Hepatitis C links hepatologists, nephrologists and transplant surgeons.
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Gastroenterology↗
Biomedical subjects
G Alexander
Publications and source records attributed to G Alexander.
Mutational analysis of the hydrolytic activity of yeast RNA polymerase III.
For 25 mutant alleles of ret1, encoding the second largest subunit of yeast RNA polymerase III, we have studied the polymerase III nuclease activity, measuring both the total yield and dinucleotide product composition. Mutations affecting amino acids 309-325 gave slightly elevated nuclease activity. In region 367-376, two mutations gave 12-15-fold increased nuclease activity. Our results do not support the catalytic role in nuclease activity proposed for the conserved DDRD motif in this region (Shirai, T., and Go, M. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 9056-9060). Mutations centered on a basic region from amino acids 480 to 490, which aligns with Escherichia coli beta-subunit sequences between Rif(r) clusters I and II, produce changes in the relative yields of A- and G-containing dinucleotides. Four such mutant polymerases pause during elongation at GPy sequences and, in addition, have a reduced frequency of termination at T(5) terminator sequences. We propose that the side chains of these mutationally altered amino acids are in direct contact with bases in the RNA-DNA hybrid very near the growing 3'-end. Two mutations in domain I near the C terminus produced very large increases in exonuclease activity and strongly increased termination, suggesting that this region also contacts the nascent RNA in the hybrid region.
Amino Acid Sequence↗
Sirolimus: a potent new immunosuppressant for liver transplantation.
BACKGROUND: Sirolimus (rapamycin) is a new immunosuppressant that appears to be synergistic with cyclosporine in kidney transplantation, but with a different side-effect profile. This pilot study evaluated sirolimus in liver transplantation. METHODS: Patients undergoing orthotopic liver transplantation for primary tumors (8), and later for nonmalignant disease (7), received one of three sirolimus-based immunosuppressive regimens. Protocol A comprised sirolimus, microemulsion cyclosporine (target whole blood concentration: 100 ng/ml), and prednisolone; protocol B omitted prednisolone; and protocol C was sirolimus alone. By 3 months after transplantation, all patients were receiving sirolimus as monotherapy. RESULTS: Fifteen patients were treated with a follow-up of 117-806 days. Rejection was more common on monotherapy than double therapy, and absent on triple therapy. The drug was generally well tolerated, with only three patients discontinuing sirolimus: one for hyperlipidemia, one for pneumocystis pneumonia, and one for inability to tolerate the taste of the drug. Two patients discontinued cyclosporine early, both as a result of neurological complications; they continued on sirolimus monotherapy. Five patients died; one suffered a cardiac arrest, and four died from sepsis in association with graft-versus-host disease, recurrent tumor, a paralyzed right hemidiaphragm, and primary nonfunction. CONCLUSIONS: Sirolimus combined with cyclosporine provided potent immunosuppression of liver allografts, and sirolimus monotherapy was adequate and well tolerated as maintenance therapy. Side effects of sirolimus over the short period of follow-up were uncommon and reversible with dose reduction or cessation of therapy.
Adult↗
Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein, Tat.
The broad range of histological lesions associated with HIV-1 are somewhat subtle relative to the clinical manifestations that occur as a result of HIV infection. Although it is clear that HIV has a causative role in CNS disease, dementia appears to be a consequence of the infiltration of inflammatory cells and cytokine dysregulation rather than the amount of virus in CNS. The HIV transregulatory protein Tat plays an important intracellular as well as extracellular role in the dysregulation of cytokines. The cytokines and possibly chemokines that are induced by Tat modify the action of astrocytes such that the survival of neurons is compromised. Pathogenetic alteration induced by Tat involves a series of interactions between circulating monocyte/macrophages, endothelial cells, and astrocytes. Cytokine dysregulation induced by viral infection and extracellular Tat leads to alterations in expression of adhesion molecules and promotes migration of non-infected inflammatory cells into the CNS compartment. We demonstrate here that recombinant HIV-1 Tat protein introduced by stereotaxic injection into mouse brain can induce pathologically relevant alterations including macrophage invasion as well as astrocytosis. The mechanism of destruction of the CNS by Tat appears to involve autocrine and paracrine pathways that depend not only on Tat, but cytokine and chemokine signaling pathways that are altered by viral infection. In this review, we discuss various pathogenic effects of Tat in brain cells and provide experimental evidence for an increased TNF-alpha level in CSF in mice injected intracerebrally with Tat protein.
Animals↗
Associative learning impairments in patients with frontal lobe damage.
The performance of 18 frontal lobe lesion (FL) and 10 frontal lobe dementia (FLD) patients on an associative memory test was compared with the performance of their matched normal controls. The FL group was severely impaired on cued and free recall and was moderately impaired on a recognition condition. Left FL patients performed the poorest on the cued and free recall conditions. The FLD patients were moderately impaired on the free recall condition only but there was a subgroup of FLD patients with additional left temporal atrophy who appeared severely impaired on both cued and free recall. These findings indicate that both left frontal and temporal lobe damage can impair associative learning and that this impairment is more strikingly seen with free rather than cued recall.
Adult↗
Influence of positive crossmatch in the outcome of liver transplantation.
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Graft Rejection↗
Thermal modulation of the toxicokinetics of benzo[a]pyrene in isolated hepatocytes of sablefish (Anoplopoma fimbria), black rockfish (Sebastes melanops), and chub mackerel (Scomber japonicus).
Hepatocytes from sablefish (Anoplopoma fimbria), black rockfish (Sebastes melanops) and chub mackerel (Scomber japonicus) were isolated from 11 degrees C acclimated animals. The uptake, metabolism, and excretion of benzo[a]pyrene (B[a]P) in hepatocytes was measured at 6, 11 and 19 degrees C. Chub mackerel hepatocyte uptake rates were significantly lower (0.012 +/- 0.003 microg/s per g cell) at 11 degrees C than black rockfish (0.028 +/- 0.009 microg/s per g cell) or sablefish (0.032 +/- 0.012 microg/s per g cell) hepatocytes at all temperatures. Hepatocytes metabolized B[a]P to phase I (1-8%) and phase II (92-99%) metabolites. Accumulation of phase II metabolites was lower in chub mackerel hepatocytes (0.016 +/- 0.004 microg/h per g cell), than black rockfish (0.052 +/- 0.012 microg/h per g cell), or sablefish hepatocytes (0.060 +/- 0.015 microg/h per g cell). Phase II metabolite accumulation increased greatest with temperature in chub mackerel hepatocytes (Q10 = 1.94 +/- 0.30), followed by sablefish (Q10 = 1.65 +/- 0.30), and rockfish (Q10 = 1.38 +/- 0.30). Sablefish hepatocytes had higher excretion rates of phase II metabolites (0.010 +/- 0.0023 microg/h per g cell), than mackerel (0.0046 +/- 0.0009 microg/h per g cell) or rockfish hepatocytes (0.0029 +/- 0.0008 microg/h per g cell). Phase II metabolite excretion rates increased with temperature only in sablefish hepatocytes (Q1O = 1.67 +/- 0.76). These differences in toxicokinetics may indicate distinct consequences for various species exposed to xenobiotics.
Animals↗
Differential expression of protein kinase C isoforms in streptozotocin-induced diabetic rats.
BACKGROUND: The cellular effects of hyperglycemia are mediated by protein kinase C (PKC). However, PKC consists of several distinct isoforms, and their contribution to the pathogenesis of diabetic complications in different organs is not clear. We investigated the expression and translocation of PKC isoforms alpha, betaI, betaII, delta, epsilon, and zeta in kidney, heart, and aorta from diabetic rats. METHODS: Hyperglycemia was induced with streptozotocin (70 mg/kg) in the rat. After four weeks, PKC isoform expression was assessed by Western blot after tissue fractionation and by immunohistochemistry. RESULTS: Streptozotocin increased blood glucose from 117.0 +/- 3.6 to 510.0 +/- 19.4 mg/dl (N = 8, P < 0.01) and induced albuminuria. PKC isoforms alpha, beta, delta, epsilon, and zeta were all detected in control animals. Western blot showed increased PKC alpha expression in kidney and heart (160% and 170%, respectively). PKC betaI, betaII, and delta expression was not influenced by hyperglycemia. PKC zeta was decreased in diabetic animals in both tissues by 60%. The membrane association of PKC alpha and PKC epsilon was increased; however, the relative amount of PKC in the particulate fraction was not influenced by hyperglycemia. Immunohistochemistry revealed a marked increase in PKC alpha immunoreactivity in renal glomeruli and interstitial capillaries, cardiac capillaries, and skeletal muscle, as well as in the endothelial cells of larger arteries. PKC beta showed a small decrease in the glomeruli. PKC epsilon was increased in renal tubules in diabetic rats but was decreased in the myocardium. PKC zeta was expressed in both myocardial and glomerular cells but was decreased during hyperglycemia. Our results demonstrate that PKC isoforms are differentially regulated in kidney and heart in diabetes. High glucose increases PKC alpha expression, whereas PKC zeta is down-regulated. The finding that PKC alpha is mostly increased in endothelial cells supports a role for PKC alpha in functional endothelial disturbances observed in diabetes.
Animals↗
Randomized controlled trial on the effective dose of anti-snake venom in cases of snake bite with systemic envenomation.
Snake bite is the common cause of morbidity and mortality in India. Snake antivenom, although very effective, is expensive, scarce, and associated with side effects. The conventional dose may not be required in all cases and a smaller dose may be as effective. A randomized double blind controlled trial was conducted to compare the effect of lower versus the conventional (high) dose. Patients presenting within 24 hours of snake bite with hematological or neurological evidence of systemic envenomation were included in the study. Patients were randomized either to receive high dose (2 vials over 1 hour, followed by 2 vials over 4 hours and repeated 4 hourly until clotting parameters normalized and then 2 vials as infusion over 24 hours) or low dose (2 vials over 1 hour, followed by 1 vial over four hours, repeated 4 hourly until clotting parameters were normalized and then 1 vial as an infusion over 24 hours). Thirty one patients received high dose and 29 a low dose. The mean dose of antivenom used was significantly different in the two groups (8.9 and 4.7, respectively). There was no mortality. The duration of stay was 4.94 and 3.48 days, respectively. There was no difference in the transfusion, dialysis or ventilation requirement of the two groups. Low dose regimen is more effective and required 5 vials less than the conventional dose. Each vial costs Rs. 200, so the estimated savings is Rs. 1000 per patient.
Adult↗
Use of collaborative audit to assist local implementation of the SIGN guideline for prevention of visual impairment in diabetes.
OBJECTIVES: To use audit to inform the local implementation of a national clinical guideline for the prevention of visual impairment in diabetes. DESIGN: Computer and patient record search in hospital and general practice to determine levels of morbidity and follow-up. Questionnaire to each practice to determine models and techniques of eye screening. SETTING: Ayrshire and Arran Health Board area, Scotland. SUBJECTS: All known diabetic patients. MAIN MEASURES: Proportion of diabetic patients who have had diabetic eye review and monitoring of risk factors within one year. Proportion of diabetic patients who have risk factors recorded within target level. Proportion of eye screening centres with recommended mechanisms in place. RESULTS: Both district general hospitals, and 59 of the 63 general practices, in the area took part in the audit. A total of 6,217 diabetic patients were included; the prevalence of diabetes in this population was 1.65%. Twenty-seven per cent were insulin treated. Seventy-two per cent of diabetics who were not registered blind had a record of having had fundoscopy performed through dilated pupils within one year. Sixty-nine per cent of those who were not registered blind had had corrected visual acuity measured within one year. Eighty-five per cent of diabetics had HbA1C recorded within one year and of these 65% had a level of 8% or less. Eighty-eight per cent had a blood pressure recording within twelve months and 52% of recorded pressures were 140/90 mmHg or less. Smoking status was recorded for 89% of patients and 75% of patients with a record were non-smokers. Representatives of 57 practices returned a completed questionnaire. All these practices had a Snellen chart, but only 83% had near vision testing equipment and only 54% had a pinhole occluder. CONCLUSIONS: An area wide collaborative audit provided local data to inform the process of guideline implementation and baseline data from which to evaluate this process. Wide stakeholder involvement increased interest, motivation and support for the process. The audit highlighted specific areas for change and provided the local stimulus for change.
Cooperative Behavior↗
Perinatal mortality and its relationship to the reporting of low-birthweight infants.
OBJECTIVES: This study examined changes in the reporting of very low-birthweight infants in Alabama from 1974 to 1994 and the impact on perinatal mortality rates. METHODS: Linked live birth, neonatal death, and stillbirth records of infants born weighing less than 1500 g were compared. RESULTS: The changes in mortality over time ranged from a drop from 100% to 92% in the under-500-g group to a drop from 39% to 4% in the 1000-to 1499-g group. The percentage of total births weighing less than 500 g increased by 155%; the percentage of 1000- to 1499-g births increased by only 7%. As a result, the percentage of neonatal mortality attributable to live births below 500 g increased from 3% to 32%. CONCLUSIONS: Increased reporting of births below 500 g has masked improvements in neonatal mortality.
Alabama↗
Comparison of warfarin use in total knee replacement vs total hip replacement.
The purpose of this retrospective study was to determine the efficacy of warfarin prophylaxis against deep vein thrombosis (DVT) in total hip arthroplasty (THA) vs total knee arthroplasty (TKA). A review of venograms in 223 patients with THA and in 189 cases of TKA was carried out. The overall DVT rate in THA was 22%. The overall DVT rate in TKA was 46%. We conclude that combined or alternate methods need to be used to decrease the rate of DVT following TKA to that of THA.
Aged↗
Early increase in plasma parathyroid hormone levels following liver transplantation.
BACKGROUND/AIMS: The pathogenesis of post-transplantation bone loss is poorly understood, although glucocorticoid therapy is believed to play an important role. In the present study we have measured plasma parathyroid hormone concentrations in the first few months after orthotopic liver transplantation, in order to examine the potential contribution of hyperparathyroidism to bone disease. PATIENTS AND METHODS: Twenty-seven patients aged 32-54 years, 12 male, undergoing liver transplantation were studied prospectively before and for 3 months after operation. Plasma parathyroid hormone and serum 25-hydroxyvitamin D concentrations were measured by radioimmunoassay. RESULTS: Plasma parathyroid hormone levels were normal in all but two patients prior to transplantation. There was a highly significant increase in plasma parathyroid hormone concentrations at 1 and 2 months (p < 0.0005 and 0.001, respectively, versus baseline); by 3 months, values were close to those obtained preoperatively. Serum 25-hydroxyvitamin D concentrations showed no significant change over the study period. However, 74% of the patients had subnormal values at baseline. CONCLUSIONS: An early and transient increase in plasma parathyroid hormone after liver transplantation may be responsible for the high rates of bone loss which occur during the first few post-operative months. Prevention of post-transplantation bone disease is most likely to be achieved by peri-operative intervention with an anti-resorptive agent.
Adult↗
Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study.
The effect of testosterone (T) replacement on changes in mood was studied for 60 days in 51 hypogonadal men. All patients were withdrawn from their prior T replacement for at least 6 weeks before enrollment. Of these patients, 18 received T enanthate 200 mg im every 20 days, 16 received sublingual T cyclodextrin (SLT) at a dose of 2.5 mg three times daily, and 17 received SLT at a dose of 5.0 mg three times daily. The total treatment period was 60 days. The patients were asked to respond to a questionnaire on 7 consecutive days before the start of treatment and on 7 consecutive days before their visits to the clinic on days 21, 41, and 60 of treatment. The following mood parameters were assessed using a 7-point Likert rating scale: angry, alert, irritable, full of pep (energy), sad/blue, tired, friendly, nervous, and well/good. When compared with the baseline period, T replacement led to significant decreases in anger (P = 0.0045), irritability (P = 0.0009), sadness (P = 0.0033), tiredness (P = 0.0035), and nervousness (P = 0.0291), and significant improvement in energy level (P = 0.0020), friendliness (P = 0.0072), and sense of well-being (P = 0.024) in all subjects as a group. Analyses of the area under the curve (AUC) of baseline serum T levels before T replacement showed significant positive correlations between serum T (AUC) and friendliness (r = 0.29, P < 0.05) and sense of well-being (r = 0.27, P < 0.05), and significant negative correlations with nervousness (r = -0.27, P < 0.05), irritability (r = -0.29, P < 0.05) and tiredness (r = -0.28, P < 0.05). Similar correlations were found between serum dihydrotestosterone (DHT) and some of the mood parameters. After T replacement in the hypogonadal men, these correlations between AUC of serum T levels and the positive and negative mood scores disappeared. These results were corroborated in a subsequent study in which 30 hypogonadal men were supplemented with SLT 5 mg three times daily for 6 months. The patients were less nervous (P = 0.0025) and more alert (P = 0.0004), friendly (P = 0.042), and energetic (P = 0.0001) during the 6-month treatment period compared with baseline. We conclude that T replacement therapy in hypogonadal men improved their positive mood parameters, such as energy, well/good feelings, and friendliness and decreased negative mood parameters including anger, nervousness, and irritability, and direct correlations between serum T and DHT with mood scores were only observed in the baseline period when serum androgen levels were below the normal range. The latter observation suggests that once a minimally adequate serum T/DHT level was achieved by T replacement therapy, further increases in serum T/DHT levels did not further contribute to the improvement in mood variables.
Administration, Sublingual↗
Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men--a clinical research center study.
To study the effects of androgen replacement therapy on muscle mass and strength and bone turnover markers in hypogonadal men, we administered sublingual testosterone (T) cyclodextrin (SLT; 5 mg, three times daily) to 67 hypogonadal men (baseline serum T, < 8.4 nmol/L) recruited from 4 centers in the U.S.: Torrance (n = 34), Durham (n = 12), New York (n = 9), and Salem (n = 12). Subjects who had received prior T therapy were withdrawn from injections for at least 6 weeks and from oral therapy for 4 weeks. Body composition, muscle strength, and serum and urinary bone turnover markers were measured before and after 6 months of SLT. We have shown previously that this regimen for 60 days will maintain adequate serum T levels and restore sexual function. Total body (P = 0.0104) and lean body mass (P = 0.007) increased with SLT treatment in the 34 subjects in whom body composition was assessed. There was no significant change in total body fat or percent fat. The increase in lean body mass was mainly in the legs; the right leg lean mass increased from 8.9 +/- 0.3 kg at 0 months to 9.2 +/- 0.3 kg at 6 months (P = 0.0008). This increase in leg lean mass was associated with increased leg muscle strength, assessed by leg press (0 months, 139.0 +/- 4.0 kg; 6 months, 147.7 +/- 4.2 kg; P = 0.0038). SLT replacement in hypogonadal men led to small, but significant, decreases in serum Ca (P = 0.0029) and the urinary calcium/creatinine ratio (P = 0.0066), which were associated with increases in serum PTH (P = 0.0001). At baseline, the urinary type I collagen-cross linked N-telopeptides/creatinine ratio [75.6 +/- 7.9 nmol bone collagen equivalents (BCE/mmol] was twice the normal adult male mean (41.0 +/- 3.6 nmol BCE/mmol) and was significantly decreased in response to SLT treatment at 6 months (68.2 +/- 7.7 nmol BCE/mmol; P = 0.0304) without significant changes in urinary creatinine. Serum skeletal alkaline phosphatase did not change. In addition, SLT replacement caused significant increases in serum osteocalcin (P = 0.0001) and type I procollagen (P = 0.0012). Bone mineral density did not change during the 6 months of SLT treatment. We conclude that SLT replacement therapy resulted in increases in lean muscle mass and muscle strength. Like estrogen replacement in hypogonadal postmenopausal females, androgen replacement therapy led to decreased bone resorption and urinary calcium excretion. Moreover, androgen replacement therapy may have the additional benefit of increasing bone formation. A longer term study for several years duration would be necessary to demonstrate whether these changes in bone turnover marker levels will result in increased bone mineral density decreased fracture risks, and reduced frailty in hypogonadal men.
Administration, Sublingual↗
Neoral in liver transplantation.
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Administration, Oral↗
Heart-lung-liver transplantation.
We report three patients with cystic fibrosis and one patient with primary biliary cirrhosis and plexogenic pulmonary hypertension who have undergone heart-lung-liver transplantation as a combined procedure. Liver transplantation was necessary in the three patients with cystic fibrosis because of portal hypertension secondary to either hepatic fibrosis or established cirrhosis in addition to their advanced lung disease. Three of the four patients were alive at 20, 50, and 100 months after transplantation (one patient with cystic fibrosis died on day 16 of pneumonia) with well-preserved pulmonary function (forced expiratory volume in 1 second 110%, 49%, and 100% predicted, respectively), normal hepatic function and New York Heart Association class 1 performance status. Heart-lung and concurrent liver transplantation is a feasible and successful procedure with a satisfactory long-term outcome in selected patients with advanced pulmonary and hepatic disease.
Adult↗
Patient decision-making in relation to extensive restorative dental treatment. Part II: Evaluation of a patient decision-making model.
A theoretical model was proposed and tested to evaluate some of the factors involved in patients' decisions to undergo extensive restorative dental treatment. This model incorporates aspects of the environment within which the decision occurred (the patient/provider relationship, social influence and the role of cues in initiating treatment) and internal values held by the individual (perceptions of value of and barriers to treatment). Value of treatment was measured using aesthetics, function, health motivation and self-esteem. Barriers to treatment included fears and anxieties about treatment, the costs of treatment, the time involved in obtaining treatment and access to care. Data were collected by mailed questionnaire from 188 patients at a North American state university dental school who had received over $1,500 of restorative dental treatment during 1990/91. Data were analysed using path analysis multiple regression. The most important determinant in the decision to undergo treatment was patient/provider relationship. As expected, barriers exerted an inverse effect upon the outcome and had twice the influence compared with the patients' perceived value of treatment. Cues and social influence were not shown to play a significant role in initiating restorative dental treatment.
Adult↗