Biomedical subjects
Publications and source records attributed to L Weaver.
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BACKGROUND: Once Helicobacter pylori infection is established, it is difficult to eradicate despite a persistent systemic and local immune response. It is not known whether immunisation can be used to prevent H pylori infection in humans. AIMS: To evaluate the effect of the human immune response on adherence of H pylori to gastric cells. METHODS: Human milk from a woman infected with H pylori and milk from a non-infected woman were each fractionated by chromatography on DEAE cellulose. Bacteria were incubated with either serum, human milk, human milk fractions, or secretory IgA before incubation with Kato III cells (cells from a gastric adenocarcinoma cell line). Bacterial adherence to the cells was assessed using flow cytometry. RESULTS: Serum from both the H pylori infected and non-infected women killed H pylori. This resulted from the action of complement as heating the serum to 56 degrees C for 30 minutes abolished the bactericidal activity. Immunoglobulin fractions from serum of both infected and non-infected women did not inhibit H pylori adherence to Kato III cells. Human milk from the woman infected with H pylori and from the non-infected woman inhibited binding of H pylori to Kato III cells by 50 to 70%. Secretory IgA isolated from human milk had minimal inhibitory effect on adherence and this was notably less than the inhibitory effect of whole human milk. CONCLUSIONS: Human milk inhibits adherence of H pylori to Kato III cells and this inhibition is independent of whether or not the donor is infected with H pylori. Secretory IgA has minimal inhibitory effect on H pylori adherence.
Bradykinins have only recently been identified in fish, and a detailed analysis of their cardiovascular actions is lacking. The present study examines the cardiovascular effects of trout bradykinin ([Arg0,Trp5,Leu8]bradykinin; tBK) in conscious trout, Oncorhynchus mykiss. tBK (1-10 nmol/kg body wt bolus) produced triphasic pressor-depressor-pressor responses. In phase 1, cardiac output (CO), ventral aortic (P(VA)), dorsal aortic (P(DA)), and central venous pressure increased, whereas systemic (R(S)) and gill resistance (R(G)) were unchanged. In phase 2, R(G) increased, whereas R(S), CO, and heart rate decreased, reducing P(VA) and P(DA). Plasma prostaglandin E2 and the prostacyclin metabolite, 6-ketoprostaglandin F1alpha, were significantly elevated during phase 2, whereas leukotrienes C4 and B4 and thromboxane B2 were unaffected. Phase 3 was produced by an increased CO and R(S) and the return of R(G) to control. Phase 1 pressor response was not blocked by inhibitors of cyclooxygenase, angiotensin-converting enzyme (ACE) or alpha-adrenoceptors (alpha-AD), whereas phase 2 depressor and plasma prostaglandin responses were prevented by cyclooxygenase inhibition. Phase 3 was partially blocked by ACE and alpha-AD inhibitors and is a response to the preceding hypotension. In vitro, tBK only decreased vascular resistance in the perfused splanchnic or skeletal muscle-kidney preparations. These results show that although tBK has multiple effects on the trout cardiovascular system, none of the effects are due to direct tBK stimulation of vascular smooth muscle. Phase 2 vasodilation has features consistent with release of vasodilator prostaglandins while the mechanism of phase 1 constriction is unknown.
Active venous regulation of cardiovascular function is well known in mammals but has not been demonstrated in fish. In the present studies, the natriuretic peptides (NP) rat atrial natriuretic peptide (ANP) and trout ventricular natriuretic peptide (VNP), clearance receptor inhibitor SC-46542, and sodium nitroprusside (SNP) were infused into unanesthetized trout fitted with pressure cannulas in the ventral aorta, dorsal aorta, and ductus Cuvier, and a ventral aorta (VA) flow probe was used to measure cardiac output (CO). In another group, in vivo vascular (venous) capacitance curves were obtained during ANP or SNP infusion. The in vitro effects of NP on vessels and the heart were also examined. ANP, VNP, and SC-46542 decreased central venous pressure (PVen), CO, stroke volume (SV), and gill resistance (RG), whereas systemic resistance (RS) and heart rate (HR) increased. Dorsal aortic pressure (PDA) transiently increased and then fell even though RS remained elevated. ANP decreased mean circulatory filling pressure (MCFP), increased vascular compliance at all blood volumes, and increased unstressed volume in hypovolemic fish. ANP had no direct effect on the heart. ANP responses in vivo were not altered in trout made hypotensive by prior treatment with the angiotensin-converting enzyme inhibitor lisinopril. SNP reduced ventral aortic pressure (PVA), PDA, and RS, increased CO and HR, but did not affect PVen, SV, or RG. SNP slightly decreased MCFP but did not affect compliance or unstressed volume. In vitro, large systemic arteries were more responsive than veins to NP, whereas SNP relaxed both. These results show that, in vivo, NP decrease venous compliance, thereby decreasing venous return, CO, and arterial pressure. Conversely, SNP hypotension is due to decreased RS. This is the first evidence for active regulation of venous capacitance in fish, which probably occurs in small veins or venules. The presence of venous baroreceptors is also suggested.
The physiological functions of the neurohypophyseal hormone arginine vasotocin (AVT) in teleosts are not clear. In the present studies, the sites and mechanisms of action of AVT on the rainbow trout Oncorhynchus mykiss cardiovascular system were examined in unanesthetized instrumented fish, perfused organs and isolated vessels. Injection of AVT (1, 10 or 100 pmol kg-1 body mass) into trout with dorsal aortic cannulas produced a modest, but dose-dependent, increase in dorsal aortic pressure (PDA). Bolus injection of AVT (100 pmol kg-1 body mass), or continuous infusion (6.7 pmol kg-1 min-1), into trout instrumented with dorsal aortic, ventral aortic and central venous cannulas and a ventral aortic flow probe significantly increased PDA as well as ventral aortic (PVA) and central venous (PVEN) blood pressure. Bradycardia accompanied the rapid rise in PVA while gill resistance (RG) increased. Maximum response to the AVT bolus was reached within 13­21 min and the response decayed slowly over the ensuing 90 min. AVT infusion (6.7 pmol kg-1 min-1) significantly increased PVEN and mean circulatory filling pressure and decreased unstressed blood volume, whereas venous compliance was unaffected. These in vivo studies indicate that AVT increases venous tone, thereby mobilizing blood from the unstressed compartment into the stressed compartment. This increases PVEN, which increases venous return and helps maintain, or slightly elevate, cardiac output. This, combined with an elevated RG and slightly elevated systemic resistance (RS), increases both PVA and PDA; however, the rise in PDA is mitigated by a disproportionate increase in RG relative to RS. In vitro, the effects of AVT are consistent with in vivo responses. AVT increased vascular resistance in the perfused gill and perfused trunk and contracted isolated vascular rings from both rainbow and steelhead trout. The general order of sensitivity of isolated vessels to AVT was (in decreasing order): anterior cardinal vein, celiacomesenteric artery, ductus Cuvier, efferent branchial artery, ventral aorta and coronary artery. Extracellular Ca2+ accounted for over 70 % of the tension in the AVT-contracted efferent branchial artery, but only 57 % of the tension in the anterior cardinal vein. Vascular AVT receptor sensitivity (EC50) in vitro ranged from 0.3 to 6 nmol l-1 and was similar to the estimated ED50 for the dose-dependent increase in PDA in vivo (approximately 1 nmol l-1). AVT was not inotropic in paced ventricular rings nor did it exhibit vasorelaxant activity in perfused organs or vascular rings. These results show that AVT is a potent vasoconstrictor in trout and that its two primary cardiovascular targets are the systemic veins and the branchial vasculature.
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Previous work has shown that incubation of heat-denatured plasma from the rainbow trout Oncorhynchus mykiss with porcine pancreatic kallikrein generates [Lys0, Trp5, Leu8]bradykinin (trout [Lys0]BK). We have now isolated a second BK-related peptide from kallikrein-treated trout plasma with the primary structure: Arg-Arg-Pro-Gly-Trp-Ser-Pro-Leu-Arg (trout [Arg0]BK). Bolus injections of both trout [Arg0]BK and [Lys0]BK (> 100 pmol/kg) into the dorsal aorta of conscious trout produced multiphasic effects on arterial blood pressure. An initial pressor response of short duration (1-2 min) was followed by a fall in pressure (to below basal values in 11 out of 15 animals) and then by a sustained rise in pressure lasting up to 60 min. The maximum rise in pressure produced by trout [Arg0]BK (10 nmol/kg) was approximately one-fourth of the maximum rise produced by angiotensin II in the same animals. Intracerebroventricular injections of trout [Arg0]BK (500 pmol) into conscious trout had no effect on arterial blood pressure or heart rate. Trout [Arg0]BK did not affect the tension of vascular rings from trout efferent branchial and caeliacomesenteric arteries and anterior cardinal vein. Trout des [Arg9]BK had no effect on cardiovascular parameters, either in vivo or in vitro, indicating that the C-terminal arginine residue of the peptide is important in interaction with the trout kinin receptor(s).
The adenovirus fiber protein is responsible for attachment of the virion to cell surface receptors. The identity of the cellular receptor which mediates binding is unknown, although there is evidence suggesting that two distinct adenovirus receptors interact with the group C (adenovirus type 5 [Ad5]) and the group B (Ad3) adenoviruses. In order to define the determinants of adenovirus receptor specificity, we have carried out a series of competition binding experiments using recombinant native fiber polypeptides from Ad5 and Ad3 and chimeric fiber proteins in which the head domains of Ad5 and Ad3 were exchanged. Specific binding of fiber to HeLa cell receptors was assessed with radiolabeled protein synthesized in vitro, and by competition analysis with baculovirus-expressed fiber protein. Fiber produced in vitro was found as both monomer and trimer, but only the assembled trimers had receptor binding activity. Competition data support the conclusion that Ad5 and Ad3 interact with different cellular receptors. The Ad5 receptor distribution on several cell lines was assessed with a fiber binding flow cytometric assay. HeLa cells were found to express high levels of receptor, while CHO and human diploid fibroblasts did not. A chimeric fiber containing the Ad5 fiber head domain blocked the binding of Ad5 fiber but not Ad3 fiber. Similarly, a chimeric fiber containing the Ad3 fiber head blocked the binding of labeled Ad3 fiber but not Ad5 fiber. In addition, the isolated Ad3 fiber head domain competed effectively with labeled Ad3 fiber for binding to HeLa cell receptors. These results demonstrate that the determinants of receptor binding are located in the head domain of the fiber and that the isolated head domain is capable of trimerization and binding to cellular receptors. Our results also show that it is possible to change the receptor specificity of the fiber protein by manipulation of sequences contained in the head domain. Modification or replacement of the fiber head domain with novel ligands may permit adenovirus vectors with new receptor specificities which could be useful for targeted gene delivery in vivo to be engineered.
We developed a method for measurement of the in situ tensions in the ligaments of the palmar side of the wrist in cadaver specimens. The technique is based on deflecting the ligaments transversely (i.e., perpendicular to their longitudinal axis) using an instrumented probe. Based on measurement of the load required to deflect the ligament, magnitude of the transverse deflection, and axial length of the ligament, the axial tension in the ligament can be determined without otherwise disturbing it. The tensions in 8 palmar ligaments in 10 functional positions of the wrist in each of 5 fresh cadaver specimens were assessed. The position of the wrist was monitored, but the specimen was not loaded. We concluded that (1) the palmar ligaments are in tension, even with the wrist in neutral position and unloaded; (2) the following ligaments act as passive stabilizers: in neutral the triquetrocapitate and distal part of the radioscaphocapitate, in radial deviation the radiolunate, in ulnar deviation the ulnolunate, in pronation the proximal part of the radioscaphocapitate, in supination the ulnolunate, and in extension the ulnolunate, radiolunate, and radioscaphocapitate; (3) in any position some ligaments are in a state of greater tension than others. The radiolunate, ulnolunate, radioscaphocapitate had the greatest tension; and the lunotriquetral, trapeziocapitate, and scaphocapitate had the least.
To facilitate clinical applications of retroviral-mediated human gene transfer, retroviral vectors must be of high titer and free of detectable replication-competent retroviruses. The purpose of this study was to optimize methods of retroviral vector production and transduction. Studies were conducted using 22 retroviral vector producer cell lines. Inactivation of retroviral vectors was greater at 37 degrees C than at 32 degrees C. A 5- to 15-fold increase of vectors was produced at 32 degrees C compared to 37 degrees C; the vector increase at 34 degrees C was intermediate. For example, PA317/G1Na.40 grew to a titer of 1.8 x 10(7) cfu/ml at 32 degrees C, compared to 5.0 x 10(5) cfu/ml at 37 degrees C. The production of retroviral vectors was scalable achieving similar results in flasks, roller bottles, or a CellCube Bioreactor. Retroviral vectors were concentrated 15-24 times with vector recovery ranging from 91 to 96% in a Pellicon tangential flow filtration system. Retroviral supernatants were successfully lyophilized. The combination of glucose or sorbitol with gelatin resulted in recovery rates of 64-83%. In studies on transduction by retroviral vectors, centrifugation of vector supernatants onto target cells significantly increased transduction efficiency as measured by vector titration for G418 resistance, fluorescence-activated cell sorting (FACS), and polymerase chain reaction (PCR) analyses. The combination of the above methods has significantly increased the growth and transduction by this vector system.
Changes in employment opportunities and medical services are exploited by men and women in different ways. This paper examines gender-based variation in the selective use of employment and health opportunities in a Gambian village which has been the subject of medical and nutritional research by the Medical Research Council (MRC) for 43 years. The seasonal workloads of 105 men and women in Keneba were compared during one calendar year. Women carried a heavier burden of agricultural labour, while men had a higher rate of waged employment. The impact of the MRC field station on the local economy was assessed and evidence of associated male dependence on MRC employment found. Illness reporting patterns and the treatment choices of men and women were examined. Women made greater use of the MRC medical service, while men resorted more frequently to local remedies and healers. Female dependence on the MRC medical services is suggested by the data, and may be linked to the greater attention paid to them by researchers and medical practitioners.
Ethical issues related to the use of computerized protocols to control mechanical ventilation of patients with Acute Respiratory Distress Syndrome (ARDS) are identical to the ethical issues surrounding the use of any therapy or intervention. Four ethical principles must be considered: nonmaleficence, beneficence, autonomy, and distributed justice. The major ethical challenges to computerized protocol use as a specific application of clinical decision support tools are found within the principles of nonmaleficence and of beneficence. The absence of credible outcome data on which ARDS patient survival probabilities with different therapeutic options could be based is a constraint common to most ICU clinical decision making. Clinicians are thus deprived of the knowledge necessary to define benefit and are limited to beneficent intention in clinical decisions. Computerized protocol controlled decision making for the clinical management of mechanical ventilation for ARDS patients is ethically defensible. It is as well supported as most ICU therapy options.
OBJECTIVE: To determine fluctuation in mixed venous oxygen saturation in critically ill medical patients during a period of rest. DESIGN: Nonexperimental, descriptive. SETTING: The medical and coronary intensive care units in a large county hospital in south-central Texas. PATIENTS: Twenty critically ill patients, aged 19 to 85, who had placement of a pulmonary artery catheter capable of continuous monitoring of mixed venous oxygen saturation. The majority had a diagnosis of respiratory failure and required mechanical ventilation. METHODS: Mixed venous oxygen saturation was recorded each minute for a 2-hour period in either early morning or late afternoon hours. Minute-by-minute values obtained during a 30-minute period of rest were used to determine fluctuation. The lowest and highest mixed venous oxygen saturation values during the period were used to calculate percent changes from average values (fluctuation). RESULTS: The range of fluctuation was +/- 6% of the average mixed venous oxygen saturation value for 80% of the sample. Four patients had a greater range of fluctuation: however, their actual mixed venous oxygen saturation values were within a clinically acceptable range. No significant differences in percentage of low or high fluctuation were noted for the following variables: time of day, medication administration, oxygen delivery, oxygen consumption and average mixed venous oxygen saturation. The percentage of low fluctuation was significantly lower for four patients who were not mechanically ventilated. CONCLUSIONS: Knowledge of normal fluctuation enables the care giver to evaluate changes in mixed venous oxygen saturation in response to activities and/or treatments. Additional study of fluctuation in homogenous groups of critically ill patients is warranted.
Cryosurgery, the in situ freezing of cancer, has been proposed in the past as a possible treatment for unresectable hepatic tumors. Its advantage lies in the fact that it is a very focal treatment sacrificing less normal tissue than surgical resection, allowing treatment of multiple lobes. Because cryosurgery does not affect large vessels, tumors in difficult locations, such as adjacent to the inferior vena cava (IVC), can be treated. With the use of intraoperative ultrasound to place the cryoprobes and monitor the freezing process, 18 patients with unresectable metastatic colon carcinoma confined to the liver were treated. Of the 18 patients treated, 4 (22%) are in complete remission as determined by computed tomography (CT) scans and carcinoembryonic antigen (CEA) levels, with a mean follow-up of 28.8 months. Four patients (22%) were not adequately treated at the time of cryosurgery. The number of lesions frozen in each patient ranged from 1 to 12, with a mean of 6 lesions. Fourteen patients had bilobar disease; three patients had previous right lobectomies with recurrences in their remaining left lobes prior to cryosurgery, and one patient had unilobar disease. Mean survival of the 14 cases with recurrence was 21.4 months, with 2 of the 14 still alive. Ultrasound-guided hepatic cryosurgery appears to be an effective treatment for metastatic colon carcinoma to the liver that is unresectable (including patients with bilobar and multiple lesions). These preliminary results indicate that the procedure warrants further study.
Low birthweight (LBW) infants are at risk of increased mortality, impaired growth, and increased morbidity. We studied the progress of all LBW infants (less than 2.5 kg) born in a West African village where there is a resident pediatrician and midwife. There were 426 live births during the 8 years studied of which 42 (10 per cent) were of LBW. There were 17 infant deaths (IMR = 40/1000). Mean birthweight and gestation of infants dying in the first year were significantly lower than those of all live birth (2.33 kg v. 2.99 kg, P less than 0.001; 36.9 w v. 38.9 w, P less than 0.05). The mean weights of the 32 surviving LBW infants (15 preterm, 17 full term, small for gestational age) were compared with those of 32 full term, appropriate for gestational age matched controls over the first year. Growth velocities of paired groups were identical. The significant differences in weight at 1 year (P less than 0.005) reflected those at birth (P less than 0.001). There were no significant differences in clinic attendance rate or incidence of diarrhoea and respiratory disease between the four groups. We conclude that LBW is a strong risk factor for infant mortality, but not for diarrhoeal and respiratory morbidity in a community with ready access to obstetric and pediatric care.
Serial samples of synovial fluid aspirated from two patients with septic arthritis were assayed for proteinases and proteinase inhibitors. Active metalloproteinases but no proteinase inhibitors were present in all samples taken prior to treatment. The levels of active metalloproteinases fell with time although proenzyme forms were still present in the fluids. Both alpha 2-macroglobulin and the tissue inhibitor of metalloproteinases were found in the septic synovial fluids after treatment commenced. It is proposed that the lack of inhibitors and the presence of active proteinases capable of digesting collagen, gelatin and proteoglycan accounts for the rapid loss of cartilage found in septic arthritis.
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