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Biomedical subjects

M Haq

Publications and source records attributed to M Haq.

At least 19 recordsLinked to original sources
PubMed2005

Differentiated thyroid carcinoma with distant metastases at presentation: prognostic factors and outcome.

BACKGROUND: Differentiated thyroid cancer (DTC) presenting with distant metastases is uncommon. Prognostic factors that affect survival remain unclear. AIM: To evaluate factors influencing the survival of patients with DTC presenting with distant metastases. METHOD: A retrospective study of 111 patients (62 F, 49 M) with DTC who presented with distant metastases (M1) treated at the Royal Marsden Hospital from 1940 to 2002. RESULTS: The median follow-up of living patients was 3.9 years (0.3-48) with a 10-year cause-specific survival rate of 31%. Histology identified 46 papillary, 60 follicular and five Hürthle cell cancers. Sites of metastases comprised 54 lung (49%), 27 bone (24%), 21 multiple sites (19%) and nine with other single sites affected (8%). Near-total, total or completion thyroidectomy was performed in 56% of patients, radioiodine ablation in 76% and radioiodine therapy in 67%. External beam radiotherapy was given to 12 patients and the same number received chemotherapy. Univariate analysis was performed with cause-specific survival as the main outcome measure. Age over 70, poorly differentiated tumours and Hürthle cell cancers were associated with worse outcomes (P < 0.01). Patients with multiple organ metastases had a worse survival (P = 0.02). Radical surgery did not significantly improve outcome compared to more conservative forms of surgery (subtotal thyroidectomy, hemi-thyroidectomy or lobectomy) but patients receiving radioiodine ablation and therapy had improved survival (P < 0.01). Multivariate analysis identified age over 70, poorly differentiated tumours and Hürthle cell variant to be the only independent factors associated with worse outcome (P < 0.01). Treatment in the 1991-2002 era was associated with an improved survival compared to all previous decades (P = 0.009). CONCLUSIONS: Patients with DTC presenting with distant metastases have a worse outcome if aged over 70, have poorly differentiated tumours or have Hürthle cell variant. Despite their unfavourable prognosis, a dramatic improvement in survival was observed in the most recent era (1991-2002).

Adenocarcinoma↗
PubMed2003

Detection of a mammalian-like group A rotavirus in diarrhoeic chicken.

The present investigation describes detection of a mammalian-like electropherogroup A rotavirus in chicken with diarrhoea. This also records the first detection of a rotavirus in an avian species from India. During the investigation 75 diarrhoeic faecal samples collected from adult chicken were screened for the presence of group A rotavirus antigen by sandwich ELISA. All three samples positive for rotavirus antigen revealed 11 bands of RNA in polyacrylamide gel electrophoresis (PAGE). In contrast to avian group A rotavirus, segment 5 was found to migrate closer to 6 as is the case with mammalian group A rotaviruses. Segments 7, 8 and 9 were found to migrate as a tight triplet, which is characteristic of group A rotavirus.

Animals↗
PubMed2001

IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury.

In vitro studies have suggested that targeting interleukin (IL)-1 and tumor necrosis factor (TNF) can be used to regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and potentially treat kidney inflammation. We therefore evaluated ICAM-1 and VCAM-1 regulation in knockout (KO) mice deficient in both IL-1 receptor 1 (R1) and TNF-R1 during renal ischemia reperfusion injury. ICAM-1 and VCAM-1 mRNA expression was measured with specific murine probes and Northern blotting (n =4/group). Protein expression was measured using immunohistochemistry. Serum creatinine (SCr), tubular histology, and neutrophil infiltration into postischemic kidneys were also quantified. ICAM-1 and VCAM-1 mRNA expression increased in both wild-type (WT) and KO mice at 2, 6, and 24 h. Protein expression of ICAM-1 and VCAM-1 was also increased at 24 h postischemia. SCr levels and tubular necrosis scores were comparable in WT and KO mice at 24 and 48 h. Neutrophil migration in KO mice was decreased at 24 h but comparable to WT at 48 h. These data demonstrate that IL-1 and TNF are not essential for postischemic increases in ICAM-1 and VCAM-1.

Animals↗
PubMed2000

Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer.

Matrix metalloproteinases (MMPs) participate in basement membrane degradation, a critical step in invasion of cancer cells. We have previously shown that MMP inhibition of pancreatic cancers improves survival and decreases MMP production in vivo. The purpose of this study was to determine whether BB-94 was better than cytotoxic therapy and would increase the efficacy of cytotoxic therapy (gemcitabine) in a murine model of human pancreatic cancer. A human pancreatic adenocarcinoma cell line (HPAC) was injected into the pancreata of BALB/c nu/nu mice. The mice were randomized 7 days after cancer cell injection to receive vehicle control, BB-94, gemcitabine, or gemcitabine and BB-94 until death or sacrifice at 84 days. At necropsy, tumors were harvested, and the relative enzyme activities of MMP-2 and MMP-9 were determined by gelatin zymography. Active MMP-2 levels in serum were determined using an ELISA technique. Combination treatment with gemcitabine and BB-94 significantly reduced implantation rates and improved survival in mice with documented orthotopic tumors compared with either therapy alone or control. Tumor levels of active and latent MMP-2 were higher than those of MMP-9 in both treated and control mice. There was a significant reduction of tumor MMP-2 activity in mice treated with BB-94, gemcitabine, or gemcitabine and BB-94. Serum levels of active MMP-2 were reduced in all treated groups, with the greatest reduction occurring in mice treated with gemcitabine and BB-94. Combination therapy with gemcitabine and BB-94 reduces cancer implantation and improves survival compared to treatment with BB-94, gemcitabine, or vehicle control alone. MMP production was reduced in all treated groups, reflecting reduced tumor progression, which was particularly seen with combination therapy with gemcitabine and BB-94. This study supports combining MMP inhibition with cytotoxic therapy (gemcitabine) for patients with pancreatic cancer.

Animals↗
PubMed2000

Genetic susceptibility to renal ischemia reperfusion injury revealed in a murine model.

BACKGROUND: The development of genetically engineered mice has led to increased use of mouse models to study renal ischemic reperfusion injury (IRI). We hypothesized that susceptibility to IRI could result from strain differences due to genetic factors. METHODS: Our study compared recovery subsequent to renal IRI in NIH Swiss, C57BL/6, and BALB/c mice. Serum creatinine (SCr) and blood urea nitrogen (BUN) levels were evaluated postischemia. We also conducted reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of renal cytokines and adhesion molecules postischemia. RESULTS: At 48 hr postischemia, renal dysfunction in NIH Swiss mice was significantly reduced, compared with other groups (P<0.01). BUN measurements confirmed renal protection at 48 hr in the NIH Swiss group. RT-PCR analysis of mRNA postischemia demonstrated that, between strains, there was little difference in mRNA expression for renal cytokines and adhesion molecules. CONCLUSIONS: NIH Swiss mice appear to be resistant in susceptibility to renal IRI. Early expression of pro-inflammatory genes was not associated with resistance to IRI, thus genetic factors could be important in outcome after renal IRI.

Animals↗
PubMed2000

Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice.

Mononuclear cell infiltrates are found in human renal ischemia-reperfusion injury (IRI), and peritubular T lymphocytes have been identified in experimental IRI. However, the role of T cells in the pathogenesis of renal IRI is unknown. We hypothesized that T cells are one of the important mediators of renal IRI. To test this hypothesis, we used an established mouse model of renal IRI, and evaluated mice with genetically engineered deficiency of both CD4+ and CD8+ T cells. At 48 h postischemia, CD4/CD8-knockout (KO) mice had marked improvement in renal function compared with control C57BL/6 mice (serum creatinine: 0.7 +/- 0.4 vs. 2.5 +/- 0.3 mg/dl, respectively; P < 0.05). Neutrophil infiltration into postischemic kidney was reduced in CD4/CD8 KO mice, compared with control mice, at both 24 h [polymorphonuclear neutrophils (PMNs)/10 high power fields: 714 +/- 354 vs. 3,514 +/- 660, respectively; P < 0.05] and 48 h (88 +/- 32 vs. 1,979 +/- 209, respectively; P < 0.05). Tubular necrosis score in CD4/CD8 KO mice, compared with control mice, was significantly less at 48 h (0.4 +/- 0.1 vs. 2.4 +/- 0.2, respectively; P < 0.05). Because adhesion between T cells and renal tubular epithelial cells (RTECs) may underlie the pathophysiological role of T cells in renal IRI, we also measured T cell adhesion to primary murine RTECs in vitro. Exposure of RTECs to 2 h of hypoxia followed by 1 h of reoxygenation increased T cell adhesion more than twofold. Phorbol ester treatment, which activates integrins, increased T cell adhesion threefold. These data suggest that T lymphocytes can mediate experimental renal IRI. Moreover, adhesion of infiltrating T cells to renal tubular cells may provide a potential mechanism underlying postischemic tubular dysfunction.

Acute Kidney Injury↗
PubMed2000

In vitro and in vivo matrix metalloproteinase production by pancreatic cancer cells and by distant organs.

BACKGROUND: Matrix metalloproteinases (MMP), especially MMP-2 and MMP-9, are thought to play major roles in pancreatic cancer growth and metastasis. MMP inhibition prolongs survival in a murine model of human pancreatic cancer. To establish an in vitro model of human pancreatic cancer, we sought to determine in vitro MMP production by two human pancreatic cancer cell lines, compare in vitro to in vivo production, and, if different, determine if in vitro MMP production could be made to mimic in vivo production by altering the in vitro environment of the cell lines. We also sought to document that in vivo production of MMP was unique to orthotopic pancreatic cancer cells. METHODS: HPAC and PANC-1 cell lines were grown in vitro and in a murine model of orthotopic pancreatic cancer. MMP-2 and MMP-9 production by the cell lines was determined. Noting differences between in vitro and in vivo production, the cell lines were stimulated in vitro with PMA. Orthotopic pancreatic tumor MMP production was compared to splenic, hepatic, and renal production of MMP. MMP-2 and MMP-9 production was sought in both active and latent forms utilizing gelatin zymography. Results were confirmed by Western blot. Densitometry allowed comparisons: scale 0 (none) to ++++ (most). RESULTS: In vitro, HPAC and PANC-1 produce modest amounts of MMP-2 and MMP-9, mostly in latent form. In vivo, both cell lines produce more MMP, particularly in the active forms. In vitro stimulation of the cell lines with the PMA increased MMP production, particularly of active MMP-2 and latent MMP-9, resulting in a profile of MMP production similar to that seen in vivo. Hepatic, renal and splenic MMP levels, especially active forms, were very low relative to the tumors. CONCLUSIONS: Pancreatic cancer cell lines produce less MMP, especially active form, in vitro than in vivo. With in vitro stimulation, the MMP profile of cell lines mimic those of tumors in vivo, suggesting that cancer cells are stimulated in vivo. Both in vitro and in vivo, the poorly differentiated cell line PANC-1 is associated with broadened and enhanced MMP activity. Healthy solid organs produce little MMP-2 or MMP-9, most of which is latent form.

Animals↗
PubMed1999

Matrix metalloproteinase inhibition suppresses MMP-2 activity and activation of PANC-1 cells in vitro.

BACKGROUND: We have shown previously that the metalloproteinase inhibitor, BB-94, prolongs survival and attenuates MMP-2 activity in a murine model of pancreatic cancer. The purpose of this study was to determine the effect of BB-94 on the activity and activation of MMP-2 by PANC-1 cells in vitro. MATERIALS AND METHODS: The poorly differentiated pancreatic cancer cell line PANC-1 was stimulated in vitro with the phorbol ester PMA (20 nM) and grown in the presence of increasing doses of BB-94 (0, 40, 200, and 400 ng/ml) for 24 h. Activation of MMP-2 was determined by gel zymography. In a separate experiment detailing the effects of BB-94 on MMP-2 activity, PANC cells were stimulated for 24 h with PMA and run out on four separate zymograms, each incubated in the previously noted concentrations of BB-94. Using densitometry, band intensity on all gels was determined and compared for each concentration of BB-94. The Matrigel assay was used to determine BB-94's effect on the invasive potential of PANC cells at the previously studied concentrations. The presence of MT-MMP (a putative component of MMP-2 activation) was confirmed using Western blot in each group. RESULTS: BB-94 inhibited the conversion of latent to active MMP-2 in a dose-dependent fashion. BB-94 also inhibited the activity of MMP-2 when run out on gel zymograms incubated with increasing concentrations of BB-94. Decreased activity and activation of MMP-2 by BB-94 were manifested by a significant reduction in the invasive potential of PANC as determined by the Matrigel assay. MT-MMP was universally present in each study group. CONCLUSIONS: The previously described salutary effects of MMP blockade in mice implanted with pancreatic cancer can be explained in vitro by a dose-dependent diminution of MMP-2 activity and activation in PANC cells exposed to BB-94.

Animals↗
PubMed1998

A possible molecular basis of natriuresis during ischemic-reperfusion injury in the kidney.

Ischemic renal injury is associated with increased fractional excretion of sodium, suggesting a Na+ reabsorption deficiency in renal tubules. To determine whether alterations in expression of the major Na+ transporter genes might contribute to the natriuresis that follows ischemic acute renal failure, the expression of these genes was analyzed in renal cortex and medulla after ischemic-reperfusion injury. Rats were subjected to 30 min of renal pedicle clamping and then sacrificed at 12, 24, or 48 h after reperfusion. Serum creatinine increased significantly at 12 and 24 h, indicative of acute renal failure, but decreased substantially by 48 h. mRNA levels for the NHE-3 Na/H exchanger of the proximal tubule, the apical Na-K-2Cl cotransporter of the thick ascending limb of Henle, the Na-Cl cotransporter of the distal convoluted tubule, the epithelial Na+ channel of the collecting duct, and the basolateral Na(+)-K(+)-ATPase were measured by Northern hybridization. NHE-3 mRNA decreased by approximately 75% at 12 h and remained suppressed at 24 and 48 h after reperfusion. Na-K-2Cl cotransporter mRNA decreased by approximately 88% at 12 h and remained suppressed at 24 and 48 h. Na-Cl cotransporter mRNA remained unchanged at 12 h, decreased by approximately 60% at 24 h, and returned to almost control levels at 48 h. mRNA levels for sodium channels (beta subunit) remained unchanged. Na(+)-K(+)-ATPase mRNA in the medulla decreased by approximately 35 to 40% at 12 and 24 h and by 70% at 48 h, whereas in cortex it decreased by only < 15% at 12 or 48 h after reperfusion. These results suggest that sharp reductions in expression of the NHE-3 Na/H exchanger and the apical Na-K-2Cl cotransporter are major factors in the natriuresis/diuresis that is one of the hallmarks of ischemic acute renal failure. Lasting suppression of these transporters, despite improvement in renal function, could contribute to the deranged NaCl and water excretion that often leads to volume depletion during recovery from ischemic acute renal failure.

Analysis of Variance↗
PubMed1998

Role of IL-1 in renal ischemic reperfusion injury.

Interleukin-1 (IL-1) is a central component of many acute inflammatory processes. Blocking IL-1 receptor (IL-1R) with IL-1R antagonist (IL-1Ra) has attenuated ischemic reperfusion injury in brain, heart, and liver models. However, the role of IL-1 in renal ischemic reperfusion injury (IRI) is not known. Therefore, the role of IL-1 in renal IRI was evaluated using the complementary approaches of IL-1R blockade in wild-type mice in addition to the study of renal IRI in IL-1R knockout (KO) mice. Ischemia was induced by bilateral renal pedicle clamping for 30 min. IL-1Ra was administered at 10 mg/kg every 4 h, high doses that have been protective in previous organ injury models in mice. IL-1R KO animals, previously characterized as insensitive to IL-1, had the absence of IL-1R1 confirmed by DNA blots. IL-1Ra, IL-1R KO, and control groups had similar elevations of blood urea nitrogen (114 +/- 13, 133 +/- 11, and 120 +/- 11 mg/dl) and serum creatinine (1.7 +/- 0.3, 2.1 +/- 0.2, and 1.6 +/- 0.3 mg/dl) 24 h after ischemia. Furthermore, acute tubular necrosis scores were also similar in IL-1Ra-treated mice (3.0 +/- 0.3), IL-1R KO mice (2.7 +/- 0.3), and control mice (3.1 +/- 0.2). However, both IL-1Ra and IL-1R KO groups, compared with control animals, developed significantly less infiltration of polymorphonuclear leukocytes per 10 high-power fields in postischemic renal tissue (1111 +/- 228 and 967 +/- 198 versus 1820 +/- 190, P < 0.05). In contrast to the comparable renal functions at 24 h, recovery of renal function was significantly accelerated in the IL-1R KO group compared with control at both 48 (P < 0.05) and 72 (P < 0.05) h. Recovery in the IL-1Ra group was similar to that in the control animals. These data demonstrate that IL-1 is unlikely to be beneficial in the recovery of renal function after ischemia and may play a deleterious role.

Analysis of Variance↗
PubMed1997

Serum sialic acid and its relationship to various haematological parameters, including erythrocyte sedimentation rate.

Serum total sialic acid (TSA) has been reported to be a marker or risk factor for cardiovascular disease. The reason for this is not clear, although it has been suggested that serum TSA is a marker of the acute phase response. We measured serum TSA and various haematological parameters in 40 subjects. Significant correlations of serum TSA with erythrocyte sedimentation rate (ESR) (r = 0.65, P < 0.0001), platelet count (r = 0.65, P < 0.0001) and neutrophil count (r = 0.33, P < 0.05) were found. There was an inverse correlation with haemoglobin concentration (r = -0.62, P < 0.0001) and erythrocyte count (r = -0.42, P < 0.01).

Adolescent↗
PubMed1994

The relationship of serum total sialic acid with serum acute phase proteins and lipoprotein (a) in patients with severe hypertriglyceridaemia.

Total serum sialic acid (TSA), recently shown to be a cardiovascular risk factor, was measured in 15 patients with severe hypertriglyceridaemia (fasting triglyceride > 2.3 mmol l-1) and 15 age and sex matched normal control subjects. To test the hypothesis that serum TSA is related in some way to serum acute phase proteins we also measured five acute phase proteins, namely alpha-1-antichymotrypsin (ACT), alpha-1-acid-glycoprotein (AGP), alpha-2-macroglobulin (AMG), C-reactive protein (CRP) and haptoglobin (HAP) in both groups. Of note was the significantly elevated serum TSA in the severely hypertriglyceridaemic group as compared to normal subjects. Serum TSA being 71.9 +/- 11.7 mg dl-1 and 59.6 +/- 10.2 mg dl-1 respectively (P < 0.01 Mann-Whitney test). Serum CRP was significantly elevated in the type IV patients as compared to controls (6.4 +/- 4.5 mg l-1 vs. 3.3 +/- 1.9 mg l-1 P < 0.05 Mann Whitney test) as was serum AMG (2.1 +/- 0.89 g l-1 vs. 1.5 +/- 0.53 g l-1 P < 0.05 Mann Whitney test). There was no correlation between serum TSA and lipoprotein (a) in either the normal or severely hypertriglyceridaemic subjects. We suggest that serum TSA could in part be related to hypertriglyceridaemia and serum acute phase proteins but that its property as a cardiovascular risk factor is not related to serum lipoprotein (a) concentrations.

Acute-Phase Proteins↗
PubMed1994

Plasma sialic acid and acute-phase proteins in patients with myocardial infarction.

Plasma total sialic acid (TSA) and lipid-associated sialic acid (LASA) were measured in 19 patients with a myocardial infarction (MI) on days 1, 2, and 5 and in 19 normal subjects. On each day plasma TSA was elevated in the MI patients as compared with that of normal subjects, although no significant difference was seen in the plasma LASA between the two groups. The following plasma acute-phase proteins were also assayed in the MI patients and the normal subjects: C-reactive protein (CRP), alpha-1 acid glycoprotein (AGP), alpha-1 antichymotrypsin (ACT), alpha-2 macroglobulin (AMG), and fibrinogen (FIB). Significantly elevated plasma concentrations were found in the MI patients as compared with normal subjects. Furthermore, a significant correlation was found between some of these plasma acute-phase proteins (ACT, AMG, and FIB) and plasma TSA in the MI patients and also in normal subjects (ACT, AMG, CRP, and FIB). However, no significant difference was noted in any of the plasma acute-phase proteins, or plasma TSA, or plasma LASA between survivors and patients who died of their MI.

Acute-Phase Proteins↗
PubMed1994

Serum total sialic acid and acute phase proteins in elderly subjects.

Serum total sialic acid has gained recent interest as a cardiovascular risk factor. We measured serum total sialic acid and three acute phase proteins; C-reactive protein, alpha 1-antichymotrypsin and alpha 1-acid glycoprotein in 37 geriatric patients (age 80.1 +/- 7.0 years) and 50 younger subjects (age 40.3 +/- 11.4 years). Serum total sialic acid was higher in the geriatric subjects 2.41 +/- 0.39 mmol/l versus 2.04 +/- 0.35 mmol/l, P < 0.04. Serum alpha 1-acid glycoprotein, alpha 1-antichymotrypsin and C-reactive protein were also elevated in the geriatric patients; serum alpha 1-acid glycoprotein being 1.16 +/- 0.32 g/l versus 0.41 +/- 0.28 g/l, P < 0.0001, serum alpha 1-antichymotrypsin being 0.80 +/- 0.20 g/l versus 0.52 +/- 0.10 g/l, P < 0.0001 and serum C-reactive protein being 9.71 +/- 21.0 mg/l versus 4.73 +/- 1.30 mg/l, P < 0.04. There was a correlation with serum total sialic acid and serum alpha 1-acid glycoprotein and alpha 1-antichymotrypsin in the geriatric subjects and with alpha 1-acid glycoprotein, alpha 1-antichymotrypsin and C-reactive protein in the younger group.

Acute-Phase Proteins↗
PubMed1994

Serum lipids, acute phase proteins and serum cholinesterase in normal subjects.

Although serum cholinesterase (CHE) is elevated in some hyperlipidaemic subjects, the relationship between serum CHE and lipids in normolipidaemic subjects is scanty. Furthermore, serum CHE is reduced in conditions in which there is an acute phase response. Serum CHE activity was measured in 46 normal individuals (22 males and 24 females). There was no significant difference between the activity of serum CHE in males or females being 6.2 +/- 1.8 U1(-1) vs. 6.4 +/- 1.5 U1(-1) respectively (mean +/- SD). There was, however, a significant correlation between serum CHE and subject age (Spearman rho 0.35, p < 0.05). There was also a significant correlation between serum CHE and serum nonfasting triglyceride concentration (rho 0.34, p < 0.05) and also apolipoprotein B (rho 0.38, p < 0.05) but not serum cholesterol or HDL-cholesterol. Five serum acute phase proteins were measured namely serum alpha-1 antichymotrypsin (ACT), alpha-1-acid-glycoprotein (AGP), alpha-2-macroglobulin (AMG), C-reactive protein (CRP), haptoglobin (HAP). Only serum AGP showed a significant negative correlation with serum CHE (rho - 0.43, p < 0.02).

Acute-Phase Proteins↗