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Biomedical subjects

R B Kelly

Publications and source records attributed to R B Kelly.

174 records · Page 10Linked to original sources
PubMedDate not supplied

Chloroquine diverts ACTH from a regulated to a constitutive secretory pathway in AtT-20 cells.

AtT-20 cells, a mouse pituitary line, externalize a viral membrane glycoprotein and the precursor of ACTH constitutively, that is, rapidly without storage or regulation. They also have a regulated pathway in which they cleave the precursor to mature hormones, ACTH and beta-endorphin, store them in secretory granules and discharge them only in the presence of a secretagogue. An analogy exists for newly synthesized lysosomal enzymes which are either delivered to the lysosome or secreted from the cell. Targeting to the lysosomes may require a low pH step, since chloroquine causes the enzymes to be secreted from the cell. Here we show that chloroquine (200 microM) also appears to block the storage of newly synthesized ACTH in secretory granules and instead diverts it to the outside of the cell via the constitutive pathway. Chloroquine has no effect on the constitutive pathway and does not block the exocytosis of pre-packaged ACTH. Thus like lysosomal enzymes, peptide hormones are not sent to their correct destinations in the presence of chloroquine, but are diverted instead to a constitutive pathway that is chloroquine-insensitive.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Presynaptic neurones may contribute a unique glycoprotein to the extracellular matrix at the synapse.

As the extracellular matrix at the original site of a neuromuscular junction seems to play a major part in the specificity of synaptic regeneration, considerable attention has been paid to unique molecules localized to this region. Here we describe an extracellular matrix glycoprotein of the elasmobranch electric organ that is localized near the nerve endings. By immunological criteria, it is synthesized in the cell bodies, transported down the axons and is related to a glycoprotein in the synaptic vesicles of the neurones that innervate the electric organ. It is apparently specific for these neurones, as it cannot be detected elsewhere in the nervous system of the fish. Therefore, neurones seem to contribute unique extracellular matrix glycoproteins to the synaptic region. Synaptic vesicles could be involved in transporting these glycoproteins to or from the nerve terminal surface.

Animals↗
PubMedDate not supplied

Re-routing of a secretory protein by fusion with human growth hormone sequences.

Cells with electron-dense secretory vesicles use them to store only specialized secretory products such as peptide hormones; other types of secreted proteins are externalized by an alternative, constitutive route. One possible mechanism for such segregation is that proteins destined for dense secretory vesicles contain unique 'sorting domains' that allow for selective targeting. Here, we set out to determine whether a constitutively secreted protein could be diverted to the dense secretory vesicles by attachment to a peptide hormone sequence. We made use of the ability of the mouse pituitary tumour cell, AtT-20, to correctly sort exogenous secretory proteins introduced into them by DNA transfection. We constructed a plasmid encoding a hybrid protein in which a constitutively secreted viral protein was fused to the carboxy terminus of human growth hormone (hGH). Cells expressing the hybrid protein were found to target it to dense secretory vesicles with an efficiency close to that observed for the parental hGH. These results support the hypothesis that sorting domains on peptide hormones direct their packaging into dense secretory vesicles. The results also suggest that proteins secreted by the constitutive pathway either do not contain any sorting domain, or their sorting signals can be overridden by those which direct peptide hormones.

Animals↗
PubMedDate not supplied

Conjugation rescue of exocytosis mutants in Tetrahymena thermophila indicates the presence of functional intermediates in the regulated secretory pathway.

Tetrahymena thermophila possesses a regulated secretory pathway in which mucin proteins are stored in dense-core granules, called mucocysts. Exocytosis-defective mutants exist that fail to secrete mucin in response to secretagogues. Four of the mutants (SB281, SB283, SB285 and SB715) appear to be blocked at different steps of the regulated secretory pathway. SB281 and SB285 accumulate mucin proteins in heterogeneous cytoplasmic organelles which have not yet been identified; SB283 makes mucocyst-like structures but they contain no immunologically identifiable 80-kDa or 50-kDa mucin proteins; and SB715 has more than normal amounts of immature and undocked mucocysts. The organelles that accumulate in exocytosis-defective mutants could be either normal intermediates in the biosynthetic pathway or aberrant structures that form as a result of the mutations. We have used conjugation rescue to analyze steps in the biogenesis of exocytosis-competent mucocysts and to identify functional intermediates. The cytoplasmic organelles that accumulate in SB281 appear to be unidentified biosynthetic intermediates, and the defect is in a cytosolic protein essential for mucocyst maturation. The organelles which accumulate in the other mutants are likely biosynthetic, but their mutations are in proteins which are labile or not free to diffuse into the mutant conjugant.

Animals↗
PubMedDate not supplied

Controlled trial of a time-efficient method of health promotion.

Integrating health promotion into daily clinical practice is a challenging undertaking. This project was a prospective trial of a brief physician intervention program, performed as part of routine patient care, that addressed six areas of patients' lifestyle risks (nutrition, exercise, alcohol use, smoking, stress, and seat belt use). The components of the program were lifestyle assessment, physician prescription of lifestyle change, and educational materials. Patients visiting a family practice residency model office for any reason were selected to receive all program components, parts of the program, or no program components. Lifestyle behavior changes over the ensuing four-week period were measured for all groups by a structured phone interview. Patients who received one or more components of the program reported significantly more change at follow-up than those who received no program components (P = .001); the greatest change was seen in the group that received all of the program components. Demographic variables that were significantly related to a higher degree of change were female sex, previous contact with the physician, and being married. In this sample age, income, and education were not related to behavior change. Motivation to change--an expressed desire to work on a given lifestyle area--was a stronger predictor of change than any demographic variable.

Adult↗
PubMedDate not supplied

Comparison of three prenatal risk scores in a series of low-risk pregnancies.

Three prepartum obstetrical risk-scoring methods (Goodwin, Halliday, Hobel) were retrospectively applied to a consecutive series of 795 singleton pregnancies. The study population was low risk overall, with a perinatal mortality rate of 11 per 1000 and a primary cesarean section rate of 9.7%. The predictive ability of the scores was tested for individual outcomes as well as for a "combined measure" designed to group outcomes of clinical interest. Outcome variables examined included labor arrests, need for augmentation of labor, fetal heartrate abnormalities during labor, selection of or transfer to a more intensive level of care, indicated forceps delivery, cesarean section, resuscitation, Apgar scores, permanent injury, and perinatal deaths. Along with expected differences in sensitivity and specificity, there were differences among the three scores in performance as measured by positive and negative predictive value. Goodwin's system performed somewhat better overall. All three systems performed better in multiparous than in primiparous patients, but primiparas experienced more adverse outcomes.

Adult↗
PubMedDate not supplied

Influence of income, hours worked, and loan repayment on medical students' decision to pursue a primary care career.

OBJECTIVE: To assess the specialty plans of current fourth-year medical students and, for those not choosing primary care specialties, to investigate the potential effect that changes in key economic or lifestyle factors could have in attracting such students to primary care. DESIGN AND PARTICIPANTS: A survey study was sent to 901 fourth-year medical students in the 1993 graduating classes of six US medical schools. OUTCOME MEASURES: Comparisons were made between students choosing and not choosing primary care specialties. For the non-primary care students, we also evaluated whether alteration of income, hours worked, or loan repayment could attract them to primary care careers. RESULTS: Of the 688 responses (76% response rate), primary care specialties were chosen by 27% of the students and non-primary care specialties by 73%. One quarter (25%) of the non-primary care students indicated they would change to primary care for one of the following factors: income (10%), hours worked (11%), or loan repayment (4%). For students whose debt was $50,000 or greater, the loan repayment option became much more important than for students with lesser debt. In all, a total of 45% (n = 313) of the students indicated either they were planning to enter primary care (n = 188) or they would change to a primary care specialty (n = 125) with appropriate adjustments in income, hours worked, or loan repayment. CONCLUSION: Significant changes in economic and lifestyle factors could have a direct effect on the ability to attract students to primary care. Including such changes as part of health system reform, especially within the context of a supportive medical school environment, could enable the United States to approach a goal of graduating 50% generalist physicians.

Career Choice↗