Search PubMed⌕ Search

Biomedical subjects

J A Clark

Publications and source records attributed to J A Clark.

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

Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated.

PURPOSE: We determined long-term symptoms in patients after brachytherapy (radioactive seed implantation) for early (nonmetastatic) prostate cancer. MATERIALS AND METHODS: We performed a cross-sectional survey of 105 (80% of those contacted) men treated at least 2 years 9 months (median 5.2 years) previously with brachytherapy alone (72 patients) or brachytherapy plus external beam radiation therapy (33) at a pioneering referral center for ultrasound guided brachytherapy. RESULTS: Median patient age was 70 years at treatment and 75 years when surveyed. Bowel symptoms were uncommon (range 4% to 9%) unless patient had also received external beam radiation therapy. Urinary incontinence occurred in 45% of men, although leakage of more than a few drops, daily leakage and wearing absorptive pads occurred in 11%, 11% and 16%, respectively. Men who underwent documented transurethral prostatic resection were much more likely to report incontinence (83% versus 39%, p = 0.005) and those who underwent implantation less than 5 years earlier were less likely (33% versus 53%, respectively, p = 0.04). Complete impotence was common (50%) but impaired erections were more so (73%). Patients who received combined radiation treatment had more frequent erectile dysfunction. CONCLUSIONS: Long-term bowel symptoms are infrequent after brachytherapy alone. Urinary incontinence is common, although usually only a few drops and not daily. Erectile dysfunction, prevalent in populations of older men, was found in most men. However, because our study design precluded documenting baseline symptoms before treatment and subsequent clinical interventions, the contribution of factors other than brachytherapy is unclear. The morbidity of patients receiving more recent brachytherapy may be less.

Aged↗
PubMed2000

Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium.

Members of the protein kinase C (PKC) family of signal transduction molecules have been widely implicated in regulation of cell growth and differentiation, although the underlying molecular mechanisms involved remain poorly defined. Using combined in vitro and in vivo intestinal epithelial model systems, we demonstrate that PKC signaling can trigger a coordinated program of molecular events leading to cell cycle withdrawal into G(0). PKC activation in the IEC-18 intestinal crypt cell line resulted in rapid downregulation of D-type cyclins and differential induction of p21(waf1/cip1) and p27(kip1), thus targeting all of the major G(1)/S cyclin-dependent kinase complexes. These events were associated with coordinated alterations in expression and phosphorylation of the pocket proteins p107, pRb, and p130 that drive cells to exit the cell cycle into G(0) as indicated by concomitant downregulation of the DNA licensing factor cdc6. Manipulation of PKC isozyme levels in IEC-18 cells demonstrated that PKCalpha alone can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells. Notably, analysis of the developmental control of cell cycle regulatory molecules along the crypt-villus axis revealed that PKCalpha activation is appropriately positioned within intestinal crypts to trigger this program of cell cycle exit-specific events in situ. Together, these data point to PKCalpha as a key regulator of cell cycle withdrawal in the intestinal epithelium.

Animals↗
PubMed2000

Molecular determinants of tuberoinfundibular peptide of 39 residues (TIP39) selectivity for the parathyroid hormone-2 (PTH2) receptor. N-terminal truncation of TIP39 reverses PTH2 receptor/PTH1 receptor binding selectivity.

Tuberoinfundibular peptide of 39 residues (TIP39) and the parathyroid hormone-2 (PTH2) receptor form part of an extended family of related signaling molecules that includes the PTH1 receptor, which responds to PTH and PTH-related protein. TIP39 does not appreciably activate the PTH1 receptor, but in this study it is shown to bind the receptor with moderate affinity (59 nm). In this study, we investigated the molecular determinants of both ligand and receptor for the PTH2 receptor selectivity of TIP39 and quantitatively evaluated the role of molecular elements in the binding of TIP39 to the PTH2 and PTH1 receptors. A chimeric receptor composed of the N-terminal extracellular domain of the PTH1 receptor and the remainder (juxtamembrane domain) of the PTH2 receptor (P2-NP1) was fully activated by TIP39 (E(max) = 98% of the rPTH-(1-34), E(max), EC(50) = 2.0 nm). This receptor chimera bound TIP39 with an equivalent affinity to the wild-type PTH2 receptor (2. 3 and 2.0 nm, respectively). The reciprocal chimeric receptor (P1-NP2) was not activated by TIP39 and bound the ligand with an affinity equivalent to that of the PTH1 receptor. Thus, the juxtamembrane receptor domain specifies the signaling and binding selectivity of TIP39 for the PTH2 receptor over the PTH1 receptor. Removing six N-terminal residues of TIP39 eliminated activation of the PTH2 receptor and reduced binding affinity 70-fold. In contrast, this truncation increased affinity for the PTH1 receptor 10-fold, reversing the PTH2/PTH1 receptor binding selectivity and resulting in a high affinity interaction of TIP-(7-39) with the PTH1 receptor (6 nm). These findings can be explained by a strong interaction between the N-terminal region of TIP39 and the juxtamembrane domain of the PTH2 receptor, with the corresponding domain of the PTH1 receptor acting as a selectivity barrier against high affinity binding of TIP39. As a result, TIP-(7-39) is a highly potent, selective antagonist for the PTH1 receptor.

Amino Acid Sequence↗
PubMed2000

Distribution of the GABA(B) receptor subunit gb2 in rat CNS.

We have identified and isolated human and rat cDNAs for a novel receptor, gb2, with 38% homology to the GABA(B) receptors gb1a and gb1b. These receptors comprise a new subfamily of seven transmembrane G protein-coupled receptors (GPCRs) that share structure and sequence similarities with the metabotropic glutamate receptors. In situ hybridization histochemistry using an antisense probe to this novel receptor mRNA shows a distribution in rat CNS nearly identical to that for the gb1 receptor, although some regions showed significant differences. Specifically, message levels for gb2 were virtually absent in the caudate/putamen, and significantly lower in the medial basal hypothalamus, septum and brainstem as compared with gb1 message levels. In contrast to gb1, gb2 mRNA was never detected in white matter suggesting that gb2 message is found exclusively in neurons. Finally, in rat brain regions showing significant overlap of message for gb1 and gb2, the transcripts are often found in the same cells. Data from our previous work showing that coexpression of gb2 with gb1 is necessary for expression of a functional receptor together with the detailed anatomical data presented here indicate that native GABA(B) receptors function as heteromeric proteins, the most abundant form being the gb1/gb2 receptor. However, the more limited distribution of gb2 receptor mRNA suggests that there are brain regions where GABA(B) receptors are composed of gb1 and as yet unidentified family members.

Amino Acid Sequence↗
PubMed2000

Frequency of adverse reactions to prochlorperazine in the ED.

Prochlorperazine (Compazine, PCZ) is a frequently used medication in the emergency department (ED). Akathisia and dystonia are known adverse reactions to the use of this medication, but their incidence in the ED has not been well studied. We conducted a prospective, descriptive study to evaluate the frequency of akathisia and dystonia in the ED from the use of IV or IM PCZ in patients with nausea/vomiting or headache. Two hundred-twenty nine patients (> or =18 years old) were enrolled and contacted within 2 weeks of ED discharge to access the incidence of these adverse reactions. After the use of PCZ in the ED, 16% of patients developed akathisia and 4% developed dystonia. Emergency physicians and our patients need to be aware of these potential adverse reactions to the use of PCZ in the ED.

Adolescent↗
PubMed2000

Auditory and behavioral responses of bottlenose dolphins (Tursiops truncatus) and a beluga whale (Delphinapterus leucas) to impulsive sounds resembling distant signatures of underwater explosions.

A behavioral response paradigm was used to measure masked underwater hearing thresholds in two bottlenose dolphins and one beluga whale before and after exposure to impulsive underwater sounds with waveforms resembling distant signatures of underwater explosions. An array of piezoelectric transducers was used to generate impulsive sounds with waveforms approximating those predicted from 5 or 500 kg HBX-1 charges at ranges from 1.5 to 55.6 km. At the conclusion of the study, no temporary shifts in masked-hearing thresholds (MTTSs), defined as a 6-dB or larger increase in threshold over pre-exposure levels, had been observed at the highest impulse level generated (500 kg at 1.7 km, peak pressure 70 kPa); however, disruptions of the animals' trained behaviors began to occur at exposures corresponding to 5 kg at 9.3 km and 5 kg at 1.5 km for the dolphins and 500 kg at 1.9 km for the beluga whale. These data are the first direct information regarding the effects of distant underwater explosion signatures on the hearing abilities of odontocetes.

Animals↗
PubMed2000

Induction of mammary gland development in estrogen receptor-alpha knockout mice.

Mammary glands from the estrogen receptor-a knockout (alphaERKO) mouse do not undergo ductal morphogenesis or alveolar development. Disrupted ERalpha signaling may result in reduced estrogen-responsive gene products in the mammary gland or reduced mammotropic hormones that contribute to the alphaERKO mammary phenotype. We report that circulating PRL is reduced in the female alphaERKO mouse. Implantation of an age-matched, heterozygous ERalpha pituitary isograft under the renal capsule of 25-day-old or 12-week-old alphaERKO mice increased circulating PRL and progesterone levels, and induced mammary gland development. Grafted alphaERKO mice also possessed hypertrophied corpora lutea demonstrating that PRL is luteotropic in the alphaERKO ovary. By contrast, ovariectomy at the time of pituitary grafting prevented mammary gland development in alphaERKO mice despite elevated PRL levels. Hormone replacement using pellet implants demonstrated that pharmacological doses of estradiol induced limited mammary ductal elongation, and estradiol in combination with progesterone stimulated lobuloalveolar development. PRL alone or in combination with progesterone or estradiol did not induce alphaERKO mammary growth. Estradiol and progesterone are required for the structural development of the alphaERKO mammary gland, and PRL contributes to this development by inducing ovarian progesterone levels. Therefore, the manifestation of the alphaERKO mammary phenotype appears due to the lack of direct estrogen action at the mammary gland and an indirect contributory role of estrogen signaling at the hypothalamic/pituitary axis.

Animals↗
PubMed1999

Changes in quality of life following treatment for early prostate cancer.

OBJECTIVES: To explore the effects of urinary, bowel, and sexual symptoms following treatment for early (nonmetastatic) prostate cancer on health-related quality of life through an examination of the responsiveness of the Medical Outcomes Study Short Form Health Survey (SF-36). METHODS: We conducted a prospective observational cohort study of 125 men with early prostate cancer who underwent either radical prostatectomy or radical, external beam radiotherapy. Patients completed questionnaires, which included assessments of urinary, bowel, and sexual symptoms and the SF-36 at the time of their clinical consultation prior to deciding on primary therapy and at 3 and 12-month follow-up. RESULTS: Although cross-sectional analysis showed substantial associations between symptoms and the eight scales of the SF-36 12 months after the initiation of treatment, longitudinal analyses of changes in these scales showed only modest effects. Three scales registered changes associated with the development of new symptoms: General Health Perceptions, Vitality, and Social Function. Role Performance with Emotional Limitations demonstrated a surprising response: slight improvements in men with new symptoms, compared with substantial gains in men who survived treatment without developing new urinary, bowel, or sexual symptoms. Overall, the SF-36 demonstrated a pattern of decline at 3 months and recovery to baseline at 12 months. Rather than registering declines in response to increasing symptoms, negative changes occurred primarily in men who presented symptoms prior to treatment and whose symptoms were unchanged 12 months later. CONCLUSIONS: The SF-36 is associated with the presence of physical symptoms but demonstrates a complicated pattern of change following treatment and the development of new urinary, bowel, and sexual problems. Multidimensional approaches to the outcomes of treatment for early prostate cancer help to clarify the magnitude of both gains and losses in quality of life.

Adult↗
PubMed1999

Characterization of the internalization pathways for the cystic fibrosis transmembrane conductance regulator.

Mutations in the gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) chloride channel give rise to the most common lethal genetic disease of Caucasian populations, CF. Although the function of CFTR is primarily related to the regulation of apical membrane chloride permeability, biochemical, immunocytochemical, and functional studies indicate that CFTR is also present in endosomal and trans Golgi compartments. The molecular pathways by which CFTR is internalized into intracellular compartments are not fully understood. To define the pathways for CFTR internalization, we investigated the association of CFTR with two specialized domains of the plasma membrane, clathrin-coated pits and caveolae. Internalization of CFTR was monitored after cell surface biotinylation and quantitation of cell surface CFTR levels after elution of cell lysates from a monomeric avidin column. Cell surface levels of CFTR were determined after disruption of caveolae or clathrin-coated vesicle formation. Biochemical assays revealed that disrupting the formation of clathrin-coated vesicles inhibited the internalization of CFTR from the plasma membrane, resulting in a threefold increase in the steady-state levels of cell surface CFTR. In contrast, the levels of cell surface CFTR after disruption of caveolae were not different from those in control cells. In addition, although our studies show the presence of caveolin at the apical membrane domain of human airway epithelial cells, we were unable to detect CFTR in purified caveolae. These results suggest that CFTR is constitutively internalized from the apical plasma membrane via clathrin-coated pits and that CFTR is excluded from caveolae.

Biotinylation↗
PubMed1999

Rapid progression following cardiac surgery.

This article examines one institution's transition into rapid progression after cardiac surgery. This includes clinical guidelines and the integral use of outcomes measures to govern care. Fast-track initiatives are examined in the scope of cost containment. A comprehensive, multidisciplinary approach is emphasized throughout.

Cardiac Surgical Procedures↗
PubMed1998

Cloning and characterization of a general amino acid control transcriptional activator from the chestnut blight fungus Cryphonectria parasitica.

We have cloned and characterized a homologue of the Neurospora crassa general amino acid control gene cpc-1 from the chestnut blight fungus Cryphonectria parasitica. The deduced amino acid sequence of C. parasitica CPC1 (cpCPC1) contains regions with significant homology to the transcriptional activation, DNA binding, and dimerization domains previously defined for N. crassa CPC1 (ncCPC1) and the equivalent "b-ZIP" transcription factor from Saccharomyces cerevisiae, GCN4 (scGCN4). Treatment of C. parasitica with low levels of the protein synthesis inhibitor cycloheximide caused cpc-1 transcript levels to undergo a rapid, transient increase similar to that reported for the mammalian b-ZIP transactivators, c-Jun and c-Fos. Northern analysis also revealed that amino acid starvation of C. parasitica elicits an increase in cpc-1 transcript levels. Hypovirus infection did not affect this increase, although transcript accumulation for several amino acid biosynthetic genes was slightly diminished in the hypovirus-containing strain. Recombinant cpCPC1 specifically bound to the consensus DNA binding element (AP-1), 5'-A/GTGACTCAT-3', also located upstream of the C. parasitica cpc-1 coding region. Constitutive transgenic expression of a DNA binding defective cpCPC1 mutant impaired the ability of C. parasitica to adjust to amino acid starvation. Moreover, these transformants showed reduced ability to grow on host chestnut tissue. Our results define a general amino acid control transactivator in a plant pathogenic fungus and suggest that functional modulation of this factor can influence fungal virulence.

Amino Acid Sequence↗
PubMed1998

Consumer turnover in service utilization patterns: implications for capitated payment.

Risk-adjusted capitation rates based on a group's expected cost to a provider have been proposed to create incentives for including people with severe mental disabilities in managed healthcare systems. The most appropriate methods for classifying people according to levels of risk, however, have yet to be determined. This research employed cluster analysis statistical techniques to identify patterns of services delivered to a sample of 4,346 consumers in Ohio. Findings about the extent of client movement in and out of service clusters over time suggest caution in the implementation of risk-adjusted capitation plans, particularly those based primarily on past service utilization.

Capitation Fee↗
PubMed1998

Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats.

One of the most consistent results in the epidemiology of human breast cancer is the inverse relationship of risk and early full-term parity. The goal of this study was to investigate the molecular mechanisms through which early full-term pregnancy protects the breast from cancer development. We used Wistar-Furth (WF) rats as our experimental system and mimicked pregnancy using estrogen and progesterone (E/P). Sexually mature female rats were treated with steroid hormones for 21 days and after 28 days of gland involution, the rats were administered MNU. Rats that received a high dose of 20 microg E and 20 mg P exhibited an 82% reduction in the incidence of mammary adenocarcinomas as compared to the rats receiving only blank pellets. Decreasing doses of E/P were partially protective suggesting that complete differentiation of the gland was not required for refractoriness. We measured the RNA expression levels of several target genes involved in the regulation of mammary cell proliferation and/or differentiation including estrogen receptor (ER) and progesterone receptor (PR), cyclins D1 and D2, the cell cycle inhibitors p16, p21 and p27, and the tumor suppressor p53. At the time of MNU treatment we found no significant differences in the expression of these genes, with the possible exception of p21, indicating that hormone treatment did not result in constitutive changes in expression levels. The numbers of apoptotic cells were low and comparable in the hormone exposed and age-matched virgin gland (AMV) at the time of carcinogen challenge and remained low for 8 days after MNU treatment. The number of BrdU-labeled cells at the time of carcinogen challenge were also low in both the AMV (1.8%) and hormone exposed (0.8%) animals. In contrast, cell proliferation in the AMV (5.7%) was significantly different from both the parous involuted (1.2%) and the E/P-treated involuted (1.5%) animals 8 days after MNU treatment. We interpret these data to indicate that hormone treatment results in mammary epithelial cells that have persistent alterations in intracellular pathways governing proliferation responses to carcinogens.

Animals↗
PubMed1998

Symptom severity of osteoarthritis of the knee: a patient-based measure developed in the veterans health study.

BACKGROUND: Our objective was to develop a patient-based measure of the severity of osteoarthritis of the knee, focusing on symptomatology, that may be used in conjunction with measures of health-related quality of life in monitoring the health status of outpatients. METHODS: We surveyed a random sample of male outpatients at Boston-area Veterans Affairs medical centers who were identified as having osteoarthritis of the knee according to a three-question screen. Structured interviews included 12 items covering five domains of symptoms (global severity, 4 items; pain with activity, 3 items; pain at rest, 2 items; impaired mobility, 2 items; and sensations of crepitus, 1 item), which were derived from clinical texts, consensus statements, and previously developed severity indices. Interviews also included a detailed medical history. Health-related quality of life was measured by the Medical Outcomes Study Health Status Survey (SF-36). Factor analysis and evaluation of multiattribute scales were used to evaluate the structural relationships between and within the five domains of symptoms. RESULTS: We identified 415 of the 1770 screened outpatients as having osteoarthritis of the knee. Internal consistencies of the five domains ranged from .50 to .72, with substantial convergence between domains. The 12 items comprise a summary index with high internal consistency (alpha = .88). Overall severity, defined as the mean of the 12 items after standardization, was moderately correlated with the SF-36 component summaries: r = -.48 for physical; r = -.30 for mental. CONCLUSIONS: Our measure provides a reliable index that represents symptomatic severity of osteoarthritis of the knee, which may be useful in comparing patient groups and assessing health outcomes; subscales may help characterize temporal changes, including responses to treatment.

Adult↗