Proto-oncogenes, unlike 'harmless' genes, tend to be dispersed in the human genome: selection against out-of-register recombination?
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Genome, Human↗
Biomedical subjects
S Ahmed
Publications and source records attributed to S Ahmed.
The effect of a structured neonatal resuscitation program on delivery room practices.
PURPOSE: This study evaluated the introduction of the Neonatal Resuscitation Program (NRP) of the American Academy of Pediatrics and the American Heart Association into the delivery room of an Irish maternity hospital. DESIGN: Prospective, controlled observational study of 51 deliveries before and 51 deliveries following the training of delivery room personnel in the NRP. SAMPLE: Participants were 33 nurse-midwives and 11 pediatric resident physicians. MAIN OUTCOME VARIABLE: Evaluation of postdelivery, newborn resuscitation practices. RESULTS: The introduction of the NRP was associated with significant improvements in delivery room preparation, in the evaluation and management of the newborn infant, and in thermal protection at birth. Although there was a trend to use more free-flow oxygen following the introduction of the NRP, this was not statistically significant. Bag and mask ventilation was also used more frequently following NRP training. However, there were no significant differences in the use of endotracheal intubation, chest compressions, and medications. Fifteen of the 51 infants became hypothermic prior to the introduction of the NRP; none of the infants developed hypothermia in the post-NRP part of the study.
Cardiopulmonary Resuscitation↗
Stereoselective serum protein binding of ketoprofen in liver diseases.
The stereoselective binding of ketoprofen (KP) to human serum was studied in patients with liver diseases and was compared with that of normal volunteers. The serum protein binding of racemic KP was found to be decreased in hepatic patients whereas, interestingly, the stereoselectivity of KP was increased. The ratio of unbound concentrations of the KP enantiomers (FR/FS) showed positive linear correlation with albumin concentrations. Inhibition of KP binding to human serum albumin (HSA) induced by lithocholate, lithocholate sulfate and bilirubin was studied. The data presented in this paper strongly suggest that the variation of stereoselective binding of KP in patients suffering from liver diseases was mainly caused by the decrease of HSA levels and secondly by the stereoselective inhibition induced by the increased concentrations of bile acid and its metabolite.
Adult↗
Innovation in vaccine provision for drug users.
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Hepatitis B↗
Extensor mechanism sparing approach to the elbow for reduction and internal fixation of intercondylar fracture of the humerus.
OBJECTIVE: To evaluate the short term results of extensor mechanism sparing approach to the elbow for fixation of intercondylar fractures of the distal end of humerus and compare it with existing Surgical approaches. DESIGN: This is a prospective study conducted from June, 1992 to June, 1997. SETTING: Department of Orthopaedic Surgery, Jinnah Postgraduate Medical Centre and Mehran Clinic (Pvt.), Karachi. PRINCIPLE OF SURGICAL APPROACH: This approach is based upon the principle that by sparing the extensor mechanism, we reduce the amount of surgical trauma and help in early rehabilitation which can contribute in improving the results of this difficult fracture. RESULTS: There were nine type 2 fractures, eight type 3 fractures and four type 4 fractures according to Rise borough and Radin classification. Based upon the same authors criteria, there were over all 57.14% good 23.81% fair and 19.04% poor results. Adequate exposure was achieved in all of type 2 and seven (87.5%) out of eight type 3 fractures. We failed in type 4 fractures. Mean operating time was 107.38 (+/- 24.67) minutes. CONCLUSION: The results in this series are comparable to other studies. They can however be improved with proper selection of cases, experience with the technique along with better fixation and rehabilitations.
Elbow↗
Reality testing in cancer treatment: the phase I trial of endostatin.
Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery which provides hope to the patient, support to caregivers, and encourages the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. The September 1999 Schwartz Center Rounds addressed the growing attention around the phase I trial of Endostatin. Endostatin represents a new treatment paradigm. It is an anti-angiogenic protein, an endogenous fragment of collagen XVIII. In an attempt to ensure a fair allocation of a very limited number of treatment slots in this classical phase I trial, a lottery was established. More than 1,400 patients enrolled within two days of the lottery, all vying for three places in the first cohort. Two contrasting cases are presented, each a potentially eligible patient. The discussion focuses on the dilemma presented by patients desperate for an unproven treatment and the responsibility of staff to explain and support without compounding the hype or suffocating the hope.
Adult↗
Prenatal diagnosis of haemophilia-A: a basis for the Pakistani families.
OBJECTIVE: To determine the feasibility of a PCR based strategy for prenatal diagnosis of Haemophilia-A in Pakistani Families. DESIGN: Prospective. SETTING: Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi. SUBJECTS: Five families with at least one child affected with Haemophilia-A. Each family comprised of father, mother, affected child and fetus when present. MAIN OUTCOME MEASURES: Short Tandem Repeat (STR) analysis in the Intron 22 of factor VIII gene. RESULTS: PCR based analysis of the STR in intron 22 of factor VIII gene showed that the marker was informative in 4/5 study families and could be used in these families for the prenatal diagnosis of Haemophilia-A. In two families prenatal diagnosis was carried out by Chorionic Villus Sampling at 10-13 weeks gestation and the results in both the cases showed a carrier female fetus. CONCLUSION: Linkage based prenatal diagnosis of Haemophilia-A by an intragenic STR marker is feasible in most of the Pakistani families. The long term response of the Haemophiliac families to the availability of prenatal diagnosis remains to be seen. The STR marker can also be used for carrier detection of female subjects in the affected families.
Chorionic Villi Sampling↗
Modeling study of some inhibitors of 17,20-lyase, a component of the enzyme 17 alpha-hydroxylase/17,20-lyase: a novel approach.
A novel molecular modeling study, involving inhibitors bound to a "substrate-heme complex," is described for the binding of steroidal and non-steroidal inhibitors of the 17,20-Lyase component of the enzyme complex 17 alpha-hydroxylase/17,20-lyase to gain further insight into the active site of this enzyme. This novel approach has resulted in the construction of a simple working model using which a number of compounds and their inhibitory activity have been rationalised.
Binding Sites↗
Cytogenetic study of buffalo under pollution of environmental conditions.
Thirty-four buffalos were used in the present study. Animals were kept in three experimental groups, two groups of which were reared in polluted areas, and the third group in an agricultural area (control group). the first and second groups were exposed to industrial and automobile exhaust emissions of genotoxic agents. Comparative cytogenetic analysis was made between the three groups. The cytogenetic studies of peripheral blood lymphocytes included chromosomal aberration and sister chromatide exchange (SCE). Significant differences (P<0.05) were observed in the percentage of cells with total chromosomal aberrations and gaps between buffalo from polluted and agricultural areas (31+/-1.4% and 21.1+/-6.7% and 7.6+/-1.6% and 6.8+/-1%, respectively). The differences of frequencies of the total gaps between the first and second groups were significant, while it was non-significant in the total chromosomal aberrations. The frequency of sister chromatide exchange of buffalo from polluted areas was 11.8+/-1.4% compared to 8.3+/-1. 2% from the agricultural area, the difference was statistically significant (P<0.05). These results indicated that cytogenetic analysis of chromosomes in peripheral lymphocytes of buffalo exposed to environmental pollution allows to direct detection of mutation in somatic cell, which can be prevented.
Agriculture↗
Mechanism based representation of the active site of 5 alpha-reductase (5AR).
In the present study, we have attempted to determine a detailed representation of the 5 alpha-Reductase (5AR) active site involving the elucidation of the transition state for the steroid delta 4 reduction reaction (the 'NADPH-substrate' complex), onto which steroidal and non-steroidal inhibitors were superimposed. We conclude that: (i) there is a requirement for groups to mimic the steroid substrate A-ring; (ii) the area about C(3), C(4), C(5) and C(6) of T appears to be sterically hindered, and; (iii) the area of the active site about the C(17) of the steroid substrate does not possess hydrogen bonding groups and is not restricted.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Miss stepney till the end
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Journal Article↗
PAK promotes morphological changes by acting upstream of Rac.
The serine/threonine kinase p21-activated kinase (PAK) has been implicated as a downstream effector of the small GTPases Rac and Cdc42. While these GTPases evidently induce a variety of morphological changes, the role(s) of PAK remains elusive. Here we report that overexpression of betaPAK in PC12 cells induces a Rac phenotype, including cell spreading/membrane ruffling, and increased lamellipodia formation at growth cones and shafts of nerve growth factor-induced neurites. These effects are still observed in cells expressing kinase-negative or Rac/Cdc42 binding-deficient PAK mutants, indicating that kinase- and p21-binding domains are not involved. Furthermore, lamellipodia formation in all cell lines, including those expressing Rac binding-deficient PAK, is inhibited significantly by dominant-negative RacN17. Equal inhibition is achieved by blocking PAK interaction with the guanine nucleotide exchange factor PIX using a specific N-terminal PAK fragment. We conclude that PAK, via its N-terminal non-catalytic domain, acts upstream of Rac mediating lamellipodia formation through interaction with PIX.
Animals↗
Cryptic Rac-binding and p21(Cdc42Hs/Rac)-activated kinase phosphorylation sites of NADPH oxidase component p67(phox).
Rac1 is a member of the Rho family of small molecular mass GTPases that act as molecular switches to control actin-based cell morphology as well as cell growth and differentiation. Rac1 and Rac2 are specifically required for superoxide formation by components of the NADPH oxidase. In binding assays, Rac1 interacts directly with p67(phox), but not with the other oxidase components: cytochrome b, p40(phox), or p47(phox) (Prigmore, E., Ahmed, S., Best, A., Kozma, R. , Manser, E., Segal, A. W., and Lim, L. (1995) J. Biol. Chem. 270, 10717-10722). Here, the Rac1/2 interaction with p67(phox) has been characterized further. Rac1 and Rac2 can bind to p67(phox) amino acid residues 170-199, and the N terminus (amino acids 1-192) of p67(phox) can be used as a specific inhibitor of Rac signaling. Deletion of p67(phox) C-terminal sequences (amino acids 193-526), the C-terminal SH3 domain (amino acids 470-526), or the polyproline-rich motif (amino acids 226-236) stimulates Rac1 binding by approximately 8-fold. p21(Cdc42Hs/Rac)-activated kinase (PAK) phosphorylates p67(phox) amino acid residues adjacent to the Rac1/2-binding site, and this phosphorylation is stimulated by deletion of the C-terminal SH3 domain or the polyproline-rich motif. These data suggest a role for cryptic Rac-binding and PAK phosphorylation sites of p67(phox) in control of the NADPH oxidase.
3T3 Cells↗
Mechanism of 17 alpha-hydroxylase/17,20-lyase--an initial geometric perspective for the lyase of the C(17)-C(20) bond of C21 steroids.
Using the novel 'substrate-heme complex' approach, the mechanism of 17 alpha-Hydroxylase/17,20-Lyase (P-450(17) alpha), in particular the lyase of the C(17)-C(20) bond, is considered from a geometric perspective. The results of the study appear to suggest that the final oxidative step in the lyase of the C(17)-C(20) bond involves the use of a ferroxy attacking species as opposed to peroxy or a mixture of ferroxy and peroxy, an observation which is consistent with results previously obtained with Aromatase.
17-alpha-Hydroxypregnenolone↗
Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes.
Ruthenium red is a well known inhibitor of Ca2+ uptake into mitochondria in vitro. However, its utility as an inhibitor of Ca2+ uptake into mitochondria in vivo or in situ in intact cells is limited because of its inhibitory effects on sarcoplasmic reticulum Ca2+ release channel and other cellular processes. We have synthesized a ruthenium derivative and found it to be an oxygen-bridged dinuclear ruthenium amine complex. It has the same chemical structure as Ru360 reported previously (Emerson, J., Clarke, M. J., Ying, W-L., and Sanadi, D. R. (1993) J. Am. Chem. Soc. 115, 11799-11805). Ru360 has been shown to be a potent inhibitor of Ca2+-stimulated respiration of liver mitochondria in vitro. However, the specificity of Ru360 on Ca2+ uptake into mitochondria in vitro or in intact cells has not been determined. The present study reports in detail the potency, the effectiveness, and the mechanism of inhibition of mitochondrial Ca2+ uptake by Ru360 and its specificity in vitro in isolated mitochondria and in situ in isolated cardiac myocytes. Ru360 was more potent (IC50 = 0.184 nM) than ruthenium red (IC50 = 6.85 nM) in inhibiting Ca2+ uptake into mitochondria. 103Ru360 was found to bind to isolated mitochondria with high affinity (Kd = 0.34 nM, Bmax = 80 fmol/mg of mitochondrial protein). The IC50 of 103Ru360 for the inhibition of Ca2+ uptake into mitochondria was also 0.2 nM, indicating that saturation of a specific binding site is responsible for the inhibition of Ca2+ uptake. Ru360, as high as 10 microM, produced no effect on sarcoplasmic reticulum Ca2+ uptake or release, sarcolemmal Na+/Ca2+ exchange, actomyosin ATPase activity, L-type Ca2+ channel current, cytosolic Ca2+ transients, or cell shortening. 103Ru360 was taken up by isolated myocytes in a time-dependent biphasic manner. Ru360 (10 microM) applied outside intact voltage-clamped ventricular myocytes prevented Ca2+ uptake into mitochondria in situ where the cells were progressively loaded with Ca2+ via sarcolemmal Na+/Ca2+ exchange by depolarization to +110 mV. We conclude that Ru360 specifically blocks Ca2+ uptake into mitochondria and can be used in intact cells.
Animals↗
Structure activity relationship study of known inhibitors of the enzyme 5 alpha-reductase (5AR).
Preliminary results of a modelling study of both steroidal and non-steroidal inhibitors of 5 alpha-reductase (5AR) are described in order to elucidate the essential structural requirements needed for the design of novel non-steroidal inhibitors. The study suggests that: (i) there is a requirement for groups to mimic the C(3) = O of the steroid substrate A-ring; (ii) the area of the active site about the C(17)-OH position of the substrate does not appear to possess hydrogen bonding groups and is unrestricted.
Cholestenone 5 alpha-Reductase↗
Morning vs evening light treatment of patients with winter depression.
BACKGROUND: According to the phase-shift hypothesis for winter depression, morning light (which causes a circadian phase advance) should be more antidepressant than evening light (which causes a delay). Although no studies have shown evening light to be more antidepressant than morning light, investigations have shown either no difference or morning light to be superior. The present study assesses these light-exposure schedules in both crossover and parallel-group comparisons. METHODS: Fifty-one patients and 49 matched controls were studied for 6 weeks. After a prebaseline assessment and a light/dark and sleep/wake adaptation baseline week, subjects were exposed to bright light at either 6 to 8 AM or 7 to 9 PM for 2 weeks. After a week of withdrawal from light treatment, they were crossed over to the other light schedule. Dim-light melatonin onsets were obtained 7 times during the study to assess circadian phase position. RESULTS: Morning light phase-advanced the dim-light melatonin onset and was more antidepressant than evening light, which phase-delayed it. These findings were statistically significant for both crossover and parallel-group comparisons. Dim-light melatonin onsets were generally delayed in the patients compared with the controls. CONCLUSIONS: These results should help establish the importance of circadian (morning or evening) time of light exposure in the treatment of winter depression. We recommend that bright-light exposure be scheduled immediately on awakening in the treatment of most patients with seasonal affective disorder.
Adult↗
Poststreptococcal reactive arthritis: clinical characteristics and association with HLA-DR alleles.
OBJECTIVE: To assess the relationship of poststreptococcal reactive arthritis (ReA) to other forms of ReA and rheumatic fever by comparing the frequency of HLA-B27 and DRB1 alleles in these diseases. METHODS: The diagnosis of poststreptococcal ReA was established in 25 children seen in a pediatric rheumatology clinic. HLA-B27 and DRB1 genotyping was performed in 18 of the white American patients. The DRB1 genotyping results were compared with those in 33 patients with rheumatic fever and 190 normal individuals. RESULTS: HLA-B27 was positive in 3 of the 18 poststreptococcal ReA patients, a frequency not different from that found in normal individuals. Compared with normal controls, the frequency of the DRB1*01 allele was higher in poststreptococcal ReA patients (odds ratio [OR] 2.7, P=0.044), while DRB1*16 was increased in patients with rheumatic fever (OR 4.3, P=0.028). CONCLUSION: The association of poststreptococcal ReA with HLA-DRB1*01, but not with HLA-B27, suggests that its pathogenesis may be more similar to that of rheumatic fever than to that of ReA associated with enteric pathogens.
Adolescent↗