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Biomedical subjects

G Jacob

Publications and source records attributed to G Jacob.

At least 19 recordsLinked to original sources
PubMed1996

Clinical models of cardiovascular regulation after weightlessness.

After several days in microgravity, return to earth is attended by alterations in cardiovascular function. The mechanisms underlying these effects are inadequately understood. Three clinical disorders of autonomic function represent possible models of this abnormal cardiovascular function after spaceflight. They are pure autonomic failure, baroreflex failure, and orthostatic intolerance. In pure autonomic failure, virtually complete loss of sympathetic and parasympathetic function occurs along with profound and immediate orthostatic hypotension. In baroreflex failure, various degrees of debuffering of blood pressure occur. In acute and complete baroreflex failure, there is usually severe hypertension and tachycardia, while with less complete and more chronic baroreflex impairment, orthostatic abnormalities may be more apparent. In orthostatic intolerance, blood pressure fall is minor, but orthostatic symptoms are prominent and tachycardia frequently occurs. Only careful autonomic studies of human subjects in the microgravity environment will permit us to determine which of these models most closely reflects the pathophysiology brought on by a period of time in the microgravity environment.

Autonomic Nervous System↗
PubMed1995

Detection of hypoglycemic drugs in human urine using micellar electrokinetic chromatography.

Micellar electrokinetic chromatography (MEKC) is evaluated as a potential analytical method for the separation and detection of a series of sulfonylurea drugs used in the treatment of hyperglycemia. These drugs are often surreptitiously abused, producing extremely low blood glucose levels and symptoms indistinguishable from those associated with an insulin-secreting tumor. Separation buffer containing 50 mM sodium dodecyl sulfate (SDS) was found to be adequate for the MEKC separation of the third generation drugs (glipizide and glyburide) but not the second generation drugs (acetohexamide chlorpropamide, tolazamide, and tolbutamide). At a pH of 8.5 in the presence of 20 mM borate/20 mM phosphate and 150 mM SDS, all seven components were adequately resolved with an analysis time of 17 min. Altering the concentration of the buffering components to either 5 mM borate/5 mM phosphate or 40 mM borate alone reduced the analysis time to less than 10 min with no observable loss in resolution. A series of other micelle-forming surfactants were evaluated, and only sodium cholate provided an improvement over the SDS-based system. Optimal separation was obtained with 75 mM sodium cholate and led to complete analysis with baseline resolution of all seven components in less than 8 min. These conditions were shown to be adequate for the detection of the hypoglycemic drugs spiked into normal urine and in patients taking these drugs. The precision associated with nine consecutive injections of six samples (n = 54) was found to be acceptable with percent coefficient of variance for absolute migration times (MTabs) for all peaks averaging 0.89 with peak area and peak height being 8.49 and 8.26, respectively. The between-sample precision was found to average 0.92% for MTabs and 8.56% and 8.45%, respectively, for the relative peak area and peak height. With a detection limit for the drugs in urine (following extraction) in the 50 ng/mL range, the potential exists for an MEKC-based assay for the detection of sulfonylurea drugs in urine.

Chromatography, High Pressure Liquid↗
PubMed1995

DNA inhibits the catalytic activity of the alpha subunit of protein kinase CK2.

The recombinant alpha subunit of protein kinase CK2 (casein kinase 2) from Xenopus laevis is inhibited by the addition of single stranded or double stranded DNA. This inhibition is competitive with the casein substrate, having an apparent Ki of 160 nM for an 86 bp DNA fragment. Assays with a fragment containing the putative promoter of the human CK2 beta gene indicated that the affinity of CK2 for this fragment was not greater than that of other unrelated DNA. The inhibitory capacity of DNA toward the protein phosphorylating activity of CK2 alpha is greatly reduced by the presence of the beta subunit which can completely reverse the inhibition. The interaction of CK2 alpha with DNA can also be assayed by the nitrocellulose filter binding assay. This assay demonstrates that the interaction of CK2 alpha with the tested DNAs is not sequence specific and that the beta subunit can also greatly diminish the binding of CK2 alpha to DNA. Casein at substrate concentrations also is inhibitory to CK2 alpha DNA binding. Likewise, polyanionic inhibitors of the CK2 catalytic activity, such as heparin, poly(U), and copoly(Glu:Tyr) polypeptides, can compete for and inhibit the binding of DNA to CK2 alpha. However, quercetin, which also inhibits CK2 phosphorylation activity, and ATP do not affect DNA binding. A mutant CK2 alpha in which glutamic acids replace two lysine residues in positions 75 and 76 of the alpha peptide chain is less susceptible to DNA inhibition, indicating that this basic region of the molecule is involved in its interaction with DNA.

Amino Acid Sequence↗
PubMed1995

Orthostatic hypotension: epidemiology, pathophysiology and management.

Orthostatic hypotension is characterized by low upright blood pressure levels and symptoms of cerebral hypoperfusion. Whereas orthostatic hypotension is heterogeneous, correct pathophysiologic diagnosis is important because of therapeutic and prognostic considerations. Although therapy is not usually curative, it can be extraordinarily beneficial if it is individually tailored. Management of the Shy-Drager syndrome (multiple-system atrophy) remains a formidable challenge.

Humans↗
PubMed1995

Differential suppression of serum prostatic acid phosphatase and prostate-specific antigen by 5-alpha-reductase inhibitor.

OBJECTIVE: To evaluate the effect of finasteride (Proscar) on the serum levels of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) in patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Thirty patients on finasteride therapy for BPH formed the study group. Serum PSA and PAP levels were monitored for 2 years while the patients were receiving finasteride. RESULTS: During 12 months of finasteride therapy the serum PSA was suppressed but serum PAP was unaffected. The baseline mean PAP value was 1.303 ng/mL prior to finasteride therapy; this changed to 1.510 ng/mL (P = 0.195) at 6 months and 1.166 ng/mL (P = 0.383) at 12 months. The serum PSA was 2.630 ng/mL at baseline, 1.757 ng/mL (P < 0.001) at 6 months and 1.545 ng/mL (P = 0.001) at 12 months. CONCLUSIONS: Further studies are warranted to determine if PAP has a role as a tumour marker in patients whose PSA is suppressed as a result of finasteride therapy.

Acid Phosphatase↗
PubMed1994

Utility of preoperative serum prostate-specific antigen concentration and biopsy Gleason score in predicting risk of pelvic lymph node metastases in prostate cancer.

OBJECTIVES: To determine the accuracy of the preoperative serum concentration of prostate-specific antigen (PSA) plus the Gleason pathology score of biopsy specimens in predicting the presence of disease in the pelvic lymph nodes in patients with prostate cancer. METHODS: The medical records of all patients treated for prostate cancer at eight medical centers from January 1988 to June 1993 were reviewed. There were 932 patients with newly diagnosed prostate cancer for whom all relevant data were available who had undergone pelvic lymphadenectomy with (n = 912) or without (n = 20) radical prostatectomy. The rate of false-negative predictions of metastases based on combined preoperative biopsy Gleason score and serum PSA concentration was analyzed. A multivariate logistic regression analysis was performed to assess the value of preoperative serum PSA and biopsy Gleason scores individually and in combination in predicting pelvic lymph node metastases. RESULTS: The false-negative rate of metastases was 0% for preoperative PSA concentrations < or = 6 ng/mL and biopsy Gleason scores < or = 5 (n = 142) and 1.0% for PSA concentrations < or = 10 ng/mL and Gleason scores < or = 6 (n = 388). The 95% upper confidence limit for the rate of false negativity at this PSA cut-off level was 2.0%. A combination of preoperative serum PSA levels and biopsy Gleason scores provided the best prediction for the false-negative rates. CONCLUSIONS: For patients with newly diagnosed prostate cancer who have biopsy Gleason scores < or = 6 and preoperative PSA concentrations < or = 10 ng/mL (42% of our series), a staging pelvic lymphadenectomy appears to be unnecessary. The substantial cost associated with both cross-sectional imaging and staging lymphadenectomy may therefore be avoidable in this group of patients.

Biopsy↗
PubMed1993

Characteristics of phospholipase C present in membranes of Xenopus laevis oocytes. Stimulation by phosphatidic acid.

1. Phospholipase C activity present in the membranes of Xenopus laevis oocytes has been studied. 2. These membranes contain an activity capable of hydrolyzing phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. 3. Hydrolysis of PtdIns 4,5-P2 is absolutely dependent on the presence of Ca2+, however, the hydrolysis of PtdIns occurs in the absence of Ca2+ but addition of the cation stimulates the reaction. 4. Spermine, spermidine and polylysine cause significant stimulation of the phospholipase C activity. 5. Phosphatidic acid causes approximately a 2-fold stimulation of the hydrolysis of both PtdIns and PtdIns 4,5-P2. With PtdIns as substrate, this stimulatory effect of phosphatidic acid is specific and reaches a maximum at a 400 microM concentration.

Animals↗
PubMed1993

Cardiac function and responsiveness to beta-adrenoceptor agonists in rats with obstructive jaundice.

The function and role of the heart and the contribution of cardiac beta-adrenoceptors in the pathogenesis of circulatory failure in obstructive jaundice were studied in the 3-day bile duct-ligated (BDL) rat using three different techniques to measure cardiac function and beta-adrenoceptor activity, number, and affinity. The techniques were the pithed rat preparation, the isolated working heart preparation, and a competitive radioligand binding assay for beta-adrenoceptors. The results of these experiments were compared with those obtained in 3-day bile duct-manipulated (sham operated; SO) rats. Impaired indexes of basal cardiac contractility were observed in the BDL pithed rats and isolated working hearts. In these two preparations, responsiveness to norepinephrine and the beta-adrenoceptor agonists, isoproterenol and dobutamine, was unaffected by bile duct ligation. The affinity and number of cardiac beta-adrenoceptors in membranes from the hearts of SO and BDL rats were not significantly different from each other. These experiments have established for the first time that the 3-day BDL rat has a cardiac myopathy associated with intact responsiveness to beta-adrenoceptor agonists, a normal unchanged affinity and number of cardiac beta-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1993

Peripheral vascular neuroeffector mechanisms in experimental cholestasis.

Jaundiced patients have systemic hypotension and are more susceptible to hemorrhagic shock than nonjaundiced individuals. We have hypothesized that the mechanism whereby these cardiovascular complications arise is linked to a disturbance of the vascular neuroeffector process in the cardiovascular system. With the use of 3-day bile duct-manipulated (sham-operated) and bile duct-ligated rats, we have evaluated alpha-adrenoceptor function and amine uptake using in vivo and in vitro techniques. Blunted pressor responsiveness to norepinephrine, electrical stimulation, and the alpha 1-adrenoceptor agonists, methoxamine and phenylephrine, was observed in the bile duct-ligated pithed rats. In contrast, normal responsiveness to BHT-933 and clonidine, the alpha 2-adrenoceptor agonists, was seen in these animals. The uptake 1 blocker, cocaine, caused potentiation of equal magnitudes of the pressor responsiveness to electrical stimulation and norepinephrine in the sham-operated and bile duct-ligated pithed rats. In aortic rings prepared from the bile duct-ligated rats, blunted in vitro vascular reactivity to norepinephrine and the same alpha 1-adrenoceptor agonists was seen. Bile duct ligation had no effect on norepinephrine uptake or its kinetics in stressed and unstressed arterial rings and portal veins. We have thus concluded that bile duct ligation induces a defect in the functional expression of cardiovascular alpha 1-adrenoceptors without any effects on the activity of alpha 2-adrenoceptors or norepinephrine uptake.

Adrenergic alpha-Agonists↗
PubMed1991

Factors influencing the establishment of tumour-infiltrating lymphocyte cultures from human breast carcinoma and colon carcinoma tissue.

Tumour-infiltrating lymphocytes (TIL) were obtained from breast and colon tumour tissue and cultured in vitro in the presence of recombinant human interleukin-2. Seven of 35 breast tumours and five of 41 colon TIL cultures were established in vitro: proliferation rates of greater than 10(3) were achieved. The cytotoxic capacity of these cells was determined against the cell lines K562 and SW742, and percentage cytotoxicity levels of greater than 97% and 79%, respectively, were seen. An inverse relationship between the ability of TIL to kill and their proliferative capacity was observed in all cultures. The prominent phenotype was CD3 positive, with greater than 55% of TIL expressing this antigen; there was no expression of CD16. The expression of CD56 and CD25 varied, being maximumly expressed on 64% and 38% of TIL, respectively. When greater than 90% of TIL expressed CD3, the ability of the culture to kill the target cell lines was low; only when there was an increase in the proportion of cells expressing CD56 and a decrease in the expression of CD3 was there high cytotoxicity. This study indicates that the TIL which proliferate in vitro in the presence of interleukin-2 are not necessarily the mediators of cytotoxicity.

Adult↗