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Biomedical subjects

P Hale

Publications and source records attributed to P Hale.

At least 19 recordsLinked to original sources
PubMed1998

NCAM: a polymorphic microsatellite locus conserved across eutherian mammal species.

A dinucleotide microsatellite was found to be conserved at the 3' untranslated end of the neural cell adhesion molecule (NCAM) gene in cattle, rat and human. The high level of sequence conservation found in this gene allows the use of a single set of PCR primers to amplify sequence spanning the repeat in many species. Sequence analysis revealed the conservation of the dinucleotide repeat in all eutherian mammal species studied with variation in length as well as internal structure caused by base substitutions. Polymorphisms were seen across five mammalian orders, in rat, buffalo, sheep, cow, whale and dolphin, with polymorphisms predicted in pig and dugong based on the length of the uninterrupted dinucleotide repeat.

Animals↗
PubMed1998

Molecular population genetics of the red kangaroo (Macropus rufus): mtDNA variation.

The genetic population structure of a large, wide-ranging marsupial, the red kangaroo (Macropus rufus) was assessed using sequence and haplotype frequency data of mitochondrial DNA (mtDNA) from locations across the species range in Australia. Results from sequence data revealed extensive haplotype diversity within the red kangaroo (32/34 sequences were unique). Sequence diversity was distributed within rather than between geographical regions across the species range. Genetic connectivity across the range of the species has therefore been maintained over the long term. On a smaller within-region scale, significant genetic structuring was evident from heterogeneity of haplotype frequencies amongst sampling sites. The geographical scale of panmictic populations differed across the continent with more restricted genetic populations occurring in areas with greater topographic and habitat complexity. We propose that these differences in area of genetic populations are the result of population responses to limiting ecological factors during drought.

Animals↗
PubMed1998

COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer.

Extensive documentation has validated the role of UV irradiation as a tumor initiator and promoter, inducing both squamous and basal cell carcinomas. Human epidermis is a tissue which undergoes active metabolism of arachidonic acid to prostaglandins which is regulated by the action of prostaglandin H synthase (also known as cyclooxygenase). One mechanism for the promotional activity of UV light may involve its ability to induce prostaglandin formation. Work in our laboratory has demonstrated that acute exposure of human keratinocytes to UVB irradiation results in increased production of prostaglandin E2 (PGE2). When cultured human keratinocytes were examined after irradiation with 30 mJ/cm2 UVB in vitro, Western blot analysis showed a 6-fold increase in COX-2 protein which was evident at 6 h and peaked 24 h after irradiation. Furthermore, when human subjects were irradiated on sun-protected skin with up to four times their minimal erythema dosage (MED) and biopsied 24 h later, upregulation of COX-2 protein expression was observed via immunofluorescence microscopy. RNAase protection assays supported this observation, showing induction of COX-2 message which peaked at approximately 12 h following irradiation in vitro. Furthermore, human squamous cell carcinoma biopsies exhibited strongly enhanced staining for COX-2 protein via immunohistochemistry and Western analysis when compared to normal non-sun-exposed control skin. Together, these data demonstrate acute upregulation of COX-2 via UVB irradiation and suggest the need for further studies of COX-2 expression as a potential pharmacological target mediating human skin tumor development.

Basal Cell Carcinoma↗
PubMed1997

Tertiary structure of the hepatic cell protein fibrinogen in fluid revealed by atomic force microscopy.

Fibrinogen participates in important cellular physiological processes, such as cell adhesion and blood clotting. Although the primary and secondary structures of fibrinogen are known, its tertiary structure is yet to be determined. In attempts to understand the tertiary structure of this important hydrated cellular and plasma membrane protein, the present study using atomic force microscopy was carried out. The techniques presented in this manuscript may also be applicable to enhance the imaging of live cells as well as their subcellular components. The authors have imaged fibrinogen by Tapping Mode atomic force microscopy in fluid. Purified human fibrinogen, together with 15-nm colloidal gold particles serving as an internal calibration standard, were adhered to a poly-L-lysine substrate on freshly cleaved mica. Atomic force microscopy images were obtained using oxide-sharpened silicon nitride probes, either unaltered or with an electron beam deposited extended tip. Although various structures were observed, the predominant forms consisted of a bi- or trinodular slightly curved linear shape. Approximately 300 of these structures were observed with six different tips (1 unaltered and 5 electron beam deposited) and their lengths and heights were analyzed. The mean length of the fibrinogen molecules was 65.8 nm and the mean height was 3.4 nm. The quantitative measurements were little influenced by the shape of the tip, whereas the sharper electron beam deposited tips seemed to produce qualitatively superior images.

Fibrinogen↗
PubMed1997

Microsatellite genetic distances between oceanic populations of the humpback whale (Megaptera novaeangliae).

Mitochondrial DNA haplotypes of humpback whales show strong segregation between oceanic populations and between feeding grounds within oceans, but this highly structured pattern does not exclude the possibility of extensive nuclear gene flow. Here we present allele frequency data for four microsatellite loci typed across samples from four major oceanic regions: the North Atlantic (two mitochondrially distinct populations), the North Pacific, and two widely separated Antarctic regions, East Australia and the Antarctic Peninsula. Allelic diversity is a little greater in the two Antarctic samples, probably indicating historically greater population sizes. Population subdivision was examined using a wide range of measures, including Fst, various alternative forms of Slatkin's Rst, Goldstein and colleagues' delta mu, and a Monte Carlo approximation to Fisher's exact test. The exact test revealed significant heterogeneity in all but one of the pairwise comparisons between geographically adjacent populations, including the comparison between the two North Atlantic populations, suggesting that gene flow between oceans is minimal and that dispersal patterns may sometimes be restricted even in the absence of obvious barriers, such as land masses, warm water belts, and antitropical migration behavior. The only comparison where heterogeneity was not detected was the one between the two Antarctic population samples. It is unclear whether failure to find a difference here reflects gene flow between the regions or merely lack of statistical power arising from the small size of the Antarctic Peninsula sample. Our comparison between measures of population subdivision revealed major discrepancies between methods, with little agreement about which populations were most and least separated. We suggest that unbiased Rst (URst, see Goodman 1995) is currently the most reliable statistic, probably because, unlike the other methods, it allows for unequal sample sizes. However, in view of the fact that these alternative measures often contradict one another, we urge caution in the use of microsatellite data to quantify genetic distance.

Alleles↗
PubMed1994

Ultraviolet B injury increases prostaglandin synthesis through a tyrosine kinase-dependent pathway. Evidence for UVB-induced epidermal growth factor receptor activation.

To study the signal transduction mechanisms by which ultraviolet B (UVB) leads to increased prostaglandin E2 (PGE2) synthesis, human epidermal cultures were irradiated with 30 mJ/cm2 UVB and assayed for 6-h cumulative PGE2. Supernatants from irradiated cultures showed a 4-fold increase in PGE2 synthesis (113.6 +/- 26.8 pg/mg protein) when compared to supernatants from sham-irradiated cultures (25.6 +/- 3.9 pg/mg protein). Pretreatment of irradiated cultures with genistein (10 micrograms/ml) or tyrphostin-23 (50 microM), inhibitors of tyrosine kinases, blocked UVB-stimulated PGE2 synthesis. Treatment of nonirradiated cultures with epidermal growth factor (EGF), which acts through the receptor tyrosine kinase EGF-R, produced a 4-fold increase in PGE2 synthesis. However, addition of EGF to irradiated cultures did not further enhance their PGE2 synthesis, indicating irradiation rendered them refractory to EGF stimulation. In contrast, irradiated cultures could still significantly increase their PGE2 synthesis in response to the calcium ionophore A23187 or the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate, suggesting that the lack of response to EGF was selective. Furthermore, anti-phosphotyrosine immunoblot analysis revealed UVB-induced phosphorylation of tyrosine residues of EGF-R, an indicator of receptor activation. Phosphorylation was maximal 30-60 min after irradiation and was blocked by the tyrosine kinase inhibitors, genistein and tyrphostin. The antioxidant N-acetylcysteine decreased UVB-induced EGF-R tyrosine phosphorylation and PGE2 synthesis to near-basal levels. Conversely, treatment of unirradiated cultures with the potent oxidant tert-butyl-hydroperoxide (100 microM) increased both PGE2 synthesis and EGF-R phosphorylation. Collectively, these data suggest that antioxidant depletion induced by UV results in tyrosine phosphorylation and activation of the EGF-R. This activation may subsequently activate epidermal phospholipase at early time points after UVB exposure.

Calcimycin↗
PubMed1993

Significantly reduced acid detection at 10 centimeters compared to 5 centimeters above lower esophageal sphincter in patients with acid reflux.

Ambulatory pH monitoring of the esophagus is carried out by positioning a pH sensor 5 cm above the lower esophageal sphincter (LES). There are several techniques to locate the LES, and each method has a different margin of error. This work used dual pH sensors to monitor simultaneously at two different levels (5 and 10 cm above the LES) in order to establish the possible magnitude of error that could arise from inaccurate placement of a pH probe. Thirty-four patients with symptoms of gastroesophageal reflux (GER) were studied. They were grouped as 20 patients with pathological reflux (GER group) and 14 patients with physiological reflux, based on a reflux score derived by Johnson and DeMeester for distal esophageal pH monitoring. When the reflux scores were compared, the difference between the two monitoring levels was statistically significant in the GER group (p < 0.001) but not in the physiological reflux group (p = 0.09). In the GER group, the difference in the Johnson and DeMeester score accounted for a change in clinical diagnosis in nine of the 20 patients if the pH probe was placed at 10 cm above the upper margin of LES. Proximal reflux episodes (10 cm above LES) were preceded by distal reflux episodes (5 cm above LES) in 97% (878/901) of cases. Accurate probe placement is essential in the diagnosis of GER.

Esophagogastric Junction↗
PubMed1992

Poor palliation of colorectal malignancy with the neodymium yttrium-aluminium-garnet laser.

The neodymium yttrium-aluminium-garnet (NdYAG) laser was used to palliate the symptoms of 38 patients with rectal carcinoma unsuitable for radical surgery. All patients with small tumours (n = 6) reported resolution of their symptoms. In contrast, those with large tumours frequently showed little improvement (n = 18) and alternative surgical management was necessary in 12 patients. The overall early mortality rate (less than 1 month after first treatment) was 21 per cent. The NdYAG laser offers good palliation and may even cure small colorectal tumours in patients who are unsuitable for surgery. For large circumferential tumours, those associated with obstruction and those close to or involving the anal sphincters, however, the results are poor and better symptom control may be achieved by other means.

Aged↗
PubMed1990

Enhanced chromatid damage in blood lymphocytes after G2 phase x irradiation, a marker of the ataxia-telangiectasia gene.

An assay for ataxia-telangiectasia (A-T) heterozygotes, i.e., healthy carriers of the A-T gene(s), requiring only a small sample (3.5 mL) of peripheral blood, is described. Frequencies of chromatid aberrations in phytohemagglutinin-stimulated blood lymphocytes collected by demecolcine from 0.5 hour to 1.5 hours after x irradiation with 58 roentgens were twofold to threefold higher in A-T heterozygotes than in clinically normal controls and twofold to three-fold higher in A-T patients (homozygotes) than in A-T gene carriers. The persistence of chromatid breaks and gaps in lymphocytes following radiation-induced DNA damage during G2 suggests a deficiency or deficiencies in DNA repair that may be the defect at the molecular level that results in the enhanced radiosensitivity and cancer proneness characterizing A-T gene carriers and patients.

Adolescent↗
PubMed1988

Evaluation of sudden death in psychiatric patients with special reference to phenothiazine therapy: forensic pathology.

The investigation of sudden unexpected death in psychiatric patients and the ensuing litigation has brought to our attention many unusual features important in the evaluation of such deaths. Certain pathophysiologic mechanisms of death, rarely encountered in routine forensic science practice, may be important in determining the cause of death in psychiatric patients, especially in cases where the autopsy is unrevealing. Of particular concern is a tendency in the current literature to implicate phenothiazines as a cause of death when the death investigation and the autopsies are incomplete. Thus, based on our experience and on a review of the current literature, we have set forth factors that the forensic pathologist should consider when faced with a sudden psychiatric death. A case report illustrates these unique aspects of scene investigation and analysis of terminal events and autopsy findings.

Adult↗