Failure of plasma brain natriuretic peptide to identify left ventricular systolic dysfunction in the community.
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Aged↗
Biomedical subjects
S Curtis
Publications and source records attributed to S Curtis.
Venoarterial CO(2) difference during regional ischemic or hypoxic hypoxia.
To test the role of blood flow in tissue hypoxia-related increased veno-arterial PCO(2) difference (DeltaPCO(2)), we decreased O(2) delivery (&Ddot;O(2)) by either decreasing flow [ischemic hypoxia (IH)] or arterial PO(2) [hypoxic hypoxia (HH)] in an in situ, vascularly isolated, innervated dog hindlimb perfused with a pump-membrane oxygenator system. Twelve anesthetized and ventilated dogs were studied, with systemic hemodynamics maintained within normal range. In the IH group (n = 6), hindlimb DO(2) was progressively lowered every 15 min by decreasing pump-controlled flow from 60 to 10 ml. kg(-1). min(-1), with arterial PO(2) constant at 100 Torr. In the HH group (n = 6), hindlimb DO(2) was progressively lowered every 15 min by decreasing PO(2) from 100 to 15 Torr, when flow was constant at 60 ml. kg(-1). min(-1). Limb DO(2), O(2) uptake (VO(2)), and DeltaPCO(2) were obtained every 15 min. Below the critical DO(2), VO(2) decreased, indicating dysoxia, and O(2) extraction ratio (VO(2)/DO(2)) rose continuously and similarly in both groups, reaching a maximal value of approximately 90%. DeltaPCO(2) significantly increased in IH but never differed from baseline in HH. We conclude that absence of increased DeltaPCO(2) does not preclude the presence of tissue dysoxia and that decreased flow is a major determinant in increased DeltaPCO(2).
Analysis of Variance↗
Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2.
We previously reported suggestive linkage between type 2 diabetes and markers in a region on chromosome 20q using data from a collection of 29 Caucasian families in which type 2 diabetes with middle-age-onset was segregated as an autosomal-dominant disorder. To map more precisely the susceptibility locus (or loci) within this broad region, we increased the family collection and genotyped all families for additional markers, both within the critical region and spaced over the rest of chromosome 20. Altogether 526 individuals (including 241 with diabetes) from the total collection of 43 families were included in the study. All individuals were genotyped for 23 highly polymorphic markers. Positive evidence for linkage was found for a 10-cM region on the long arm of chromosome 20q13.1-q13.2 between markers D20S119 and D20S428. The strongest evidence in two-point as well as multipoint linkage analysis (P = 1.8 x 10(-5)) occurred at the position corresponding to marker D20S196. The individuals with diabetes in the seven most strongly linked families had high serum insulin levels during fasting and 2-h post-glucose load periods. We did not find any evidence for linkage between type 2 diabetes and any other region on chromosome 20. In conclusion, our larger and more comprehensive study showed very strong evidence for a susceptibility gene for insulin-resistant type 2 diabetes located on the long arm of chromosome 20 around marker D20S196.
Aged↗
Outbreak of group C meningococcal infection affecting two preschool nurseries.
Five cases of meningococcal infection caused by Neisseria meningitidis group C type 2a, subtype P1.5, P1.2 occurred within six days. Two of the affected children attended the same preschool nursery. The mother of two other children at the nursery was affected, as were the mother and sibling of another child (not a case) at the nursery. The 'sibling' case attended a different nursery. As the situation evolved, the control aspects of the outbreak changed. Antibiotic prophylaxis and vaccination were given to all staff and children attending both nurseries, and to parents, siblings, and household contacts of all children attending the first nursery.
Adult↗
Effects of ivermectin and midecamycin on ryanodine receptors and the Ca2+-ATPase in sarcoplasmic reticulum of rabbit and rat skeletal muscle.
1. Ryanodine receptor (RyR) Ca2+ channels in the sarcoplasmic reticulum (SR) of skeletal muscle are regulated by the 12 kDa FK506- (or rapamycin-) binding protein (FKBP12). Rapamycin can also activate RyR channels with FKBP12 removed, suggesting that compounds with macrocyclic lactone ring structures can directly activate RyRs. Here we tested this hypothesis using two other macrocyclic lactone compounds, ivermectin and midecamycin. 2. Rabbit skeletal RyRs were examined in lipid bilayers. Ivermectin (cis, 0.66-40 microM) activated six of eight native, four of four control-incubated and eleven of eleven FKBP12-'stripped' RyR channels. Midecamycin (cis, 10-30 microM) activated three of four single native channels, six of eight control-incubated channels and six of seven FKBP12-stripped channels. Activity declined when either drug was washed out. 3. Neither ivermectin nor midecamycin removed FKBP12 from RyRs. Western blots of terminal cisternae (TC), incubated for 15 min at 37 C with 40 microM ivermectin or midecamycin, showed normal amounts of FKBP12. In contrast, no FKBP12 was detected after incubation with 40 microM rapamycin. 4. Ivermectin reduced Ca2+ uptake by the SR Ca2+-Mg2+-ATPase. Ca2+ uptake by TC fell to approximately 40% in the presence of ivermectin (10 microM), both with and without 10 microM Ruthenium Red. Ca2+ uptake by longitudinal SR also fell to approximately 40% with 10 microM ivermectin. Midecamycin (10 microM) reduced Ca2+ uptake by TC vesicles to approximately 76% without Ruthenium Red and to approximately 90 % with Ruthenium Red. 5. The rate of rise of extravesicular [Ca2+] increased approximately 2-fold when 10 microM ivermectin was added to TC vesicles that had been partially loaded with Ca2+ and then Ca2+ uptake blocked by 200 nM thapsigargin. Ivermectin also potentiated caffeine-induced Ca2+ release to approximately 140% of control. These increases in Ca2+ release were not seen with midecamycin. 6. Ivermectin, but not midecamycin, reversibly reduced Ca2+ loading in four of six skinned rat extensor digitorum longus (EDL) fibres to approximately 90%, and reversibly increased submaximal caffeine-induced contraction in five of eight fibres by approximately 110% of control. Neither ivermectin nor midecamycin altered twitch or tetanic tension in intact EDL muscle fibres within 20 min of drug addition. 7. The results confirm the hypothesis that compounds with a macrocyclic lactone ring structure can directly activate RyRs. Unexpectedly, ivermectin also reduced Ca2+ uptake into the SR. These effects of ivermectin on SR Ca2+ handling may explain some effects of the macrolide drugs on mammals.
Animals↗
Activation and inhibition of skeletal RyR channels by a part of the skeletal DHPR II-III loop: effects of DHPR Ser687 and FKBP12.
Peptides, corresponding to sequences in the N-terminal region of the skeletal muscle dihydropyridine receptor (DHPR) II-III loop, have been tested on sarcoplasmic reticulum (SR) Ca2+ release and ryanodine receptor (RyR) activity. The peptides were: A1, Thr671-Leu690; A2, Thr671-Leu690 with Ser687 Ala substitution; NB, Gly689-Lys708 and A1S, scrambled A1 sequence. The relative rates of peptide-induced Ca2+ release from normal (FKBP12+) SR were A2 > A1 > A1S > NB. Removal of FKBP12 reduced the rate of A1-induced Ca2+ release by approximately 30%. A1 and A2 (but not NB or A1S), in the cytoplasmic (cis) solution, either activated or inhibited single FKBP12+ RyRs. Maximum activation was seen at -40 mV, with 10 microM A1 or 50 nM A2. The greatest A1-induced increase in mean current (sixfold) was seen with 100 nM cis Ca2+. Inhibition by A1 was greatest at +40 mV (or when permeant ions flowed from cytoplasm to SR lumen) with 100 microM cis Ca2+, where channel activity was almost fully inhibited. A1 did not activate FKBP12-stripped RyRs, although peptide-induced inhibition remained. The results show that peptide A activation of RyRs does not require DHPR Ser687, but required FKBP12 binding to RyRs. Peptide A must interact with different sites to activate or inhibit RyRs, because current direction-, voltage-, cis [Ca2+]-, and FKBP12-dependence of activation and inhibition differ.
Adenosine Triphosphate↗
Trimming and shoeing the chronically affected horse.
Several of the technical approaches applied to the foot overlap with regard to intent. Frog or solar support, for example, may be provided either to stabilize the distal phalanx within the hoof capsule or in an effort to unload regional pain arising from the solar surface of the foot. It is likewise obvious that some techniques such as lowering the heels to achieve phalangeal realignment and raising the heels to relieve deep digital flexor tendon tension are contradictory. In these instances, it is not that one technique is always correct but that differences exist among horses. Currently, it is something of an art to define what specific technique is needed or, alternatively, how to best apply a specific technique. As more facts regarding how the normal and foundered foot function, the farrier's role in the rehabilitation of affected horses is likely to increase.
Animals↗
Identification of new mutations in the hepatocyte nuclear factor 4alpha gene among families with early onset Type 2 diabetes mellitus.
AIMS: Mutations in hepatocyte nuclear factor (HNF)-4alpha gene located on chromosome 20q have been found to be responsible for the development of early onset Type 2 diabetes mellitus (DM). Through a national campaign, 53 families with autosomal dominant, early onset Type 2 DM (n=654) were assembled to determine the frequency of mutations in the HNF-4alpha gene and their contribution to the development of diabetes. METHODS: Twelve exons and the promoter region of the HNF-4alpha gene were screened in probands of the families by a double gradient, denaturing gradient gel electrophoresis (DG-DGGE) protocol combined with automated bi-directional sequencing of the PCR products of all heterozygous individuals. RESULTS: We detected two new mutations in the HNF-4alpha gene that changed the amino-acid sequence. The first mutation was a Gly-->Ser substitution in codon 115 within a highly conserved DNA binding domain, and all six carriers of this mutation had diabetes and low insulin secretion. The second mutation was an Ile-->Val substitution in codon 454 within the transactivation domain. It was carried by four family members, two of whom also carried a mutation in the HNF-1alpha gene. Of those having only the mutation in HNF-4alpha one had diabetes and the other had normal glucose tolerance and both were obese and hyperinsulinaemic. Thus, it is uncertain that this mutation is responsible for any of the diabetes in this family. CONCLUSION: We have found that mutations in the HNF-4alpha gene account for a small proportion, about 2-4%, of families with early onset, autosomal dominant, Type 2 DM in US Caucasians.
Adolescent↗
A pilot controlled family study of DSM-III-R and DSM-IV ADHD in African-American children.
BACKGROUND: Very little is known about attention-deficit hyperactivity disorder (ADHD) in African-American children, and although the familial transmission of ADHD has been well established in white samples, prior work has not evaluated this feature of ADHD in African-American families. METHOD: Subjects were 37 first-degree relatives of children with DSM-III-R-defined ADHD and 52 first-degree relatives of non-ADHD comparison children matched for ethnicity, age, and gender. DSM-III-R-based structured interviews (modified to include DSM-IV diagnoses) provided the basis for psychiatric diagnoses in relatives. RESULTS: The risks for both DSM-III-R and DSM-IV ADHD were significantly greater in first-degree relatives of ADHD probands than in relatives of controls. In addition, the relatives of ADHD probands also were at higher risk for oppositional defiant disorder, antisocial personality disorder, major depression, generalized anxiety, and substance use disorders. CONCLUSIONS: These results suggest that ADHD and related disorders are familial in African-Americans. Further work is needed to confirm the familial transmission of ADHD in African-American children and to explore the role of genetics as well as environmental factors in the transmission of the disorder.
Adolescent↗
Survey of risk behaviour and HIV prevalence in an English prison.
An anonymous, voluntary, linked cohort study was undertaken to determine the prevalence of HIV infection and identify risk factors for the spread of infection in an English prison. Three hundred and seventy-eight (68%) of the inmates participated. The HIV point prevalence was 0.26%. Injecting drug use (IDU) was the most significant HIV risk factor within 20% admitting IDU at any time, of whom 58% injected whilst in prison. Of those injecting in prison 73% shared needles. Two inmates admitted having sex with a male partner in prison. This study demonstrates that the potential exists in this setting for an outbreak of blood-borne virus infection; hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV infection. Injecting drug use and needle sharing represent the greatest risk.
Adult↗
The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure.
AIMS: To assess the effects of dietary creatine supplementation on skeletal muscle metabolism and endurance in patients with chronic heart failure. METHODS: A forearm model of muscle metabolism was used, with a cannula inserted retrogradely into an antecubital vein of the dominant forearm. Maximum voluntary contraction was measured using handgrip dynanometry. Subjects performed handgrip exercise, 5 s contraction followed by 5 s rest for 5 min at 25%, 50%, and 75% of maximum voluntary contraction or until exhaustion. Blood was taken at rest and 0 and 2 min after exercise for measurement of lactate and ammonia. After 30 min the procedure was repeated with fixed workloads of 7 kg, 14 kg and 21 kg. Patients were assigned to creatine 20 g daily or matching placebo for 5 days and returned after 6 days for repeat study. RESULTS: Contractions (median (25th, 75th interquartiles)) until exhaustion at 75% of maximum voluntary contraction increased after creatine treatment (8 (6, 14) vs 14 (8, 17), P = 0.025) with no significant placebo effect. Ammonia per contraction at 75% maximum voluntary contraction (11.6 mumol/l/contraction (8.3, 15.7) vs 8.9 mumol/l/contraction (5.9, 10.8), P = 0.037) and lactate per contraction at 75% maximum voluntary contraction (0.32 mmol/l/contraction (0.28, 0.61) vs 0.27 mmol/l/contraction (0.19, 0.49), P = 0.07) fell after creatine but not after placebo. CONCLUSIONS: Creatine supplementation in chronic heart failure augments skeletal muscle endurance and attenuates the abnormal skeletal muscle metabolic response to exercise.
Aged↗
An outbreak of epidemic keratoconjunctivitis caused by adenovirus type 37.
An outbreak of acute keratoconjunctivitis in an ophthalmology department affected 15 patients and seven members of staff and necessitated temporary closure of the unit. Adenovirus (Ad) was isolated from eye swabs taken during the outbreak, but typing of the isolates by virus neutralisation assay proved unsatisfactory, wrongly assigning the isolate to serotype 10. A robust and rapid method for preparing microgram amounts of Ad DNA from infected cells was devised and used as the basis of a non-radioactive method for routine genotyping of adenovirus clinical isolates. All isolates associated with the outbreak, and one from a patient presenting at a nearby hospital during the outbreak, were found to have restriction endonuclease digestion patterns characteristic of Ad 37.
Acute Disease↗
Clinical characteristics of attention deficit hyperactivity disorder in African American children.
OBJECTIVE: The authors' goal was to explore the nature of attention deficit hyperactivity disorder (ADHD) in African American children, which has received scant attention by psychiatric researchers. METHOD: Subjects were 19 African American children with DSM-III-R ADHD and 24 African American children without ADHD. Ethnically sensitive methods were used to evaluate the children comprehensively. The findings were compared with those from an earlier study of Caucasian children with ADHD. RESULTS: African American children with ADHD had higher levels of psychiatric disorders other than ADHD than did African American children who did not have ADHD. CONCLUSIONS: Among African American children, ADHD may be characterized by a narrower pattern of psychiatric comorbidity and dysfunction than has been observed in Caucasians. Given the small number of subjects studied, these findings are preliminary and must be replicated to confirm their validity.
Adolescent↗
A multi-level perspective on small-area health and mortality: a case study of England and Wales.
"This paper considers morbidity and mortality variations at the small-area level in England and Wales and their relation to socio-economic factors. Separate affluence and deprivation effects on illness and mortality are identified from a single-level analysis, both exceeding the influence of social class, urbanity or ethnicity. A multi-level perspective is then adopted to explore ecological associations operating both at micro-area and higher level spatial scales. Contextual effects (higher level variability in the impacts of ward level variables) are identified in the effects of small area deprivation on mortality and illness, as well as cross-level interactions; thus the impact of small area social structure on health is partly defined by the wider regional and district setting."
Demography↗
Radio-frequency lesioning to treat chronic lumbar facet joint pain.
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Adult↗
Effects of amlodipine in patients with chronic heart failure.
The role of calcium antagonists in patients with ischemic heart failure is currently unclear. We examined the effects of amlodipine on exercise capacity and central and regional hemodynamics in 32 patients with mild to moderate chronic heart failure in a single-center, double-blind, randomized placebo-controlled trial. All were taking at least 40 mg of furosemide daily with an angiotensin-converting enzyme inhibitor. Ischemic heart disease was the most common cause of heart failure, but no patient had symptom-limiting angina. Mean treadmill exercise capacity in patients taking amlodipine increased by 96 seconds (95% confidence interval -23 to 215) and 50 seconds (-34 to 135) in the placebo group; mean difference in change between treatments was 70 seconds (-90 to 233), p = 0.38. Active treatment with amlodipine did not affect self-paced corridor walking times. Similarly, there were no significant effects on cardiac output, oxygen uptake, heart rate, and mean arterial pressure at rest or during exercise. Calf and renal blood flow were also unchanged by treatment. The lack of significant effect demonstrated by these data suggests a limited role for amlodipine in patients with ischemic cardiomyopathy, although it may prove beneficial in those with nonischemic disease. More data are required before amlodipine can be recommended for all patients with chronic heart failure.
Aged↗
Two transcription activation functions in the amino terminus of the mouse estrogen receptor that are affected by the carboxy terminus.
To determine the characteristics of the N-terminal transactivation domain (AF-1) of the mouse estrogen receptor (ER), we constructed a number of deletion mutants. Wild-type and mutant receptors were expressed in yeast cells and assayed for their ability to transactivate an estrogen-responsive reporter plasmid (ERE-CYCl-LacZ) that contained a single estrogen response element of the vitellogenin A2 gene promoter. Deletion of the N-terminal 121 amino acids from the mouse ER resulted in a 50% reduction in transactivation activity compared with the full-length wild-type ER. Deletion of the first 150 amino acids resulted in loss of 90% transactivation activity. An ER deletion mutant lacking residues 121-154 retained full transcriptional activity, suggesting that this region plays a significant transacting role only when the first portion is deleted. A point mutation was introduced in the C-terminal region at Met-521 in order to study the possible interaction between the C-terminal ligand-binding domain and the N-terminal AF-1 region. This mutant ER, M521G, exhibited 150% of the transcriptional activity of the wild-type ER. An M521G mutant lacking the N-terminal 121 amino acids retained full transactivation activity, whereas, M521G lacking 150 amino acids resulted in only 10% of wild-type activity. These results suggest that residues 121-154 might interact with the C terminus to affect transcription. In summary, multiple N-terminal regions in the ER were identified that function in transactivation. Furthermore, a point mutation in the C-terminal portion of the ER may change the conformation of the ER ligand-binding domain, producing a more stable receptor/ligand complex that increases transcriptional activity. These data suggest that the N- and C-terminal portions of the ER interact in a cooperative manner to activate transcription from target genes.
Animals↗
Is ADHD a risk factor for psychoactive substance use disorders? Findings from a four-year prospective follow-up study.
OBJECTIVE: To evaluate whether attention-deficit hyperactivity disorder (ADHD) is a risk factor for psychoactive substance use disorders (PSUD), attending to issues of psychiatric comorbidity, family history, and adversity. METHOD: Using assessments from multiple domains, the authors examined 140 ADHD and 120 normal control subjects at baseline and 4 years later. Drug and alcohol abuse and dependence were operationally defined. RESULTS: No differences were detected in the rates of alcohol or drug abuse or dependence or in the rates of abuse of individual substances between the groups; both ADHD and control probands had a 15% rate of PSUD. Conduct and bipolar disorders predicted PSUD, independently of ADHD status. Family history of substance dependence and antisocial disorders was associated with PSUD in controls but less clearly so in ADHD probands. Family history of ADHD was not associated with risk for PSUD. ADHD probands had a significantly shorter time period between the onsets of abuse and dependence compared with controls (1.2 years versus 3 years, p < .01). CONCLUSIONS: Adolescents with and without ADHD had a similar risk for PSUD that was mediated by conduct and bipolar disorder. Since the risk for PSUD has been shown to be elevated in adults with ADHD when compared with controls, a sharp increase in PSUD is to be expected in grown-up ADHD children during the transition from adolescence to adulthood.
Adolescent↗