% kill of L. monocytogenes within 3 h at 30 degrees C. These results suggest that this bioactive lacticin 3147 food ingredient may find applications in many different foods, including those with pH close to neutrality.

Animals↗
PubMed1999

Staphylococcus aureus endocarditis presenting as meningitis and mimicking meningococcal sepsis.

A case of Staphylococcus aureus meningitis (SAM) secondary to endocarditis is presented. The presence of a petechial rash affecting the lower limbs led to an initial presumptive diagnosis of meningococcal meningitis. There were no stigmata of endocarditis at presentation, though these subsequently developed. Underlying endocarditis should be diligently sought in any patient presenting with spontaneous SAM, even if typical stigmata are initially absent. In view of the association with skin lesions and neurological complications, S. aureus endocarditis may mimic the classical presentation of meningococcal sepsis.

Bacteremia↗
PubMed1999

Community case management for mental illness.

These case vignettes clearly illustrate the complexity which is modern psychiatric case management. In the case of Mr D, one of the salient facets of case management was medication monitoring in the context of the introduction of a new depot injection. This was a function in which nursing knowledge of medications and their side effects was undoubtedly advantageous. Any adverse experience with medication is likely to have negative ramifications regarding future compliance. Therefore, a nurse case manager is ideally suited to provide the appropriate information on psychotropic medications and to confidently answer most questions about these medications, and promptly identify any possible emerging side effects. In the case of Mr X, the management began with a practical and crisis focus involving suicide prevention. This developed into supportive psychotherapy, which required sensitive but proactive intervention and, ultimately, significant counselling skills. Mr L's case management had a different focus again, characterised by the development of a new and comprehensive case formulation and a creative nurturing of an individual's identified strength in music. The vignettes not only serve to highlight the well-established heterogeneity of mental illness, but they also importantly illuminate the heterogeneity of case management, a reality obscured in the descriptions of case management models which perhaps misleadingly have given the impression of the process as being merely a number of clearly defined tasks or functions. In actual fact, though the coordination of care appears to represent a common feature, the case management relationship remains an ever changing one, with adaptability, refined clinical skills and practical problem solving skills being the essential requisites of an effective case manager. Therefore, attempts to present this important activity in terms of any one model seem to miss the point. For the consumers of psychiatric services, the experience of case management is unique, and for case managers too the experience with each 'case managed' individual is unique. This uniqueness, together with the diverse skills involved in case management needs to be acknowledged. One way of acknowledging this is, as demonstrated, in the presentation of case vignettes and comprehensive case studies. As psychiatric nursing moves toward the new millennium, case management offers psychiatric nurses (as the clinician most often cast in the role of case manager), the exciting opportunity to extend their role and responsibilities. More importantly, it offers mental health care workers the opportunity to be more actively involved in the liberation of psychiatric patients from a situation of custodial care to a new life in the community.

Case Management↗
PubMed1998

Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area.

Recent studies have identified several neuropeptide systems in the hypothalamus that are critical in the regulation of body weight. The lateral hypothalamic area (LHA) has long been considered essential in regulating food intake and body weight. Two neuropeptides, melanin-concentrating hormone (MCH) and the orexins (ORX), are localized in the LHA and provide diffuse innervation of the neuraxis, including monosynaptic projections to the cerebral cortex and autonomic preganglionic neurons. Therefore, MCH and ORX neurons may regulate both cognitive and autonomic aspects of food intake and body weight regulation. The arcuate nucleus also is critical in the regulation of body weight, because it contains neurons that express leptin receptors, neuropeptide Y (NPY), alpha-melanin-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP). In this study, we examined the relationships of these peptidergic systems by using dual-label immunohistochemistry or in situ hybridization in rat, mouse, and human brains. In the normal rat, mouse, and human brain, ORX and MCH neurons make up segregated populations. In addition, we found that AgRP- and NPY-immunoreactive neurons are present in the medial division of the human arcuate nucleus, whereas alpha-MSH-immunoreactive neurons are found in the lateral arcuate nucleus. In humans, AgRP projections were widespread in the hypothalamus, but they were especially dense in the paraventricular nucleus and the perifornical area. Moreover, in both rat and human, MCH and ORX neurons receive innervation from NPY-, AgRP-, and alpha-MSH-immunoreactive fibers. Projections from populations of leptin-responsive neurons in the mediobasal hypothalamus to MCH and ORX cells in the LHA may link peripheral metabolic cues with the cortical mantle and may play a critical role in the regulation of feeding behavior and body weight.

Agouti-Related Protein↗
PubMed1998

Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain.

A number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.

Enzyme Inhibitors↗
PubMed1998

Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

Animals↗
PubMed1998

(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent.

We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.

Alkyl and Aryl Transferases↗