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Biomedical subjects

J Kelly

Publications and source records attributed to J Kelly.

At least 37 records · Page 2Linked to original sources

Syntheses of 1,2-diamino and 1,2-aminoalcohol derivatives in the piperidine and pyrrolidine series as anti-amnesic agents.

Tacrine, one of the drugs available for Alzheimer's disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine has been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research is a continuation of our efforts in the area of 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) (cf. ref9). A serendipitous discovery led us to the biologically active open chain analogue 9, and we proceeded to elaborate on this molecule. Overall, the compounds we prepared were poor inhibitors of acetylcholinesterase as compared to tacrine. The single exception was compound 20 which exhibited an effect comparable to that of tacrine, but only at a dose in the order of 10(-3) M. However, despite the poor acetylcholinesterase inhibition by 9, this compound was found to be an effective antiamnesic agent.

Alcohols

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.

Alkyl and Aryl Transferases

Plastic bullet injuries in Northern Ireland: experiences during a week of civil disturbance.

BACKGROUND: Plastic bullets were introduced to Northern Ireland for riot-control purposes in 1973. Their use has been controversial, with a number of fatalities. In the week beginning July 7, 1996, some 8,000 plastic bullets were fired during widespread rioting. METHODS: Details of injuries attributed to plastic bullets were obtained retrospectively from patient notes for the period July 8 to 14, 1996, in six hospitals. A total of 172 injuries in 155 patients were recorded. RESULTS: Nineteen percent of injuries were to the face/head/neck, 20% were to the chest or abdomen, and 61% were to the limbs. Abbreviated Injury Scale scores ranged from I to 3. Forty-two patients were admitted for hospitalization, three to intensive care units. No fatalities occurred. CONCLUSION: Plastic bullet impact to the abdomen or above may cause life-threatening injuries. Below this site, major trauma is unlikely.

Abbreviated Injury Scale

Targeting improves the efficacy of a DNA vaccine against Corynebacterium pseudotuberculosis in sheep.

A large-scale DNA vaccination trial was performed with sheep to investigate whether an antigen targeted by CTLA-4 enhanced and accelerated the humoral immune response. Vaccination with genetically detoxified phospholipase D (DeltaPLD) has been shown to be effective, at least partially, against Corynebacterium pseudotuberculosis, the causal agent of caseous lymphadenitis in sheep. CTLA-4 binds to B7 on antigen-presenting cells and thus was used to direct the fusion antigens to sites of immune induction. Here we demonstrated that targeting DeltaPLD as a CTLA-4 fusion protein significantly enhanced the speed, magnitude, and longevity of the antibody response compared to that obtained with DNA encoding DeltaPLD. While all groups of sheep vaccinated with DNA encoding DeltaPLD were afforded better protection against an experimental challenge with C. pseudotuberculosis than those immunized with an irrelevant plasmid or those left unimmunized, the best protection was provided by the targeted DNA vaccine. We propose that targeting antigens to antigen-presenting cells offers a generic strategy for enhancing the efficacy of DNA vaccines.

Abatacept

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

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

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

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

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

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

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

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