Zidovudine for early HIV infection: yes, no, maybe.
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Decision Making↗
Biomedical subjects
J C Roberts
Publications and source records attributed to J C Roberts.
The importance of sample preparation and storage in glutathione analysis.
There is little consistency in the literature regarding the procedures for sample preparation employed for the measurement of glutathione (GSH) in biological tissues. Most procedures use an acid to homogenize tissue samples to precipitate proteins from the mixture and to minimize oxidative changes. Others employ 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) in the homogenization, which serves only to block thiol groups. The present studies were undertaken to critically compare the two methods of sample preparation on resulting GSH values determined by the Tietze method in numerous organs of mice. It was found that kidney, liver, and pancreas GSH levels were seriously underestimated when DTNB was used instead of acid to prepare the tissue samples. This discrepancy was eliminated when the animals were pretreated with AT-125, confirming the participation of gamma-glutamyltranspeptidase, the enzyme responsible for the first step in the degradation of GSH. GSH added to kidney homogenates in DTNB was degraded rapidly and continuously in a time-dependent fashion. In contrast, GSH added to acid homogenates produced stable GSH values up to 8 h after sample preparation in most cases. Storage of acid homogenates at -70 degrees C for 12 months gave results identical to original measurements, within 10% error, for 9 of 10 samples tested.
Animals↗
The influence of phthalate esters on Leydig cell structure and function in vitro and in vivo.
Phthalate esters are widely used in the manufacture of plastics and have been shown to cause testicular toxicity, purportedly, by targeting the Sertoli cell alone. Recent evidence, however, indicates that a paracrine control exists between Sertoli and Leydig cells and the breakdown of one component of this relationship is therefore detrimental to normal function. However, no data that explore the influence of testicular toxins on Leydig cell structure and function have been published hitherto. The preliminary studies reported here were initiated to test the hypothesis that phthalate intoxication may adversely alter Leydig cell structural and functional integrity. Four phthalate esters, namely, di(2-ethylhexyl) phthalate (DEHP, di-n-pentyl phthalate (DPP)., di-n-octyl phthalate (DOP), and diethyl phthalate (DEP) were investigated in vivo and their monoesters (MEHP, MPP, MOP, and MEP, respectively) in vitro for indications of Leydig cell toxicity in the rat. Rats were dosed by oral gavage with 2 g phthalate diester/kg/day in corn oil vehicle for 2 days, while Leydig cell primary cultures were incubated with 1,000 microM monoester for 2 hr. Light and electron microscopy were undertaken to determine the type and degree of any changes. Phthalate esters exerted a direct effect on Leydig cell structure and function (as determined by testosterone output) with correlation of the in vitro and in vivo effects of MEHP (DEHP) and MOP (DOP). No effects on Leydig cell structure or function were seen with MPP (DPP), although Sertoli cell cytoplasmic rarefaction and vacuolation were observed in vivo. DEP produced Leydig cell ultrastructural alterations in vivo. We conclude that individual phthalate esters may exert effects on both Sertoli and Leydig cells or one cell type alone.
Animals↗
Protective effect of RibCys following high-dose irradiation of the rectosigmoid.
UNLABELLED: Ribose-cysteine (RibCys) is a prodrug of L-cysteine that stimulates glutathione biosynthesis. Increased glutathione levels have been shown to have a protective effect against radiation-induced injury and oxidative stress. Surface oximetry has previously been used successfully to predict anastomotic leakage. PURPOSE: The following study was done to evaluate the protective effect of RibCys and the predictive value of PtO2 determinations in a swine model. METHODS: Domestic swine were divided into three groups: Group A served as a nonradiated control; Group B received 6,000 to 6,500 rad to the rectosigmoid; and Group C received RibCys (1 g/kg) prior to receiving 6,000 to 6,500 rad. Radiated animals and controls underwent rectosigmoid resection after a three-week rest period. Intraoperative anastomotic PtO2 was checked with a modified Clark electrode. Anastomoses were evaluated radiographically at three and seven days; animals were sacrificed, and bursting strength was recorded at 10 days. RESULTS: Mean bursting pressures were 243.8 +/- 59.4, 199.5 +/- 37.8, and 209.5 +/- 54.9 mmHg (NS) for Groups A, B, and C, respectively. Anastomotic PtO2 ranged from 19 to 98 mmHg and could not be correlated with anastomotic leaks or bursting pressure. There were 11/15 radiation-related deaths and leaks (eight deaths and three leaks) in the radiated group and 4/12 radiation-related deaths and leaks (three deaths and one leak) in the group receiving radiation and RibCys (P < 0.04). CONCLUSIONS: 1) RibCys protected animals against radiation-related deaths and anastomotic leaks following high doses of pelvic irradiation; 2) anastomotic PtO2 levels did not correlate with anastomotic healing in this model.
Anastomosis, Surgical↗
Immune cells mediate epinephrine secretion from bovine chromaffin cells in vitro.
Potential immunological influences on peripheral catecholamine secretion were investigated by measuring epinephrine secretion from chromaffin cells in vitro in response to cell-free conditioned media from mononuclear cells. Chromaffin cells were isolated from bovine adrenals whereas mononuclear cells were isolated from bovine spleen tissue or whole bovine blood. In secretion experiments epinephrine release and epinephrine remaining in cells was determined such that secretion was expressed as % of total cell content. After 90 minutes exposure to conditioned media, 22.8 +/- 1.1% of content was released compared to 1.7 +/- 0.2% with RPMI media. Secretion after filtration (< 3,000 MW cutoff) was 21.6 +/- 0.9% whereas after boiling and boiling in acid, secretion was 10.2 +/- 0.2 and 4.3 +/- 0.1% respectively. Dialysis (< 3,000 MW cutoff) reduced the 90 min conditioned media-stimulated epinephrine secretion from 22.5 +/- 3.8% to 2.3 +/- 0.3%. Neither atropine nor hexamethonium blockade altered the conditioned media-stimulated epinephrine secretion. These results suggest that mononuclear cells produce a low molecular weight substance--most likely a peptide--that contributes to the stimulation of epinephrine secretion.
Adrenal Glands↗
SB 201823-A, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia.
We have characterised the Ca2+ channel blocking properties of a new non-peptide Ca2+ channel antagonist, SB 201823-A, in cultures of rat sensory neurones. The IC50 for SB 201823-A against total Ca2+ current in sensory neurones was 4.9 microM. SB 201823-A showed little selectivity for sub-types of neuronal Ca2+ channel but was selective for Ca2+ channels over Na+ and K+ channels. Efficacy against other types of cation channel such as agonist gated channels was not assessed. SB 201823-A was neuroprotective in vivo when administered post-ischaemia in one focal and one global model of neuronal ischaemia. In the rat photothrombotic focal lesion model, SB 201823-A administered i.p. 10 min post-ischaemia resulted in a dramatic reduction in lesion volume. In the gerbil bilateral carotid artery occlusion global model, SB 201823-A dosed i.p. 30 min post-occlusion resulted in both histological and functional improvements when compared to vehicle treated animals. These data suggest that such novel neuronal Ca2+ channel antagonists may have potential in ameliorating both the pathological and functional consequences of stroke in man.
Animals↗
If Clinton wins.
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Financing, Government↗
Photothrombotic lesions of the frontal cortex impair the performance of the delayed non-matching to position task by rats.
The effects of photochemically induced lesions of the frontal cortex on the short-term memory capacity of the rat have been investigated using the delayed non-matching to position task. Pretrained animals received lesions and were tested 4 days after surgery and twice per week for 3 weeks. The lesions produced a profound impairment of performance of this task which was still evident 3 weeks after surgery. Spontaneous locomotor activity was recorded 7 days after surgery and no difference was found between the control and lesion group. These effects indicated a generalized disruption of performance of this task in the absence of motor dysfunction. These results suggest that photothrombotic lesions of the frontal cortex can produce reliable, long-term behavioural deficits.
Animals↗
Protection against acetaminophen hepatotoxicity by ribose-cysteine (RibCys).
2(RS)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)thiazolidine-4(R)-carb oxylic acid (Ribose-Cysteine, RibCys), a latent form of L-cysteine, releases the sulfhydryl amino acid in vivo by non-enzymatic ring opening and solvolysis. The liberated L-cysteine then stimulates hepatic glutathione biosynthesis. In the present studies, the efficacy of hepatoprotection by RibCys was evaluated to explore its potential utility as an acetaminophen (APAP) antidote. Protection was evaluated in the Swiss-Webster mouse model both by survival data as well as by quantitative histological criteria of hepatic damage. A dose-response study showed increased protection with increased intraperitoneal doses of RibCys ranging from 0.5 to 8.0 mmol/kg. RibCys administration 30 min. prior to and up to four hours after the APAP dose showed varying degrees of protection; however, the best protection was seen when RibCys was given shortly after APAP administration. A single RibCys dose given by the intraperitoneal or intravenous route gave better protection than when administered orally; however, RibCys given in three doses, one hour apart, regardless of the mode of administration, offered the best protection after an LD90 dose of APAP. Overall, RibCys continues to exhibit promising protective capabilities against APAP hepatotoxicity, which may be capitalized upon in clinical overdose situations.
Acetaminophen↗
L-cysteine prodrug protects against cyclophosphamide urotoxicity without compromising therapeutic activity.
2(R,S)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)-thiazolidine-4(R)-ca rboxylic acid (RibCys) is a prodrug of L-cysteine that releases the sulfhydryl amino acid after nonenzymatic ring opening and hydrolysis. The L-cysteine then elevates glutathione (GSH) levels by stimulating its biosynthesis. RibCys was investigated for its ability to protect CDF1 mice from the potent urotoxicity of cyclophosphamide (CTX) without compromising the therapeutic utility of the drug. RibCys induced a significant reduction in weight loss of the animals and in bladder inflammation at 48 h after CTX administration; however, bladder tissue remained inflamed as compared with that in controls. Bladder histology also showed some pathological changes in the presence of RibCys. In contrast, all parameters of toxicity (body weight loss, bladder inflammation, and pathological abnormalities) had been virtually reversed by day 21 after administration. In tests against L1210 leukemia, RibCys did not interfere with CTX anticancer activity. From these preliminary studies, RibCys appears to be a likely candidate for protecting against long-term CTX toxicity, perhaps reversing the original damage caused by a very high dose, without compromising the therapeutic utility of the alkylating agent.
Animals↗
Time course for the elevation of glutathione in numerous organs of L1210-bearing CDF1 mice given the L-cysteine prodrug, RibCys.
RibCys, a thiazolidine prodrug of L-cysteine synthesized by the condensation of the sulfhydryl-containing amino acid with the aldose monosaccharide D-ribose, successfully elevated glutathione (GSH) levels in numerous organs of tumor-bearing CDF1 mice. GSH content was assayed 1,2,4,8 and 16 h after RibCys administration (8 mmol/kg, i.p.); various organs achieved maximal GSH content at different time points. GSH in the liver was elevated 1.5-fold compared to untreated controls at the 16-h time point. Kidney GSH also was maximal at 16 h and achieved 1.6-times control values. GSH in muscle achieved 2.5 times the levels in control animals, while the bladder was elevated 2.1-fold, and the heart 1.8-fold. Other tissues tested (spleen, pancreas, lung) showed a 1.1- to 1.2-fold increase in GSH content. GSH in implanted L1210 tumors was also elevated only 1.2-fold. These data suggest the possibility of protecting organs other than the liver from toxic insults that require the intervention of GSH for detoxication and may allow such protection without compromising the utility of chemotherapy.
Animals↗
The consequences of iron overdose and its treatment with desferrioxamine in pregnancy.
A study was carried out to assess the effect on the outcome of pregnancy of iron overdose and its treatment with desferrioxamine. Sixty-eight cases were drawn from those reported to the United Kingdom National Poisons Information Centre and the Teratology Information Service at Guy's Hospital, London, and follow-up was obtained in 51 of these. Two were subsequently reported not to be pregnant and there were 49 records of pregnant patients who took iron overdoses and where outcome of the pregnancy was known. Twenty-five of these patients were treated with desferrioxamine. In 48 of the 49 patients the dose of iron allegedly taken was known and in 28 (60%) was over 20 mg kg-1, sufficient to put them at risk of toxicity. In the 36 whose serum iron levels were measured, 20 patients had levels in excess of 60 mumol l-1, indicating a risk of moderate or severe toxicity. Of the 49 pregnancies, 43 resulted in live babies, two had spontaneous abortions and there were four elective terminations. Of the live babies, three were premature, two of whom had problems, and there were three other babies with abnormalities. All babies with malformations were associated with overdoses after the first trimester and so the malformations cannot be directly related to the overdose. A total of 25 patients received desferrioxamine of whom two had malformed babies, but the desferrioxamine can be excluded as a cause. There was no correlation between the serum iron levels and the birthweights. In conclusion, iron overdose in pregnancy can be fatal and antidote treatment if appropriate should not be withheld.(ABSTRACT TRUNCATED AT 250 WORDS)
Birth Weight↗
The pattern of childhood poisoning in the western Cape.
An analysis of poisoning cases treated at the Red Cross War Memorial Children's Hospital during 1987 and of calls received on the poisons line is presented. Treatment of 1,116 children was undertaken and 922 telephone calls were logged. Of the patients treated, 60% had ingested a drug and 30% had drunk paraffin. The high prevalence of paraffin poisoning in the western Cape is examined. Constant vigilance must be maintained if childhood poisoning is to be prevented.
Child↗
Caesarean section in a patient with haemoglobin SC disease and a phaeochromocytoma.
The anaesthetic management of a patient with haemoglobin SC disease for lower segment Caesarean section and excision of a phaeochromocytoma is described. The patient was given a general anaesthetic for the surgical procedure after exchange transfusion had achieved an haemoglobin A concentration of greater than 50%. A live infant was delivered and a suprarenal phaeochromocytoma was excised during a 6.5 hour procedure. The patient's postoperative recovery was uneventful.
Adrenal Gland Neoplasms↗
Copper-67 labeled porphyrin localization in inflamed tissue.
A series of experiments compared the uptake of 5,10,15,20 tetrakis(4-carboxyphenyl) porphinato [67Cu] copper (II), 67CuTCPP, by the lymph nodes of inflamed and two sets or control rats. The results demonstrate that 67CuTCPP localizes in greater concentration in inflamed lymph nodes than in noninflamed control lymph nodes. This enhanced uptake of 67CuTCPP by inflamed lymph nodes was 3.6 times greater than was the uptake by control lymph nodes. A time course study demonstrated that the uptake of 67CuTCPP by inflamed lymph nodes reached the maximum level by 24 hours post-injection of 67CuTCPP and remained constant throughout the 96 hours examined. It was also found that the uptake of 67CuTCPP by inflamed lymph nodes was not exclusively dependent upon an increase in the weight of inflamed lymph nodes. These studies show that 67CuTCPP has potential as a lymphoscintigraphy agent.
Animals↗
The biodistribution of radiocopper-labeled compounds.
Porphyrins form extremely stable chelates with Cu2+. Two copper radionuclides, 67Cu and 64Cu, have attractive nuclear decay properties for use in nuclear medicine applications. We have investigated the use of radiocopper-labeled porphyrins for localization in inflamed tissue and for attachment to antibodies for tumor imaging and therapy. We have examined the biodistribution of a 67Cu labeled porphyrin, [5, 10, 15, 20-tetrakis(4-carboxyphenyl) porphinato [67Cu] copper (II)], 67 CuTCPP. The 67CuTCPP was intravenously injected into the tail vein of Fischer F344 male rats. The kidneys, liver, and spleen localize the greatest amounts of 67CuTCPP. The elimination of 67CuTCPP from the body is described by a normal exponential decay curve with a biological half-life of 108 hours and an effective half-life of 32 hours. We have also examined the biodistribution of 5-(4-carboxyphenyl)-10, 15,20-tris(4-sulfophenyl) porphinato [67Cu] copper (II) anti-Thy 1.2 antibody conjugates in normal and tumor-bearing male AKR/J mice. The liver, kidney, and tumor have the highest uptake of the 67Cu labeled antibody conjugate. In all 67Cu labeled compounds studied, the blood clearance was rapid and the bone concentration of the radiolabeled species was low.
Animals↗
Labeling antibodies with copper radionuclides using N-4-nitrobenzyl-5-(4-carboxyphenyl)-10,15,20-tris(4-sulfophenyl) porphine.
Antibody conjugates labeled with copper-64 and -67 (64Cu and 67Cu) were prepared using the porphyrin chelator N-4-nitrobenzyl-5-(4-carboxyphenyl)-10,15,20-tris(4-sulfophenyl) porphine (N-bzHCS3P). N-bzHCS3P was chosen because it has only one carboxylate group available for activation and coupling to antibody. The conjugates were characterized with respect to (1) the location of the porphyrin on the antibody, (2) the retention of immunoreactivity, and (3) the serum stability of the amide bond linking porphyrin to antibody. These studies showed that porphyrin attachment on the antibody surface is random. The conjugates exhibited high retention of immunoreactivity and reasonable serum stability for potential application in nuclear medicine.
Antibodies↗
Withdrawing life support--the survivors.
We studied the impact of withdrawal of life support on surviving relatives and families of patients who died when chronic dialysis was discontinued. Fifty-four (57%) relatives answered a written questionnaire. The relatives of 70% of home dialysis patients and 27% of center dialysis answered the questionnaire. The answering relative felt most angry and uncomfortable with the decision, ascribed the least anger and most comfort to the patient and an intermediate value to the rest of the family. Staff physician and resident ranked highest in involvement in making the decision, social workers and chaplains the lowest. Once the decision was made, social workers and nurses were most caring and helpful, residents and chaplains were rated the lowest. The relatives felt that they and the patients were the ones who most often brought up the decision to stop and also made the final decision. The relatives thought that the incompetent patients were most angry and uncomfortable but that they felt that decision to be right. The family and relatives were particularly angry and uncomfortable when the patient had discontinued dialysis for the stress of the procedure alone and not any medical complications. In these cases there was most family disagreement and the staff received startling low scores, both for involvement and caring and helpfulness. In answers to open-ended questions, the relatives expressed disappointment with physicians who were unwilling to talk to them, were overly optimistic and continued too long with treatment. They wished for more openness and truthfulness. No long-term psychological harm seems to have come to the relatives and families with one exception. Our finding suggests that more meetings with families and patients and openness about problems and complications during chronic dialysis and follow-up and counseling of families after the patients have died should be helpful.
Attitude to Death↗