Biomedical subjects
J Adams
Publications and source records attributed to J Adams.
A relationship between proteinuria and acute tubulointerstitial disease in rats with experimental nephrotic syndrome.
The relationship between tubulointerstitial nephritis and proteinuria was characterized in experimental nephrosis in rats. In one group, proteinuria induced by aminonucleoside of puromycin (PAN) was reduced by using an 8% protein diet and adding the angiotensin I-converting enzyme (ACE) inhibitor enalapril to the drinking water. Two control groups were injected with saline and PAN, respectively, and fed a 27% protein diet. The first group had significantly reduced albuminuria and a definite attenuation of tubular cell injury. There was a strong positive correlation between the number of interstitial macrophages and albuminuria. The beneficial effect was reproduced by dietary-protein restriction alone, whereas ACE inhibition alone had an insignificant effect on the degree of proteinuria. Depletion of circulating T lymphocytes in one group of nephrotic rats eliminated interstitial lymphocytes but did not affect interstitial macrophage influx. Inhibition of the in situ proliferation of resident interstitial macrophages by unilateral kidney irradiation failed to change the intensity of the macrophage infiltration. Treatment of rats with sodium maleate produced proximal tubular cell toxicity but interstitial inflammation did not develop, suggesting that the latter is not a nonspecific response to tubular injury. These studies demonstrate a strong relationship between tubulointerstitial nephritis and the severity of proteinuria in experimental nephrosis.
Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor.
A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a Ki of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (greater than 8000) in culture.
Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis.
Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 microgram/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fall in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NG-methyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 +/- 2.7 mmHg vs 47.8 +/- 6.8 mmHg, p = 0.01, n = 4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 +/- 5.0 mm Hg, n = 3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock.
The onset of effect of the H1-antagonist acrivastine ("Semprex") assessed by histamine bronchial challenge in volunteers.
The onset of effect of acrivastine, a new H1-antagonist, has been assessed using antagonism of histamine-induced bronchoconstriction in sensitive volunteers. Acrivastine administered 30, 45, 60 or 90 min before challenge produced a right-shift of the histamine dose-response curve of at least 8-fold indicating that a clinically desired degree of H1-antagonism was present within 30 min of ingestion of the recommended therapeutic dose.
Hemodynamic and permeability characteristics of acute experimental necrotizing enterocolitis.
We examined the local hemodynamic response of intestinal loops during acute necrotizing enterocolitis (NEC) in anesthetized rabbits. NEC was induced in ileal loops by transmural injection of a solution containing casein (10 mg/ml) and calcium gluconate (50 mg/ml) acidified to pH 4.0 with propionic or acetic acid. Control loops received casein only (pH 5.0). Mucosal damage was quantified by the blood-to-lumen movement of [51Cr]EDTA, fluid shifts into the lumen, and histology. Mean arterial pressure and loop blood flow were steady over the 3-hr period, loop fluid volume decreased, and there was no evidence of necrosis or epithelial damage. In loops receiving acidified casein and calcium gluconate, there was an immediate dramatic increase in loop blood flow that returned to baseline by 50 min. In addition, loop fluid volume was dramatically increased, necrosis was noted in the form of blunting and loss of villi, and sevenfold increase in [51Cr]EDTA permeability was evident. Administration of CV 1808 (30 mg/kg/hr), a selective adenosine2 agonist, which maintained and elevated loop blood flow throughout the 3 hr protocol, failed to alter the changes in loop fluid volume or prevent necrosis. Histamine levels in loop fluid levels were significantly elevated 20-30 min after NEC induction when compared to saline controls, indicating an early activation of mucosal defenses with this luminal insult. Thus, this model of NEC is characterized by a transient, acute hyperemia, increased intestinal permeability, and histamine release. As mucosal damage was independent of ischemia and could not be prevented by vasodilatory therapy, this model supports the clinical findings that NEC is correlated with luminal factors related to feeding and independent of cardiovascular stress.
Synthesis and biological activity of atrial natriuretic factor analogues: effect of modifications to the disulfide bridge.
A series of atrial natriuretic factor (ANF) analogues with modifications to the disulfide bridge and lacking the exocyclic N-terminal sequence was synthesized. The native cystine residue was substituted by isofunctional deamino carba, beta,beta-dimethyl carba and dehydro dicarba spanners that bridge residues 106 and 120. The compounds were prepared by segment condensation coupling using the base-labile (9-fluorenylmethyl)carboxyl protecting group. Biological evaluation revealed that the exocyclic N-terminal segment of ANF is not necessary for expression of high biological activity. The compounds retained high affinity for ANF receptors in bovine adrenal zona glomerulosa cells and were found to be potent antihypertensive and diuretic agents, indicating that the native disulfide bridge can be mimicked by isosteric spanning residues. It was noted that the reported analogues, unlike the endogenous hormone, show marked reduced inhibitory activity on PGE1-stimulated aldosterone secretion from adrenal zona glomerulosa cells. This lack of inhibition may be a contributing element to the low saluresis in spite of the high level of diuresis observed with some analogues.
NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide.
Clinical assessment of the activity of tumor necrosis factor (TNF) against human cancer has been limited by a dose-dependent cardiovascular toxicity, most frequently hypotension. TNF is also thought to mediate the vascular collapse resulting from bacterial endotoxin. The present studies address the mechanism by which TNF causes hypotension and provide evidence for elevated production of nitric oxide, a potent vasodilator initially characterized as endothelium-derived relaxing factor. Nitric oxide is synthesized by several cell types, including endothelial cells and macrophages, from the guanidino nitrogen of L-arginine; the enzymatic pathway is competitively inhibited by NG-methyl-L-arginine. We found that hypotension induced in pentobarbital-anesthetized dogs by TNF (10 micrograms/kg, i.v., resulting in a fall in mean systemic arterial pressure from 124.7 +/- 7 to 62.0 +/- 22.9 mmHg; 1 mmHg = 133 Pa) was completely reversed within 2 min following administration of NG-methyl-L-arginine (4.4 mg/kg, i.v.). In contrast, NG-methyl-L-arginine failed to reverse the hypotensive response to an equivalent depressor dose of nitroglycerin, a compound that acts by forming nitric oxide by a nonenzymatic, arginine-independent mechanism. The effect of NG-methyl-L-arginine on TNF-induced hypotension was antagonized, and the hypotension restored, by administration of excess L-arginine (100 mg/kg, i.v.). Our findings suggest that excessive nitric oxide production mediates the hypotensive effect of TNF.
Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries.
This study was designed to compare the results of treatment with, firstly, exogenous gonadotrophins, with (57 cycles) and without (65 cycles) pretreatment with a superactive analogue of luteinizing hormone releasing hormone (LHRH) and, secondly, pure follicle stimulating hormone (FSH) (50 cycles) with those of human menopausal gonadotrophin (HMG) (72 cycles) in 46 women with clomiphene-citrate-resistant anovulation associated with polycystic ovaries. Patients randomly allocated to the analogue group received buserelin (Suprefact, Hoechst, UK, Ltd, Hounslow, Middlesex), 800 micrograms/day by nasal insufflation and when hypogonadism was achieved, patients were again randomly allocated for ovarian stimulation with either FSH or HMG. Controls received FSH or HMG alone. Patients pretreated with the analogue had similar pregnancy and ovulation rates, needed larger doses and more days of gonadotrophin therapy and had more ovarian overstimulation than those receiving no pretreatment. The role of superactive LHRH analogues for induction of a single ovulation for in-vivo fertilization is thus uncertain. Pure FSH had no advantages over HMG, the LH content of HMG having no deleterious effect on the ovary.
The influence of culture on pain in Anglo and Hispanic children with cancer.
This study sought to determine if cultural heritage and acculturation influence the perception and expression of pain and anxiety. The study was based on self-report and observation of Anglo and Hispanic children with cancer undergoing invasive procedures. Seventy-eight children between the ages of 3 and 15 participated. Thirty-five were Anglo and 43 were Hispanic. A significant inverse relationship between age and observed and reported distress was noted in both ethnic groups. The Anglo and Hispanic children had remarkably similar behavioral responses. Hispanic parents, however, reported significantly higher levels of anxiety than Anglo parents.
Satisfactory resolution of Jessner's lymphocytic infiltration of the skin following treatment with etretinate.
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HLA associations in patients with polycystic ovaries and in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency.
Ninety-nine Caucasian patients with ultrasonically detected polycystic ovaries (PCO) were typed for human leucocyte (HLA) antigens. Fifty patients with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency were similarly typed. Among the patients with PCO, there was a significant increase in the frequency of HLA DRW6 (P = 0.0027) compared with that found in a control population, which remained significant (P = 0.027) when corrected for the number of antigens tested. This difference was reduced, but remained significant (P = 0.006), when the patients with CAH and PCO were added. There was also a significant decrease in the frequency of HLA DR7 (P = 0.017) among the patients with PCO compared with a control population, but there was no distortion of the frequencies of HLA A, B or Cw antigens. Among the patients with CAH, previously well documented associations of HLA B14 and DR1 with non-classical disease were confirmed. The frequency of HLA Bw47 was increased among the whole group of CAH patients (P = 0.05) but was not increased among those with classical salt-wasting (SW) or simple virilizing (SV) disease. Family studies were performed in close female relatives of 16 of the PCO patients and 21 of the CAH patients but no evidence for genetic linkage between HLA and PCO status could be found. These data suggest that there is no significant component of disturbed adrenal steroid 21-hydroxylase activity to account for the PCO morphology, although there may be some other genetic factor, more proximal to the centromere on chromosome 6, affecting the development of polycystic ovaries.
The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives.
Seventy-seven female patients (36 adults and 41 children aged under 16 years) with congenital adrenal hyperplasia (CAH) were assessed using pelvic ultrasound, as well as with standard endocrine tests and HLA typing. Forty-six close female relatives were also tested for ovarian morphology using ultrasound after assessment of their heterozygous state using HLA typing. The association of CAH with ultrasonically detected polycystic ovaries (PCO) was confirmed in 30/36 (83%) adult patients, 4/10 (40%) postpubertal girls and 1/31 (3%) pre and peripubertal girls: in all, 35/46 (76%) postmenarcheal patients. Six out of nine (67%) pre-menopausal mothers of patients with PCO, and 8/10 (80%) sisters of patients with PCO also had PCO. The proportions of both CAH patients and heterozygote subjects with PCO were significantly greater than that found in a normal population (P less than 0.0001). The finding, however, of two homozygous non-CAH-affected adult sisters with PCO and, conversely, of 10 heterozygous adult relatives and of 12 postmenarcheal CAH patients with normal ovaries, indicates that the ovarian morphological change may be independent of the adrenal lesion.
Uterine size and endometrial thickness and the significance of cystic ovaries in women with pelvic pain due to congestion.
In a group of 55 women with chronic pain due to pelvic congestion measurement by ultrasound revealed they had a larger uterus and thicker endometrium as compared with a group of normal women matched for age, parity and the presence of polycystic ovaries found on ultrasound scanning. Many women with pelvic congestion (56%) were found on ultrasound to have cystic changes in their ovaries which ranged from a classic polycystic pattern to the appearance of clusters of 4-6 cysts in bilaterally enlarged ovaries. It is suggested that uterine enlargement and thickening of the endometrium are caused by oestrogen, either from the effects on the target organs of an increased concentration or of hypersensitivity to oestrogen.
Genetic evidence that Neisseria gonorrhoeae produces specific receptors for transferrin and lactoferrin.
Transferrin (TF) and lactoferrin (LF) are probably the major sources of iron (Fe) for Neisseria gonorrhoeae in vivo. We isolated mutants of N. gonorrhoeae FA19 that were unable to grow with Fe bound to either TF (TF-) or LF (LF-) or to both TF and LF ([TF LF]-). The amount of Fe internalized by each of the mutants was reduced to background levels from the relevant iron source(s). The wild-type parent strain exhibited saturable specific binding of TF and LF; receptor activity was induced by Fe starvation. The TF(-)-specific or LF(-)-specific mutants were almost completely lacking in receptor activity for TF or LF, respectively, whereas the [TF LF]- mutants bound both TF and LF as well as the wild-type strain. All mutants utilized citrate and heme normally as Fe sources. These results demonstrate that ability to bind TF or LF is essential for gonococci to scavenge appreciable amounts of Fe from these sources in vitro. In addition, the TF and LF Fe acquisition pathways are linked by the mutual use of a nonreceptor gene product that is essential to Fe scavenging from both of these sources; this gene product is not required for Fe acquisition from other sources.
Confidentiality and Huntington's chorea.
A doctor has duties towards his patients of both confidentiality and veracity and at times these may conflict, as in the following case. A mother who has the symptoms of Huntington's chorea does not wish her daughters to know. The doctor must try to make her realise how valuable the information can be to the daughters, and thus obtain her consent to inform them. If the mother's consent cannot be obtained, then the doctor must tell the mother that he cannot allow her attitude to deprive the daughters of this information, especially at this crucial time as they plan to have children. The well-being of the daughters' future families must take precedence over the mother's desire for secrecy regarding her condition.
Pharmacological profile of SK&F 105809, a dual inhibitor of arachidonic acid metabolism.
The effects of SK&F 105809, 6,7,-dihydro-2-[4(methylsulfinyl) phenyl]-3-(4-pyridyl) -5[H]-pyrrolo[1,2-a] imidazole, on eicosanoid metabolism, inflammatory responses, algesia and ulcer formation are described. SK&F 105809 was determined to be a prodrug for the sulfide metabolite SK&F 105561 which is an inhibitor of 5-lipoxygenase (5-LO) and prostaglandin H (PGH) synthase activities seen with both the isolated enzyme (IC50S 3 microM) and human monocyte production of the eicosanoids leukotriene B4 (LTB4, IC50 1.0 microM) and prostaglandin E2 (PGE2, IC50 0.1 microM). In-vivo conversion of SK&F 105809 to the active principle SK&F 105561 was observed in both mice and rats. SK&F 105809 inhibited LTB4 and PGE2 production in vivo in inflammatory exudates as well as the production of LTB4 and thromboxane B2 (TxB2) ex vivo in rat blood. SK&F 105809 inhibited oedema and inflammatory-cell infiltration in arachidonic acid-induced inflammation in the mouse ear and rat paw as well as in carrageenan- and monosodium urate crystal-induced peritonitis. SK&F 105809 was also effective in inhibiting mouse collagen-induced arthritis and associated acute-phase reactant protein. At the same time, these acute and chronic models of inflammation were found to be resistant to the action of selective cyclooxygenase inhibitors such as naproxen. In addition, SK&F 105809 possessed analgesic activity in phenylquinone-induced abdominal constriction assay and inhibited indomethacin-induced ulcers.
Ethical issues in geriatric emergency medicine.
The emergence of ethics, geriatrics, and emergency medicine as areas of specialized interest has proceeded rapidly over the past two decades. Each of these fields continues to grow in response to patient needs, but it is clear that scientific knowledge alone cannot provide the physician with all the guidance necessary to ensure the provision of optimal care. Patient care cannot consist only of making diagnoses, prescribing medications, and performing technical procedures. Particularly in the care of the elderly, the emergency physician must be able to recognize ethical issues and to respond to them in the manner that will provide the greatest benefit to the patient. With the application of such skills, the emergency treatment of the elderly promises more benefit for elderly patients and their families and less doubt and anguish for emergency practitioners.