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Biomedical subjects

J R Palmer

Publications and source records attributed to J R Palmer.

At least 19 recordsLinked to original sources
PubMed1997

Pyrrolopyrimidines: novel brain-penetrating antioxidants with neuroprotective activity in brain injury and ischemia models.

A novel group of antioxidant compounds, the pyrrolopyrimidines, has been discovered recently. Many of these possess significantly improved oral bioavailability (56-70% in rats), increased efficacy and potency in protecting cultured neurons against iron-induced lipid peroxidative injury and as much as a 5-fold increase in brain uptake compared with the 21-aminosteroid antioxidant compound, tirilazad mesylate (U-74006F), described earlier. They appear to quench lipid peroxidation reactions by electron-donating and/or radical-trapping mechanisms. Several compounds in the series, such as U-101033E and U-104067F, demonstrate greater ability than tirilazad to protect the hippocampal CA1 region in the gerbil transient (5-min) forebrain ischemia model. Delaying treatment until 4 hr after the ischemic insult still results in significant CA1 neuronal protection. U-101033E is still effective in salvaging a portion of the CA1 neuronal population when the ischemic duration is extended to 10 min. In addition, U-101033E has been found to be protective in the context of focal cerebral ischemia, reducing infarct size in the mouse permanent middle cerebral artery occlusion model, in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage than those which are localized in the cerebral microvasculature. However, the activity of U-101033E in improving early post-traumatic recovery in mice subjected to severe concussive head injury is similar to that of tirilazad. Last, the oral bioavailability of many pyrrolopyrimidines suggests that they may be useful for certain chronic neurodegenerative disorders in which lipid peroxidation plays a role.

Animals↗
PubMed1996

Adult height and risk of breast cancer among white women in a case-control study.

Data from a hospital-based case-control study were analyzed to evaluate the relation of adult height to the risk of breast cancer among white women. The authors compared 5,358 newly diagnosed breast cancer cases and 4,555 controls interviewed from 1976 to 1992 in hospitals located mainly in the United States. Overall, there was no association between stature and risk of breast cancer. In comparison with women whose heights were less than 62 inches (< 158 cm), the adjusted odds ratios were 1.1 (95% confidence interval (Cl) 0.9-1.2), 1.0 (95% Cl 0.9-1.2), 1.0 (95% Cl 0.9-1.1), and 1.0 (95% Cl 0.8-1.2) for women with heights of 62-63, 64-65, 66-67, and > or = 68 inches (equivalent to 158-160, 163-165, 168-170, and > or =173 cm), respectively. There was no consistent evidence of modification of the effect of height by other risk factors. The results suggest that adult stature in white women is not related to the risk of breast cancer.

Adult↗
PubMed1996

Norepinephrine depletion impairs neuroendocrine responses to fear but not novel environmental stimuli in the rat.

Emotional stimuli suppress vasopressin secretion and potentiate oxytocin and prolactin secretion by the pituitary in the rat. We studied effects of central norepinephrine depletion on these hormonal responses to novel environmental or fear stimuli. Male Wistar rats were injected intracerebroventricularly with 5-amino-2,4-dihydroxy-alpha- methylphenylethylamine, a selective neurotoxin to noradrenergic fibers. The neurotoxin treatment reduced the hypothalamic content of norepinephrine by 71% but did not significantly affect the dopamine content. Novel environmental stimuli suppressed vasopressin secretion and augmented secretion of oxytocin and prolactin in the vehicle-injected rats. The neurotoxin did not block the neuroendocrine responses. Intermittently applied electric footshocks also induced the similar neuroendocrine responses in the vehicle-injected rats. The neurotoxin significantly reduced the neuroendocrine responses. The drug, however, did not significantly alter vasopressin release after continuously applied footshocks. Environmental stimuli previously paired with footshocks (conditioned fear stimuli) suppressed vasopressin secretion and augmented secretion of oxytocin and prolactin in the vehicle-injected animals. Motor activity was suppressed during the conditioned fear stimuli. The neurotoxin impaired the neuroendocrine and behavioral responses whether the drug was injected before or after the conditioning. These data demonstrate the distinction between the neural mechanisms underlying the neuroendocrine responses to fear and to novel stimuli, suggesting that noradrenergic neurons are selectively involved in the hypothalamo-hypophysial responses to fear stimuli.

Animals↗
PubMed1996

Case-control study of oral contraceptive use and risk of breast cancer.

The relation of oral contraceptive use to the risk of breast cancer in white women aged 25-59 years was assessed with data collected during 1977-1992 in a case-control surveillance system in hospitals in Boston, New York, and Philadelphia. A total of 3,540 cases with breast cancer were compared with 4,488 controls with nonmalignant nongynecologic conditions unrelated to oral contraceptive use. Relative risk estimates were obtained by unconditional logistic regression with control for major risk factors. For at least 1 year of use relative to less than 1 year, the multivariate relative risk estimate was 1.7 (95% confidence interval (CI) 1.3-2.3) in women aged 25-34 years, 0.9 (95% CI 0.7-1.0) in women aged 35-44 years, and 1.2 (95% CI 1.0-1.4) in women aged 45-59 years (p < 0.01 for the difference across age). Among women aged 25-34 years, the relative risk estimates were greatest for use of long duration, but the trend was not statistically significant (p = 0.17); in addition, the duration of use was correlated with the recency of use, and it was not possible to distinguish their effects. Among women aged 35-44 years, the relative risk estimate decreased with increasing duration of use (p = 0.01). Among women aged 45-59 years, some relative risk estimates were increased, but there was no consistent pattern. The results add to the evidence of an association between oral contraceptive use and an increased risk of breast cancer at young ages.

Adult↗
PubMed1996

Neuroprotective efficacy of microvascularly-localized versus brain-penetrating antioxidants.

The 21-aminosteroid (lazaroid) tirilazad mesylate has been demonstrated to be a potent inhibitor of lipid peroxidation and to reduce traumatic and ischemic damage in a number of experimental models. Currently, tirilazad is being actively investigated in phase III clinical trials in head and spinal cord injury, ischemic stroke and subarachnoid hemorrhage. This compound acts in large part to protect the microvascular endothelium and consequently to maintain normal blood-brain barrier (BBB) permeability and cerebral blood flow autoregulatory mechanisms. However, due to its limited penetration into brain parenchyma, tirilazad has generally failed to affect delayed neuronal damage to the selectively vulnerable hippocampal CA1 and striatal regions. Recently, we have discovered a new group of antioxidant compounds, the pyrrolopyrimidines, which possess significantly improved ability to penetrate the BBB and gain direct access to neural tissue. Several compounds in the series, such as U-101033E, have demonstrated greater ability to protect the CA1 region in the gerbil transient forebrain ischemia model with a post-ischemic therapeutic window of at least four hours. In addition, U-101033E has been found to reduce infarct size in the mouse permanent middle cerebral artery occlusion model in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage compared to those which are localized in the cerebral microvasculature. On the other hand, microvascularly-localized agents like tirilazad appear to have better ability to limit BBB damage.

Animals↗
PubMed1996

A selective role of brainstem noradrenergic neurons in oxytocin release from the neurohypophysis following noxious stimuli in the rat.

Noxious stimuli facilitate oxytocin release from the neurohypophysis. Oxytocin-secreting hypothalamic magnocellular neurosecretory neurons receive excitatory synaptic inputs from noradrenergic neurons in the medulla oblongata. The medulla oblongata includes the A2 noradrenergic and the A1 noradrenergic cells. Here we investigated whether medullary noradrenergic neurons mediate oxytocin release after noxious stimuli in male rats. 5-Amino-2,4-dihydroxy-alpha-methylphenylethylamine, a neurotoxin selective for noradrenergic fibers, was injected into the lateral cerebral ventricle or the medulla. Seven days after the injection, the hypothalamic content of noradrenaline was decreased. In the rats injected with the neurotoxin, the release of oxytocin but not vasopressin after footshocks was impaired. Surgical ablation by suction of the caudal dorsomedial medulla including the A2 cell region did not significantly affect oxytocin release after footshocks, though the surgery abolished oxytocin release after i.v. injection of cholecystokinin octapeptide. In the rats whose A2 cell region had been ablated, an i.c.v. injected alpha 1 adrenoreceptor antagonist, benoxathian, blocked oxytocin release after footshocks. These results demonstrate that brainstem noradrenergic neurons mediate oxytocin release following noxious stimuli in the rat and suggest that responsible noradrenergic neurons are the A1 cells in the caudal ventrolateral medulla.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1996

Optimal photographic imaging of the bulbar conjunctival vasculature.

A method for imaging the conjunctiva to yield greater contrast between the vasculature and the scleral background, by optimisation of the imaging system, is described. A simple modification to the image capture system, based on first principles calculations, is shown to give images with much improved information content. This will enhance the assessment of hyperaemic changes induced by foreign materials, indicating the degree of biocompatibility, e.g. with contact lenses and ophthalmic medications. Observation of vascular abnormalities associated with pathological conditions may assist in their diagnosis and monitor progressive changes.

Adult↗
PubMed1996

Phylogeny of Methanopyrus kandleri based on methyl coenzyme M reductase operons.

The mcrBDCGA operon that encodes methyl coenzyme M reductase (MR) in the hyperthermophile Methanopyrus kandleri was cloned and sequenced. The results of a phylogenetic analysis of the nine MR sequences now available support the position that M. kandleri is a separate methanogen lineage. As in other methanogens, the M. kandleri mcr operon is located immediately upstream of the mtrE gene, the promoter-proximal gene in an operon that encodes the N5-methyltetrahydromethanopterin:coenzyme M methyltransferase that catalyzes the step preceding the MR-catalyzed reaction in methanogenesis. In contrast to other methanogens and hyperthermophilic members of the Archaea, CG dinucleotides and CG-containing codons occur frequently in M. kandleri DNA. The MR subunit-encoding genes are preceded by sequences consistent with ribosome binding sites, indicating that mRNA-rRNA base pairing can still direct translation initiation in cells growing at temperatures above 100 degrees C.

Euryarchaeota↗
PubMed1995

Relation of benzodiazepine use to the risk of selected cancers: breast, large bowel, malignant melanoma, lung, endometrium, ovary, non-Hodgkin's lymphoma, testis, Hodgkin's disease, thyroid, and liver.

Some animal data have raised the possibility that benzodiazepines influence the risk of selected cancers. With data collected in 1977-1991 in a US hospital-based study, the authors assessed the relation of benzodiazepine use to the risk of 11 cancers: breast (6,056 patients), large bowel (2,203), malignant melanoma (1,457), lung (1,365), endometrium (812), ovary (767), non-Hodgkin's lymphoma (382), testis (314), Hodgkin's disease (299), thyroid (111), and liver (37). Cases were compared with cancer controls (3,777 patients with other cancers) and noncancer controls (1,919 patients admitted for acute nonmalignant disorders). Relative risks were estimated for benzodiazepine use at least 4 days a week for at least 1 month, initiated at least 2 years before admission (sustained use) by multiple logistic regression with control for confounding factors. Results derived with noncancer controls were similar to those derived with cancer controls. For sustained benzodiazepine use relative to no use, relative risk estimates for all 11 cancers were compatible with 1.0 at the 0.05 level of significance. Relative risk estimates for durations of at least 5 years were also compatible with 1.0, with the exceptions of an increased estimate, of borderline statistical significance, for endometrial cancer, and a decreased estimate for ovarian cancer. Relative risk estimates both for sustained use that continued into the 2-year period before admission and for sustained use that ended up to > or = 10 years previously were compatible with 1.0, suggesting a lack of tumor promotion and no increase in the risk after a latent interval. Results were also null for diazepam, chlordiazepoxide, and other benzodiazepines considered separately. The results suggest absence of association between benzodiazepine use and the cancers considered, with the evidence stronger for the cancers with larger numbers of subjects. The similarity of results derived with cancer and noncancer controls suggests that benzodiazepines do not influence the risk of cancer as a whole.

Adolescent↗
PubMed1995

Adult height and risk of breast cancer among US black women.

Adult height has been positively associated with the risk of breast cancer in a number of recent investigations. The authors assessed height in relation to breast cancer risk in a case-control study of US black women aged 25-69 years; 674 hospital patients with newly diagnosed breast cancer and 1,155 controls hospitalized for nonmalignant conditions unrelated to height were interviewed. After control for multiple confounders, the relative risk estimate for women < 61 inches (< 154.9 cm) tall was 0.5 (95% confidence interval (Cl) 0.3-0.7) relative to the median height of 64-65 inches (162.6-165.1 cm). Among women > or = 61 inches (> or = 154.9 cm) tall, there was little indication of any variation in risk with increasing height. The findings suggest that short stature is associated with a decreased risk of breast cancer in US black women.

Adult↗
PubMed1995

Coffee consumption and myocardial infarction in women.

Whether coffee consumption increases the risk of coronary heart disease has not yet been established. In a case-control study of nonfatal myocardial infarction among Massachusetts women aged 45-69 years in 1986-1990, 858 cases with first infarctions were compared with 858 community controls matched on age and town precinct. Detailed information on coffee drinking, cigarette smoking, and other factors was obtained by telephone interview. Relative risks (as estimated by odds ratios) and their 95% confidence intervals were computed from multiple logistic regression analyses that controlled for smoking and other risk factors. The risk of myocardial infarction increased with increasing number of cups per day among both drinkers of any type of coffee and drinkers of caffeine-containing coffee only: tests for trend, p = 0.002 and p = 0.0004, respectively. For consumption of caffeine-containing coffee alone, the relative risk estimates for 5-6 cups, 7-9 cups, and 10 or more cups per day relative to less than 1 cup per day were 1.4 (95% confidence interval (CI) 0.8-2.5), 2.1 (95% CI 0.9-4.9), and 2.5 (95% CI 1.0-6.5), respectively. No increase was observed for fewer than 5 cups per day. The positive association with heavy coffee drinking was present among nonsmokers as well as smokers. These findings and other recent studies suggest that heavy coffee consumption increases the risk of myocardial infarction.

Aged↗
PubMed1995

Oral contraceptive use and breast cancer risk among African-American women.

Recent epidemiologic studies, most of them in predominantly White populations, have suggested that long duration of oral contraceptive (OC) use may increase the risk of breast cancer at young ages. We assessed the relationship of OC use to the risk of breast cancer in African-American women aged 25 to 59 years, using interview data from a multipurpose hospital-based case-control study. Five hundred and twenty-four cases hospitalized for invasive breast cancer were compared with 1,021 controls with nonmalignant conditions unrelated to OC use. Relative risks (RR) and 95 percent confidence intervals (CI) were estimated relative to a reference category of use for less than 12 months; potential confounders were controlled by multiple logistic regression analysis. Among women under age 45, three or more years of OC use was associated with an increased risk of breast cancer: the RR estimate was 2.8 (CI = 1.5-5.0) for three to four years of use, and declined to 1.5 (CI = 08.3.0) for 10 or more years of use. Recency and timing of use did not explain the observed association. Among women aged 45 to 59, OC use was associated with little or no increase in risk: the RR estimate for three or more years of use was 1.3 (CI = 0.7-2.4). The findings add to the evidence from studies of White women and a recent study of Black women which have suggested an increased risk of breast cancer at young ages for moderate or long duration use of OCs.

Adult↗
PubMed1995

Involvement of the noradrenergic afferents from the nucleus tractus solitarii to the supraoptic nucleus in oxytocin release after peripheral cholecystokinin octapeptide in the rat.

Activation of abdominal vagal afferents by peripheral injection of cholecystokinin octapeptide induces oxytocin release into the circulation. To test the hypothesis that cholecystokinin increases oxytocin release via activation of noradrenergic afferents from the brainstem, we injected rats with 5-amino-2,4-dihydroxy-alpha-methylphenylethylamine, a selective neurotoxin to noradrenergic fibres, into a lateral cerebral ventricle. The neurotoxin treatment reduced the noradrenaline content in the hypothalamus by 75% and reduced the oxytocin secretion in response to cholecystokinin by over 90%. In separate experiments, the neurotoxin was injected unilaterally in the vicinity of the supraoptic nucleus to test whether direct noradrenergic afferents to the supraoptic nucleus are involved in the response to cholecystokinin. The injection reduced the immunoreactivity for dopamine beta-hydroxylase in the supraoptic nucleus and significantly decreased the number of the supraoptic neurons expressing Fos-like protein after cholecystokinin but not after hypertonic saline. In further experiments, rhodamine-conjugated latex microspheres were injected into the supraoptic nucleus to retrogradely label afferent neurons, and the brains were processed with double-immunohistochemistry for tyrosine hydroxylase and Fos-like protein. In the C2/A2 but not the C1/A1 region of the brainstem, cholecystokinin increased the expression of Fos-like protein in the population of retrogradely-labelled catecholaminergic cells. In the C2/A2 region, the majority of retrogradely labelled cells expressing Fos-like protein after cholecystokinin were catecholaminergic. We conclude that noradrenergic afferents from the A2 but not from the A1 region of the brainstem to the hypothalamus mediate, at least in part, oxytocin release following cholecystokinin.

Afferent Pathways↗
PubMed1995

In vivo definition of an archaeal promoter.

We have used a plasmid-based transcriptional reporter system to examine the transcriptional effects of 33 single point mutations in the box A region (TATA-like sequence) of the Haloferax volcanii tRNA(Lys) promoter. The most pronounced effects on transcriptional efficiency were found when the nucleotides corresponding to the TATA-like region were altered. Promoters with wild-type or higher levels of transcriptional activity conformed to the general archaeal box A consensus, 5'-T/CTTAT/AA-3'. The preference for a pyrimidine residue in the 5' position of this region and the exclusion of guanine and cytosine in the next four positions in the 3' direction are defining characteristics shared by all efficient archaeal promoters. We have also observed that replacement of a 10-nucleotide purine-rich sequence, located 5' of the H. volcanii tRNA(Lys) box A element, completely abolished transcription from this promoter. These data show that the H. volcanii tRNA(Lys) promoter is dependent on two separate, and essential, sequence elements. The possible functions of these sequences, in view of the recent descriptions of eucaryal-like transcription factors for Archaea, are discussed.

Archaea↗
PubMed1994

The relation of vasectomy to the risk of cancer.

We previously reported a strong positive association between vasectomy and the risk of prostatic cancer that arose in multiple comparisons made within data collected from 1976 to 1988 in an ongoing hospital-based surveillance study of many exposures and diseases. We have reassessed this association with data collected in the surveillance study during 1988-1992 from a new set of patients (355 cases of prostatic cancer and 2,048 controls with nonmalignant conditions). Because some studies have reported increased relative risks of lung cancer and testicular cancer in vasectomized men, we also used the surveillance database (4,126 men with various cancers, 7,027 men with nonmalignant conditions) to assess the relation of vasectomy to the risk of these and other cancers. In the newly collected data, the multivariate relative risk estimate for prostatic cancer in vasectomized men was 1.2 (95% confidence interval (CI) 0.6-2.7). For lung cancer and testicular cancer, the relative risk estimates were 1.3 (95% CI 0.8-2.1) and 0.8 (95% CI 0.4-1.9), respectively; for lung cancer occurring > or = 15 years after vasectomy, the relative risk estimate was 1.9 but it was not statistically significant (95% CI 0.7-5.0). For pancreatic cancer, the relative risk estimate was 1.8 (95% CI 1.0-3.1). For each of the other cancers considered--malignant melanoma, large bowel cancer, bladder cancer, kidney cancer, lymphoma, leukemia, and other cancers--the relative risk estimate was 1.3 or less and compatible with a value of 1.0. The present data provide little support for an association of vasectomy with the risk of prostatic cancer or other cancers. In addition, the data from two sets of cases of prostatic cancer and controls interviewed consecutively illustrate that increased relative risks detected in screening for statistically significant associations may tend to have an upward bias and to be lower in subsequent data.

Adult↗
PubMed1994

Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors.

A variety of analogues of 1-[4-methoxy-3,5-dimethylbenzyl]-4-[3-(ethylamino)-2-pyridyl]piperazine hydrochloride (U-80493E) were synthesized and evaluated for their inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Replacement of the substituted aryl moiety with various substituted indoles provided bis(heteroaryl)piperazines (BHAPs) that were 10-100-fold more potent than U-80493E. The pyridyl portion of the lead molecule was found to be very sensitive to modifications. Extensive preclinical evaluations of several of these compounds led to the selection of 1-[(5-methoxyindol-2-yl)carbonyl]-4-[3-(ethylamino)-2- pyridyl]piperazine methanesulfonate (U-87201E, atevirdine mesylate) for clinical evaluation.

Aminopyridines↗
PubMed1994

A case-control study of oral contraceptive use and invasive epithelial ovarian cancer.

The relation of oral contraceptive use to the risk of ovarian cancer was assessed with data collected during 1977-1991 from patients under 65 years of age in hospitals in Boston, New York, Philadelphia, and Baltimore. We compared 441 women with recently diagnosed invasive epithelial ovarian cancer to 2,065 control women. Logistic regression was used to control risk factors for ovarian cancer. The multivariate relative risk estimate decreased with the increasing duration of oral contraceptive use (p < 0.05): the estimate was close to 1.0 for duration categories of less than 3 years; it was reduced for the categories of 3-4 years of use and greater, but it did not decline further as the duration of use increased. For > or = 3 years of use, the estimate was 0.6 (95% confidence interval 0.4-0.8). The inverse association of risk with > or = 3 years of use was consistently present across categories of age, parity, interview year, and geographic area. It was apparent for as long as 15-19 years after cessation. Many different specific oral contraceptive formulations appeared related to a decreased risk; however, data were sparse for the newer types, particularly phasic preparations, and the ability to assess specific preparations in the context of use of multiple preparations was limited. The present data confirm previous reports of an inverse association of ovarian cancer risk with oral contraceptive use of several years in duration. They also suggest that the association may persist for as long as two decades and that it is not confined to any particular type of oral contraceptive formulation.

Adult↗