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Biomedical subjects

T Kelly

Publications and source records attributed to T Kelly.

At least 55 records · Page 3Linked to original sources
PubMed1995

The pathophysiology of premature rupture of the membranes.

Premature rupture of the membranes (PROM) is the condition in which the chorioamnion is disrupted before the onset of labor. This condition creates a dilemma for the practicing obstetrician, because once the membranes have broken the risk of fetal or maternal infection, or both, increases. Preterm PROM adds to this management challenge, mainly because of the added problem of prematurity. Although the epidemiology of PROM has been well defined, the exact etiology has yet to be understood. However, using the associated clinical risk factors of PROM, researchers in this field have contributed to our understanding of the causes. Various mechanisms have been proposed, including mechanical, as well as infectious or inflammatory processes. The purpose of this article is to review the various proposed mechanisms of PROM. Maternal risk factors for PROM are presented, mainly to place into context the current literature involving both in-vitro and in-vivo research. It is apparent that a single pathophysiologic mechanism is not responsible for all cases of PROM, but rather a combination of processes is in operation.

Female↗
PubMed1995

Early central nervous system response to HIV infection: sleep distortion and cognitive-motor decrements.

OBJECTIVE: To repeat and extend findings suggesting that sleep disturbance, excessive daytime sleepiness, and degraded cognitive-motor abilities may be early markers of central nervous system (CNS) involvement in HIV infection. DESIGN: A controlled, cross-sectional, prospective analysis. SETTING: Clinical research center at a teaching hospital and a military health research center. SUBJECTS: Twenty-three HIV-positive (mean CD4+ count, 387 +/- 162 x 10(6)/l) and 13 seronegative men who were Naval personnel or participants of the University of California, San Diego HIV Neurobehavioral Research Center. MAIN OUTCOME MEASURES: Nocturnal and daytime sleep electroencephalogram, electromyogram, and electrocardiogram. Simple and complex cognitive-motor performance assessed via computerized tasks. RESULTS: Comparison of sleep parameters based on HIV status, length of time infected, zidovudine use, and CD4+ count indicated that CD4+ T cells > 400 x 10(6)/l were associated with a distortion in nocturnal sleep characterized by increased stages 3 and 4 non-rapid eye movement (i.e., slow-wave) sleep in the latter portion of the night and reduced nocturnal awakenings. HIV-positive patients were no sleepier in the daytime than controls. Cognitive-motor performance revealed deficits in both accuracy and efficiency for HIV-positive patients. CONCLUSION: Asymptomatic HIV-positive patients with CD4+ counts > 400 x 10(6)/l demonstrate a statistically significant increase in slow-wave sleep during the latter portion of the night and less arousability. CD4+ lymphocyte count in the early phases of HIV infection appears to differentiate between various levels of HIV disease progression with respect to certain CNS measurements of nocturnal sleep and cognitive-motor performance. Sleep structure distortion remains one of the earliest and most consistently replicable physiological signs of HIV infection. This distortion may provide a link to immune function, disease progression, and cognitive-motor disability in HIV infection.

AIDS Dementia Complex↗
PubMed1995

Respiratory effects of occupational exposure to aerosolized pentamidine.

To determine the respiratory effects on health care workers of occupational exposure to aerosolized pentamidine (AP) used for the prophylaxis of Pneumocystis carinii pneumonia, we designed a clinical prospective study using subjects as their own controls. Sixteen health care workers whose job duties included administration of AP at one or more of nine San Francisco Bay Area medical centers participated in the study. Pentamidine concentrations ranged in breathing zone samples from < 0.03 to 62.2 micrograms/m3. Pentamidine was not detected in the urine of any of the subjects. There were no significant increases in symptoms on days when AP was administered. Cross-workshift spirometry on days when AP was administered showed a statistically significant mean decrease (0.14 liter) in forced expiratory volume in 1 second. There was no statistically significant difference in mean diurnal variation of peak expiratory flow rate on days when AP was administered. Methacholine inhalation challenge testing did not show a statistically significant mean change in airway responsiveness across the workweek. The ambient concentrations of pentamidine that we measured document that detectable occupational exposure to AP can occur in poorly ventilated treatment rooms. The cross-workshift decrement in forced expiratory volume in 1 second that we observed in association with AP administration supports the respiratory tract irritant potential of inhaled pentamidine. We recommend that steps be taken to minimize health care worker exposure to AP.

AIDS-Related Opportunistic Infections↗
PubMed1995

New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.

Analysis of the connexin32 gene in patients with X-linked Charcot-Marie-Tooth disease shows mutations distributed throughout the molecule, with all domains affected except the fourth transmembrane domain and the distal carboxy terminus. Sequence analysis of DNA from 19 unrelated patients detected six novel mutations and three previously reported mutations. Identification of additional mutations extends the distribution of connexin32 mutations in X-linked Charcot-Marie-Tooth disease and shows that specific mutations recur in additional families.

Amino Acid Sequence↗
PubMed1995

Methacholine responsiveness is not associated with O3-induced decreases in FEV1.

STUDY OBJECTIVE: Controlled human exposure studies have suggested that the National Ambient Air Quality Standard for ozone (O3) may not provide a margin of safety to protect the most susceptible members of the population from adverse health effects. Although the subgroups of the population that are most susceptible to O3 have not been identified, recent work in our laboratory suggested that methacholine responsiveness might be an important determinant of susceptibility to O3. PATIENTS AND METHODS: To test the hypothesis that methacholine responsiveness is correlated with FEV1 response after O3 exposure, we conducted methacholine challenge tests and O3 (0.20 ppm) and filtered air exposures for 4 h with moderate exercise on 66 healthy individuals. RESULTS: Repeated measures analysis of variance demonstrated significant changes in FEV1 (-0.82 +/- 0.63 L), FVC (-0.69 +/- 0.48 L), and specific airway resistance (SRaw) (+1.5 +/- 1.1 L x cm H2O/L/s) across the O3 exposure that persisted after adjusting for responses to air. Baseline PC100 (the concentration of methacholine that caused a doubling of the baseline SRaw) was weakly associated with O3-induced increases in SRaw (F1.54 = 2.85, p = 0.09), but not O3-induced declines in FEV1 or FVC. There was a weak association (r = -0.29) between O3-induced responses for SRaw and FEV1. The FEV1 responses for O3 were weakly associated with the symptoms of cough (r = -0.37), wheeze (r = -0.29), chest pain on deep inspiration (r = -0.31), and shortness of breath (r = -0.37), but not with chest discomfort or sputum production. CONCLUSIONS: Although we were unable to find support for our hypothesis, we found, somewhat surprisingly, that respiratory symptoms were weakly associated or unassociated with FEV1 responses after O3 exposure. This finding implies that individuals may experience adverse effects, ie, respiratory symptoms, without large declines in lung function. Conversely, individuals may suffer large declines in lung function without prominent symptoms and, therefore, may remain in an unhealthy environment despite evidence of toxicity.

Adult↗
PubMed1995

Definitive identification of an exceptionally high methanol concentration in an intoxication of a surviving infant: methanol metabolism by first-order elimination kinetics.

Intoxication by methanol was identified in a five-week-old infant suffering from moderate metabolic acidosis. The initial serum methanol at admission was 1148 mg/dL as measured by gas chromatography. The osmolal gap and formic acid concentrations were consistent with methanol intoxication. The child was treated with folic acid and a continuous ethanol infusion and survived without any apparent permanent problems. Because expected toxic symptoms did not develop in this case, and the methanol concentrations were at levels that might be deemed to be incompatible with life, blood and urine samples were assayed by a specific enzymatic assay, and by gas chromatography/mass spectrometry (GC/MS). Positive results definitively confirmed the presence of methanol. In contrast to previous reports, the elimination of methanol in this case appeared to following first-order kinetics. If hepatic ADH activity is low in neonates and young infants, another enzyme system such as catalase may be involved to explain this data. The lack of formic acid accumulation may have been due to folic acid therapy.

Acidosis↗
PubMed1995

Modification of the Miya hook in vaginal colpopexy.

OBJECTIVE: To evaluate a modification of the Miya hook in performing vaginal sacrospinous ligament fixation. STUDY DESIGN: The modification was performed in over 50 patients. It involves placing the needle through the ligament unloaded; then the hook is back-threaded with the appropriate suture. The hook is then withdrawn, bringing the suture with it. RESULTS: There were no complications as a result of this modification. The technique was faster, used fewer instruments and obviated fraying of the suture. It could also be adapted when retrieving the suture when the classic technique proved difficult. CONCLUSION: The ease of this modification should promote the use of this instrument in performing vaginal sacrospinous ligament fixation.

Equipment Design↗
PubMed1994

A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells.

Seprase, a large, gelatin-degrading membrane-protease complex, is expressed at the invasive front of malignant melanoma cells on invadopodia, and its surface expression contributes to the invasive phenotype. An in vitro assay was used to determine the matrix-degrading activity of four malignant human melanoma cell lines. The lines differ in matrix-degrading activity with LOX > RPM17951 > A375 > SKMEL28. The seprase and Gelatinase A activities of these cell lines were also investigated. Seprase and active gelatinase A are found in cell membranes of LOX and RPM17951 cells but not those of SKMEL28 cells. Experiments using anti-seprase monoclonal antibodies in conjunction with a cell fractionation technique indicate that seprase consists of M(r) 97,000 polypeptides and is enriched on the ventral membrane of LOX in contact with planar extracellular matrix substratum. Confocal microscopy further substantiates our biochemical findings that seprase, as well as Gelatinase A, is localized on invadopodia membranes with a 6-fold increase of seprase and 4-fold increase of Gelatinase A intensity over the level expressed on dorsal membranes. In addition, LOX cells expressing higher levels of seprase at the cell surface, as selected by fluorescence-activated cell sorting, are significantly more degradative than LOX cells with lower seprase expression. Taken together, our data show a concordance between seprase and Gelatinase A expression on the cell surface at invadopodia and the matrix-degrading activity of human malignant melanoma cells. Seprase and major secreted proteases may act in concert to degrade components of the extracellular matrix during invasion.

Biomarkers, Tumor↗
PubMed1994

Invadopodia promote proteolysis of a wide variety of extracellular matrix proteins.

Chicken embryo fibroblasts (CEF) transformed by Rous sarcoma virus invade the extracellular matrix (ECM) using plasma membrane protrusions, termed invadopodia, that contact and dissolve the matrix. Normal cells neither form invadopodia nor degrade the ECM. Here we show that cells expressing invadopodia degrade and enter into a fibronectin-rich matrix produced by normal fibroblasts. Within 6 h after seeding onto the matrix, the invasive cells create an area devoid of matrix fibrils surrounding the cell body. Proteolysis mediates this matrix clearing because sevenfold more radiolabeled matrix is released into the growth media by the transformed cells relative to the normal cells. In addition to this assembled matrix, transformed cells were grown on thin layers of purified ECM proteins, revealing that invadopodia can degrade fibronectin, collagen type I, collagen type IV, and laminin. A 160 kDa protease that is extracted from transformed cells by Triton X-114 partitions into the detergent phase and is prominent in ventral plasma membranes that contact the ECM suggesting that it is a membrane associated protease.

Animals↗
PubMed1994

Membrane proteases as potential diagnostic and therapeutic targets for breast malignancy.

Metastasizing cancer cells can invade the extracellular matrix using plasma membrane protrusions, termed invadopodia, that contact and dissolve the matrix. Various membrane associated proteases localized on the invadopodial membranes are responsible for the extracellular matrix degradation. Work from our laboratory shows that secreted proteases including Gelatinase A, and high molecular weight integral membrane proteases are associated with cell surface invadopodia. Three cell types, including chicken embryonic cells transformed by Rous sarcoma virus, human malignant melanoma cell line LOX, and human breast carcinoma cell line MDA-MB-231, retain the invasive phenotype in vitro, express invadopodia, degrade and enter into a fibronectin-rich collagenous matrix. We suggest that invadopodium-associated proteases are ideal targets for the diagnosis and treatment of cancer as their presence in association with primary tumors may signal increased metastatic potential. An approach toward the development of new prognostic markers for breast malignancy involved production of monoclonal antibodies directed against membrane proteases in a mixture of glycoproteins. Double immunofluorescent technique using a known invadopodium marker is designed to select specific monoclonal antibodies colocalizing at the invasion front, on invadopodia of cancer cells. Membrane protease accessibility at the cell surface can therefore be exploited for therapeutic advances by the development of specific antibodies and inhibitors that block their activities, and by the use of monoclonal antibodies to target cytotoxic molecules to micrometastases. Also, this same accessibility may potentially be used to detect surface proteases on micrometastases or to detect components shed by micrometastases in serum.

Antigens, Neoplasm↗
PubMed1994

Dual-energy X-ray absorptiometry for measuring total bone mineral content in the rat: study of accuracy and precision.

Sequential studies of osteopenic bone disease in small animals require the availability of non-invasive, accurate and precise methods to assess bone mineral content (BMC) and bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA), which is currently used in humans for this purpose, can also be applied to small animals by means of adapted software. Precision and accuracy of DXA was evaluated in 10 rats weighing 50-265 g. The rats were anesthetized with a mixture of ketamine-xylazine administrated intraperitoneally. Each rat was scanned six times consecutively in the antero-posterior incidence after repositioning using the rat whole-body software for determination of whole-body BMC and BMD (Hologic QDR 1000, software version 5.52). Scan duration was 10-20 min depending on rat size. After the last measurement, rats were sacrificed and soft tissues were removed by dermestid beetles. Skeletons were then scanned in vitro (ultra high resolution software, version 4.47). Bones were subsequently ashed and dissolved in hydrochloric acid and total body calcium directly assayed by atomic absorption spectrophotometry (TBCa[chem]). Total body calcium was also calculated from the DXA whole-body in vivo measurement (TBCa[DXA]) and from the ultra high resolution measurement (TBCa[UH]) under the assumption that calcium accounts for 40.5% of the BMC expressed as hydroxyapatite. Precision error for whole-body BMC and BMD (mean +/- S.D.) was 1.3% and 1.5%, respectively. Simple regression analysis between TBCa[DXA] or TBCa[UH] and TBCa[chem] revealed tight correlations (n = 0.991 and 0.996, respectively), with slopes and intercepts which were significantly different from 1 and 0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1994

Effect of genetic switching of capsular type on virulence of Streptococcus pneumoniae.

To assess the role of capsular serotypes in the virulence of Streptococcus pneumoniae, we have constructed isogenic derivatives differing only in the type of capsule expressed. Strains of types 2, 5, and 6B were converted to type 3 by transformation and selection for an erythromycin resistance marker linked to the type 3 capsule locus. Characterization studies revealed that these type 3 derivatives were indistinguishable from the type 2, type 5, and type 6B parental strains in terms of restriction enzyme fragment pattern and expression of pneumococcal surface protein A (PspA). Expression of the type 3 capsule did not alter the mouse virulence of the similarly virulent type 2 strain. However, alteration of capsule type had a profound effect on the virulence of the type 5 and type 6B derivatives. The highly virulent type 5 strain was essentially avirulent when expressing the type 3 capsule. Conversely, the 50% lethal dose of the relatively avirulent type 6B strain was reduced > 100-fold when the type 3 capsule was expressed. Thus, the serotype of capsule expressed has a major effect on virulence, and this effect is dependent upon the genetic background of the recipient strain.

Animals↗
PubMed1994

Risk factors for suicidal behavior in borderline personality disorder.

OBJECTIVE: This study identified potential risk factors for suicidal behavior in patients with borderline personality disorder defined by the Diagnostic Interview for Borderline Patients and by DSM-III-R criteria for patients who did and did not attempt suicide. METHOD: Histories of suicide attempts and attempt characteristics were obtained by Schedule for Affective Disorders and Schizophrenia interviews from 84 patients with borderline personality disorder and were related to severity of borderline pathology, diagnostic comorbidity, and state and trait symptoms. RESULTS: There were 61 patients with a lifetime history of suicide attempts (72.6%), with an average of 3.39 (SD = 2.87) attempts per patient. Attempters were significantly older than nonattempters, with more impulse actions, antisocial personality disorder comorbidity, and state depression. State depression was significantly less severe in patients who had attempted suicide in the present episode (or past year) than in patients who had attempted suicide only in the past. A comorbid diagnosis of major depression, alcoholism, or drug use disorder did not distinguish attempters from nonattempters. Suicide attempt in the present episode was best predicted by the number of prior lifetime attempts. A highly serious intent to commit suicide was predicted by the number of lifetime attempts and subjective depression, while a low intent was predicted by a mixed subtype of borderline personality disorder plus schizotypal personality disorder and paranoid ideation. A high degree of medical lethality was predicted by number of lifetime attempts, older age, and hysteroid dysphoria, while low lethality attempts were associated with high degrees of anger. CONCLUSIONS: Risk factors for suicidal behavior in patients with borderline personality disorder include older age, prior suicide attempts, antisocial personality, impulsive actions, and depressive moods but not comorbid affective disorder, alcoholism, or drug use disorders.

Adult↗
PubMed1994

Depressed neutrophil chemotaxis in children suffering blunt trauma.

OBJECTIVE: Impaired neutrophil (PMN) function, due in part to release of immature PMNs into the circulation, contributes to the increased rate of infection observed in adults suffering blunt trauma. The objective of this study was to determine whether similar events occur in children. METHODS: We assessed PMN chemotaxis and PMN maturation in 25 children (7 young children and 18 adolescents) and 25 adults 1 to 9 days after suffering blunt trauma, and in healthy adult control subjects. PMN chemotaxis was determined using a standard micropore filter assay, whereas PMN maturation was determined with 31D8, a novel monoclonal antibody that binds to mature PMNs more avidly than immature PMNs and band forms. RESULTS: In patients suffering blunt trauma, mean PMN chemotactic values were similar among children (44.6 +/- 2.3 microns) and adults (41.3 +/- 2.1 microns) and both were significantly less than among healthy adults (53.5 +/- 2.4 microns, P < .0005). PMN chemotactic values increased significantly in the 9 days after trauma for both children and adults (F = 13.8, df = 1, P < .0002). Mean PMN 31D8 binding among children with trauma (92.5 +/- 5.2) was significantly less than among healthy adults (117.6 +/- 5.4, P < .0009). CONCLUSIONS: Impairment in PMN chemotaxis occurs in children after blunt trauma and is due in part to release of immature PMNs into the circulation.

Adolescent↗
PubMed1993

Binding and localization of M(r) 72,000 matrix metalloproteinase at cell surface invadopodia.

Degradation (turnover) of collagenous matrix occurs on the surface of specialized membrane extensions termed "invadopodia," which are sites of cell invasion into the extracellular matrix. Here we show the localization of the M(r) 72,000 type IV collagenase of the matrix metalloproteinase family at invadopodia. When added exogenously, latent M(r) 72,000 collagenase binds to invadopodia of chicken embryo fibroblasts transformed by Rous sarcoma virus, whereupon the bound collagenase loses its propeptide. The collagenase binds to a component contained within the detergent extract of transformed cells, and increased levels of the active M(r) 62,000 form of the collagenase are seen here. Such an association is not detected in the detergent extract derived from normal cells. Using a recently developed cell fractionation procedure to collect cell surfaces enriched in invadopodia, we show that the M(r) 72,000 collagenase associates with the invadopodial fraction and active forms of the enzyme become immobilized on the collagenous surface. Thus, invadopodia direct intense localized degradation of the extracellular matrix by concentrating active membrane-associated collagenases at sites of cellular invasion.

Amino Acid Sequence↗
PubMed1993

Purification of a novel glycosylated ferritin from horse heart.

We have previously shown that mRNA coding for ferritin L subunit is present on both cytosolic ribosomes and endoplasmic reticulum-bound ribosomes in rat heart tissue [Campbell et al. (1989) Arch Biochem Biophys 273:89-98]; from this we infer that heart tissue is capable of making a secreted ferritin. We now report the purification from horse heart, of a ferritin that specifically binds to Concanavalin A-Sepharose and is immunologically cross-reactive with antibodies raised against both horse cellular ferritin and horse serum ferritin. Where cellular ferritin is 10 nm in diameter and contains primarily 21-kDa subunits (as determined by gel exclusion chromatography and electron microscopy), the glycosylated heart ferritin is smaller with diameters of 3-5 nm. Antisera raised against serum ferritin cross-reacted with the glycosylated heart ferritin did but did not show significant cross-reactivity with cellular ferritin thus indicating that serum ferritin and glycosylated heart ferritin have antigenic determinants which may not be present on cellular ferritin. The glycosylated ferritin also differs from cellular ferritin in subunit composition, with subunits of 66, 60.5, 53.5, 43.5, and 29.5 kDa, as shown by SDS-PAGE and Western blot analysis. Interestingly, ferritin purified from horse serum contains subunits of similar size.

Animals↗