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Biomedical subjects

Atul Mehta

Publications and source records attributed to Atul Mehta.

At least 19 recordsLinked to original sources
PubMed2006

Ocular manifestations of Fabry's disease: data from the Fabry Outcome Survey.

BACKGROUND: Fabry's disease is an X-linked lysosomal storage disorder characterised by deficient activity of the enzyme alpha-galactosidase A. AIM: To study eye abnormalities in patients with Fabry's disease in the Fabry Outcome Survey (FOS). METHODS: This is the largest study of ocular manifestations in patients with Fabry's disease. In all, 173 of the 688 patients enrolled in FOS underwent a detailed ophthalmic examination, with a special focus on abnormalities of the cornea, lens, conjunctival and retinal vessels. RESULTS: Cornea verticillata was reported in 76.9% of females and 73.1% of males; vessel tortuosity was observed in 21.9% of females and in 48.7% of males. Fabry cataract was recorded in 9.8% of females and in 23.1% of males. Cornea verticillata was therefore the most frequently reported ophthalmic abnormality in Fabry's disease in both hemizygotic males and heterozygotic females. Tortuous conjunctival and retinal vessels and Fabry cataract were more frequently found in males than in females. Vessel tortuosity was more frequently observed in patients with a higher severity score and greater impairment of renal and cardiac function, suggesting that it may be associated with a more severe disease. The youngest patient with ocular changes was 3 years old. The prevalence of tortuous vessels in males increased with age. CONCLUSION: The presence of cornea verticillata is a useful aid in the diagnosis of Fabry's disease, as it is often present at the time of diagnosis. Vessel tortuosity may have some predictive value for systemic involvement.

Adolescent↗
PubMed2006

Prevalence of uncontrolled hypertension in patients with Fabry disease.

BACKGROUND: Fabry disease is a rare X-linked disease arising from deficiency of alpha-galactosidase A. It results in early death related to renal, cardiac, and cerebrovascular disease, which are also important outcomes in patients with elevated blood pressure (BP). The prevalence of uncontrolled hypertension, as well as the effect of enzyme replacement therapy on BP, in patients with Fabry disease is unknown. METHODS: We examined uncontrolled hypertension (systolic BP [SBP] >or=130 mm Hg or diastolic BP [DBP] >or=80 mm Hg) among 391 patients with Fabry disease who were participating in the Fabry Outcome Survey (FOS). RESULTS: Uncontrolled hypertension was present in 57% of men and 47% of women. In patients with chronic kidney disease (CKD) stage 1 (n100), median SBP was 120 mm Hg and median DBP was 74 mm Hg. In patients with CKD stage 2 (n172), median SBP was 125 mm Hg and median DBP was 75 mm Hg. In patients with CKD stage 3 (n63), median SBP was 130 mm Hg and median DBP was 75 mm Hg. There was a significant decrease in both SBP and DBP during a 2-year course of enzyme replacement therapy. CONCLUSIONS: This study revealed a high prevalence of uncontrolled hypertension among patients with Fabry disease. Thus there is a need to improve BP control and renoprotection in patients with Fabry disease.

Antihypertensive Agents↗
PubMed2006

Clinical experience with substrate reduction therapy.

The introduction of substrate reduction therapy (SRT) using miglustat (Zavesca(R)) gives physicians and patients a choice of treatment options for type 1 Gaucher's disease. Enzyme replacement therapy (ERT) has proven a successful approach to treating the haematologic abnormalities and organomegaly. However, long-term complications such as skeletal disease and subtle abnormalities in the nervous system do not respond as well, if at all, to ERT. The basic concept behind ERT is acceleration of the degradation of accumulated cerebroside. In contrast, SRT prevents the accumulation of glucocerebroside by inhibiting the enzyme responsible for its synthesis. We have used the European Working Group on Gaucher's disease guidelines as a basis for switching patients, all of whom had previously been treated with ERT, to miglustat. Our initial experience with our cohort of six patients with type I Gaucher's disease indicates that oral miglustat provides an effective alternative for patients unsuitable for ERT. The successful use of enzyme replacement therapy over the past decade has completely changed the outlook for patients with Gaucher's disease in the developed world such that for most adults, treatment successfully improves the organomegaly and blood counts. However, intravenous therapy is not suitable for all patients. In addition, it is clear that enzyme replacement therapy does not reverse all of the pathology of adult Gaucher's disease. Future challenges include improving therapy, offering patients choice, improving our understanding of the pathophysiology and making treatment available worldwide.

Journal Article↗
PubMed2006

Epidemiology and natural history of Gaucher's disease.

Gaucher's disease was first described by Philippe Gaucher in 1882, who recognized that this was a systemic disease. The biochemical defect, genetic basis and molecular epidemiology have subsequently been characterized. Gaucher's disease arises as a result of a deficiency of glucocerebrosidase and is the commonest of the lysosomal storage disorders. The overall incidence is approximately 1:40,000 individuals, but it is much commoner amongst individuals of Ashkenazi Jewish origin. A small number of genotypes are characteristically encountered amongst this population and the commonest of these (N370S) encodes an enzyme that has sufficient residual enzyme activity to ensure that significant neurologic disease does not occur. The main clinical features of adult Gaucher's disease are organ enlargement (liver and spleen), bone marrow infiltration leading to anaemia, thrombocytopenia and leucopenia, and skeletal involvement leading to bone pain and pathological fracture. There is also an association with Parkinson's disease, cancer and lymphoproliferative disease, illustrating that Gaucher's disease is a multi-system disorder with manifestations in most organ systems. The underlying pathophysiology is imperfectly understood, but it is increasingly clear that inflammation mediated by cytokines is responsible for a significant part of the pathology.

Journal Article↗
PubMed2006

Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey.

BACKGROUND: Fabry disease is a rare X-linked disorder caused by deficient activity of the enzyme alpha-galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. AIM: Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS--the Fabry Outcome Survey--a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal). METHODS: Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 42 girls) who were below 18 y of age. The median age at evaluation (defined as the median age at entry into FOS) was 12.5 and 13.2 y for boys and girls, respectively. RESULTS: The most frequent early clinical manifestations of Fabry disease were neurological (acroparaesthesiae, altered temperature sensitivity) and gastrointestinal symptoms (altered bowel habits and abdominal pain), which were documented in about 80% and 60% of patients, respectively, at the time of evaluation and subsequent entry into FOS. Tinnitus, vertigo, fatigue and angiokeratoma were present in over 40% of patients. Symptoms were noted in early childhood and occurred with similar frequency in boys and girls, although the onset of symptoms was 2-5 y later in girls than in boys. There was an approximately 3-y delay from onset of symptoms to diagnosis, and patients were frequently misdiagnosed. CONCLUSION: Although the life-threatening complications of Fabry disease, such as stroke and renal and heart failure, are not seen in children, the present analysis shows that other symptoms are common and may have an impact on quality of life.

Adolescent↗
PubMed2006

Real-time electromagnetic navigation bronchoscopy to peripheral lung lesions using overlaid CT images: the first human study.

STUDY OBJECTIVES: To characterize the feasibility, accuracy, and safety of the superDimension/Bronchus system (SDBS) [superDimension, Ltd; Hertzliya, Israel] in navigating to previously unreachable peripheral lung lesions and obtaining biopsy specimens. DESIGN: Open-label, prospective, controlled clinical study. SETTING: Pulmonary institute of a university-affiliated municipal hospital. PATIENTS: Thirteen adult candidates for nonemergency bronchoscopy who gave informed consent to participate. INTERVENTIONS: The patients underwent flexible bronchoscopy using the SDBS, which is based on real-time CT-guided electromagnetic navigation and is capable of reaching peripheral lung masses beyond the reach of the bronchoscope. A position sensor was used to navigate to and sample the various target lesions for biopsy. MEASUREMENTS AND RESULTS: Three-dimensional chest CT was followed by SDBS methodology for marking anatomic landmarks and the target lesion on a virtual bronchoscopy screen and for sampling the lesion. The SDBS assisted in obtaining positive biopsy diagnoses in 9 of 13 cases (69%), with an average navigation accuracy of 5.7 mm. There were no SDBS-related adverse events. CONCLUSIONS: The SDBS is safe and effective in navigating to peripheral lung lesions located beyond the optic limits of a standard flexible bronchoscope.

Adult↗
PubMed2005

Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease.

Fabry disease (FD) is an X-chromosomal disorder caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A. We performed mutation screening on a cohort of 121 patients including 84 male and 37 female index cases and identified a total of 90 different mutations, 34 of which are reported for the first time here. Both point mutations (74.4%) and 'short length' rearrangements (25.6%) were found, including missense (54.4%), nonsense (14.4%), and splice site point mutations (5.6%), deletions (17.8%) or insertions/duplications (5.6%) of a few nucleotides, and complex rearrangements including larger deletions (2.2%). GLA mutations were identified in 82 (97.6%) of the 84 unrelated male patients.

Adolescent↗
PubMed2005

Evidence for motor axon depolarization in Fabry disease.

To investigate the pathophysiology of neuropathy in Fabry disease, multiple nerve excitability properties of median motor axons in 20 patients with this disorder but without hyperkalemia were compared with 35 age-matched normal controls. In the patients, depolarizing threshold electrotonus was reduced (P < 0.0001) and superexcitability was reduced (P < 0.001), but late subexcitability was normal. These findings indicate that the axons were mildly depolarized, probably due to ischemia, and are consistent with the hypothesis that poor nerve perfusion in Fabry disease contributes to axonal damage.

Action Potentials↗
PubMed2005

Anemia is a new complication in Fabry disease: data from the Fabry Outcome Survey.

BACKGROUND: The prevalence and causes of anemia among patients with Fabry disease are unknown. METHODS: In a cross-sectional study we examined hemoglobin concentrations of patients with Fabry disease using a large international database, the Fabry Outcome Survey (FOS), and analyzed the association of renal function, heart failure, gastrointestinal symptoms, and inflammation, with anemia (hemoglobin <12 g/dL in females and <13 g/dL in males). RESULTS: Anemia was present in 34% of 345 patients with Fabry disease. Median hemoglobin in 158 females was 12.9 g/dL and the median hemoglobin of 187 male patients was 13.2 g/dL. The prevalence of anemia among females was 20%, and among males 47%. Among patients with normal renal function [estimated glomerular filtration rate (GFR) >90 mL/min/1.73 m(2)] and anemia, heart failure [New York Heart Association (NYHA) class II to IV] and/or elevated C-reactive protein (CRP) levels were documented in 82% of patients. Up to 67% of patients with decreased estimated GFR presented with anemia. There was also a trend for lower hemoglobin levels among patients with signs of inflammation (defined by an elevated CRP level). We observed no association of the presence of gastrointestinal symptoms with anemia. Analyses in 53 patients receiving enzyme replacement therapy for up to 2 years, suggest no effect on anemia. CONCLUSION: The results of this study point to a high prevalence of anemia among patients with Fabry disease that is in most instances related to impaired renal function, heart failure, and inflammation. This finding may be of clinical relevance, because anemia is a major risk factor for patients with kidney disease, heart failure, or stroke, which are important manifestations of Fabry disease.

Adult↗
PubMed2004

Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCl (LY335979).

PURPOSE: The impact of zosuquidar.3HCl, an inhibitor of P-glycoprotein, on the pharmacokinetics of daunorubicin and daunorubicinol was examined in a phase I trial using a population approach. Pharmacokinetic and pharmacodynamic properties of zosuquidar.3HCl were also determined. METHODS: The pharmacokinetics of daunorubicin and daunorubicinol were studied following daunorubicin administration on day 1 (50 mg/m2 i.v. infusion over 10 min) alone and on day 3 concomitantly with zosuquidar.3HCl (i.v. 200 or 300 mg/m2 over 6 h or 400 mg over 3 h). Of a total of 18 patients entered, 16 with acute leukemia completed the study. RESULTS: A three-compartment pharmacokinetic model adequately described daunorubicin concentration-time profiles. Five- and four-compartment models adequately described the daunorubicin-daunorubicinol pharmacokinetics in the absence and presence of zosuquidar.3HCl, respectively. The impact of zosuquidar.3HCl on coadministered daunorubicin was minimal, with a 10% reduction in daunorubicin clearance. The model predicted a 50% decrease in daunorubicinol apparent clearance in the presence of zosuquidar.3HCl. A direct concentration-effect relationship between zosuquidar.3HCl concentrations and inhibition of rhodamine 123 (Rh123) efflux in CD56 lymphocytes was defined by a sigmoid E(max) model. The IC(50) was 31.7 microg/l. The zosuquidar.3HCl dosing regimen led to concentrations in excess of the IC(90) (169.6 microg/l) and provided maximal P-glycoprotein inhibition during the distribution phases of daunorubicin. CONCLUSIONS: The decrease in daunorubicin and daunorubicinol clearance in the presence of zosuquidar.3HCl likely reflects inhibition of P-glycoprotein in the bile canaliculi impeding their biliary excretion. The results need to be interpreted carefully due to the sequential nature of daunorubicin administration and analysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes.

The combination of fludarabine (FDR), high dose cytarabine and granulocyte colony stimulating factor (FLAG) with or without idarubicin (Ida) was used in the treatment of poor risk acute leukaemia or myelodysplastic syndrome (MDS) in a single centre experience. A total of 105 patients were treated over a 4-year period with 59% achieving a complete remission (CR); no statistical difference observed between FLAG and FLAG-Ida. For patients responding to FLAG +/- Ida, the median event-free survival (EFS) was 11 months and 23% at 5 years. Such patients proceeded either to further chemotherapy or a haematopoietic stem cell transplant (HSCT). The median EFS (13 months vs. 8 months) and projected 5-year survival (37% vs. 13%) of patients undergoing HSCT was significantly better than those who did not (P = 0.021). In all, 14 of 72 patients remain alive in continuing CR (median duration 43 months) with 10 of 31 having had a HSCT vs. four of 41 that did not (P = 0.033). Both regimens were well tolerated, with the majority of patients experiencing grade 1 or less non-haematological toxicity (mainly nausea and vomiting). The median time to neutrophil and platelet recovery was 28 and 31 d, respectively. No significant differences were seen with the addition of ida. There was a 17% incidence of treatment-related deaths, of which 39% was caused by invasive aspergillus infection. The results show that FLAG +/- Ida is an effective and well-tolerated remission induction regimen for poor risk leukaemia and MDS.

Acute Disease↗
PubMed2004

Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages.

Although the existence of anti-inflammatory alternatively activated macrophages (aamphi) has been accepted widely based on in vitro studies, their in vivo location, phenotype, and function still are debated. Gaucher disease (GD) is caused by a genetic deficiency in the lysosomal enzyme glucocerebrosidase and is characterized by accumulation of glycosphingolipids in so-called Gaucher cells (GCs). By using immunohistochemical analysis, we investigated whether this results in an aamphi phenotype. GCs are macrophage-like cells, expressing acid phosphatase, CD68, CD14, and HLA class II, but not CD11b, CD40, or dendritic cell markers. GCs show infrequent immunoreactivity for mannose receptor GCs did not express proinflammatory cytokines such as tumor necrosis factor alpha and monocyte chemoattractant protein 1, but did express the aamphi markers CD163, CCL18, and interleukin-1 receptor antagonist. Furthermore, CD36 and signal receptor protein alpha, involved in lipid uptake, also were observed on GCs. Thus, GCs represent a distinctive population of myeloid cells that resemble aamphi but differ from previously described in vitro aamphi.

Biomarkers↗
PubMed2003

Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium.

AIMS: Anderson-Fabry Disease (AFD), an X-linked disorder of sphingolipid metabolism, is a cause of idiopathic left ventricular hypertrophy but the mechanism of hypertrophy is poorly understood. Gadolinium enhanced cardiovascular magnetic resonance can detect focal myocardial fibrosis. We hypothesised that hyperenhancement would be present in AFD. METHODS AND RESULTS: Eighteen males (mean 43+/-14 years) and eight female heterozygotes (mean 48+/-12 years) with AFD underwent cine and late gadolinium cardiovascular magnetic resonance. Nine male (50%) had myocardial hyperenhancement ranging from 3.4% to 20.6% (mean 7.7+/-5.7%) of total myocardium; in males, percentage hyperenhancement related to LV mass index (r=0.78, P=0.0002) but not to ejection fraction or left ventricular volumes. Lesser hyperenhancement was also found in four (50%) heterozygous females (mean 4.6%). In 12 (92%) patients with abnormal gadolinium uptake, hyperenhancement occurred in the basal infero-lateral wall where, unlike myocardial infarction, it was not sub-endocardial. In two male patients with severe LVH (left ventricular hypertrophy) and systolic impairment there was additional hyperenhancement in other myocardial segments. CONCLUSIONS: These observations suggests that myocardial fibrosis occurs in AFD and may contribute to the hypertrophy and the natural history of the disease.

Adolescent↗
PubMed2003

Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results.

The cytogenetic picture in multiple myeloma (MM) is highly complex, from which non-random numerical and structural chromosomal changes have been identified. Specifically, translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and either monosomy or deletions of chromosome 13 have been reported in a significant number of patients from both cytogenetic and interphase fluorescence in situ hybridization (FISH) studies. Importantly, these abnormalities of chromosome 13 have recently been associated with a poor prognosis. In view of the highly complex nature of the karyotypes in MM patients, interphase FISH results may be difficult to interpret. In this study, cytogenetics and/or interphase FISH were carried out on bone marrow samples or purified plasma cells from 37 MM patients. Abnormal karyotypes, characterized by multiplex FISH (M-FISH) were found in 11 patients, all of which were highly complex. Interphase FISH revealed translocations involving the IGH locus in 16 (43%) patients. The IGH/cyclin D1 (CCND1) gene fusion characteristic of the translocation, t(11;14)(q13;q32), was seen in 12 (32%) of these patients and other rearrangements of IGH in four (11%) patients. Fourteen patients had additional copies of chromosome 11. Twenty patients (54%) had 13q14 deletions, 10 of whom also had t(11;14) or another IGH translocation. By comparing cytogenetic and FISH results, this study has revealed that significant chromosomal abnormalities might be hidden within highly complex karyotypes. Therefore, extreme caution is required in the interpretation of interphase FISH results in MM, particularly in relation to certain abnormalities, such as 13q14 deletions, which have an impact on prognosis.

Adult↗
PubMed2002

Nephron-sparing nephrectomy for giant renal angiomyolipoma associated with lymphangioleiomyomatosis.

Renal angiomyolipomas are benign tumors known to occur sporadically and in association with genetic syndromes, including tuberous sclerosis and lymphangioleiomyomatosis. Surgical removal or radiographic embolization of angiomyolipomas larger than 4 cm is usually indicated because of an increased risk of spontaneous hemorrhage. We describe successful nephron-sparing surgery for a giant angiomyolipoma and discuss relevant management issues in a patient with lymphangioleiomyomatosis who had previously undergone bilateral pulmonary transplantation.

Adult↗
PubMed2002

A novel treatment approach for low grade lymphoproliferative disorders using PKC412 (CGP41251), an inhibitor of protein kinase C.

INTRODUCTION: PKC412 (formally CGP41251) selectively inhibits protein kinase C (PKC) isoforms and has been shown to be cytotoxic to malignant cells in vitro. We have undertaken a single centre, open-label, multi-dose, exploratory Phase II clinical trial of PKC412 in patients with CLL and low grade NHL. METHODS: Thirteen CLL patients and eight stage IV NHL patients were treated at three oral dose levels of 25, 150 and 225 mg/day for 14 days. RESULTS: There was a median decrease of 29.4% in the lymphocyte count in 11 out of 18 patients with circulating disease following treatment. Two NHL patients without circulating disease showed loss of immunophenotypic evidence of marrow disease and a third showed an improvement in blood counts and transfusion requirements. Adverse events were mostly gastrointestinal (16 patients) requiring little or no intervention. In nine patients there was an asymptomatic rise in serum amylase and/or transaminases. Asymptomatic hyperglycemia was also observed in eight patients. All returned to normal following cessation of treatment. In 14 out of 20 patients total PKC activity measured in peripheral blood and/or bone marrow lymphocytes was reduced during treatment to a mean of 54% of pre-treatment level. CONCLUSION: PKC412 is safe, well tolerated and reduces the tumor load in chronic B-cell malignancies. Inhibition of PKC offers a novel approach to the chemotherapy of B-cell malignancies.

Aged↗