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Biomedical subjects

G Alexander

Publications and source records attributed to G Alexander.

At least 37 records · Page 2Linked to original sources
PubMed2000

Planning impairments in frontal lobe dementia and frontal lobe lesion patients.

Patients with frontal lobe brain damage are reportedly impaired on tasks that require plan development and execution. In this study, we examined the performance of 15 patients diagnosed with frontal lobe dementia and 14 patients with focal frontal lobe lesions on the Tower of London planning task. Patients with frontal lobe dementia committed a significantly higher number of rule violations, made more moves, and demonstrated longer solution time latencies compared to their matched controls. Patients with frontal lobe lesions demonstrated significantly delayed solution times and also made more moves compared to their matched controls. Frontal lobe lesion patient performance suggests an impairment in execution-related processes, while frontal lobe dementia patients appear to be impaired in both plan development and execution. Despite these findings, the identification of a specific cognitive impairment that induces these planning problems remains elusive.

Adult↗
PubMed2000

Prediction of neurologic morbidity in extremely low birth weight infants.

OBJECTIVE: (1) Identify major determinants of adverse neurodevelopmental outcome in extremely low birth weight (ELBW) infants. (2) Compare neural networks and regression analysis in the prediction of major handicaps and Bayley scores (MDI and PDI) in individual ELBW neonates followed to 18 months. STUDY DESIGN: Retrospective cohort study of regional tertiary care NICU database. A database with 21 selected variables was divided into training (n = 144) and test sets (n = 74). The training set was used to train a neural network and develop regression equations to predict outcomes in the test set. RESULTS: Determinants (descending order of contribution to variance): Major handicap: intraventricular hemorrhage (IVH) grade, necrotizing enterocolitis > or = stage II, black race, and no chorioamnionitis; low MDI: IVH grade, plurality, bronchopulmonary dysplasia (BPD), lower maternal grade, and no chorioamnionitis; low PDI: IVH grade, BPD, periventricular leukomalacia, lower maternal grade, and no chorioamnionitis. Regression techniques and neural networks were comparable and had relatively low sensitivity and correlation with adverse outcomes. CONCLUSION: Much of the variance in ELBW neurologic outcome cannot be explained by either regression analysis or neural network approaches.

Brain Diseases↗
PubMed2000

Identification and characterization of a novel gastric peptide hormone: the motilin-related peptide.

BACKGROUND & AIMS: This study looked for new proteins with expression restricted to the gastric epithelium that may provide insight to the differentiation and function of the gastric unit. METHODS: A novel complementary DNA was isolated and sequenced, and its expression was examined in mouse tissues at both messenger RNA and protein levels. Subcellular localization was studied using immunoelectron microscopy. The posttraductional processing of the protein was analyzed in vitro by protein microsequencing and in vivo by Western blotting. RESULTS: We identified a novel protein that is mainly expressed by the secretory granules of the stomach enteroendocrine cells. This protein has sequence similarity with prepromotilin, the precursor of the motilin hormone and the motilin-associated peptide. As for the prepromotilin, a posttraductional maturation leads to a secreted peptide that is further cleaved at a dibasic site and gives rise to the motilin-related peptide (MTLRP) and MTLRP-associated peptide. CONCLUSIONS: We have identified and characterized a novel gene encoding the preproMTLRP protein. MTLRP presents similarity to motilin and is specifically expressed by enteroendocrine cells of the stomach and therefore represents a novel hormone.

Animals↗
PubMed2000

Alarm reaction in the crucian carp is mediated by the medial bundle of the medial olfactory tract.

Experiments were performed to determine which bundles of the olfactory tracts were essential for mediating alarm reaction in crucian carp (Carassius carassius L.). The fish were maintained in physiological saline after surgery to preserve the remaining tracts and postoperative inspections revealed the functionality of the intact tracts. Operations on the tracts were performed symmetrically on both sides. Sham-operated and non-operated fish showed the typical alarm behaviour of fast swimming to the bottom, dashing movements and aggregation when exposed to skin extract which contain alarm substance. Fish with only the medial bundle of the medial olfactory tract intact also displayed the alarm behaviour upon exposure; however, these fish did not react to the amino acid, L-alanine with either feeding response or alarm reaction. Crucian carp which had the medial bundle of the medial olfactory tract cut, leaving both the lateral bundle of the medial olfactory tract and the lateral olfactory tract intact, did not display any alarm reaction to skin extract; however, these fish reacted to exposure to L-alanine with feeding behaviour. There were statistically significant differences between the behaviour scores for the fish subject to different treatments. The present study demonstrates that the medial bundle of the medial olfactory tract appears to be both necessary and sufficient for mediation of the alarm reaction. The results also show that the sensory neurons which respond to alarm substance terminate and make synaptic connections with the secondary neurons that make up the medial bundle of the medial olfactory tract; thereby demonstrating the specificity of the spatial aspect of olfactory processing. The results are discussed with respect to the spatial aspect of organization within the olfactory system, the pattern of generalization across orders of fish, and the functional implications of the spatial arrangement of information transmission between the peripheral olfactory organ and the brain.

Animals↗
PubMed2000

Protein kinase calpha targeting is regulated by temporal and spatial changes in intracellular free calcium concentration [Ca(2+)](i).

Protein kinase C (PKC) isoforms exert specific intracellular functions, but the different isoforms display little substrate specificity in vitro. Selective PKC isoform targeting may be a mechanism to achieve specificity. We used a green fluorescent fusion protein (GFP) to test the hypothesis that local changes in [Ca(2+)](i) regulate translocation of PKCalpha and that different modes of Ca(2+) and Ca(2+) release play a role in PKCalpha targeting. We constructed deletion mutants of PKCalpha to analyze the Ca(2+)-sensitive domains and their role in targeting. Confocal microscopy was used and [Ca(2+)](i) was measured by fluo-3. The fusion protein PKCalpha-GFP was expressed in vascular smooth muscle cells and showed a cytosolic distribution similar to the wild-type PKCalpha protein. The Ca(2+) ionophore ionomycin induced a speckled cytosolic PKCalpha-GFP distribution, followed by membrane translocation, while depolarization by KCl induced primarily membrane translocation. Selective voltage-operated Ca(2+) channel opening led to a localized accumulation of PKCalpha-GFP near the plasma membrane. Opening Ca(2+) stores with InsP(3), thapsigargin, or ryanodine induced a specific PKCalpha-GFP targeting to distinct intracellular areas. The G-protein-coupled receptor agonist thrombin induced a rapid translocation of the fusion protein to focal domains. The tyrosine kinase receptor agonist PDGF induced Ca(2+) influx and led to a linear PKCalpha-GFP membrane association. PKCalpha-GFP deletion mutants demonstrated that the C2 domain, but not the catalytic subunit, is necessary for Ca(2+)-induced PKCalpha targeting. Targeting was also abolished when the ATP binding site was deleted. We conclude that PKCalpha can rapidly be translocated to distinct intracellular or membrane domains by local increases in [Ca(2+)](i). The targeting mechanism is dependent on the C2 and ATP binding site of the enzyme. Localized [Ca(2+)](i) changes determine the spatial and temporal targeting of PKCalpha.

Adenosine Triphosphate↗
PubMed2000

Midazolam: effects on amnesia and anxiety in children.

BACKGROUND: The minimum time interval between administration of oral midazolam and separation of children from their parents that ensures good anterograde amnesia has not been previously determined. This is of particular importance in a busy operating room setting where schedule delays secondary to midazolam administration may not be tolerated. METHODS: Children (n = 113) undergoing general anesthesia and surgery completed preoperative baseline memory testing using a validated series of picture cards and were randomly assigned to one of three midazolam groups or a control group. Exactly, 5, 10, or 20 min after receiving oral midazolam (0.5 mg/kg) or 15 min after receiving placebo, children were administered a second memory test that used pictures. Anxiety of children was assessed during induction of anesthesia with use of a validated anxiety measurement tool. Postoperatively, recall and recognition for picture cards seen during baseline testing and postintervention testing were assessed. RESULTS: Postoperatively, recall and recognition of pictures presented to patients after drug administration (anterograde amnesia) showed significant group differences (P = 0.0001), with recall impaired in the 10- (P = 0.004) and 20-min groups (P = 0.0001). Similarly, recognition memory was impaired in the 5- (P = 0.0008), 10- (P = 0.0001) and 20-min (P = 0.0001) groups. Significant anxiolytic effects of midazolam were observed as early as 15 +/- 4 min after midazolam administration (P = 0.02). CONCLUSIONS: Midazolam administered orally produces significant anterograde amnesia when given as early as 10 min before a surgical procedure.

Amnesia↗
PubMed2000

Alcoholic liver disease.

Alcohol is a major cause of liver cirrhosis in the Western world and accounts for the majority of cases of liver cirrhosis seen in district general hospitals in the UK. The three most widely recognised forms of alcoholic liver disease are alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic cirrhosis. The exact pathogenesis of alcoholic liver injury is still not clear but immune mediated and free radical hepatic injury are thought to be important. There is increasing interest in genetic factors predisposing to hepatic injury in susceptible individuals. Diagnosis is based on accurate history, raised serum markers such as gamma-glutamyltransferase, mean corpuscular volume, and IgA and liver histology when obtainable. Abstinence is the most important aspect of treatment. Newer drugs such as acamprosate and naltrexone are used to reduce alcohol craving. Vitamin supplements and nutrition are vital while corticosteroids have a role in acute alcoholic hepatitis where there is no evidence of gastrointestinal haemorrhage or sepsis. Liver transplantation has excellent results in abstinent patients with end stage liver disease but there are concerns about recidivism after transplant.

Cytokines↗
PubMed2000

Chronic viral hepatitis.

Both hepatitis B and hepatitis C are spread parenterally. Chronic hepatitis C is fast becoming the leading indication for liver transplantation. Most infected patients go on to develop chronic hepatitis, with approximately 20% developing liver cirrhosis or hepatocellular carcinoma after 20 years. Standard treatment now is with a combination of alpha-interferon and ribavirin, which is successful in up to 40% of patients. A vaccine is still a remote possibility and prevention remains all-important. Despite having a successful vaccine, chronic hepatitis B remains an important cause of liver cirrhosis and hepatocellular carcinoma. Treatments for active hepatitis include alpha-interferon and the newer nucleoside analogues such as lamivudine and adefovir. In patients undergoing liver transplantation, recurrence of hepatitis B in the graft can be reduced with a combination of hepatitis B immunoglobulin and these nucleoside analogues.

Antiviral Agents↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗