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Biomedical subjects

K Kahn

Publications and source records attributed to K Kahn.

At least 19 recordsLinked to original sources
PubMed2004

Undiagnosed pulmonary tuberculosis deaths in rural South Africa.

This research explores death from pulmonary tuberculosis (PTB) using a verbal autopsy (VA) tool within the established Agincourt Health and Demographic Surveillance System site in South Africa's rural northeast. Previous work on active case finding in the area highlighted a modest burden of undiagnosed PTB in the community. This VA research confirms the existence of undiagnosed PTB deaths, with 13 (46%) of 28 PTB deaths among the permanent adult population (n = 38,251) going undetected by the health service. There was a median duration of coughing in the community of 16 weeks among these undiagnosed PTB deaths. As most undiagnosed cases present to the health service at some point during their illness, intervention strategies to support early diagnosis at this level can only be re-emphasised by this work.

Adult↗
PubMed2001

Diphtheria toxin catalyzed hydrolysis of NAD(+): molecular dynamics study of enzyme-bound substrate, transition state, and inhibitor.

The mechanism of the diphtheria toxin-catalyzed hydrolysis of NAD(+) was investigated by quantum chemical calculations and molecular dynamics simulations. Several effects that could explain the 6000-fold rate acceleration (Delta Delta G(++) approximately 5 kcal/mol) by the enzyme were considered. First, the carboxamide arm of the enzyme-bound NAD(+) adopts a trans conformation while the most stable conformation is cis. The most stable conformation for the nicotinamide product has the amide carbonyl trans. The activation energy for the cleavage of the ribosidic bond is reduced by 2 kcal/mol due to the relaxation of this ground state conformational stress in the transition state. Second, molecular dynamics simulations to the nanosecond time range revealed that the carboxylate of Glu148 forms a hydrogen bond to the substrate's 2' hydroxyl group in E.S (approximately 17% of the time) and E.TS (approximately 57% of the time) complexes. This interaction is not seen in crystal structures. The ApUp inhibitor is held more tightly by the enzyme than the transition state and the substrate. Analysis of correlated motions reveals differences in the pattern of anticorrelated motions for protein backbone atoms when the transition state occupies the active site as compared to the E.NAD(+) complex.

Catalysis↗
PubMed2001

Development and validation of a clinical prediction rule for major adverse outcomes in coronary bypass grafting.

In this study, we develop and internally validate a clinical prediction rule for in-hospital major adverse outcomes, defined as death, renal failure, reinfarction, cardiac arrest, cerebrovascular accident, or coma, in patients who underwent coronary artery bypass grafting (CABG). All adult patients (n = 9,498) who underwent a CABG and no other concomitant surgery at 12 academic medical centers from August 1993 to October 1995 were included in the study. We assessed in-hospital major adverse outcomes and their predictors using information on admission, coronary angiography, and postoperative hospital course. Predictor variables were limited to information available before the procedure, and outcome variables were represented only by events that occurred postoperatively. We developed and internally validated a clinical prediction rule for any major adverse outcome after CABG. The rule's ability to discriminate outcomes and its calibration were assessed using receiver-operating characteristic analysis and the Hosmer-Lemeshow goodness-of-fit statistic, respectively. A major adverse outcome occurred in 6.5% of patients in the derivation set and 7.2% in the validation set. Death occurred in 2.5% of patients in the derivation set and 2.2% in the validation set. Sixteen variables were independently correlated with major adverse outcomes, with the risk score value attributed to each risk factor ranging from 2 to 12 points. The rule stratified patients into 6 levels of risk based on the total risk score. The spread in probability between the lowest and highest risk groups of having a major adverse outcome was 1.7% to 32.3% in the derivation set and 2.2% to 22.3% in the validation set. The prediction model performed well in both outcome discrimination and calibration. Thus, this clinical prediction rule allows accurate stratification of potential CABG candidates before surgery according to the risk of experiencing a major adverse outcome postoperatively.

Aged↗
PubMed2001

Tissue-dependent enhancement of transgene expression by introns of replacement histone H3 genes of Arabidopsis.

Intron-bearing replacement histone H3 genes in Arabidopsis and other plants are highly and constitutively expressed. We demonstrate that the introns located within the 5'-untranslated regions (5'-UTR) of the two Arabidopsis replacement H3 genes will abolish the cell cycle dependence of an endogenous histone H4 promoter. We demonstrate that these introns, functionally combined with their endogenous promoters, could produce the high and constitutive expression of the replacement H3 genes observed in planta. They strongly increase gene expression whatever the promoter, from the strong 35S CaMV promoter to complete and resected promoters of cell cycle-dependent and replacement histone genes. Quantitative analysis of the extent of reporter gene enhancement in different parts of developing transgenic plantlets, ranging from 2-fold to 70-fold, supports the notion that trans-acting factors are responsible for this effect. Such factors appear most abundant in roots.

Arabidopsis↗
PubMed2000

The importance of reactant positioning in enzyme catalysis: a hybrid quantum mechanics/molecular mechanics study of a haloalkane dehalogenase.

Hybrid quantum mechanics/molecular mechanics calculations using Austin Model 1 system-specific parameters were performed to study the S(N)2 displacement reaction of chloride from 1,2-dichloroethane (DCE) by nucleophilic attack of the carboxylate of acetate in the gas phase and by Asp-124 in the active site of haloalkane dehalogenase from Xanthobacter autotrophicus GJ10. The activation barrier for nucleophilic attack of acetate on DCE depends greatly on the reactants having a geometry resembling that in the enzyme or an optimized gas-phase structure. It was found in the gas-phase calculations that the activation barrier is 9 kcal/mol lower when dihedral constraints are used to restrict the carboxylate nucleophile geometry to that in the enzyme relative to the geometries for the reactants without dihedral constraints. The calculated quantum mechanics/molecular mechanics activation barriers for the enzymatic reaction are 16.2 and 19.4 kcal/mol when the geometry of the reactants is in a near attack conformer from molecular dynamics and in a conformer similar to the crystal structure (DCE is gauche), respectively. This haloalkane dehalogenase lowers the activation barrier for dehalogenation of DCE by 2-4 kcal/mol relative to the single point energies of the enzyme's quantum mechanics atoms in the gas phase. S(N)2 displacements of this sort in water are infinitely slower than in the gas phase. The modest lowering of the activation barrier by the enzyme relative to the reaction in the gas phase is consistent with mutation experiments.

Acetates↗
PubMed2000

Organizational systems used by California capitated medical groups and independent practice associations to increase cancer screening.

BACKGROUND: Patients in health maintenance organizations (HMOs) appear to have higher utilization of cancer screening tests than patients with fee-for-service insurance. METHODS: The authors surveyed the medical directors of 174 physician organizations in a California network model HMO to obtain information regarding their organizational structure, implementation of guidelines, and use of systems to increase cancer screening. RESULTS: The majority of independent practice associations (IPAs) and medical groups (IMGs) in this California HMO had guidelines and office systems aimed at improving cancer screening. These activities were reported more frequently for mammography and Papanicolaou (Pap) smears than for colorectal carcinoma screening. IMGs reported using flow sheets more often than IPAs. Chart audits were performed more frequently for mammography (48% for IMGs and 40% for IPAs) and Pap smears (45% and 40%, respectively) than for colorectal carcinoma screening (38% and 30%, respectively). Approximately 50% of IPAs and IMGs reported mailing reminders to patients for mammography and Pap smears, but only a few did so for colorectal carcinoma screening. Annual fecal occult blood testing was believed by most medical directors to be a reasonable strategy for managed care patients (86% of IPAs and 96% of IMGs); however, fewer believed that screening sigmoidoscopy for patients ages 50-70 years was a reasonable expectation (71% and 78%, respectively). CONCLUSIONS: The majority of IPAs and IMGs in this California HMO reported using both guidelines and office systems to improve cancer screening rates. Further research is needed to understand the effect of these systems, as well their complex interactions with competing incentives, on cancer screening in managed care patients.

Adult↗
PubMed2000

Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein--initial observations.

Immunohistochemistry was used to analyse 18- and 26-month-old transgenic mice overexpressing the human beta-amyloid precursor protein under the platelet-derived growth factor-beta promoter with regard to presence and distribution of neuropeptides. In addition, antisera/antibodies to tyrosine hydroxylase, acetylcholinesterase, amyloid peptide, glial fibrillary acidic protein and microglial marker OX42 were used. These mice have been reported to exhibit extensive amyloid plaques in the hippocampus and cortex [Masliah et al. (1996) J. Neurosci. 16, 5795-5811]. The most pronounced changes were related to neuropeptides, whereas differences between wild-type and transgenic mice were less prominent with regard to tyrosine hydroxylase and acetylcholinesterase. The main findings were of two types; (i) involvement of peptide-containing neurites in amyloid beta-peptide positive plaques, and (ii) more generalized changes in peptide levels in specific layers, neuron populations and/or subregions in the hippocampal formation and ventral cortices. In contrast, the parietal and auditory cortices were comparatively less affected. The peptide immunoreactivities most strongly involved, both in plaques and in the generalized changes, were galanin, neuropeptide Y, cholecystokinin and enkephalin. This study shows that there is considerable variation both with regard to plaque load and peptide expression even among homozygotes of the same age. The most pronounced changes, predominantly increased peptide levels, were observed in two 26-month-old homozygous mice, for example, galanin-, enkephalin- and cholecystokinin-like immunoreactivities in stratum lacunosum moleculare, and galanin, neuropeptide Y, enkephalin and dynorphin in mossy fibers. Many peptides also showed elevated levels in the ventral cortices. However, decreases were also observed. Thus, galanin-like immunoreactivity could not any longer be detected in the diffusely distributed (presumably noradrenergic) fiber network in all hippocampal and cortical layers, and dynorphin-like immunoreactivity was decreased in stratum moleculare, cholecystokinin-like immunoreactivity in mossy fibers and substance P-like immunoreactivity in fibers around granule cells. The significance of generalized peptide changes is at present unclear. For example, the increase in the mainly inhibitory peptides galanin, neuropeptide Y, enkephalin and dynorphin and the decrease in the mainly excitatory peptide cholecystokinin in mossy fibers (and of substance P fibers around granule cells) indicate a shift in balance towards inhibition of the input to the CA3 pyramidal cell layer. Moreover, it may be speculated that the increase in levels of some of the peptides represents a reaction to nerve injury with the aim to counteract, in different ways, the consequences of injury, for example by exerting trophic actions. Further studies will be needed to establish to what extent these changes are typical for Alzheimer mouse models in general or are associated with the V717F mutation and/or the platelet-derived growth factor-beta promoter.

Acetylcholine↗
PubMed2000

Alpha-ketoamides and alpha-ketocarbonyls: conformational analysis and development of all-atom OPLS force field.

The molecular structures and barriers for the internal rotation around the OC-CO single bond in four alpha-ketoamides and eight alpha-ketocarbonyls have been determined from the MP3/aug-cc-pVDZ and MP2/aug-cc-pVDZ calculations. Alpha-ketocarbonyls with non-bulky substituents adopt planar conformations with two carbonyl oxygens in s-trans arrangement. The s-cis conformation is significantly less stable due to the electrostatic repulsion between the two carbonyl groups. Primary and secondary alpha-ketoamides are planar when the substituent at the carbonyl carbon is hydrogen or methyl group but tertiary alpha-ketoamides adopt a conformation where the OC-CO unit is significantly bent. Based on current ab initio structural data, a set of OPLS-AA force field parameters has been derived. These parameters can be used for the modeling of a variety of alpha-ketoamide or alpha-ketocarbonyl containing drugs such as novel protease inhibitors or neuroregenerative polyketides.

Amides↗
PubMed2000

Computational enzymology.

Recent advances in computational methods and the availability of fast, affordable computers have made the modeling of enzymatic reactions practical. The remaining challenges include achieving the accuracy level at which thermodynamic parameters and kinetic constants for different substrates, mutant enzymes, or in the presence of allosteric effectors can be predicted quantitatively.

Catalysis↗
PubMed2000

Validation and application of verbal autopsies in a rural area of South Africa.

OBJECTIVE: To validate the causes of death determined with a single verbal autopsy instrument covering all age groups in the Agincourt subdistrict of rural South Africa. METHODS: Verbal autopsies (VAs) were conducted on all deaths recorded during annual demographic and health surveillance over a 3-year period (1992-95) in a population of about 63 000 people. Trained fieldworkers elicited signs and symptoms of the terminal illness from a close caregiver, using a comprehensive questionnaire written in the local language. Questionnaires were assessed blind by three clinicians who assigned a probable cause of death using a stepwise consensus process. Validation involved comparison of VA diagnoses with hospital reference diagnoses obtained for those who died in a district hospital; and calculation of sensitivity, specificity and positive predictive value (PPV) for children under 5 years, and adults 15 years and older. RESULTS: A total of 127 hospital diagnoses satisfied the criteria for inclusion as reference diagnoses. For communicable diseases, sensitivity of VA diagnoses among children was 69%, specificity 96%, and PPV 90%; among adults the values were 89, 93 and 76%. Lower values were found for non-communicable diseases: 75, 91 and 86% among children; and 64, 50 and 80% among adults. Most misclassification occurred within the category itself. For deaths due to accidents or violence, sensitivity was 100%, specificity 97%, and PPV 80% among children; and 75, 98 and 60% among adults. Since causes of death were largely age-specific, few differences in sensitivity, specificity and PPV were found for adults and children. The frequency distribution of causes of death based on VAs closely approximated that of the hospital records used for validation. CONCLUSION: VA findings need to be validated before they can be applied to district health planning. In Agincourt, a single verbal autopsy instrument provided a reasonable estimate of the frequency of causes of death among adults and children. Findings can be reliably used to inform local health planning and evaluation.

Adolescent↗
PubMed2000

Causes of death in a rural area of South Africa: an international perspective.

The study compares the cause of death profile in a rural area of South Africa (Agincourt), with that in a rural area of West Africa (Niakhar), and in a developed country with the same life expectancy (France, 1951) in order to determine causes with high and low mortality and priorities for future health interventions. In the two African sites, causes of death were assessed by verbal autopsies, whereas they were derived from regular cause of death registration in France. Age-standardized death rates were used to compare cause-specific mortality in the three studies. Life expectancy in Agincourt was estimated at 66 years, similar to that of France in 1951, and much higher than that of Niakhar. Causes of death with outstandingly high mortality in Agincourt were violent deaths (homicide and suicide), accidents (road traffic accidents and household accidents), certain infectious diseases (HIV/AIDS, tuberculosis, diarrhea and dysentery), certain chronic diseases (cancer of genital organs, liver cirrhosis, gastrointestinal hemorrhage, maternal mortality, epilepsy, acute rheumatic fever, and pneumoconiosis) and malnutrition of young children (kwashiorkor). Causes of death with lower mortality than expected were primarily respiratory diseases (pneumonia, bronchitis, influenza, lung cancer), other cancers, vaccine preventable diseases (measles, whooping cough, tetanus), and marasmus. Verbal autopsies could be used in a rural area of a developing country without formal cause of death registration to identify the most salient health problems of the population, and could be compared with a formal cause of death registration system of a developed country.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Prediction rules for complications in coronary bypass surgery: a comparison and methodological critique.

BACKGROUND: Clinical prediction rules have been developed that use preoperative information to stratify patients according to risk of complications after cardiac surgery. OBJECTIVES: To assess the methodological standards and performance of 7 models. PARTICIPANTS: The validation portion of the Quality Measurement and Management Initiative (QMMI) cohort included a random sample of all adult patients (n = 3,261) who underwent coronary artery bypass grafting (CABG) surgery not involving valvular or other concomitant procedures at 12 medical centers from August 1993 to October 1995. OUTCOME MEASURES: Methodological standards used for model comparison were adapted from published criteria. Model performance was assessed by receiver-operating characteristic (ROC) analysis, and calibration was evaluated with the Hosmer-Lemeshow (HL) statistic and observed-expected plots. METHODS: We performed cross-validation by applying the published criteria for the development of each model to the validation subset of the QMMI cohort and by assessing the performance of each model in discriminating outcomes. RESULTS: Wide variations existed in the methodologies used to develop and validate the 5 additive scores evaluated. Cross-validation of all 5 additive scores revealed degradation in their abilities to discriminate outcomes. The 2 logistic models examined performed similarly to the additive scores examined in predicting mortality. CONCLUSIONS: Substantial variation existed both in the methodologies used to develop models and in the ability of the models to predict outcomes. Models developed at single institutions or using fewer patients may be less generalizable when applied to diverse clinical settings. Additive and logistic regression models performed similarly, as assessed by ROC and HL analyses.

Adult↗
PubMed2000

Premarital fertility in rural South Africa: a challenge to existing population policy.

The age pattern of fertility in a rural area of South Africa under demographic surveillance (Agincourt subdistrict) was investigated over the 1992-97 period. The total fertility rate (TFR) averaged 3.3 births per woman of reproductive age over the period, a major drop from earlier estimates in the same area (6.0 births in 1970-74). Age-specific fertility rates showed an atypical bimodal pattern. They were decomposed into two components of similar magnitude: premarital fertility (among women aged 12-26) and marital fertility (among women aged 15-49). The decomposition revealed the two underlying modes: a mode of premarital fertility (among women aged 18-20) and a mode of marital fertility (among women aged 28-30). Premarital fertility accounted for 21 percent of all births and for 47 percent of births among women aged 12-26. This pattern of high premarital fertility appears to reflect a low incidence of contraceptive use before the first birth, especially among adolescents, a low prevalence of abortion, and a high contraceptive prevalence thereafter. This finding calls for a reorientation of the family planning policy, which until now has targeted married women and women who have been pregnant once, but has failed to address the contraceptive needs of young women before their first pregnancy, especially adolescents.

Adolescent↗
PubMed1999

Identification and purification of hydroxyisourate hydrolase, a novel ureide-metabolizing enzyme.

We report the identification and purification of a novel enzyme from soybean root nodules that catalyzes the hydrolysis of 5-hydroxyisourate, which is the true product of the urate oxidase reaction. The product of this reaction is 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline, and the new enzyme is designated 5-hydroxyisourate hydrolase. The enzyme was purified from crude extracts of soybean root nodules approximately 100-fold to apparent homogeneity with a final specific activity of 10 micromol/min/mg. The enzyme exhibited a native molecular mass of approximately 68 kDa by gel filtration chromatography and migrated as a single band on SDS-polyacrylamide gel electrophoresis with a subunit molecular mass of 68 +/- 2 kDa. The purified enzyme obeyed normal Michaelis-Menten kinetics, and the K(m) for 5-hydroxyisourate was determined to be 15 microM. The amino-terminal end of the purified protein was sequenced, and the resulting sequence was not found in any available data bases, confirming the novelty of the protein. These data suggest the existence of a hitherto unrecognized enzymatic pathway for the formation of allantoin.

Amino Acid Sequence↗
PubMed1999

Reversal in mortality trends: evidence from the Agincourt field site, South Africa, 1992-1995.

OBJECTIVE: To examine changes in mortality in rural South Africa over the period 1992-1995 by age, sex and cause of death. DESIGN: As with much of sub-Saharan Africa, South Africa lacks effective vital registration and information on mortality is lacking. The Agincourt demographic and health surveillance system was established to inform health policy and practice with regard to rural subdistrict populations. METHODS: Prospective community-based study involving annual update of a household census with enquiry into all birth, death and migration events. All reported deaths (n = 1001) are the subject of a verbal autopsy. RESULTS: An increasing trend in overall mortality relative to general population growth in the study area is apparent. There is evidence for a reversal in the previously declining trend in mortality among women 20-44 years. A comparison of 1992-1993 with 1994-1995 shows that most of the increase in mortality is concentrated in the younger adult (20-49 year) age group. AIDS and related diseases, particularly tuberculosis, appear primarily responsible. Injuries and violence (especially homicide) and circulatory disease are important, under-recognized causes of death, although their levels have remained constant over the period. CONCLUSIONS: Mortality from AIDS and related diseases appears responsible for the probable reversal in mortality emerging in South Africa's rural northeast. Findings carry implications for the emerging system of decentralized health care.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Vaginal birth after cesarean and uterine rupture rates in California.

OBJECTIVE: To describe attempted and successful vaginal birth after cesarean (VBAC) rates and uterine rupture rates for women with and without prior cesareans, and compare delivery outcomes in hospitals with different attempted VBAC rates. METHODS: We used California hospital discharge summary data for 1995 to calculate attempted and successful VBAC rates and uterine rupture rates. We used multivariate logistic regression models to evaluate and adjust for age, ethnicity, and payment source. We report the relative risk (RR), attributable fraction, and 95% confidence intervals (CIs) for uterine rupture. RESULTS: There were 536,785 delivery discharges during 1995. The cesarean rate was 20.8%, and 12.5% of women had histories of cesareans. Of women with histories of cesareans, 61.4% attempted VBAC and 34.8% were successful. There were 392 uterine ruptures (0.07%). Women with prior cesareans were 16.98 (95% CI 13.51, 21.43) times more likely to experience uterine rupture, attributable fraction 66% (95% CI 60%, 73%). Among women with prior cesareans, those who attempted VBAC were 1.88 (95% CI 1.45, 2.44) times as likely to have uterine rupture, attributable fraction 34% (95% CI 21%, 46%). Women who delivered in hospitals with high attempted VBAC rates were less likely to have cesarean deliveries, more likely to have successful VBACs, and more likely to experience uterine ruptures. CONCLUSION: Uterine rupture occurs at a low rate in women with and without prior cesarean delivery. Risk of rupture is increased among women with prior cesarean delivery and among those who attempt VBAC.

Adult↗
PubMed1999

Who dies from what? Determining cause of death in South Africa's rural north-east.

Information on cause of death is essential for rational public health planning, yet mortality data in South Africa is limited. In the Agincourt subdistrict, verbal autopsies (VA) have been used to determine cause of death. A VA is conducted on all deaths recorded during annual demographic and health surveillance. Trained lay fieldworkers interview a close caregiver to elicit signs and symptoms of the terminal illness. Each questionnaire is reviewed by three medical practitioners blind to each other's assessment, who assign a 'probable cause of death' where possible. Of 1001 deaths of adults and children identified between 1992 and 1995, 932 VAs were completed. The profile of deaths reflects a mixed picture: the 'unfinished agenda' of communicable disease and malnutrition (diarrhoea and kwashiorkor predominantly) are responsible for over half of deaths in under-fives, accidents are prominent in the 5-14 age-group, while the 'emerging agenda' of violence and chronic degenerative disease (particularly circulatory disease) is pronounced among the middle-aged and elderly. This profile shows the social and demographic transition to be well underway within a rural, underdeveloped population. Validation of VA findings demonstrate that the cause of death profile derived from VA can be used with confidence for planning purposes. Findings of note include the high death rates from kwashiorkor and violence, emerging AIDS and pulmonary tuberculosis, and circulatory deaths in the middle-aged and young elderly. A deeper understanding of the causal factors underlying these critical health problems is needed to strengthen policy and better target interventions.

Accidents↗