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Biomedical subjects

A Lala

Publications and source records attributed to A Lala.

At least 19 recordsLinked to original sources
PubMed2006

Diabetic control after total pancreatectomy.

BACKGROUND: Diabetes after total pancreatectomy is commonly described as 'brittle' with most series reporting outcomes after resection for pancreatitis alone. The aim of this study was to determine glycaemic control in patients resected for benign and malignant disease. METHODS: A retrospective analysis of all patients undergoing total pancreatectomy (1989-2003) from a single institution was done. Data of diabetic control were obtained from case notes, general practitioners and telephonic consultation. Comparison was made against a matched type 1 diabetic population. RESULTS: Forty-seven patients with a median age of 59 years (range 17-85 years) and median follow-up of 50 months (range 5-136 months) were identified. Thirty-five underwent primary resection with 11 receiving completion procedures. Thirty were for malignancy (19 deceased) and 17 for benign/indeterminate histology (2 deceased). Thirty-three patients were available for detailed follow-up. There was no significant difference between median HbA(1c) of the study group and the control (8.2% versus 8.1%). The majority of patients reported diabetic control and daily performance as excellent or good. Resection for pancreatitis gave poorer subjective control (p < 0.05) than those resected for malignancy. Two patients required in-patient treatment for diabetic complications, with no deaths related to diabetes observed. CONCLUSION: Diabetes after total pancreatectomy is not necessarily associated with poor glycaemic control and in the majority results in equivalent biochemical control compared to a normal type 1 diabetic population.

Adolescent↗
PubMed2005

A regional audit of iatrogenic perforation of tumours of the oesophagus and cardia.

INTRODUCTION: With the rising incidence of oesophageal cancer, palliative treatment has an increasingly important role. With median survival unlikely to exceed 6 months, in advanced disease the palliative therapy chosen must not hasten patient's demise. AIM: To establish the outcome of both modern and historical palliative treatment in oesophageal tumours, with emphasis on the aetiology and outcome of iatrogenic perforation. METHODS: Patients with oesophageal or cardia carcinoma treated within the West Midlands between 1992 and 1996 were identified retrospectively. Information was gathered from hospital case notes and the regional cancer intelligence unit with hospitals visited to capture data. All episodes were entered into a dedicated database. RESULTS: Of the 3660 patients who were treated, 2529 received palliation as primary treatment, with 5259 palliative procedures performed; 164 iatrogenic perforations were recorded; 83 were due to diagnostic endoscopy (endoscopic perforation) with the reminder due to interventional palliative procedures. Median survival from all forms of palliation was 138 days. Following perforation survival was 95 days after interventional palliative procedure and 58 days after endoscopic perforation (P > 0.05). Thirty-day mortality after emergency surgery was 11.8% with mean survival of 7.5 months. CONCLUSION: Perforation at diagnostic endoscopy is associated with substantial mortality despite rapid intervention. Patients with suspected cancer must be investigated with extreme care to reduce iatrogenic complications.

Aged↗
PubMed2001

Urinary mevalonate excretion rate in type 2 diabetes: role of metabolic control.

An increased cholesterogenesis has been described in obese dyslipidemic type 2 diabetic patients and in a small number of patients with poor glucose control. So far, it is not clear if increased cholesterogenesis in type 2 diabetes is related to the degree of glycemic control or depends on the commonly associated dyslipidemia or both. Therefore, the aim of the present study was to investigate the relationships among cholesterogenesis and degree of metabolic control in a group of non-obese normolipidemic type 2 diabetic patients. Fifty four (25 men and 29 postmenopausal women) non-obese type 2 diabetic patients with cholesterol and triglyceride plasma levels, respectively, below 6.40 and 2.85 mmol/l and 20 normal subjects matched for age and sex were studied. Endogenous cholesterol synthesis was evaluated by the determination of 24-h urinary mevalonate excretion (MVA). In the diabetic group the mean glycated hemoglobin was 8.47+/-2.2% (range 4.6-14.6%), the mean total cholesterol, triglycerides, HDL and LDL cholesterol were, respectively, 4.86+/-0.7, 1.64+/-0.5, 1.19+/-0.3 and 2.87+/-0.7 mmol/l. The mean 24-h MVA urine excretion rates were 1.41+/-0.3 micromol/24 h in control subjects and 1.66+/-0.7 micromol/24 h in diabetics (P=0.05). In diabetics, urinary mevalonate excretion was significantly correlated with glycated hemoglobin concentrations (HbA(1c)) (r=0.65; P=0.0001) and body mass index (BMI) (r=0.33; P=0.009). In the multivariate analysis both HbA(1c) and BMI were independent predictors of urinary mevalonate. These data demonstrate that lower the degree of blood glucose control, higher is the whole body cholesterol production even in the absence of overt dyslipidemia. In conclusion, the relationship between mevalonate excretion rate and glycated hemoglobin gives further weight to the importance of intensive blood-glucose control in diabetic disease and adds a new element to the list of potentially atherogenic factors strictly related to hyperglycemia in type 2 diabetic patients.

Aged↗
PubMed2001

Carotid intima-media thickness in patients with Type 2 diabetes and hypercholesterolemia.

Both patients with Type 2 diabetes mellitus (T2DM) and with hypercholesterolemia have a more extensive and accelerated atherosclerosis with higher common carotid artery intima-media thickness (CIMT) values than the general population. The aim of this study was to compare the CIMT in polygenic hypercholesterolemia (HP; n=41: 30 females and 11 males, aged 52+/-15 yr) and in T2DM (n=43: 22 females and 21 males, aged 59+/-11 yr), with a duration of disease less than 5 yr and no evidence of coronary heart disease. A control group (C) of 40 sex- and age-matched healthy subjects was studied. We evaluated the CIMT on the far wall of the distal segment of the common carotid arteries on sites free of plaque. The mean of the CIMT measurements (Tmean; 9 on each side) and the maximal CIMT measured (Tmax) were used as the representative values for each subject. Tmax values were 0.96+/-0.2 mm and 0.82+/-0.2 mm in T2DM and HP, respectively, which were significantly higher than C (0.74+/-0.1 mm). Corresponding values of Tmean were 0.8+/-0.1 mm and 0.71+/-0.2 mm, both significantly higher than C (0.68+/-0.1 mm). In HP, both Tmax and Tmean values were positively correlated to age (p=0.0001 and p=0.0001, respectively), body mass index (BMI; p=0.05 and p=0.05, respectively), presence of hypertension (p=0.003 and p=0.0008, respectively) and fibrinogen (p=0.0009 and p=0.001, respectively); Tmean was also correlated to apolipoprotein B (ApoB; p=0.03). The multiple "stepwise" regression analysis revealed fibrinogen and age as the only significant determinants of Tmax and Tmean. In T2DM Tmax and Tmean were positively correlated to age only (p=0.04 and p=0.01, respectively). In conclusion, T2DM patients have a more accelerated atherosclerosis than subjects with HP. This is evident after a short duration of disease, probably for a longer latency period of disease and the presence of multiple risk factors.

Age Factors↗
PubMed2000

Pyk2 and Syk participate in functional activation of granulocytic HL-60 cells in a different manner.

The roles of the protein tyrosine kinases Pyk2 (also called RAFTK or CAK beta) and Syk in the process of functional activation of human myeloid cells were examined. During granulocytic differentiation of HL-60 cells with dimethyl sulfoxide (DMSO), the amounts of Pyk2 and beta2 integrin increased, whereas the amount of Syk was abundant before differentiation and did not change during differentiation. When the granulocytic cells were stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), tyrosine phosphorylation of Pyk2 occurred promptly and subsequent association of Pyk2 with beta2 integrin was detected. In contrast, Syk was not tyrosine phosphorylated by fMLP stimulation but constitutively associated with beta2 integrin. Stimulation with fMLP also caused the alteration of beta2 integrin to an activated form, a finding that was confirmed by the observation of fMLP-induced cell attachment on fibrinogen-coated dishes and inhibition of this attachment by pretreatment with anti-beta2 integrin antibody. Cell attachment to fibrinogen caused the enhanced tyrosine phosphorylation of Pyk2 and the initial tyrosine phosphorylation of Syk, which was also inhibited by pretreatment with anti-beta2 integrin antibody. In vitro kinase assays revealed that Pyk2 and Syk represented kinase activities to induce tyrosine phosphorylation of several molecules in the anti-beta2 integrin immunoprecipitates of the attached cells. These results showed that Pyk2 is involved in the functional activation of granulocytic cells in 2 signaling pathways: an fMLP receptor-mediated "inside-out" signaling pathway that might cause beta2 integrin activation and a subsequent beta2 integrin-mediated "outside-in" signaling pathway. Syk was activated in relation to cell attachment to fibrinogen as a result of "outside-in" signaling, although it was already associated with beta2 integrin before fMLP stimulation. (Blood. 2000;96:1733-1739)

CD18 Antigens↗
PubMed1999

Human formyl peptide receptor function role of conserved and nonconserved charged residues.

In this study, we investigated the role of charged residues in ligand binding interactions of f-Met-Leu-Phe receptors (FPR). Charged residues of FPR, both conserved and nonconserved, which are located close to the membrane interface were mutated to alanine to determine their role in ligand binding. The mutated residues belonged to specific domains of FPR which have previously been implicated in FPR ligand binding interactions. We demonstrate that nonconserved charged residues such as Arg84, Lys85, Arg205 and Asp284 and conserved charge residue Arg163 seem to play a role in ligand binding. However, alteration of nonconserved charged residue Asp106 did not have any effect. In conclusion, specific charged residues of FPR, both conserved nonconserved, may contribute to FPR function either directly or indirectly.

Amino Acid Sequence↗
PubMed1998

Apolipoprotein E genotype and cholesterogenesis in polygenic hypercholesterolemia.

We studied 22 normal-weight patients with polygenic hypercholesterolemia (PH), of which 11 (two males and nine females) had the apolipoprotein (apo) E3/4 genotype and 11 (one male and 10 females) the E3/3 genotype. The two groups were comparable for age, body mass index, total and low-density lipoprotein (LDL) cholesterol levels. The diagnosis of PH was made on the basis of clinical assessment, the criteria being type IIa hypercholesterolemia without tendon xanthomas and/or family history and clinical criteria indicative of familial hypercholesterolemia and/or familial combined hyperlipidemia. To avoid the influence of the habitual individual diet on cholesterogenesis, daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, was evaluated in the steady-state condition while patients were on a low-fat, low-cholesterol diet for at least 3 months. Urinary MVA excretion rates were 2.52 +/- 0.8 micromol/24 h in E3/4 patients, significantly higher (P < .001) than in E3/3 patients (1.38 +/- 0.6 micromol/24 h). This is the first evidence of a higher rate of cholesterogenesis in PH patients carrying the epsilon4 allele versus the epsilon3 allele under a standardized lipid-lowering diet. We conclude that the higher rate of cholesterogenesis in PH patients with the epsilon4 allele might partly explain the interindividual differences in response to treatment with cholesterol synthesis inhibitors such as statins.

Alleles↗
PubMed1997

Expression and purification of recombinant human N-formyl-L-leucyl-L-phenylalanine (FMLP) receptor: generation of polyclonal antibody against FMLP receptor.

The recombinant formyl peptide receptor has been successfully expressed and purified, utilizing an Escherichia coli expression system. Purification of formyl peptide receptor was performed using gel filtration chromatography and affinity chromatography, and the purified protein migrated at an apparent molecular mass of 36,000 Da. The purified recombinant receptor retained functional activity as determined by a ligand binding assay. The yield of the recombinant purified receptor was approximately 1 mg/2 L of culture, and the binding activity was determined to be approximately 8 nM, which suggests the conclusion that glycosylation does not affect significantly ligand binding of the N-formyl-L-leucyl-L-phenylalanine (FMLP) receptor molecule. The recombinant receptor protein yield was found to be significantly higher than that obtained from neutrophils. The purified recombinant receptor was then utilized to generate antibody against the same. The reaction of the antibody against recombinant formylpeptide receptor and against native formylpeptide receptor on neutrophils was confirmed by western blot analysis and flow cytometric analysis, respectively. The antibody was also used successfully to detect recombinant formylpeptide receptor expression on transfected 293 cells. These results describe for the first time the expression, purification, and characterization of recombinant FMLP receptor with ligand binding activity and the generation of polyclonal antibody against the same. This work also provides a foundation for future biophysical studies of the FMLP receptor molecule, which have not been possible until now.

Antibodies↗
PubMed1997

Plasma mevalonate concentrations in uremic patients.

Mevalonic acid (mevalonate or MVA), is an obligate precursor in the biosynthetic pathway of cholesterol. It is partially metabolized by the kidneys and its plasma concentrations are an index of endogenous cholesterol synthesis. The aim of the present study was to evaluate plasma MVA concentrations in uremic patients with different degrees of chronic renal failure (CRF; group A), and the effects of a single hemodialysis treatment on plasma MVA in a group of patients with end-stage renal disease (ESRD; group B). CRF patients exhibited a higher mean basal mevalonate concentration (13.3 +/- 6.5 ng/ml) than control subjects (4.68 +/- 1.32 ng/ml; P < 0.001). A statistically significant direct correlation was evident in CRF patients between mevalonate and creatinine plasma levels (r = 0.86; P < 0.001). A single hemodialysis treatment was associated with a significant reduction of plasma mevalonate concentrations four hours after the hemodialysis session (-57%; P < 0.001) and an increase up to the basal values 24 hours after the end of the treatment. In conclusion, our results demonstrated: (i) higher plasma MVA concentrations in patients with decreased renal function; (ii) a direct relationship between plasma MVA levels and the degree of kidney failure as expressed by creatinine plasma concentrations; and (iii) a clear cut reduction of elevated plasma MVA levels after a single hemodialysis treatment.

Adult↗
PubMed1995

Effects of insulin on cholesterol synthesis in type II diabetes patients.

OBJECTIVE: To evaluate the effects of intensive insulin therapy and subsequent optimized metabolic control on daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, and the acute effects of insulin on plasma MVA concentrations in type II diabetes. RESEARCH DESIGN AND METHODS: Ten (five men and five postmenopausal women) nonobese, normolipidemic (total cholesterol < 6.2 mmol/l, triglycerides < 2.82 mmol/l), type II diabetic patients in poor metabolic control (HbA1c > 10%, fasting plasma glucose > 11 mmol/l) and receiving sulfonylurea treatment were selected. The 24-h urinary MVA excretion and plasma lipid values were determined before and after intensive insulin therapy. The acute effects of insulin on plasma MVA concentrations were also evaluated during a 3-h euglycemic hyperinsulinemic clamp study. RESULTS: Urinary MVA excretion rates (mumol/24h) were 1.82 +/- 0.21 in control subjects and 2.49 +/- 0.35 (P < 0.01 vs. control subjects) and 1.78 +/- 0.28 in patients before and after intensive insulin therapy, respectively. Total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides decreased by 9, 8, and 12%, respectively, after blood glucose optimization. Acute insulin infusion during the euglycemic clamp studies reduced mean plasma MVA concentrations at 120 and 180 min by 29 and 38%, respectively (P < 0.01 for both vs. baseline). CONCLUSIONS: Our study demonstrates that in nonobese, normolipidemic, type II diabetic patients under poor metabolic control, an increased cholesterol synthesis is normalized by insulin therapy. Hyperinsulinemia in the presence of euglycemia acutely decreases the circulating levels of MVA, the immediate product of hydroxymethylglutaryl-CoA reductase activity and an index of whole-body cholesterol synthesis.

Apolipoprotein A-I↗
PubMed1994

Porphyromonas gingivalis trypsin-like protease: a possible natural ligand for the neutrophil formyl peptide receptor.

Porphyromonous gingivalis is a periodontopathic Gram-negative anaerobe associated with chronic adult periodontitis. P. gingivalis proteases are considered important virulence factors in the pathogenesis of periodontal diseases. In addition, defective bactericidal activity of neutrophils has also been observed in periodontitis. In this report we describe the effects of trypsin-like protease(s) secreted from P. gingivalis cells on the ligand binding of FMLP receptor on neutrophils. It was observed that trypsin-like protease(s) from P. gingivalis stimulate neutrophils by means of superoxide anion production. Subsequently, the proteases were found to cleave the FMLP receptor protein as evident by direct labeling of the FMLP receptor molecule. These results suggest that trypsin-like protease(s) secreted from P. gingivalis cells contribute to attenuate the bactericidal activity of neutrophils by cleaving the polypeptide chain of the FMLP receptor molecule. The finding that neutrophils after the incubation with P. gingivalis released protease preparation fail to respond to further stimulation by FMLP suggests that P. gingivalis trypsin-like protease(s) may be a possible ligand for the FMLP receptor.

Affinity Labels↗
PubMed1994

The in vitro effect of human polymorphonuclear leukocyte azurophil granule components on natural killer cell cytotoxicity.

We previously demonstrated that human polymorphonuclear leukocyte (PMN) secretions are capable of activating and inhibiting natural killer cell (NK) cytotoxicity depending on the eliciting PMN stimulus. Serum-opsonized zymosan induced PMN to secrete substances that enhanced NK activity in vitro. Serum-opsonized zymosan stimulates the release of PMN azurophil granules, which contain both human neutrophil peptides (HNPs) and neutral serine proteases (NSPs). When HNPs and NSPs were tested for their ability to activate NK cells in peripheral blood lymphocytes, all but cathepsin G consistently enhanced cytotoxicity above control values. HNP-induced cytotoxicity was significantly enhanced within 12 h, peaking at approximately 24 h. Of the HNPs, HNP-1 was the most potent activator, enhancing NK activity at 1.25 micrograms/ml. Interleukin-2 and interferon-gamma were not involved in this activational process, as antibodies to interleukin-2 and interferon-gamma did not block activation by HNPs and NSPs, and interleukin-2 receptor expression was unaltered after 24 h of incubation. Enzymatically inactivated elastase and cathepsin G produced equivalent activational effects to their active counterparts. Antisera to elastase and cathepsin G decreased but did not eliminate NK activation over untreated peripheral blood lymphocytes. These data suggest that certain PMN azurophil granule components, including HNPs and NSPs directly increase the cytotoxic activity of NK cells.

Animals↗
PubMed1994

The effects of insulin on plasma mevalonate concentrations in man.

Mevalonate production is a limiting step in cholesterol synthesis. We studied the effects of insulin on plasma mevalonate concentrations during a 3-hour euglycemic hyperinsulinemic clamp study in 10 healthy males starting at 9 h a.m. after 14 h of fasting. Physiological variations in plasma mevalonate were evaluated on a different day from 9 to 12 h a.m. under saline infusion. During the clamp studies, slight but significant decreases were noted for VLDL-triglyceride and VLDL-cholesterol at 120 and 180 min (p < 0.05) and for apolipoprotein B-100 from 60 min on (p < 0.05). Plasma mevalonate decreased significantly by 34 and 41% at 120 and 180 min, respectively (p < 0.001), while the mean percent decrease due to diurnal variations was 12% at 12 h a.m. In conclusion, hyperinsulinemia in the presence of euglycemia acutely decreases the circulating levels of mevalonic acid, the immediate product of HMG CoA reductase in the cholesterol pathway.

Adult↗
PubMed1993

Recombinant expression and partial characterization of the human formyl peptide receptor.

FMLP-receptor DNA was expressed in Escherichia coli. The expressed product could specifically bind FMLP. This is the first-reported expression of a functional FMLP receptor in Escherichia coli. We confirm that receptor glycosylation is not essential for ligand binding. A deletion mutant did not bind FMLP, suggesting that the deleted portion plays a role in ligand binding.

Amino Acid Sequence↗
PubMed1992

The differential effects of polymorphonuclear leukocyte secretion on human natural killer cell activity.

We studied the differential effects of polymorphonuclear leukocyte (PMN) secretion on human natural killer cells (NK) and lymphokine-activated killer cell (LAK) activity. Supernatant fluids from PMN stimulated by serum-opsonized zymosan (SOZ), n-formylmethionylleucylphenylalanine (FMLP) and interleukin-8 (IL-8) were incubated with peripheral blood lymphocytes (PBL) for 1 d and 4 d. Supernates from unstimulated PMN and PMN induced by FMLP and IL-8 decreased NK and LAK cytotoxicity in a dose-dependent fashion against K562 and M14 targets, respectively. Only the suppression caused by supernates from unstimulated PMN was ablated by incubation of PMN with indomethacin. Secretions from PMN stimulated by SOZ increased both NK and LAK cytotoxicity and induced PBL proliferation synergistically with IL-2. This enhancing factor was heat-labile, nondialyzable (MWCO 3500), and not blocked by anti-interferon-gamma. Anaerobic conditions did not influence the modulatory activity of PMN supernates, indicating that oxygen metabolites were not involved. We conclude that PMN release factors that modulate in vitro NK and LAK activities.

Cell Line↗
PubMed1991

Regression of microalbuminuria in type II diabetic, hypertensive patients after long-term indapamide treatment.

The influence of hypertension on the progression of persistent microalbuminuria in type II diabetes has not yet been clarified. We have studied the effects of 36 months of indapamide treatment (2.5 mg once daily) on blood pressure (BP), albumin excretion rate (AER), urinary immunoglobulin G4 (IgG4), and glomerular filtration rate (GFR) in 10 patients who were mildly hypertensive and had type II microalbuminuric diabetes (AER greater than 30 mg/24 hours and less than 300 mg/24 hours). BP, AER, and IgG4 significantly decreased after 6 months until the end of the study. Mean GFR was 94.4 +/- 7.5 ml/min/1.73 m2 in the baseline and did not change significantly throughout the course of the antihypertensive therapy. AER and IgG4 were directly related (r = 0.57; p less than 0.004), whereas BP did not relate to GFR, AER, or IgG4. The nephropathy index (45.5 +/- 4 in the baseline) significantly decreased at 12 months (38.7 +/- 2.1), 24 months (35.4 +/- 1.6), and 36 months (36.5 +/- 1.5) (at least p less than 0.01). Long-term indapamide treatment reduced BP and urinary protein loss without affecting GFR. These results indicate a potential role of this drug in the long-term renal protection of patients with type II diabetes, mild hypertension, and microalbuminuria.

Adult↗