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Biomedical subjects

M K Sharief

Publications and source records attributed to M K Sharief.

At least 37 records · Page 2Linked to original sources
PubMed2002

Upregulated survivin expression in activated T lymphocytes correlates with disease activity in multiple sclerosis.

Programmed cell death (apoptosis) is critical for the normal development and homeostasis of the immune system. There is emerging evidence that failure of apoptosis to eliminate potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). This failure is related to multiple abnormalities of apoptosis-regulatory molecules that involve survivin, a recently described cell cycle-regulated anti-apoptosis protein. In this study, we investigated the relationship between survivin expression in peripheral T lymphocytes and clinical features of MS. We detected a significant over-expression of survivin in mitogen stimulated T lymphocytes from patients with active MS when compared with corresponding expression in patients with stable MS or those with inflammatory and non-inflammatory neurologic disorders. This over-expression of survivin in patients with active MS correlated with cellular resistance to apoptosis and with features of disease activity, such as disease duration and the number of enhanced lesions on cranial magnetic resonance imaging. There was no correlation between cellular survivin levels and the expression of other apoptosis-inhibitory proteins, such as Bcl-2 and Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP). Our findings indicate that cellular over-expression of the novel anti-apoptosis protein survivin is a feature of clinically active MS.

Age of Onset↗
PubMed2001

Interferon-beta therapy downregulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis.

Interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that may involve augmentation of programmed cell death (apoptosis) of T lymphocytes. The anti-apoptosis protein FLIP (Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein) has been recently identified as a potent regulator of T lymphocyte susceptibility to apoptosis. In a prospective study, we evaluated the expression of FLIP and other apoptosis regulatory proteins in ex vivo activated T lymphocytes from MS patients, before and serially after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on T cell apoptosis in a cross-sectional study of MS patients receiving chronic drug therapy. Treatment with interferon-beta reduced the expression of FLIP isoforms in activated T lymphocytes. This reduced expression correlated with augmented T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of the anti-apoptotic protein Bcl-2. This downregulatory effect of interferon-beta on cellular FLIP expression was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through a pro-apoptosis mechanism that involves the downregulation of cellular FLIP expression.

Adult↗
PubMed2001

Upregulation of the inhibitor of apoptosis proteins in activated T lymphocytes from patients with multiple sclerosis.

The pathogenesis of multiple sclerosis (MS) may involve failure of programmed cell death (apoptosis) to eliminate potentially pathogenic, autoreactive T lymphocytes. This failure may be caused by multiple abnormalities of the cell death machinery. In this study, we investigated the expression of the inhibitors of apoptosis (IAP) proteins, cellular IAP-1, IAP-2, and X-linked IAP (XIAP), in T lymphocytes from patients with active relapsing-remitting MS and appropriate controls. The expression of IAP proteins was significantly higher in mitogen-stimulated intrathecal and peripheral T lymphocytes from MS patients when compared to corresponding expressions from inflammatory and non-inflammatory neurologic controls, and healthy individuals. IAP proteins were also expressed in resting (unstimulated) T lymphocytes predominantly from MS patients. The heightened expression of IAP proteins in MS patients correlated with T lymphocyte resistance to apoptosis, and was independent of cellular expression of the death receptor protein Fas. In contrast, cellular expression of the anti-apoptosis protein Bcl-2 was relatively similar between MS patients and the control groups. These findings suggest that over-expression of IAP proteins in mitogen-stimulated T lymphocytes is a feature of multiple sclerosis.

Apoptosis↗
PubMed2001

Heightened expression of survivin in activated T lymphocytes from patients with multiple sclerosis.

The perpetuation of the inflammatory process in multiple sclerosis (MS) may arise from the failure to eliminate potentially pathogenic autoreactive lymphocytes by programmed cell death (apoptosis). Such impairment may be caused by multiple abnormalities of apoptosis regulatory proteins. In this study, we investigated the expression of survivin, a recently described cell cycle-regulated antiapoptosis protein, in lymphocytes from patients with active relapsing-remitting MS and appropriate controls. Survivin reactivity was detected in intrathecal lymphocytes from some MS patients, but not in resting peripheral lymphocytes. However, mitogen stimulation of resting lymphocytes induced survivin expression, which was significantly higher in stimulated intrathecal and peripheral T lymphocytes from MS patients when compared to controls. In contrast, cellular expression of the antiapoptosis protein Bcl-2 was relatively similar between MS patients and the control groups. Moreover, heightened survivin expression in MS patients correlated with T lymphocyte resistance to apoptosis, and was independent of cellular expression of the death receptor Fas. These findings suggest that upregulation of the antiapoptotic protein survivin in mitogen-stimulated T lymphocytes is a feature of multiple sclerosis.

Apoptosis↗
PubMed2001

Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis.

The cellular caspase-inhibitory protein FLIP has been recently identified as a potent regulator of T lymphocyte susceptibility to Fas-mediated programmed cell death (apoptosis). Since impairment of apoptosis may be involved in multiple sclerosis (MS), we investigated the dynamics of cellular FLIP in unstimulated and activated T lymphocytes from MS patients, inflammatory and non-inflammatory neurological disorders, and healthy subjects. Cellular expression of the long and short forms of FLIP protein was similar in unstimulated T cells from MS patients and controls, but was significantly higher in activated T cells from patients with clinically active MS. This high FLIP expression in active MS correlated with cellular resistance to Fas-mediated apoptosis. In contrast, cellular expression of the anti-apoptotic protein Bcl-2 did not differ between active and stable disease, and was relatively similar between the MS group and controls. These findings suggest that cellular overexpression of the anti-apoptotic protein FLIP is a feature of clinically active multiple sclerosis.

Apoptosis↗
PubMed2001

A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy.

A randomized, double-blind, placebo-controlled study of brain-derived neurotrophic factor (rhBDNF) was conducted in 30 patients with insulin-treated diabetes mellitus, with obligatory abnormalities of sural nerve conduction studies and vibration perception threshold (VPT) at the great toe on recruitment. Nine patients received placebo, 11 rhBDNF (25 microg/ kg) and 10 rhBDNF (100 microg/kg) s.c. daily for 3 months, and were assessed at days 0, 8, 15, 29, 43, 57 and 85 with nerve conduction and quantitative sensory and autonomic tests including VPT, thermal and light touch thresholds, and cutaneous axon-reflexes. No statistically significant differences were found among the 3 treatment groups between baseline and day 85 values. To examine possible reasons for lack of effect, post hoc analysis was performed. In the subset of patients with abnormal but detectable cool detection threshold (CDT) at baseline, there was improvement of CDT at day 85 when compared to baseline in the treated (p < 0.02) but not placebo group. Further, from days 43 to 85, in the treated group but not the placebo group, CDT was indistinguishable from a group of matched normal subjects (p > 0.05). Skin biopsies failed to show evidence of structural change; assessment of innervation of hair follicles, which is partly dependent on BDNF, was not possible because of the marked loss of this end-organ in diabetic neuropathic skin. The only side effects of rhBDNF were infrequent non-painful injection-site skin reactions and increased gut motility at the higher dose. We conclude that further preclinical studies are warranted before any future clinical trials to see if rhBDNF improves CDT and constipation in diabetics.

Adult↗
PubMed2000

Increased cellular expression of the caspase inhibitor FLIP in intrathecal lymphocytes from patients with multiple sclerosis.

Failure of Fas-mediated apoptosis of potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis. The intracellular protein FLIP, a naturally occurring caspase-antagonist, is a potent inhibitor of the Fas signalling pathway that may block Fas-mediated apoptosis of activated lymphocytes. This study reports specific overexpression of both long and short forms of FLIP in intrathecal lymphocytes from patients with multiple sclerosis. The overexpression of FLIP is independent of cellular expressions of Fas receptor or the anti-apoptotic protein Bcl-2. These results provide a better understanding of some of the intrinsic immunoregulatory mechanisms that are involved in multiple sclerosis.

Adolescent↗
PubMed2000

Impaired Fas-independent apoptosis of T lymphocytes in patients with multiple sclerosis.

The homeostasis of the immune system is maintained by apoptotic (programmed cell death) elimination of potentially pathogenic, autoreactive mononuclear cells. There is emerging evidence that apoptosis mediated by the cell death receptor Fas is impaired in activated lymphocytes from patients with multiple sclerosis (MS), but other forms of apoptosis have not yet been fully evaluated. To further explore the dynamics of programmed cell death in MS, spontaneous and induced apoptosis of both peripheral and intrathecal mononuclear cells was investigated in clinically active MS patients and appropriate controls. In the MS group, spontaneous apoptosis of unfractionated mononuclear cells was significantly reduced, and activated intrathecal and peripheral T cells were found to be predominantly resistant to Fas-independent apoptosis. These results indicate that in clinically active MS, the reduced susceptibility of mononuclear cells to apoptosis is partly due to impairment of Fas-independent apoptotic pathways.

Adult↗
PubMed1999

Axonal degeneration in the pathogenesis of multiple sclerosis.

Axonal degeneration plays an important role in the accumulation of disability in patients with multiple sclerosis (MS). Pathological studies have demonstrated axonal damage, particularly in areas of acute inflammation and demyelination, and in chronic lesions. Axonal loss and its progression, which is associated with neurological disability, has also been demonstrated by magnetic resonance imaging (MRI) studies. The mechanisms of axonal loss are uncertain, but may involve axonal degeneration secondary to demyelination, or damage to the axonal cytoskeleton. Inflammatory mediators, including cytokines and proteolytic enzymes may contribute to axonal damage, as may nitric oxide. Axonal destruction may also be due to immune attack directed at axonal components. The realisation that axonal degeneration is a fundamental component of MS that may occur early in the disease course should alter the approach to management and open avenues to a more targeted immunotherapy aimed at reducing the progression of disability.

Axons↗
PubMed1999

I.v. immunoglobulin reduces circulating proinflammatory cytokines in Guillain-Barré syndrome.

BACKGROUND: Treatment with human i.v. immunoglobulin (IVIg) modifies the course of Guillain-Barré syndrome (GBS), but its specific mode of action is unknown. Cellular interactions mediated through the release of cytokines play a role in the pathogenesis of GBS and may be regulated by IVIg therapy. OBJECTIVE: To delineate possible immunoregulatory mechanisms of IVIg in patients with GBS. METHODS: Circulating levels of the proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, were assayed in 21 patients with GBS before and serially after IVIg therapy. Comparisons were made with serum concentration of the anti-inflammatory cytokines, soluble TNF-alpha receptor and IL-10. Serial measurements were also performed in 12 untreated patients with relatively mild disease and 7 patients treated by plasma exchange. RESULTS: Circulating levels of TNF-alpha and IL-1beta decreased after treatment with IVIg but remained relatively high in untreated patients and in those treated by plasma exchange. Clinical improvement in patients treated with IVIg was associated with a reduction in unbound TNF-alpha during the acute phase of the illness. Circulating levels of anti-inflammatory cytokines were not affected by IVIg treatment. CONCLUSION: Data presented here suggest a novel mechanism of action of IVIg that involves selective modulation of circulating proinflammatory cytokines.

Adult↗
PubMed1999

Occupational exposure to methyl methacrylate monomer induces generalised neuropathy in a dental technician.

A 36-year-old dental technician for 14 years developed paraesthesia and numbness in her legs. Neurophysiological studies revealed absent sensory nerve action potentials (SNAPs) from her lower limbs and normal upper limb SNAPs on presentation. Motor nerve studies were normal. Repeat studies 2 months after leaving her job showed some improvement in the lower limb SNAPs. It is suggested that her symptoms were caused by occupational exposure to methyl methacrylate monomer.

Adult↗
PubMed1999

Heightened intrathecal release of proinflammatory cytokines in Creutzfeldt-Jakob disease.

The authors report high intrathecal release of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta in five patients with sporadic or new-variant Creutzfeldt-Jakob disease (CJD) without activation of the humoral or lymphocytic immune responses. Increased release of TNF-alpha and IL-1beta was also detected in some patients with progressive dementias. CJD is associated with a local cerebral host response that involves the release of proinflammatory cytokines.

Creutzfeldt-Jakob Syndrome↗
PubMed1999

Paraneoplastic painful ulnar neuropathy.

A 58-year-old woman developed painful, bilateral ulnar neuropathy in conjunction with small cell lung carcinoma and high serum titer of anti-Hu antibody. An incidental stage I plasma cell dyscrasia, with immunoglobulin G kappa monoclonal protein, was also present. Electropysiological assessment excluded a generalized neuropathy, and nerve biopsy showed marked loss of myelinated and small unmyelinated fibers, without inflammatory changes or amyloid deposition. High titers of circulating anti-Hu antibody can be associated with symptoms resembling a paraneoplastic mononeuropathy.

Antibodies↗
PubMed1999

Quantitative sensory and autonomic testing in male diabetic patients with erectile dysfunction.

OBJECTIVE: To correlate abnormalities of nerve fibres in the lower limbs with erectile dysfunction in male diabetic patients, using a range of quantitative sensory and autonomic function tests. PATIENTS AND METHODS: The study included 68 male diabetic patients with symptomatic erectile dysfunction and 11 matched diabetics without erectile dysfunction; none had clinical evidence of peripheral vascular disease or psychological disorder. Patients were evaluated with a symptom questionnaire based on the Michigan Neuropathy Screening Instrument questionnaire and examined clinically. Sural and peroneal nerve-conduction studies, and quantitative sensory and autonomic tests (vibration, thermal, light-touch thresholds, sensory and autonomic cutaneous axon-reflexes) were used to detect nerve abnormalities in the lower limbs, which were correlated with erectile dysfunction. RESULTS: Symptoms of neuropathy were more common in the group with male erectile dysfunction (MED), but statistically significant only for neuropathic pain (53% MED, 18% nonMED, P<0.05, chi-square test) and gastroparesis (44% MED, 0% nonMED, P<0.05). Tests of unmyelinated afferents (warming perception and capsaicin-induced sensory axon-reflex vasodilatation) were most often abnormal, sometimes with no other abnormalities on tests or neurological examination. However, abnormality of warm perception was not significantly different between groups (81% MED, 70% nonMED), suggesting that it is a poorer discriminant than abnormal sensory axon-reflex vasodilatation (89% MED, 22% nonMED, P<0.001). The only other significant test difference was decreased sural nerve action potential (70% MED, 22% non-MED, P<0.01). CONCLUSIONS: There appeared to be preferential involvement of unmyelinated sensory fibres that mediate axon-reflex vasodilatation in the limbs of diabetic patients with erectile dysfunction. This test appears to be a helpful indicator of neurological involvement in erectile dysfunction, and may be used to monitor the effect of new treatments.

Adult↗
PubMed1998

Cytokines in multiple sclerosis: pro-inflammation or pro-remyelination?

The targets of the inflammatory response in multiple sclerosis (MS) are myelin and the myelin producing cells, oligodendrocytes. The infiltration of activated immune cells and recruitment of endogenous glia lead to the destruction of myelin and oligodendrocytes, a process that is compounded by the release of cytokines by infiltrating cells. Recent evidence suggests that key cytokines that are responsible for the destruction of myelin may also mediate the process of remyelination and repair. It appears that both inflammatory and repair processes are governed by the temporal and spatial relation of cytokines to their targets.

Cytokines↗
PubMed1997

Circulating tumor necrosis factor-alpha correlates with electrodiagnostic abnormalities in Guillain-Barré syndrome.

Autoimmune damage to peripheral nerves, mediated by activated T lymphocytes and macrophages, underlies the pathogenesis of inflammatory demyelination in Guillain-Barré syndrome. Both T lymphocytes and macrophages secrete tumor necrosis factor-alpha, a cytokine that exerts toxic effects on myelin, Schwann cells, and endothelial cells. The reportedly high serum levels of this cytokine in patients with Guillain-Barré syndrome may reflect the degree of immune activation rather than a direct pathogenic effect. We compared serum levels of tumor necrosis factor-alpha, interleukin-1 beta, and soluble interleukin-2 receptor with well-established electrodiagnostic criteria for primary demyelination in 23 patients with Guillain-Barré syndrome, to assess the relationship between these cytokines and peripheral myelin damage. High serum levels of tumor necrosis factor-alpha were associated with prolonged distal motor latencies and slowed motor conduction velocities, prolonged or absent F-wave responses, and reduced amplitude of distal compound muscle action potentials. No significant correlation was observed between electrodiagnostic criteria for primary demyelination and serum levels of interleukin-1 beta or soluble interleukin-2 receptor. These findings suggest a putative role of tumor necrosis factor-alpha in the pathogenesis of peripheral nerve demyelination in Guillain-Barré syndrome.

Adult↗
PubMed1997

Hypokalaemic myopathy in alcoholism.

We describe the clinical and pathological features of a patient with an acute painless proximal myopathy due to hypokalaemia associated with alcoholism. There was an excellent response to treatment with potassium supplements. The importance of recognition of low potassium states in alcohol-dependent patients with muscular weakness is emphasized.

Adult↗