Biomedical subjects

M Akhtar

Publications and source records attributed to M Akhtar.

At least 55 records · Page 3Linked to original sources

PubMed1999

Fine-needle aspiration biopsy diagnosis of small round cell tumors of childhood: A comprehensive approach.

Fine-needle aspiration biopsy findings in small round cell malignant tumors of children are briefly reviewed. All of these tumors usually have characteristic cytomorphology which, when recognized, may lead to a definitive diagnosis. However, when these tumors are undifferentiated, morphologic criteria may not be sufficient for arriving at a correct diagnosis. A variety of ancillary studies including electron microscopy, immunohistochemistry and DNA ploidy, cytogenetics, and fluorescent in situ hybridization may provide valuable additional information for precise characterization of these neoplasms. Some of the ancillary studies may also be used for assigning these cases to prognostically significant subgroups. This information may also help in defining the most suitable chemotherapeutic regimens for these tumors. Since most of these special studies require only a small amount of cellular material, fine-needle aspiration biopsy is ideally suited for obtaining samples for these procedures. It is hoped that as cytogenetic and molecular techniques become available in many diagnostic laboratories, a comprehensive evaluation of aspiration biopsies from round cell malignant tumors, encompassing a precise pathologic diagnosis, determination of prognosis, and prediction of response to therapy, will be possible in a majority of cases. Diagn. Cytopathol. 1999;21:81-91.

Biopsy, Needle↗

PubMed1999

Quantitative image cell analysis of cytologic smears for DNA ploidy in renal parenchymal neoplasms.

Quantitative image cell analysis for DNA ploidy was performed on cytologic smears from a series of 19 histologically proven cases of renal parenchymal tumors. These cases included chromophobe-cell carcinoma (n = 5), oncocytoma (n = 5), papillary carcinoma (n = 2), and conventional renal-cell carcinoma (n = 7). All chromophobe renal-cell carcinomas were composed predominantly of hypodiploid cells, while the five oncocytomas were virtually entirely composed of diploid cells. The papillary and conventional renal-cell carcinomas, on the other hand, showed a variety of ploidy profiles. Scatterplots generated by plotting nuclear DNA mass against nuclear area produced patterns that correlated with the morphologic type of the neoplasms. These findings indicate that quantitative image cell analysis for DNA ploidy may provide valuable clues that could be helpful in arriving at a precise diagnosis of renal parenchymal tumors. Diagn. Cytopathol. 1999;21:223-229.

Adenoma, Oxyphilic↗

PubMed1999

Ultrasound-guided biopsy of abdominal and pelvic lesions in children. A comparison between fine-needle aspiration and 1.2 mm-needle core biopsy.

BACKGROUND: Tissue diagnosis is mandatory prior to treatment of an abdominal or pelvic lesion in a child. OBJECTIVES: To compare the diagnostic yield and complications of fine-needle aspiration biopsy (FNAB) and 1.2-mm needle core biopsy (NCB) for abdominal and pelvic lesions in children using US guidance. MATERIAL AND METHODS: Ninety consecutive abdominal or pelvic US-guided biopsies in 61 children; 53 FNAB procedures in 43 children and 37 NCB procedures in 34 children were retrospectively analysed. Fifty-seven biopsies were performed on malignant lesions and 33 on benign lesions. In 15 children, both FNAB and NCB were performed at the same occasion. RESULTS: FNAB was diagnostic in 41 (77 %) of 53 biopsies while NCB provided a correct diagnosis in 35 (95 %) of 37 biopsies. Results were similar in both malignant and benign conditions. Clinically important bleeding complicated three biopsies (3.3 %); in two after FNAB and in one after combined FNAB and NCB. CONCLUSION: If FNAB were to be replaced with 1.2-mm NCB using an automatic gun, the diagnostic yield for abdominal and pelvic focal lesions in children would improve significantly (P < 0.05) while the complication rate would remain low. NCB may reduce the need for diagnostic and staging surgery and repeated procedures.

Abdominal Neoplasms↗

PubMed1999

Is primary antiarrhythmic drug therapy for ventricular arrhythmias obsolete?

Sudden cardiac death (SCD) remains a major public health threat. Patients with aborted SCD have a high incidence of recurrent life-threatening ventricular arrhythmias. Antiarrhythmic drug approaches dominated early attempts to prevent SCD; however, several trials with sotalol and amiodarone revealed an unacceptably high rate of recurrent arrhythmic events. With the advent of the implantable cardioverter defibrillator (ICD), the primary role of antiarrhythmic drug therapy for the secondary prevention of SCD has been called into question. Two recently completed trials, the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial and the Canadian Implantable Defibrillator Study (CIDS), confirm the superiority of the ICD over the best medical therapy for saving lives.

Amiodarone↗

PubMed1999

Sudden cardiac death.

SCD continues to be an important cause of death and morbidity. Despite expanding insight into the mechanisms causing SCD, the population at high risk is not being effectively identified. Although there is still much to do in the management phase of SCD (predicting the efficacy of various therapies), recent clinical trials have helped define the relative risks and benefits of therapies in preventing SCD. Trials are underway to determine whether treating other patient populations, including asymptomatic patients after MI, will improve survival rate. The approach to reducing mortality rate will always be multifaceted; primary prevention of coronary artery disease and prompt salvage of jeopardized myocardium are 2 important aspects of this approach. In addition to interventions for MI, such as myocardial revascularization when indicated, simple and easily administered therapies that are likely to remain the most effective prophylactic interventions are aspirin, ACE inhibitors, beta-blockers, and cholesterol-lowering agents. However, the MADIT and AVID data clearly demonstrate a role for ICD therapy in a subgroup of patients who have VT/VF and are at risk of cardiac arrest. Even though the absolute magnitude of benefit associated with ICDs is still to be determined, the AVID study and other recent reports provide convincing evidence that patients who have VT/VF fare better with ICDs than with antiarrhythmic drug therapy. For the high-risk population described in this article, in addition to aggressive anti-ischemic and heart failure therapy, ICDs are now a mainstay of life-saving treatment. Still to be surmounted is the challenge of identifying patients who have nonischemic substrates and of providing them with the appropriate therapy. Guided by genetic studies and new insight into the mechanisms of such problems as congenital long QT syndrome, life-saving and life-enhancing therapies may soon be available for the management of SCD.

Adrenergic beta-Antagonists↗

PubMed1999

Ventricular arrhythmias, electrophysiologic studies, and devices.

Because of the high incidence of heart disease in the elderly, ventricular tachyarrhythmias are not infrequent. Determining the nature and extent of the underlying heart disease and identifying precipitating causes is required prior to instituting long-term therapy. Recent studies suggest that for hemodynamically unstable ventricular tachyarrhythmias, mortality is lower with the implantable cardioverter-defibrillator compared with pharmacologic therapy. This benefit is likely to be more modest in the elderly because of competing cardiac and noncardiac causes of death. For similar reasons, the favorable results reported with the prophylactic use of the implantable cardioverter-defibrillator are likely to be attenuated in the elderly.

Aged↗

PubMed1999

Mechanism of 3-methylaspartase probed using deuterium and solvent isotope effects and active-site directed reagents: identification of an essential cysteine residue.

The mechanism of the L-threo-3-methylaspartate ammonia-lyase (EC 4.3.1.2) reaction has been probed using deuterium and solvent isotope effects with three different substrates, (2S,3S)-3-methylaspartic acid, (2S)-aspartic acid and (2S,3R)-3-methylaspartic acid. Each substrate appears to form a covalent adduct with the enzyme through the amination of a dehydroalanine (DehydAla-173) residue. The true substrates are N-protonated and at low pH, the alkylammonium groups are deprotonated internally in a closed solvent-excluded pocket after K+ ion, an essential cofactor, has become bound to the enzyme. At high pH, the amino groups of the substrates are able to react with the dehydroalanine residue prior to K+ ion binding. This property of the system gives rise to complex kinetics at pH 9.0 or greater and causes the formation of dead-end complexes which lack Mg2+ ion, another essential cofactor. The enzyme-substrate adduct is subsequently deaminated in two elimination processes. Hydrazines act as alternative substrates in the reverse reaction direction in the presence of fumaric acid derivatives, but cause irreversible inhibition in their absence. Borohydride and cyanide are not inhibitors. N-Ethylmaleimide also irreversibly inactivates the enzyme and labels residue Cys-361. The inactivation process is enhanced in the presence of cofactor Mg2+ ions and Cys-361 appears to serve as a base for the removal of the C-3 proton from the natural substrate, (2S,3S)-3-methylaspartic acid. The dehydroalanine residue appears to be protected in the resting form of the enzyme by generation of an internal thioether cross-link. The binding of the substrate and K+ ion appear to cause a conformational change which requires hydroxide ion. This is linked to reversal of the thioether protection step and generation of the base for substrate deprotonation at C-3. The deamination reaction displays high reverse reaction commitments and independent evidence from primary deuterium isotope effect data indicates that a thiolate acts as the base for deprotonation at C-3.

Ammonia↗

PubMed1999

Tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA is elevated in advanced stages of thyroid carcinoma.

Tumour cell invasion and metastasis is a multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative regulators of MMPs and thus prevent tumour cell invasion and metastasis by preserving extracellular matrix (ECM) integrity. In the present study we examined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour specimens and two thyroid carcinoma cell lines (NPA and SW579). We also investigated the effect of high TIMP-1 expression on the invasive potential of NPA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcripts was found in stages III and IV vs benign goitre (P < 0.0001). However, TIMP-1 expression was not increased in NPA and SW579 cells, both of which are derived from poorly differentiated thyroid tumours. Immunohistochemical study showed strong TIMP-1 staining in the stroma cells of advanced stages of carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a significant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of TIMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyroid tumour invasion/metastasis suppressor.

Adult↗

PubMed1999

Reversing the initial phase polarity in biphasic shocks: is the polarity benefit reproducible?

The effect of initial phase polarity (IPP) reversal using biphasic shocks on DFT at the time of implantation of implantable cardioverter defibrillator and the reproducibility of this effect during predischarge testing was evaluated in a randomized fashion. Twenty-two patients with ventricular tachycardia or ventricular fibrillation (VF) who received either the Medtronic 7219D (7 patients), 7219C (12 patients), 7223 (1 patient), or CPI Ventak MINI (2 patients) were studied. The DFT was determined in a randomized fashion at implantation and during predischarge testing using a binary search protocol. Initial shock was delivered at 12 J. If successful, subsequent shock was delivered at 6 J, following which the shock was incremented or decremented by 3 J depending upon the success. The DFT for right ventricular (RV)- and RV + IPP was 10.9 +/- 4.1 J and 11.1 +/- 4.0 J, respectively, at implant (P = ns) and 9.7 +/- 4.3 J and 8.4 +/- 6 J, respectively, (P = ns) at predischarge testing. Of the six patients who had better DFT with RV + at implantation, only one patient maintained the benefit during predischarge testing. The differences observed in IPP in individual patients may not be demonstrable during repeated testing. These findings may have implications on how these devices should be programmed.

Adult↗

PubMed1999

Driving safety among patients with neurocardiogenic (vasovagal) syncope.

Neurocardiogenic syncope is one of the most common causes of syncope. However, the important issue of driving related injury due to syncope in this population is not well defined. Risk of injury due to syncope while driving and driving behavior was evaluated in 155 consecutive patients (92 women and 63 men; mean age 49 +/- 19 years) with history of syncope in whom hypotension and syncope or presyncope could be provoked during head-up tilt testing. Patients with syncope and positive head-up tilt table test were treated with pharmacological therapy. All participants were asked to fill out a detailed questionnaire regarding any driving related injuries and their driving behavior before tilt table testing and during follow-up. Prior to head-up tilt testing two patients had syncope while driving, and one of these patients had syncope related injury during driving. The mean duration of syncopal episodes was 50 +/- 14 months (range 12-72 months). Of the 155 patients, 52 (34%) had no warning prior to syncope, while 103 (6%) had warning symptoms such as dizziness prior to their clinical syncope. Following a diagnosis of neurocardiogenic syncope established by head-up tilt testing, six patients stopped driving on their own. During a median follow-up of 22 months recurrent syncope occurred in five (3.2%) patients. No patient had syncope or injury during driving. In conclusion, syncope and injury while driving in patients with neurocardiogenic syncope is rare. The precise mechanism of this is unclear but may be related to posture during driving. Consensus among the medical community will be needed to provide specific guidelines in these patients.

Accidents, Traffic↗

PubMed1999

Electroanatomic mapping for radiofrequency ablation of cardiac arrhythmias.

Radiofrequency catheter ablation is the current treatment of choice for several cardiac arrhythmias. The conventional approach utilizing intracardiac electrograms during sinus rhythm and during tachycardia has inherent limitations including limited two-dimensional fluoroscopic imaging and the ability to evaluate several potential sites for ablation and to go precisely to the most suitable site. Recently, a nonfluoroscopic three-dimensional electroanatomic system has been developed for mapping arrhythmias. We describe in this report the advantage of utilizing the system in facilitating a successful outcome in three patients with different arrhythmias.

Adult↗

PubMed1999

Ventricular arrhythmias, electrophysiologic studies, and devices

Journal Article↗

PubMed1998

Obtaining and characterization of EF-hand mutants of recoverin.

Several EF-hand recoverin mutants were obtained and their abilities to bind to photoreceptor membranes and to inhibit rhodopsin kinase were determined. The mutants with the 'spoiled' 2nd, 3rd or (2nd+3rd) EF-hand structures did not act upon the kinase activity in the microM range of Ca2+ concentrations. Mutations of the 4th EF hand, which 'repaired' its Ca2+-binding activity, resulted in recoverin with three 'working' Ca2+-binding sites. The latter mutant inhibited rhodopsin kinase even more effectively than the wild-type recoverin, containing two working Ca2+-binding structures.

Animals↗

PubMed1998

Use of sublingual nitroglycerin during head-up tilt-table testing in patients >60 years of age.

Previous work had demonstrated a reduced specificity associated with head-up tilt protocols using high-dose isoproterenol in patients between 20 and 50 years of age. We evaluated the specificity of head-up tilt testing using different isoproterenol infusion doses and administration of nitroglycerin in patients aged >60 years. In addition, whether the same protocols have impact on the sensitivity of the test was also assessed. One hundred sixty subjects were included in this study. Seventy-six were volunteers randomized to either head-up tilt test with low-dose, 3- and 5-microg/min of isoproterenol (group I) or to a protocol including 0.4 mg of sublingual nitroglycerin (group II). In addition, after an upright tilt drug-free state, 58 patients with a history of syncope underwent repeat head-up tilt with increasing doses of isoproterenol infusion, followed by sublingual nitroglycerin if the test result remained negative. The remaining 33 patients were subjected to the nitroglycerin protocol after the drug-free state phase. In the control groups, the incidence of false-positive responses was 88% and 95%, respectively. In patients with syncope after a negative test result during 5 microg of isoproterenol infusion, nitroglycerin administration increased the number of positive responses from 45% to 79%. The percentage of positive tilt in patients undergoing nitroglycerin administration after the drug-free state part of the protocol was 78%. Administration of nitroglycerin was the most significant predictor of a positive upright tilt in patients with syncope. In subjects aged >60 years, head-up tilt protocols with high-dose isoproterenol infusion and nitroglycerin maintained an adequate specificity. In this subset of patients, nitroglycerin seemed to provide a better sensitivity than isoproterenol.

Administration, Sublingual↗

PubMed1998

Atrioverter: an implantable device for the treatment of atrial fibrillation.

BACKGROUND: During atrial fibrillation, electrophysiological changes occur in atrial tissue that favor the maintenance of the arrhythmia and facilitate recurrence after conversion to sinus rhythm. An implantable defibrillator connected to right atrial and coronary sinus defibrillation leads allows prompt restoration of sinus rhythm by a low-energy shock. The safety and efficacy of this system, called the Atrioverter, were evaluated in a prospective, multicenter study. METHODS AND RESULTS: The study included 51 patients with recurrent atrial fibrillation who had not responded to antiarrhythmic drugs, were in New York Heart Association Heart failure class I or II, and were at low risk for ventricular arrhythmias. The atrial defibrillation threshold had to be </=240 V during preimplant testing. Atrial fibrillation detection, R-wave shock synchronization, and defibrillation threshold were tested at implantation and during follow-up. Shock termination of spontaneous episodes of atrial fibrillation was performed under physician observation. Results are given after a minimum of 3 months of follow-up. During a follow-up of 72 to 613 days (mean, 259+/-138 days), 96% of 227 spontaneous episodes of atrial fibrillation in 41 patients were successfully converted to sinus rhythm by the Atrioverter. In 27% of episodes, several shocks were required because of early recurrence of atrial fibrillation. Shocks did not induce ventricular arrhythmias. Most patients received antiarrhythmic medication during follow-up. In 4 patients, the Atrioverter was removed: in 1 because of infection, in 1 because of cardiac tamponade, and in 1 because of frequent episodes of atrial fibrillation requiring His bundle ablation. CONCLUSIONS: With the Atrioverter, prompt and safe restoration of sinus rhythm is possible in patients with recurrent atrial fibrillation.

Adult↗

PubMed1998

Inactivation of a serotonin-gated ion channel by a polypeptide toxin from marine snails.

The venom of predatory marine snails is a rich source of natural products that act on specific receptors and ion channels within the mammalian nervous system. A 41-amino acid peptide, final sigma-conotoxin GVIIIA, was purified on the basis of its ability to inactivate the 5-HT3 receptor, an excitatory serotonin-gated ion channel. final sigma-Conotoxin contains a brominated tryptophan residue, which may be important for peptide activity because the endogenous ligand for the 5-HT3 receptor is a hydroxylated derivative of tryptophan. final sigma-Conotoxin inactivates the 5-HT3 receptor through competitive antagonism and is a highly selective inhibitor of this receptor. Serotonin receptors can now be included among the molecular targets of natural polypeptide neurotoxins.

Amino Acid Sequence↗

PubMed1998

Control of androgen biosynthesis in the human through the interaction of Arg347 and Arg358 of CYP17 with cytochrome b5.

The lyase activity of human CYP17 (17alpha-hydroxylase-17,20-lyase also P-450c17 or P-45017alpha) is greatly dependent on the presence of cytochrome b5, and this effect has been ascribed an important regulatory role [Lee-Robichaud, Wright, Akhtar and Akhtar (1995) Biochem. J. 308, 901-908]. This facet was further investigated by site-directed mutagenesis of selected basic residues of human CYP17. The purified mutant proteins were subjected to detailed kinetic analysis. It was found that the mutation of Lys83, Arg347 and Arg358 produced proteins that were deficient in their responsiveness to cytochrome b5, and the effect was most pronounced for the two arginine mutants (Arg347-->His and Arg358-->Gln) which have been found in male patients suffering from genital ambiguity. These residues are invoked to mediate protein-protein interaction between cytochrome b5 and CYP17, which 'awakens' the lyase activity of the enzyme required for androgen formation.

17-alpha-Hydroxypregnenolone↗

PubMed1998

An analysis of the role of active site protic residues of cytochrome P-450s: mechanistic and mutational studies on 17alpha-hydroxylase-17,20-lyase (P-45017alpha also CYP17).

Certain cytochrome P-450s involved in the transformation of steroids catalyse not only the hydroxylation process associated with the group of enzymes, but also an acyl-carbon cleavage reaction. The hydroxylation occurs using an iron-monooxygen species while the acyl-carbon cleavage has been suggested to be promoted by an iron peroxide. In this paper we have studied the role of active site protic residues, Glu305 and Thr306, in modulating the two activities. For this purpose, the kinetic parameters for the hydroxylation reaction (pregnenolone-->17alpha-hydroxypregnenolone) and two different versions of acyl-carbon cleavage (17alpha-hydroxypregnenolone-->dehydroepiandrosterone and 3beta-hydroxyandrost-5-ene-17beta-carbaldehyde-->3beta-hydroxya ndrost -5,16-diene+androst-5-ene-3beta,17alpha-diol) were determined using the wild-type human CYP17 and its eight different single and double mutants. In addition the propensity of the proteins to undergo a subtle rearrangement converting the 450 nm active-form into an inactive counterpart absorbing at 420 nm, was monitored by measuring the t12 of the P-450-->P-420 conversion. The results are interpreted to draw the following conclusions. The functional groups of Glu305 and Thr306 do not directly participate in the two proton delivery steps required for hydroxylation but may be important participants for the provision of a net work of hydrogen bonds for 'activating' water that then acts as a proton donor. The loss of any one of these residues is, therefore, only partially debilitating. That the mutation of Thr306 impairs the hydroxylation reaction more than it does the acyl-carbon cleavage is consistent with the detailed mechanistic scheme considered in this paper. Furthermore attention is drawn to the fact that the mutation of Glu305 and Thr306 subtly perturbed the architecture of the active site, which affects the geometry of this region of the protein and therefore its catalytic properties.

Amino Acid Substitution↗