Biomedical subjects
Publications and source records attributed to H Nelson.
A mass of statistics indicates that the health of the nation as a whole has benefited under the Sandinistas' unified health system. Nevertheless, many physicians and the principal coalition of opposition parties that will oppose the Ortega regime in this month's election advocate replacing it with a three-tiered system aimed at different segments of the population.
T lymphocytes normally recognize antigens through the antigen receptor complex (TCR/CD3) but can be redirected to bind and lyse unrecognized tumor cells by anti-tumor X anti-CD3 heteroconjugates. Chemical coupling of an antibody directed against the T cell receptor complex and an antibody directed against tumor antigen produces a conjugated antibody that activates the T cell lytic mechanism and bridges the T cell and tumor cell. We tested the lytic activity of heteroconjugate-treated cultured human peripheral blood lymphocytes (PBLs) in 4-h radioactive chromium release assays with human colon tumor cell targets. PBLs were enriched for T cells by the depletion of Leu11a+ and Leu19+ cells, prior to culture in rIL-2 and anti-CD3. Cultured human PBLs depleted of Leu11a+ and Leu19+ cells produced low levels of tumor cell lysis in the absence of antibodies. Anti-tumor X anti-CD3 heteroconjugates significantly enhanced tumor cell lysis by cultured PBLs when tested against four different colon tumor cell lines (P less than 0.005), but, heteroconjugates in the absence of PBLs did not augment tumor cell lysis. Cultured PBLs treated with monoclonal anti-tumor antibody, with monoclonal anti-CD3 antibody, or with irrelevant heteroconjugate did not enhance tumor cell lysis. We conclude that heteroconjugate-directed lysis is mediated by PBLs and that both the anti-tumor antibody and the anti-CD3 antibody are essential for heteroconjugate function. In addition, heteroconjugate-enhanced tumor cell lysis is mediated through a mechanism other than antibody-dependent cellular cytotoxicity or nonspecific T cell receptor crosslinking.(ABSTRACT TRUNCATED AT 250 WORDS)
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The main function of vacuolar H(+)-ATPases in eukaryotic cells is to generate proton and electrochemical gradients across the membranes of the vacuolar system. The enzyme is composed of a catalytic sector with five subunits (A-E) and a membrane sector containing at least two subunits (a and c). We disrupted two genes of this enzyme, in yeast cells, one encoding a subunit of the membrane sector (subunit c) and another encoding a subunit of the catalytic sector (subunit B). The resulting mutants did not grow in medium with a pH value higher than 6.5 and grew well only within a narrow pH range around 5.5. Transformation of the mutants with plasmids containing the corresponding genes repaired the mutations. Thus failure to lower the pH in the vacuolar system of yeast, and probably other eukaryotic cells, is lethal and the mutants may survive only if a low external pH allows for this acidification by fluid-phase endocytosis.
Nimodipine is a calcium entry blocker that shows promise in the therapy for cerebral ischemia. This study was undertaken to examine the interaction of nimodipine with the use of hypocapnia to control cerebral blood volume by reduction in cerebral blood flow (CBF), as might be applicable to patients undergoing anesthesia for neurosurgical procedures. Male adult Sprague-Dawley rats were anesthetized with pentobarbital 50 mg/kg i.p. and were mechanically ventilated at either normocapnia (Paco2 35-40 mm Hg) or hypocapnia (Paco2 23-25 mm Hg). Animals were randomized into four experimental groups in a 2 x 2 factorial design, employing Paco2 level and drug group as between-group factors: vehicle plus normocapnia (group 1, n = 6), nimodipine plus normocapnia (group 2, n = 7), vehicle plus hypocapnia (group 3, n = 6), and nimodipine plus hypocapnia (group 4, n = 6). Nimodipine (1 mug/kg/min) or vehicle was administered i.v. for a period of 45 min. CBF was then measured using [C]iodoantipyrine autoradiography. Hypocapnia decreased global CBF (p <0.0001) and nimodipine increased CBF (p <0.05). Although nimodipine increased global CBF (p <0.05) during normocapnia (89 +/- 8 versus 61 +/- 4 ml/100 g/min), during hypocapnia there was no significant difference between nimodipine and vehicle (45 +/- 3 versus 40 +/- 2 ml/100 g/min). Hypocapnia decreased local CBF in all structures examined, whereas nimodipine increased local CBF in some, but not all structures. In this model, prior institution of hypocapnia prevented nimodipine-induced global CBF increases.
The gene encoding the proteolipid of the vacuolar H+-ATPase of yeast was cloned and sequenced. The deduced amino acid sequence of the yeast protein is highly homologous to that of the proteolipid from bovine chromaffin granules. In contrast to other membrane proteins the transmembrane segments of the bovine and yeast proteolipids were much more conserved than the hydrophilic parts. The fourth transmembrane segment, which contains the DCCD-binding site, was conserved 100%. Comparison of vacuolar and eubacterial proteolipids revealed a homology which pointed to a common ancestral gene that underwent gene duplication to form the vacuolar proteolipids. Additional support for this notion came from the amino acid sequences of subunits involved in the catalytic sectors of archaebacterial ATP synthase and plant and yeast vacuolar H+-ATPases, which reveal extensive sequence homology. Slight, but significant, homology between the archaebacterial and eubacterial ATP synthases was observed. These observations might suggest that the progenitor of ATP synthases was closely related to the present vacuolar H+-ATPases.
The peripheral (catalytic) sector of vacuolar H+-ATPases contains five different polypeptides denoted as subunits A-E in order of decreasing molecular masses from 72 to 33 kDa. The gene encoding subunit B (57 kDa) of yeast vacuolar H+-ATPase was cloned on a 5-kilobase pair genomic DNA fragment and sequenced. Four open reading frames were identified in the sequenced DNA. One of them encodes a protein of 504 amino acids with a calculated Mr of 56,557. Hydropathy plot revealed no apparent transmembrane segments. Southern analysis demonstrated that a single gene encodes this polypeptide in the yeast genome. The amino acid sequence exhibits extensive identity with the homologous protein from the plant Arabidopsis (77%). This polypeptide also contains regions of homology with the alpha subunits of H+-ATPases from mitochondria, chloroplasts, and bacteria. However, less similarity was detected when it was compared with the beta subunits of those enzymes. The implication of these phenomena on the evolution of proton pumps is discussed.
In a previous study of factors influencing the development of acquired subglottic stenosis (SS) we proposed choosing an endotracheal tube (ETT) size such that the ratio of the external diameter divided by the gestational age of the infant in weeks was less than 0.1. We have prospectively followed 44 patients intubated longer than 25 days. One of 36 patients intubated according to the above protocol developed significant SS compared to 3 of 8 patients intubated with an ETT larger than suggested. In a previous study, 9 of 49 patients intubated longer than 25 days developed SS. The incidence of SS in patients intubated with "appropriate-sized" ETT was less than either other group of patients (P less than 0.005 and P less than 0.05, respectively). This study confirms the suggestion that choosing ETT size by the above protocol will lessen, although by itself not eliminate, the incidence of acquired SS.
Since 1981, a total of 729 ileal pouch-anal anastomoses have been performed at the Mayo Clinic-affiliated hospitals. Three hundred fifty-four were in women. Twenty of these patients subsequently had at least one successful pregnancy and delivery. Eleven deliveries were vaginal with episiotomy, and nine were cesarean sections. No maternal deaths occurred. One child died of hyaline membrane disease. The frequency of nocturnal stooling increased in the ileal pouch-anal anastomosis patients during pregnancy (P less than .01), and the increase persisted for three months after delivery (P less than .05). In contrast, the frequency of daytime stools, the incidence of incontinence, the consistency of the stool, and the development of perineal seepage or skin irritation were not greatly altered by pregnancy or delivery. Moreover, postpartum pouch function was not influenced by the type of delivery (vaginal vs. cesarean section). In conclusion, pregnancy and delivery are safe in patients with the ileal pouch-anal anastomosis, but they lead to more frequent nocturnal stools. The type of delivery (vaginal vs. cesarean section) does not influence pouch functional outcome.
The effectiveness of prophylactic mastectomy in the prevention of breast tumors was studied in spontaneous breast-tumor-forming C3H mice. Prolactin levels were assayed to determine if this hormone was related to the incidence of mammary tumors. Two-hundred and fifty-six 1-month-old C3H mice were divided into four groups (control, 1; sham surgery, 2; mammectomy 50 percent, 3; and mammectomy 100 percent, 4). At the time of sacrifice (0 to 1 year postoperatively) estrus cycles were determined, ventral skin (breast) and ovaries were removed for histology, and serum was collected for prolactin assays. Prolactin levels 24 hours postoperatively were significantly elevated (p less than 0.01) in groups 2 to 4 when compared with group 1. Six months postoperatively, prolactin levels were significantly higher (p less than 0.05) in mice with tumors compared with those without tumors in groups 3 and 4. There were no differences in tumor incidence between the four groups. At 12 months postoperatively, no differences in prolactin levels were noted, but group 2 animals had the highest incidence of mammary tumors (89 percent; p less than 0.01) when compared to groups 3 and 4. Mammary tumor incidence was not decreased by 50 percent or 100 percent mammectomy in C3H mice. Prolactin levels rose in response to surgery and/or anesthesia and remained elevated only in tumor-bearing mice who underwent mammectomy, an occurrence similar to that reported in humans.
The purified H+-ATPase from chromaffin granules is composed of several polypeptides, one of which has an apparent molecular weight of 39,000. Immunoblots with the antibody against this protein and various membrane preparations showed that similar or even identical polypeptides may be associated with the H+-ATPases from synaptic vesicle, kidney microsomes, and lysosomes. A cDNA library was constructed from bovine adrenal medulla, and the cDNA encoding the polypeptide was isolated and sequenced. Search in DNA and protein data banks revealed no significant homology to known genes. Hydrophobicity plot revealed no obvious transmembrane segments with the exception of one stretch of hydrophobic and neutral amino acid starting at leucine 16. The cDNA was shown to encode the entire polypeptide by the virtue of an amino acid sequence corresponding to the N terminus of the open reading frame and by subunit and site-specific antibodies. The cDNA was cloned into an expression vector, transcribed by T7 polymerase, and translated by reticulocyte lysate. Even though the cDNA encodes a protein with a molecular weight of 31,495, the translation product comigrated on sodium dodecyl sulfate gels with the subunit of the purified H+-ATPase. In line with several other subunits of vacuolar H+-ATPases, no signal sequence was detected in the translated gene. Northern blots revealed the presence of a single mRNA of about 1.6 kb in bovine adrenal medulla. However, liver, lung, and kidney may contain additional mRNA of about 1.7 kb.
After tissue heart valve replacement 108 patients were randomised to standard anticoagulant control with rabbit brain thromboplastin (Dade C reagent, therapeutic range 18-24 s; international normalised ratio 2.5-40) and 102 to a less intensive regimen controlled with human brain thromboplastin (Manchester Comparative Reagent, therapeutic range 26-30 s; INR 2.0-2.25). Treatment was continued for three months, outcome measures being major or minor embolism or haemorrhage. 2 patients in each group had major embolic events and 11 in each group had minor embolic events. The 95% confidence intervals on the differences are -3.4% to 3.2% for major embolism and -9.3% to 8.2% for minor embolism. Haemorrhagic complications were significantly more frequent with standard treatment (15 patients) than with the less intensive regimen (6 patients); and of the 5 patients with major haemorrhagic complications, all were in the standard treatment group, again a significant difference. The less intensive regimen is thus no less effective and safer than standard anticoagulant therapy in patients with tissue heart valve replacement.
A case of primary retroperitoneal cystadenocarcinoma is presented as the fourth reported case in the world literature to date. The cyst was removed intact and demonstrated an infiltrating malignant process with nuclear pleomorphism and mitotic activity. No ovarian tissue was identified and a cancer antigen 125 (CA 125) test was normal. The patient underwent a staging procedure subsequently that included peritoneal washings, hysterectomy, bilateral salpingoophorectomy, and iliac node dissection. No metastases were found and the patient is without recurrence 22 months postoperative. The literature is reviewed to better define the origin and prognosis of these tumors.
Vacuolar H+-ATPases function in generating protonmotive force across the membranes of organelles connected with the vacuolar system of eukaryotic cells. This family of H+-ATPases is distinct from the two other families of H+-ATPases, the plasma membrane-type and the eubacterial-type. One of the subunits of the vacuolar H+-ATPase binds N,N'-dicyclohexylcarbodiimide (DCCD) and has been implicated in the proton-conducting activity of these enzymes. We have cloned and sequenced the gene encoding the DCCD-binding protein (proteolipid) of the H+-ATPase of bovine chromaffin granules. The gene encodes a highly hydrophobic protein of 15,849 Da. Hydropathy plots revealed four transmembrane segments, one of which contains a glutamic residue that is the likely candidate for the DCCD binding site. Sequence homology with the vacuolar proteolipid and with the proteolipids of eubacterial-type H+-ATPases was detected. The proteolipids from Escherichia coli, spinach chloroplasts, and yeast mitochondria matched better to the NH2-terminal part of the vacuolar protein. The proteolipids of bovine mitochondria and Neurospora mitochondria matched better to the COOH-terminal end of the vacuolar proteolipid. These findings suggest that the proteolipids of the vacuolar H+-ATPases were evolved in parallel with the eubacterial proteolipid, from a common ancestral gene that underwent gene duplication.
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Burns as a result of priming carburetors with gasoline resulted in 4% of all burn admissions to the Oregon Burn Center from 1980-1982. The burns most frequently involved the head and neck and upper extremities. Although most of them involved less than 10% of the total body surface area, half of all the injuries included areas of full-thickness tissue loss. This type of preventable accident inflicts substantial morbidity and may be a major financial burden. Professional and public awareness of the risk of serious gasoline burns incurred during carburetor priming should decrease its incidence.
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The maximal aerobic performance (VO2 max) and energy costs of cycling at various power outputs and equivalent road speeds of a highly trained endurance cyclist (age 23.4 yrs, height 1.95 m, weight 73.1 kg), were measured in the laboratory on an eddy-current cycle ergometer, and the physiological responses related to determinations made during a 24 h cycling time trial event, using continuous ECG recording from which estimates of ergogenic demands were obtained. The cyclist covered a distance of 694 km during the event at an average speed of 28.9 km.h-1 which corresponded to an equivalent oxygen cost of 38.5 ml.kg-1 min-1 and represented approximately 55% of his VO2 max. During the event, the cyclist expended an estimated 82,680 kJ of energy, of which approximately 44,278 kJ (54%) were supplied by repeated feedings of liquids, solids and semi-solids and some 38,402 kJ (46%) came from the stored energy reserves which resulted in a 1.19 kg loss of body weight during the event. The energy demands of the activity were more than three times greater than the highest recorded values of severe industrial work, and similar to the hourly rates of expenditure of shorter duration competitive events, but above the highest values reported over other extreme endurance events over the same period of time. The results thus represent near maximal levels of sustainable ergogenic effort by man over a complete 24 h cycle.