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Biomedical subjects

A Khan

Publications and source records attributed to A Khan.

At least 199 records · Page 11Linked to original sources
PubMed2000

The delivery of antisense therapeutics.

Antisense oligonucleotides, ribozymes and DNAzymes have emerged as novel, highly selective inhibitors or modulators of gene expression. Indeed, their use in the treatment of diseases arising from genetic abnormalities has become a real possibility over the past few years. The first antisense drug molecule is now available for clinical use in Europe and USA. However, their successful application in the clinic will require improvements in cellular targeting and intracellular delivery. This review aims to look at recent advances in the in vitro and in vivo delivery of antisense oligodeoxynucleotides and ribozymes.

Animals↗
PubMed2000

Primary hyperparathyroidism: pathophysiology and impact on bone.

Primary hyperparathyroidism has been associated with bone loss, especially at cortical skeletal sites. Results from studies evaluating the mineral density of cancellous bone have been more difficult to interpret. Most densitometry studies support the concept that the parathyroid hormone appears to be catabolic at cortical sites and may have anabolic effects at cancellous bone sites. Studies completed to date, however, have been limited by design, definitions of fracture and inadequate control groups. Primary hyperparathyroidism is now increasingly being detected during the asymptomatic phase. The need for parathyroidectomy has been questioned in such patients because there may be no disease progression in the absence of surgery. Medical management of primary hyperparathyroidism has to date been limited to estrogen replacement therapy in postmenopausal women. Identification of the calcium receptor has improved our understanding of calcium homeostasis, and significant reductions in calcium receptor levels have been detected in parathyroid adenomas. Thus, a new class of therapeutics may include the calcimimetic agents. Bisphosphonates are also currently being evaluated with regard to their impact on fracture prevention and their beneficial effects on bone mineral density.

Bone Density↗
PubMed2000

Indium-111 capromab pendetide (ProstaScint) uptake in neurofibromatosis.

We report on the demonstration of nonspecific accumulation of indium-111 capromab pendetide (ProstaScint) in neurofibromas in a patient with a rising prostate-specific antigen level after prostatectomy. Although the immunoconjugate is targeted to a specific membrane antigen present in human prostate carcinoma, nonspecific uptake can occur in other entities. Indium-111 capromab pendetide scintigraphy is a valuable diagnostic tool that should always be interpreted within the context of the clinical history and the laboratory and radiologic findings to avoid misinterpretation.

Antibodies, Monoclonal↗
PubMed2000

A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy.

OBJECTIVE: To investigate the analgesic efficacy of lamotrigine in the treatment of painful HIV-associated distal sensory polyneuropathy (DSP). BACKGROUND: The pathogenesis of HIV-associated DSP is unknown and there is no effective treatment. A novel anticonvulsant, lamotrigine, blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. There have been anecdotal reports of efficacy of lamotrigine in the treatment of painful neuropathy and trigeminal neuralgia. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, lamotrigine was initiated at 25 mg per day and slowly titrated over 7 weeks to 300 mg per day. Study duration was 14 weeks. The primary outcome measure was change in pain on the modified Gracely scale with secondary outcome measures including change in neurologic examination, use of concomitant analgesic medications, and global pain relief. RESULTS: Of 42 enrolled subjects, 13 did not complete the 14-week study endpoint. In five of these, rash was the cause for dropout. In the remaining 29 evaluable subjects, 20 patients received placebo and 9 received lamotrigine. The pain scores at baseline were not significantly different. The reduction in average pain from baseline to week 14 was greater (p = 0.03) in the lamotrigine group (-0.55) than in the placebo group (-0.18), adjusting for baseline levels of pain. There was no difference between the groups on the change in peak worst pain. CONCLUSIONS: In this small trial, lamotrigine showed promise in the treatment of pain associated with HIV-related DSP. The frequency of rash was greater than in lamotrigine studies in epilepsy. A larger controlled study of lamotrigine is warranted.

Adult↗
PubMed2000

Somatic mutation screening: identification of individuals harboring K-ras mutations with the use of plasma DNA.

BACKGROUND: Many cancers are attributed to somatic mutation of DNA. We investigated whether it is feasible to detect cancer-associated somatic mutations in patients with neoplasms by using plasma DNA. METHODS: Plasma samples were prospectively collected from 240 patients undergoing colonoscopy. Colorectal biopsies were performed as clinically indicated in 135 patients, and risk factor information was available from 232 patients. DNA was extracted from plasma and colorectal tissue and was amplified by use of a polymerase chain reaction method that enriches for mutations in codon 12 of the K-ras oncogene. Molecular, histologic, and clinical data were compared by use of two-sided Fisher's exact test. RESULTS: Mutations in the K-ras gene detected in the plasma of 64 (28%) of 232 patients were statistically significantly associated with colorectal cancer risk factors (P =.0002). Of those patients having tissue available for comparison (n = 135), mutations in the K-ras gene were found in the tissues of 35 patients, and 29 (83%) of these 35 showed mutations in plasma samples. In contrast, the plasma assay was negative in 93 of the 100 patients whose tissue K-ras was wild-type. Among patients without biopsies (n = 105), 28 had mutated K-ras in their plasma DNA, despite the absence of remarkable colonoscopy findings; 24 of these 28 patients had risk factors for colorectal cancer. Overall, 25 (39%) of 64 patients showing mutations in plasma DNA had colorectal neoplasms with K-ras mutations compared with five (3%) of 176 patients without K-ras mutations in plasma DNA. CONCLUSION: Plasma DNA assays for the detection of mutations in K-ras codon 12 may provide a feasible method to screen populations for somatic mutations frequently found in neoplasms. The clinical utility of using this test in screening populations requires further study.

Adenoma↗
PubMed2000

Prognostic value of treadmill exercise testing in elderly persons.

BACKGROUND: Recent exercise testing guidelines recognized a gap in knowledge about the prognostic value of treadmill exercise testing in elderly persons. OBJECTIVE: To test the hypothesis that treadmill exercise testing has equal prognostic value among elderly (> or =65 years of age) and younger (<65 years of age) persons and to examine the incremental value of this testing over clinical data. DESIGN: Inception cohort with a median follow-up of 6 years. SETTING: Olmsted County, Minnesota. PATIENTS: All elderly (n = 514) and younger (n = 2593) residents of Olmsted County who underwent treadmill exercise testing between 1987 and 1989. MEASUREMENTS: Overall mortality and cardiac events (cardiac death, nonfatal myocardial infarction, and congestive heart failure). RESULTS: Compared with younger patients, elderly patients had more comorbid conditions, achieved a lower workload (6.0 and 10.7 metabolic equivalents; P < 0.001), and had a greater likelihood of a positive exercise electrocardiogram (28% and 9%; P < 0.001). With median follow-up of 6 years, overall survival (63% and 92%; P < 0.001) and cardiac event-free survival (66% and 95%; P < 0.001) were worse among elderly persons than among younger persons. Workload was the only treadmill exercise testing variable associated with all-cause mortality in both age groups, and the strength of association was similar. Workload and angina with exercise testing were associated with cardiac events in both age groups, whereas a positive exercise electrocardiogram was associated with cardiac events only in younger persons (P < 0.05 for all comparisons). After adjustment for clinical variables, workload was the only additional treadmill exercise testing variable that was predictive of death (P < 0.001) and cardiac events (P < 0.05); the strength of the association was similar in both age groups. Each 1-metabolic equivalent increase in exercise capacity was associated with a 14% and 18% reduction in cardiac events among younger and elderly persons, respectively. CONCLUSIONS: In elderly persons, treadmill exercise testing provided prognostic information that is incremental to clinical data. After adjustment for clinical factors, work-load was the only treadmill exercise testing variable that was strongly associated with outcome, and its prognostic effect was of the same magnitude in elderly and younger persons.

Age Factors↗
PubMed2000

Borato-1,2-diaminocyclohexane platinum (II), a novel anti-tumor drug.

Borato-1,2-diaminocyclohexane platinum (II) (BDP) was synthesized and compared to cisplatin (cisPt) as a potential anti-tumor drug. BDP and cisPt (0.2-20 microM) dose-dependently inhibited DNA synthesis in L1210 murine leukemia cells, DU-145 prostate cancer cells, A549 lung carcinoma cells, and MCF-7 breast cancer cells, as judged by measuring [(3)H]-thymidine incorporation. BDP and cisPt induced killing of L1210 murine cells by 97 and 78%, respectively. The LD(50) was 35 and 14 mg/kg for BDP and cisPt, respectively. Interestingly, while cisPt (at optimal dose) induced a 100% increase in life span (ILS) of BDF1 mice bearing L1210 tumor cells, BDP (at optimal dose) induced a 200% increase in ILS in the same tumor model. In conclusion, BDP is a novel platinum derivative compound that appears more effective in increasing the ILS than cisplatin against the leukemia tumor mouse model.

Animals↗
PubMed2000

A Cryo-TEM Study of Protein-Surfactant Gels and Solutions.

Oppositely charged globular protein and surfactant systems, such as lysozyme-sodium dodecyl sulfate (SDS) and ovalbumin-dodecyltrimethylammonium chloride (DOTAC) form precipitate, gel, and colorless solution in water over a wide concentration range. Bluish solutions are also recognized in connection with the redissolution of precipitate as well as prior to the gel formation. For the lysozyme-SDS system the bluish solution has been suggested to consist of finely dispersed gel particles in solution. The oppositely charged bovine serum albumin (BSA)-DOTAC-water system forms only a large, clear solution phase and a narrow, bluish solution region within a very limited surfactant concentration range. In the lysozyme-SDS system the formation of protein-surfactant aggregates and their growth and breakdown are studied in detail by cryogenic-transmission electron microscopy (cryo-TEM) method. In particular a series of samples with an increased surfactant concentration at fixed 4 wt% of lysozyme is studied. Imaging of the bluish solution at different protein concentrations exhibits large aggregates in the form of rod-like, sheet-like, and star-like objects which are attributed to the gel. At excess amounts of SDS, in the colorless solution, only small objects are detected. In the ovalbumin-DOTAC-water and BSA-DOTAC-water systems large aggregates are also observed in the bluish solutions. Colorless solutions for these two systems show the presence of small objects in the cryo-TEM micrographs. Ultrathin sections of the lysozyme and ovalbumin gels fixed with OsO(4) also show the presence of aggregated structures as judged from the transmission electron microscopy observations. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

Ring chromosome 8 syndrome: further characterization.

We describe two de novo cases of extra r(8) confirmed by fluorescent in situ hybridization (FISH). Based on these two and eight additional cases of extra r(8) confirmed by FISH, the phenotype is better documented. One of our patients had minor facial anomalies, near-normal growth, and neurological development. She had a ring in each cell analyzed. The second had minor craniofacial anomalies and growth and mental retardation. He had a small or double-sized ring in each cell. The phenotype of these 10 cases ranges from almost normal in an adult with 10% mosaicism to variable degrees of minor anomalies, growth retardation, and mental retardation overlapping the mosaic +8 syndrome.

Chromosomes, Human, Pair 8↗
PubMed2000

Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database.

The assumption that depressed patients who are assigned to placebo in antidepressant clinical trials are exposed to substantial morbidity and mortality is not based on research data. We assessed suicides, suicide attempts, and depressive symptom reduction in studies of 7 new antidepressants using the Food and Drug Administration database. Among 19,639 participating patients, 34 committed suicide (0.8% per year), and 130 attempted suicide (2.9% per year). Rates of suicide and attempted suicide did not differ significantly among the placebo- and drug-treated groups. Annual rates of suicide and attempted suicide were 0.4% and 2.7% with placebo, 0.7% and 3.4% with active comparators, and 0.8% and 2.8% with investigational antidepressants, respectively. Symptom reduction was 40.7% with investigational drugs (n = 4,510), 41.7% with active comparators (n = 1,416), and 30.9% with placebo (n = 2,805). These data may help inform discussions about the use of placebo in antidepressant clinical trials.

Antidepressive Agents↗
PubMed2000

Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebo-controlled trial.

STUDY OBJECTIVE: Despite widespread use of adjunctive benzodiazepines during ketamine sedation, their efficacy in reducing recovery agitation in children has never been studied. We wished to characterize the nature and severity of recovery agitation after ketamine sedation in children treated in the emergency department and to determine whether the addition of adjunctive midazolam reduces the magnitude of such recovery agitation. METHODS: The study was a randomized, double-blind, clinical trial of adjunctive midazolam versus placebo during ketamine sedation. We enrolled 104 children aged 12 months to 15 years (median age, 6 years) at a combined university medical center and children's hospital. Subjects received either intravenous midazolam (0.05 mg/kg up to 2 mg) or placebo after intravenous administration of a ketamine loading dose (1.5 mg/kg). Treating physicians and nurses independently noted the presence of crying, hallucinations, and nightmares during recovery and graded recovery agitation by using a 100-mm visual analog scale. Preprocedure agitation and external stimulation during recovery were also graded. The time from ketamine injection until each subject met the recovery criteria was recorded. RESULTS: Fifty-three subjects received midazolam, and 51 received placebo. Potentially confounding variables were similar between the groups. Sedation efficacy, adverse effects, and recovery time were also similar between groups. Interobserver agreement between physician and nurse assessments was substantial. Median physician assessment of recovery agitation was 4 mm (interquartile range, 2 to 19) in the midazolam group and 5 mm (interquartile range, 3 to 14) in the placebo group (difference -1; 95% confidence interval -3 to 2; P =.705). Recovery agitation was moderately correlated with preprocedure agitation (rho=0.486) but not with external stimulation during recovery (rho=0.147). CONCLUSION: Recovery agitation is common but generally of very low magnitude after ketamine sedation in children in the ED. We observed a median physician rating of 5 mm on a 100-mm visual analog scale, a score that we believe to be clinically insignificant. The degree of recovery agitation after ketamine sedation is significantly related to the degree of preprocedure agitation. In this study, concurrent midazolam did not diminish such agitation and had no measurably beneficial effect. Use of adjunctive benzodiazepines in pediatric ketamine sedation appears unnecessary.

Adjuvants, Anesthesia↗
PubMed2000

Tuberculosis in Pakistan: socio-cultural constraints and opportunities in treatment.

This study explores the extent to which factors related to individuals, the care provision process, and the cultural context influence the behaviour of tuberculosis patients attending TB clinics in rural Pakistan, and examines the effects of disease on their personal lives. Thirty-six patients attending three TB treatment clinics were interviewed in depth. These patients were stratified by stage of treatment (treatment proceeding, treatment completed, default), sex and by rural/urban status. Results indicate that the majority of patients were very poor, but nonetheless initially chose to attend private practitioners. Normally their disease was correctly diagnosed as tuberculosis only after repeated visits to a succession of health care providers. Patients' knowledge about their disease was limited, and doctors gave incorrect or only very limited health education. Most patients reported dissatisfaction with care provided. Almost all patients reported problems with access to treatment, both in terms of time and money; this was particularly true of women, whose freedom to travel in Pakistan is limited. Potential causes of default appeared to be more closely linked to deficiencies in treatment provision rather than patients' unwillingness to comply. Largely because of a perception that TB was incurable, respondents were generally unwilling to disclose that they were undergoing or had undergone TB treatment. For reasons related to confidential access to treatment, this could lead to default, perpetuating the perception of incurability, and hence causing a vicious circle. For TB programmes to be successful in Pakistan, it is essential that this circle is broken; and this can only be done through provision of good quality TB care and education to improve the population's understanding that TB can be cured. In addition, patients' unwillingness to disclose to health care providers that they had already received previous treatment meant that many patients were prescribed incorrect treatment regimes, potentially leading to the emergence of drug-resistant TB. In common with other researchers' findings, no clear differences were found between those who had completed treatment and those who had defaulted from treatment. This study was performed to provide information to assist the researchers to design potential TB treatment delivery strategies, and has proved invaluable for this purpose. Strategies based on findings from the study are currently being assessed using a randomised controlled trial.

Adolescent↗
PubMed2000

Elevated temperatures enhance KCCl activity in sickle cells.

The maintenance of red blood cell volume is important in the pathophysiology of sickle cell disease. The KCl cotransporter (KCCl) is capable of mediating sickle cell dehydration. In this study, we have determined the effect of increased temperature (over the range 37-41 degrees C) on basal K+ transport and K+ transport following activation of KCCl by urea or N-ethylmaleimide (NEM). An increased temperature was found to have only a small effect (approximately a 20% increase) on basal K+ transport. In contrast, the increase was much greater (about 60%) after activation of KCCl by urea. Following activation of KCCl by NEM, the increase in K+ transport with increasing temperature was small (about 10%). This suggests that it is the signalling system rather than the transporter itself that is sensitive to temperature.

Anemia, Sickle Cell↗
PubMed2000

Latency as a function of intensity in auditory neurons: influences of central processing.

The response latencies of sensory neurons typically shorten with increases in stimulus intensity. In the central auditory system this phenomenon should have a significant impact on a number of auditory functions that depend critically on an integration of precisely timed neural inputs. Evidence from previous studies suggests that the auditory system not only copes with the potential problems associated with intensity-dependent latency change, but that it also modifies latency change to shape the response properties of many cells for specific functions. This observation suggests that intensity-dependent latency change may undergo functional transformations along the auditory neuraxis. The goal of our study was to explore these transformations by making a direct, quantitative comparison of intensity-dependent latency change among a number of auditory centers from the lower brainstem to the thalamus. We found two main ways in which intensity-dependent latency change transformed along the neuraxis: (1) the range of latency change increased substantially and (2) one particular type of latency change, which has been suggested to be associated with sensitivity to temporally segregated stimulus components, occurred only at the highest centers tested, the midbrain and thalamus. Additional testing in the midbrain (inferior colliculus) indicated that inhibitory inputs are involved in shaping latency change. Our findings demonstrate that the central auditory system modifies intensity-dependent latency changes. We suggest that these changes may be functionally incorporated, actively enhanced, or modified to suit specific functions of the auditory system.

Animals↗
PubMed2000

Renal medullary carcinoma: sonographic, computed tomography, magnetic resonance and angiographic findings.

Renal medullary carcinoma is a recently described, highly aggressive tumour, occurring predominantly in young patients of African descent with sickle cell trait (SCT). All have been metastatic at surgery. Surgery, radiotherapy and chemotherapy do not appear to alter the course of the disease. The survival time is very short. Presentation is usually with haematuria, abdominal pain and weight loss. Forty-nine patients have been reported from the USA, of these 47 were African/Americans. The reports have mostly appeared in pathology journals. On review of the imaging findings reported in the radiological journals, it becomes apparent that it is possible for a radiologist to suggest a specific diagnosis in the appropriate demographic and clinical setting. Here the first British patient of Afro-Caribbean decent in whom a pre-operative diagnosis was suggested on the imaging findings of a centrally located renal pelvic tumour, encasing the pelvis on a background of SCT in a 28-year-old is described. It is expected that a high index of suspicion in the appropriate clinical setting may lead to earlier diagnosis, treatment and survival of patients. The patient is alive and reasonably well 9 months after surgery. The full range of imaging findings in renal medullary carcinoma are described.

Adult↗
PubMed2000

Three novel monotetrahydrofuran annonaceous acetogenins from Annona montana.

Three new monotetrahydrofuran (mono-THF) acetogenins, anmontanins A-C (1-3) were isolated from the leaves of Annona montana. Anmontanin C (3) is the first stereochemically pure acetogenin reported to have a gamma-hydroxymethyl-gamma-lactone moiety. Two known mono-THF acetogenins, murisolin and annonacin, were isolated from the seeds of the plant. The structures of compounds 1-3 were elucidated by spectral methods and chemical derivatization.

Furans↗