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Biomedical subjects

T Khan

Publications and source records attributed to T Khan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Hair loss in psychopharmacology.

Medication-induced alopecia is an occasional side effect of many psychopharmaceuticals. Most of the mood stabilizer and antidepressant drugs can lead to this condition. Some antipsychotic and antianxiety agents induce alopecia. Hair loss is also related to hypothyroidism, which can be induced by lithium and other agents. Alopecia might not be reported by some people, but physicians should be aware of this potential problem which may contribute to noncompliance. Lithium causes hair loss in 12-19% of long-term users. Valproic acid and/ or divalproex precipitates alopecia in up to 12% of patients in a dose-dependent relationship. Incidences up to 28% are observed with high valproate concentration exposures. These pharmaceuticals also can change hair color and structure. The occurrence of carbamazepine-induced alopecia is at or below 6%. Hair loss is less common with other mood stabilizers. Tricyclic antidepressants, maprotilene, trazodone, and virtually all the new generation of antidepressants may on rare occasions lead to alopecia. The same applies to haloperidol, olanzepine, risperidone, clonazepam, and buspirone, but not to other neuroleptics, benzodiazepines, or barbiturates, selected antihistamines, and antiparkinsonians. Discontinuation of the medication or dose reduction almost always leads to complete hair regrowth. The therapeutic value of mineral supplements remains unclear.

Adolescent↗
PubMed1999

Improved artificial death switches based on caspases and FADD.

A number of "suicide genes" have been developed as safety switches for gene therapy vectors or as potential inducible cytotoxic agents for hyperproliferative disorders, such as cancer or restenosis. However, most of these approaches have relied on foreign proteins, such as HSV thymidine kinase, that primarily target rapidly dividing cells. In contrast, novel artificial death switches based on chemical inducers of dimerization (CIDs) and endogenous proapoptotic molecules function efficiently in both dividing and nondividing cells. In this approach, lipid-permeable, nontoxic CIDs are used to conditionally cross-link target proteins that are fused to CID-binding domains (CBDs), thus activating signaling cascades leading to apoptosis. In previous reports, CID-regulated Fas and caspases 1, 3, 8, and 9 were described. Since the maximum efficacy of these artificial death switches requires low basal and high specific activity, we have optimized these death switches for three parameters: (1) extent of oligomerization, (2) spacing between CBDs and target proteins, and (3) intracellular localization. We describe improved conditional Fas and caspase 1, 3, 8, and 9 alleles that function at subnanomolar levels of the CID AP1903 to trigger apoptosis. Further, we demonstrate for the first time that oligomerization of the death effector domain of the Fas-associated protein, FADD, is sufficient to trigger apoptosis, suggesting that the primary function of FADD, like that of Apaf-1, is oligomerization of associated caspases. Finally, we demonstrate that nuclear-targeted caspases 1, 3, and 8 can trigger apoptosis efficiently, implying that the cleavage of nuclear targets is sufficient for apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Decreased activity of the L-arginine-nitric oxide metabolic pathway in patients with congestive heart failure.

BACKGROUND: Impaired endothelium-dependent, nitric oxide (NO)-mediated vasodilation may contribute to increased vasomotor tone in patients with heart failure. Whether decreased endothelium-dependent, NO-mediated vasodilation in patients with heart failure is due to decreased synthesis or increased degradation of NO is unknown. METHODS AND RESULTS: To specifically assess the synthetic activity of the L-arginine-NO metabolic pathway, urinary excretion of [15N]nitrates and [15N]urea was determined after a primed continuous intravenous infusion of L-[15N]arginine (40 micromol/kg) in 16 patients with congestive heart failure and 9 age-matched normal control subjects at rest and during submaximal treadmill exercise. After infusion of L-[15N]arginine, 24-hour urinary excretion of [15N]nitrates was decreased in patients with congestive heart failure at rest (2.2+/-0.5 versus 8.0+/-2.3 micromol/24 h) and during submaximal exercise (2.4+/-1.2 versus 11. 4+/-4.0 micromol/24 h) compared with control subjects (both P<0.01). After infusion of L-[15N]arginine, 24-hour urinary excretions of [15N]urea at rest in patients with congestive heart failure and control subjects were not different (1.1+/-0.3 versus 1.2+/-0.2 mmol/24 h, P>0.20). CONCLUSIONS: A specific decrease in synthetic activity of the L-arginine-NO metabolic pathway contributes to decreased endothelium-dependent vasodilation in patients with congestive heart failure.

Adult↗
PubMed1999

Assessment of endothelium-mediated vasodilation of the peripheral circulation by transcutaneous ultrasonography and venous occlusion plethysmography.

Transcutaneous ultrasonography is a non-invasive technique with the ability to measure the volumetric blood flow of the peripheral circulation. Peripheral blood flow can be determined by high-resolution imaging of vessel diameter coupled with Doppler assessment of flow velocity. This method, however, has not been validated in vivo. Accordingly, brachial artery flow in response to intraarterial infusion of vasodilators was assessed by ultrasonography in 16 healthy subjects and compared to values obtained simultaneously by venous occlusion plethysmography. Blood flow calculated from ultrasound-derived vessel diameter and flow velocity was found to highly correlate with plethysmographic flow, with r values ranging from 0.83 to 0.99. Using this ultrasound technique combined with plethysmography, the response of conduit and resistance vessels to endothelium-mediated vasodilation was characterized. Doppler velocity rose dramatically with endothelium-dependent acetylcholine (970%), but only modestly with endothelium-independent vasodilators, nitroglycerin (292%) and nitroprusside (340%). Despite eliciting the greatest overall forearm flow response, acetylcholine resulted in a smaller increase in conduit diameter (15.4%) than nitroglycerin (21.8%), and only a comparable change than nitroprusside (14.6%). Taken together, these results suggest that acetylcholine acts predominantly on resistance vessels, whereas nitrovasodilators affect mainly conduit vessels. In summary, transcutaneous ultrasonography can be used reliably to assess flow changes in the peripheral circulation. Combined with plethysmography, this technique is useful for determining the relative contribution of conduit and resistance vessels to peripheral flow, particularly in the assessment of endothelium-mediated vasodilation.

Adult↗
PubMed1999

Regulation of the contact sensitivity response to urushiol with anti-urushiol monoclonal antibody ALG 991.

The objective of the studies was to demonstrate that the contact sensitivity (CS) response to poison ivy/oak could be downregulated following treatment with a monoclonal antibody (mAb) reacting with the allergen urushiol. Conjugation of urushiol and its synthetic analogue 3-n-pentadecylcatechol (PDC) to N-acetylcysteine yielded hydrosoluble derivatives which induced humoral immune responses in BALB/c mice. Hybridomas secreting monoclonal antibodies (mAbs) reacting with urushiol and PDC were generated by fusion of B lymphocytes from immunized mice with mouse myeloma P3NS0 cells. The specificity of mAb ALG 991 (IgM isotype) was defined by inhibition of antibody binding by PDC analogues. This demonstrated that mAb ALG 991 reacted with the catechol moiety of urushiol, the region of the allergen being critically important in the induction of contact dermatitis. The CS response to urushiol in BALB/c mice was suppressed by stimulation with mAb ALG 991 and the role of sensitized T cells, including suppressor T cells, has been considered. Suppression of CS was most effective with low doses (1 microg) of mAb incorporated into a vaccine with Freund's adjuvant. This treatment suppressed CS responses in BALB/c mice already sensitized to urushiol.

Allergens↗
PubMed1999

Carbon filaments direct the growth of postlesional plastic axons after spinal cord injury.

The effect of implantation of carbon filaments and fetal tissues on the axonal regeneration following contusion injury in a rat model was investigated by in situ immunofluorescence. Female Sprague-Dawley rats were subjected to severe contusion injury to the spinal cord at T9-T10. All animals were divided into 5 groups (N = 5/group): normal controls. surgical controls, with carbon filament implants, with fetal tissue implants and with implants consisting of fetal tissue cocultured with carbon filaments. After a 10-week survival period, the astroglial response was assessed by immunoreactive glial fibrillary acidic protein and the neuro-axonal profile by immunoreactive phosphorylated and nonphosphorylated neurofilament proteins. The contusion injury resulted in: (a) dramatically increased immunoreactivity of glial fibrillary acidic protein indicating injury-associated reactive astrogliosis, (b) increase in immunoreactive phosphorylated neurofilament protein indicating upregulated phosphorylation of neurofilament protein, (c) with no change in the highly differentiated nonphosphorylated neurofilament protein which normally occur in the nonregenerating mature neurons. Implantation of fetal tissues alone following contusion injury did not show any appreciable change with regard to the immunoreactivities for the glial and neuronal markers studied, compared to the injury controls. However, the implantation of carbon filaments alone or together with fetal tissues directed the growth of glial fibrillary acidic protein-positive astroglia and phosphoneurofilament-positive neurites along the carbon fibers, with no effect on nonphosphoneurofilament protein. In conclusion, implantation of carbon filaments appears to be critical for facilitating the attachment of astroglia forming a substrate and scaffolding that can further support and direct the growth of postlesional plastic axons across the lesion. In addition, carbon filament prostheses in combination with fetal tissue implants provides an improved combinational approach to promote regrowth of injured neurons following injury.

Animals↗
PubMed1999

The effect of glutamate uptake inhibitors on hippocampal evoked potentials in vitro.

The influence of four inhibitors of the high-affinity glutamate uptake system (DL-aspartic acid beta-hydroxymate, DL-AHM; L-aspartic acid beta-hydroxymate, L-AHM; threo-beta-methylaspartate, DLM; L-transpyrrolidine-2, 4-dicarboxylate, PDC) on potentials recorded from hippocampal slices was investigated. At low concentrations of DL-AHM, L-AHM and DLM (50-150 microM) the population spike was permanently amplified. NMDA receptor antagonists blocked this facilitatory effect of L-AHM, DL-AHM and DLM. At higher concentrations (400-700 microM) DL-AHM and DLM abolished the population spike, while L-AHM did not eliminate the population spike at any concentration tested. None of these uptake inhibitors influenced an antidromic potential recorded in Ca(2+)- free Ringer solution. PDC at lower concentrations (75 microM) did not affect the population spike and at higher concentrations (150 microM-500 microM) induced only a transient elevation in population spike. Our data demonstrate that modification of glutamate uptake may be an important factor in the regulation of synaptic efficiency of glutamergic pathways.

Animals↗
PubMed1999

Animal models of spinal cord contusion injuries.

BACKGROUND AND PURPOSE: Traumatic spinal cord injury causes initial mechanical disruption of tissue, leading to a complex secondary sequence of pathophysiologic changes and neurologic impairment. These sequelae depend on the impact force delivered to the spinal cord at the time of injury. Successful clinical evaluation of the efficacy of any therapeutic regimen depends on the reliability and reproducibility of an experimental animal model. We describe a trauma device and the biomechanical parameters required to induce severe or moderate spinal cord contusion injury in cats and rats. METHODS: Recovery after injury was determined by behavioral, electrophysiologic, and histologic evaluations. RESULTS: Behavioral and electrophysiologic tests after injury clearly identified the experimental groups. A stable severe paraplegic state (defined as 6 months for cats and 8 weeks for rats), without evidence of behavioral or electrophysiologic recovery, was induced by a 65-Newton (N) load for cats and a 35-N load for rats. Moderate spinal cord contusion injury, from which cats and rats partially recovered after approximately 3 months and 4 weeks, respectively, was induced by a 45- and 25-N load, respectively. CONCLUSION: Use of these injury conditions provides reliable animal models for studies designed to evaluate potential therapeutic regimens for spinal cord injury.

Animals↗
PubMed1998

Preparation of brain-derived neurotrophic factor- and neurotrophin-3-secreting Schwann cells by infection with a retroviral vector.

One reason that the central nervous system of adult mammals does not regenerate after injury is that neurotrophic factors are present only in low concentrations in these tissues. Recent studies have shown that the application of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) acts to encourage the regrowth of motor and sensory fibers after spinal cord injury. Other studies have reported that the regrowth of axons after injury was enhanced by the implantation of Schwann cells, which normally secrete BDNF and NT-3. The purpose of the present study was to genetically modify Schwann cells to secrete increased amounts of BDNF or NT-3 by infection with a retroviral vector. Retroviral vectors were constructed by the ligation of BDNF or NT-3 cDNA to the LXSN vector. Viruses were generated from the plasmid forms of the vectors by transient transfection of PA317 amphotrophic retroviral packaging cells. Viruses were harvested and used to infect the human Schwann cell line designated NF-1T. Northern blot analysis of poly (A+) RNA prepared from Schwann cells that were infected with BDNF- or NT-3-containing virus showed the presence of BDNF or NT-3 mRNA. An enzyme-linked immunosorbent assay (ELISA) for BDNF and NT-3 was performed on media the cells were grown in, and on cellular extracts prepared from the BDNF- and NT-3-infected Schwann cells. The ELISA results demonstrated that the Schwann cells were secreting increased levels of immunologically active BDNF or NT-3. Immunocytochemical staining of these cells revealed the presence of these two neurotrophic factors located in perinuclear granules. These neurotrophic factor-secreting Schwann cells are currently being evaluated for their efficacy in the treatment of spinal cord injury.

Adult↗
PubMed1998

Scar quality from partial or complete wound closure using the Cincinnati incision for clubfoot surgery.

The method of skin closure in using the Cincinnati incision for clubfoot surgery may influence the quality of the scar obtained and the postoperative outcome. We retrospectively reviewed two groups of patients who underwent either primary skin closure (14 feet in 11 patients) or partial wound closure and healing by secondary intention (15 feet in 11 patients). The quality of the scars from both of these methods were equally acceptable cosmetically, and neither technique predisposed the patient to any long-term wound complications. In addition, we noted that closing the skin may act as a soft tissue tether, and that the initial position of the postoperative splinting of the foot may influence the surgical outcome. Both of these factors may contribute to the recurrence of equinovarus deformity.

Cicatrix↗
PubMed1997

Apoptosis induced by gliotoxin is preceded by phosphorylation of histone H3 and enhanced sensitivity of chromatin to nuclease digestion.

The fungal toxin gliotoxin induces apoptotic cell death in a variety of cells. Apoptosis induced in thymocytes by gliotoxin is rapid, and DNA fragmentation is observable within 4 h treatment. Apoptosis induced by gliotoxin is calcium-independent and unaffected by protein synthesis inhibitors. We have previously shown that gliotoxin results in phosphorylation of a 16.3-kDa protein within 10 min treatment of thymocytes. Here we show that this protein is histone H3 and phosphorylation occurs on Ser-10. Cyclic AMP levels and activity of protein kinase A (PKA) are raised in cells treated with gliotoxin. Apoptosis is inhibited by genistein which also inhibits PKA and histone H3 phosphorylation. Apoptosis is also inhibited by a number of specific inhibitors of PKA suggesting apoptosis induced by gliotoxin is modulated by this kinase. The agents forskolin and cholera toxin do not induce rapid phosphorylation of H3 although some increase in phosphorylation of H3 does occur after 8 h with these agents. Forskolin and cholera toxin also induce apoptosis but over a longer time course than gliotoxin. In all cases levels of apoptosis correlate with degree of H3 phosphorylation. Cells treated with gliotoxin show an early sensitivity to micrococcal nuclease and DNase I digestion indicating a functional relationship between DNA fragmentation and H3 phosphorylation.

Amino Acid Sequence↗
PubMed1997

Delayed reversal of impaired metabolic vasodilation in patients with end-stage heart failure during long-term circulatory support with a left ventricular assist device.

BACKGROUND: Whether increased cardiac output during chronic circulatory support with a left ventricular assist device (LVAD) is associated with improved metabolic vasodilation in the peripheral circulation of patients with congestive heart failure is unknown. METHODS: Forearm blood flow, determined by venous occlusion plethysmography, mean arterial pressure, and cardiac output were measured at rest and after 5 minutes of arterial occlusion (a maximal metabolic vasodilatory stimulus) in 14 patients with severe heart failure before LVAD implantation, and in the early (<4 weeks) and late (8 to 12 weeks) postoperative recovery phases after LVAD implantation. Nine normal subjects served as controls. Vascular conductance was calculated as the ratio of forearm blood flow and mean arterial pressure. RESULTS: Mean arterial pressure and cardiac output increased to normal values in the early and late recovery phases after LVAD implantation. Resting forearm blood flow and vascular conductance were similar to normal subjects in the early and late recovery phases after LVAD implantation. Peak forearm blood flow and vascular conductance were significantly less than control subjects in the early preoperative recovery phase (p < 0.05) but were similar to control subjects in the late postoperative recovery phase after LVAD implantation. CONCLUSIONS: In spite of early normalization of cardiac output, mean arterial pressure, and resting forearm blood flow during chronic circulatory support with the LVAD, peak forearm blood flow, and peak vascular conductance did not increase to values similar to those observed in normal subjects until the late postoperative recovery period. The delayed effect of the LVAD on metabolic vasodilation may be related to flow-dependent changes in the peripheral vasculature of patients with heart failure.

Adolescent↗
PubMed1996

Multiple mechanisms may contribute to the cellular anti-adhesive effects of phosphorothioate oligodeoxynucleotides.

Phosphorothioate oligodeoxynucleotides complementary to the p65 (Rel A) subunit of the NF-kappaB nuclear transcriptional regulatory factor have been suggested to be sequence specific blockers of cellular adhesion. We studied the effects of Rel A antisense, Rel A sense and other phosphorothioate oligodeoxynucleotides on cellular adhesion and found that blockade of adhesion was predominately non-sequence specific. Phosphorothioate oligodeoxynucleotides bind to the extracellular matrix (ECM) of NIH 3T3 cells, and to the ECM elements laminin and fibronectin. By use of a gel mobility shift assay, the association of the A subunit of laminin with a probe 12mer phosphodiester oligodeoxynucleotide could be demonstrated. This interaction was described by a single-site binding equation (K d = 14 microM). Human Rel A antisense and sense oligodeoxynucleotides, and two synthetic persulfated heparin analogs were excellent competitors of the binding of the probe oligodeoxynucleotide to laminin. Taken together, these data indicate that oligodeoxynucleotide binding occurred at or near the heparin-binding site. Competition for 5' 32p- SdT18 (an 18mer phosphorothioate homopolymer of thymidine) binding to fibronectin with the discrete heparin analogs, as well as with SdC28, was also observed. Phosphorothioate oligodeoxynucleotides (Rel A antisense >> Rel A sense) inhibited the binding of laminin to bovine brain sulfatide, but not to its cell surface receptors on MCF-7 cells. By flow cytometric analysis we have also shown, in contrast to what was observed with laminin, that phosphorothioates a non-specifically block the specific binding of fluoresceinated fibronectin to its cell surface receptors on phorbol-12,13-myristate acetate treated Jurkat cells. Blockade of specific binding occurred in the oligodeoxynucleotide treated cells in the presence or absence of oligomer in the media.

3T3 Cells↗
PubMed1996

Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure: role of endothelium-derived nitric oxide.

OBJECTIVES: This study was undertaken to investigate the role of endothelium-derived nitric oxide in the regulation of forearm blood flow during exercise in normal subjects and patients with congestive heart failure. BACKGROUND: Nitric oxide-mediated vasodilation in response to muscarinic stimulation is impaired in the peripheral circulation of patients with congestive heart failure. Whether nitric oxide-mediated vasodilation during exercise is also impaired in patients with congestive heart failure is unknown. METHODS: Forearm blood flows (ml/min per 100 ml) were determined during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction by venous occlusion plethysmography before and after regional inhibition of nitric oxide synthesis with administration of L-NG-monomethylarginine (L-NMMA) in the brachial artery of 17 patients with congestive heart failure (mean age 49 years, mean left ventricular ejection fraction 0.22) and 10 age-matched normal subjects. RESULTS: Before administration of L-NMMA in the brachial artery, forearm blood flows in patients with congestive heart failure during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction were slightly but not significantly lower than that of normal subjects ([mean +/- SE] 6.8 +/- 1.0, 8.5 +/- 1.0 and 12.9 +/- 1.7 ml/min per 100 ml, respectively, in patients with congestive heart failure vs. 6.6 +/- 1.2, 11.6 +/- 1.9 and 16.2 +/- 1.9 ml/min per 100 ml, respectively, in normal subjects, p = NS). After administration of L-NMMA in the brachial artery, forearm blood flows in normal subjects significantly decreased by 10% to 21% during hand grip exercise but did not change during exercise in patients with congestive heart failure. CONCLUSIONS: Regional inhibition of nitric oxide synthase with administration of L-NMMA in the brachial artery significantly decreased forearm blood flows during rhythmic hand grip exercise in normal subjects but not in patients with congestive heart failure. These findings suggest that nitric oxide-mediated vasodilation during submaximal exercise is impaired in the forearm circulation of patients with congestive heart failure.

Adult↗