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Biomedical subjects

S Ball

Publications and source records attributed to S Ball.

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

The debranching enzyme complex missing in glycogen accumulating mutants of Chlamydomonas reinhardtii displays an isoamylase-type specificity.

To investigate the functions of debranching enzymes in starch biosynthesis, we have partially purified and characterized these activities from wild type and mutant sta7 Chlamydomonas reinhardtii. Mutants of the STA7 locus substitute synthesis of insoluble granular starch by that of small amounts of glycogen-like material. The mutants were previously shown to lack an 88 kDa debranching enzyme. Two distinct debranching activities were detected in wild-type strains. The 88 kDa debranching enzyme subunit missing in glycogen-producing mutants (CIS1) is shown to be part of a multimeric enzyme complex. A monomeric 95 kDa debranching enzyme (CLD1) cleaved alpha-1,6 linkages separated by as few as three glucose residues while the multimeric complex was unable to do so. Both enzymes were able to debranch amylopectin while the alpha-1,6 linkages of glycogen were completely debranched by the multimeric complex only. Therefore CLD1 and the multimeric debranching enzyme display respectively the limit-dextrinase (pullulanase) and isoamylase-type specificities. Various mutations in the STA7 locus caused the loss of both CIS1 and of the multimeric isoamylase complex. In contrast to rice and maize mutants that accumulate phytoglycogen owing to mutation of an isoamylase-type DBE, isoamylase depletion in Chlamydomonas did not result in any qualitative or quantitative difference in pullulanase activity.

Journal Article↗
PubMed2000

Familial cryptic (20;21) translocation identified by in situ hybridization technologies.

We report on a familial cryptic (20;21) translocation [(t20;21)] that was initially suspected with the observation of a single chromosome 21 specific signal in an interphase nuclei by in situ hybridization (FISH) study performed on a 34-week gestation amniotic fluid specimen. The genetic amniocentesis was prompted by the presence of fetal anomalies detected by ultrasound. In addition, there was a family history of a maternal uncle with mental retardation and multiple malformations and an apparently normal karyotype. No obvious aberration could be detected in the G-banded karyotype prepared from the amniotic fluid specimen. A FISH study using a chromosome 21 specific long arm probe and chromosome 20 whole chromosome paint, however, showed an unbalanced rearrangement in the fetus [46,XY, der(21)t(20;21)(q13.2;q22.13 or 22.2) mat]. The mother and maternal grandmother were demonstrated to be balanced translocation carriers. These results were confirmed by multicolor karyotyping. This familial aberration was discovered by chance in the interphase FISH analysis. Our experience with this case, however, serves to emphasize the importance of the reevaluation of patients with mental retardation and congenital malformations of unknown cause and prudent use of multicolor karyotyping in the detection of cryptic cytogenetic rearrangements.

Abnormalities, Multiple↗
PubMed2000

Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.

BACKGROUND: We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS: Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method. FINDINGS: Overall 12,763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5,966), mortality was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite of these events (1049 [35.0%] vs 1244 [41.9%]; 0.75 [0.67-0.83]; all p<O.001). For all five trials the ACE inhibitor group had lower rates of death than the placebo group (1,467/6,391 [23.0%] vs 1,710/6,372 [26.8%]; 0.80 [0.74-0.87]) and lower rates of reinfarction (571 [8.9%] vs 703 [11.0%]; 0.79 [0.70-0.89]), readmission for heart failure (876 [13.7%] vs 1202 [18.9%]; 0.67 [0.61-0.74]), and the composite of these events (2161 [33.8%] vs 2610 [41.0%]; 0.72 [0.67-0.78]; all p<0.0001). The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, benefit was apparent over the range examined.

Aged↗
PubMed2000

Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group.

CONTEXT: Results from recent studies on the effects of beta1-blockade in patients with heart failure demonstrated a 34% reduction in total mortality. However, the effect of beta1-blockade on the frequency of hospitalizations, symptoms, and quality of life in patients with heart failure has not been fully explored. OBJECTIVE: To examine the effects of the beta1-blocker controlled-release/extended-release metoprolol succinate (metoprolol CR/XL) on mortality, hospitalization, symptoms, and quality of life in patients with heart failure. DESIGN: Randomized, double-blind controlled trial, preceded by a 2-week single-blind placebo run-in period, conducted from February 14, 1997, to October 31, 1998, with a mean follow-up of 1 year. SETTING: Three hundred thirteen sites in 14 countries. PARTICIPANTS: Patients (n = 3991) with chronic heart failure, New York Heart Association (NYHA) functional class II to IV, and ejection fraction of 0.40 or less who were stabilized with optimum standard therapy. INTERVENTIONS: Patients were randomized to metoprolol CR/XL, 25 mg once per day (NYHA class II), or 12.5 mg once per day (NYHA class III or IV), titrated for 6 to 8 weeks up to a target dosage of 200 mg once per day (n = 1990); or matching placebo (n = 2001). MAIN OUTCOME MEASURES: Total mortality or any hospitalization (time to first event), number of hospitalizations for worsening heart failure, and change in NYHA class, by intervention group; quality of life was assessed in a substudy of 741 patients. RESULTS: The incidence of all predefined end points was lower in the metoprolol CR/XL group than in the placebo group, including total mortality or all-cause hospitalizations (the prespecified second primary end point; 641 vs 767 events; risk reduction, 19%; 95% confidence interval [CI], 10%-27%; P<.001); total mortality or hospitalizations due to worsening heart failure (311 vs 439 events; risk reduction, 31%; 95% CI, 20%-40%; P<.001), number of hospitalizations due to worsening heart failure (317 vs 451; P<.001); and number of days in hospital due to worsening heart failure (3401 vs 5303 days; P<.001). NYHA functional class, assessed by physicians, and McMaster Overall Treatment Evaluation score, assessed by patients, both improved in the metoprolol CR/XL group compared with the placebo group (P = .003 and P = .009, respectively). CONCLUSIONS: In this study of patients with symptomatic heartfailure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being.

Adrenergic beta-Antagonists↗
PubMed2000

Gram positive infection in trauma patients: new strategies to decrease emerging Gram-positive resistance and vancomycin toxicity.

Bacterial resistance to antibiotics has become a serious problem in medicine. Particularly worrisome is the increasing incidence of multi-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Not surprisingly, in view of the high incidence of life-threatening infections and heavy antibiotic use, resistance has become very frequent and problematic in intensive care units. The standard approach for the treatment of MRSA is vancomycin or teicoplanin. Long-term therapeutic and unrestricted prophylactic use of vancomycin has given rise to VRE which in turn may lead to the emergence of vancomycin-resistant S. aureus (VRSA) through plasmid mediated transmission. In order to reduce the incidence of VRE and to avoid the emergence of VRSA, vancomycin use should be restricted and alternative antibiotic strategies should be developed. Using those antibiotics to which MRSA are still generally sensitive, perhaps in combination with new ones, such as, quinupristin/dalfopristin, should be entertained. We performed a retrospective review of the Gram-positive infections in our Level 1 Trauma Center Intensive Care Unit, and an analysis of the resistance patterns of the NMSA infections showed that additional resistance rarely develops within less than 5 days. We then designed a new strategy for the treatment of MRSA infections. This strategy consists of the sequential use of a range of antibiotics with activity against MRSA in short 5-7 day pulses until the full clinical course is completed. Studies validating the benefit of this approach are currently in preparation.

Anti-Bacterial Agents↗
PubMed2000

Inhibition of platelet-dependent prothrombinase activity and thrombin generation by glycoprotein IIb/IIIa receptor-directed antagonists: potential contributing mechanism of benefit in acute coronary syndromes.

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.

Abciximab↗
PubMed2000

Co-occurrence of Axis I and Axis II disorders in substance abusers.

OBJECTIVE: This study examined the co-occurrence of anxiety/mood and personality disorders (PDs) in substance abusers, the impact of anxiety/ mood disorders on the symptom profiles of PDs, and the impact of anxiety/mood disorders and PDs on pre-treatment status. METHOD: Current anxiety/mood disorders and PDs and pre-treatment status were assessed using semi-structured interviews in 370 treated substance abusers. RESULTS: Anxiety/mood disorders and PDs frequently co-occurred, with the overall pattern of associations being non-specific. The strongest associations were of social phobia with avoidant and schizotypal PD, and of major depression with borderline PD. However, symptom profiles of PDs were not associated with anxiety/mood disorders. Finally, anxiety/mood disorders and PDs were both independently and differentially associated with poor pre-treatment characteristics. CONCLUSION: The findings suggest the clinical importance of obtaining both Axis I and Axis II diagnoses in treated substance abusers, and highlight the distinctiveness of the Axis I and Axis II disorders.

Adult↗
PubMed2000

Axis I and Axis II disorders in alcoholics and drug addicts: fact or artifact?

OBJECTIVE: It has been argued that Axis I and Axis II disorders diagnosed in substance users refer to substance-induced conditions rather than to independent psychiatric conditions; this argument will be referred to as the substance-related artifact hypothesis. Furthermore, Axis II symptoms co-occurring with Axis I disorders have been attributed to the contamination of personality assessment by mood and/or anxiety state effects (the trait-state artifact hypothesis). The present study is the first to prospectively examine the validity of these two hypothesized "artifacts" in substance users. METHOD: In 276 individuals (57.6% female) applying for substance use treatment, current substance use disorders, mood/anxiety disorders and Axis II disorders were diagnosed using semistructured interviews both at baseline and at 1-year follow-up. The substance-related artifact hypothesis is tested by examining the covariation between recovery from substance use disorders on the one hand and recovery from and/or improvement of mood/anxiety and Axis II disorders on the other hand. The trait-state artifact hypothesis is tested by examining the covariation between recovery from mood/anxiety disorders on the one hand and recovery from and/or improvement of Axis II disorders on the other hand. RESULTS: Recovery from substance use disorders covaried with recovery from and improvement of mood/anxiety disorders, but not with recovery from or improvement of Axis II pathology. Furthermore, recovery from mood/anxiety disorders covaried with recovery from and improvement of personality disorders, in particular Cluster C disorders. CONCLUSIONS: Results from this study suggest that mood/anxiety disorders, but not personality disorders, diagnosed among people with substance use disorder may partly reflect substance-related artifacts. Furthermore, this study provides evidence for the contention that semistructured interview assessment of Axis II, at least without inquiry on an item-by-item basis, is susceptible to contamination by mood/anxiety state effects.

Adult↗
PubMed2000

Induced lactation in prepubertal Holstein heifers.

Lactation was hormonally induced in six prepuberal Holstein heifers by seven daily injections of estrogen and progesterone and three injections of dexamethasone on d 18, 19, and 20, followed by twice daily hand milking beginning on d 21. Heifers were about 6 mo old and weighed 162 kg at the beginning of the experiment. Secretions were obtained from five of six of heifers, and twice daily milking continued for 75 d in three of five heifers. The volume of milk obtained on d 7 ranged from 32 to 500 ml and averaged 4.7, 4.1, and 3.7% lactose, protein, and fat, respectively. In the first natural lactation, milk yield and composition were nearly identical for controls and induced heifers. Serum alpha-lactalbumin was increased in induced heifers after treatment with dexamethasone and was highest on d 10 after onset of milking. Our data suggest that sufficient secretions for extensive biochemical testing can be obtained following hormonal induction of lactation in a majority of prepubertal heifers. Moreover, hormonal induction of lactation had no apparent effect on reproduction or first natural lactation. While it is unlikely that hormonal induction of lactation in prepubertal heifers is practical from a dairy production viewpoint, the advent of biotechnology for production of therapeutic recombinant proteins in the mammary gland of transgenic livestock has made early detection of these transgenic proteins very desirable. We conclude that induction of lactation in prepubertal heifers is a viable technique for testing the expression of mammary-linked gene constructs in transgenic cattle.

Analysis of Variance↗
PubMed2000

Use of a novel real-time quantitative reverse transcription-polymerase chain reaction method to study the effects of cytokines on cytochrome P450 mRNA expression in mouse liver.

In this study, we developed a real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) method to study cytochrome P450 (CYP) mRNA regulation by cytokines in mouse liver. The method combines standard RT-PCR with a fluorogenic probe in which the intensity of fluorescence is proportional to the amount of target template present. We show that this method provides very rapid, sensitive, and reproducible quantification of mouse Cyp mRNA with a wide dynamic range of starting target molecule. We validated the method by using several prototypic CYP inducers. As expected, the mRNA levels of Cyp3a11, Cyp2b10, and Cyp1a2 were induced by a single dose of dexamethasone (100 mg/kg), phenobarbital (80 mg/kg), and 3-methylcholanthrene (80 mg/kg), respectively. The method of real-time RT-PCR was then used to evaluate the effects of interleukin (IL)-6 (100 ng/mouse), IL-1beta (500 ng/mouse), and tumor necrosis factor (TNF)-alpha (2 microgram/mouse) on Cyp mRNA expression in the mouse. Constitutive Cyp2b10 mRNA was reduced to 40% by IL-6 and 15% by IL-1beta, whereas Cyp2d9 mRNA was reduced to 70% by TNF-alpha administration. The level of Cyp1a2 mRNA was suppressed to 67% by IL-6 and 59% by TNF-alpha. Cyp3a11 and Cyp2e1 mRNAs were not affected by any of the cytokines that were studied. We conclude that the real-time RT-PCR method is a powerful new tool to study CYP mRNA expression and regulation. Using this method, we are the first to report that the expression of constitutive Cyp2b10, 1a2, and 2d9 mRNAs was suppressed by proinflammatory cytokines.

Animals↗
PubMed1999

Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression.

Mutations of the ribosomal protein S19 (RPS19) gene were recently identified in 10 patients with Diamond Blackfan anemia (DBA). To determine the prevalence of mutations in this gene in DBA and to begin to define the molecular basis for the observed variable clinical phenotype of this disorder, the genomic sequence of the 6 exons and the 5' untranslated region of the RPS19 gene was directly assessed in DBA index cases from 172 new families. Mutations affecting the coding sequence of RPS19 or splice sites were found in 34 cases (19.7%), whereas mutations in noncoding regions were found in 8 patients (4.6%). Mutations included nonsense, missense, splice sites, and frameshift mutations. A hot spot for missense mutations was identified between codons 52 and 62 of the RPS19 gene in a new sequence consensus motif W-[YFW]-[YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]-[ILV]-Y. No correlation between the nature of mutations and the different patterns of clinical expression, including age at presentation, presence of malformations, and therapeutic outcome, could be documented. Moreover, RPS19 mutations were also found in some first-degree relatives presenting only with isolated high erythrocyte adenosine deaminase activity and/or macrocytosis. The lack of a consistent relationship between the nature of the mutations and the clinical phenotype implies that yet unidentified factors modulate the phenotypic expression of the primary genetic defect in families with RPS19 mutations.

Adolescent↗
PubMed1999

The kinesin light chain gene: its mapping and exclusion in mouse and human forms of inherited motor neuron degeneration.

The underlying genetic cause is known for only 10-20% of familial motor neuron disease (MND). Thus the genes involved in the aetiology of 80-90% of familial MND remain to be determined, and animal models are powerful tools for undertaking this task. We have mapped a heritable form of motor neuron degeneration in the mouse to a region that has homology to human chromosome 14q32.1-qter. This region contains the kinesin light chain gene (KLC1), which is a candidate for involvement in motor neuron degeneration because of its function in the motor-protein kinesin, and its neuronal expression. To investigate the role of KLC1 in a mouse motor neuron degeneration mutant that we are studying, we have identified mouse Klc1 gene sequences and mapped them with respect to our mutant locus. We have also investigated KLC1 in human patients with familial MND. Based on recombination and the absence of mutations in the coding region of KLC1, this gene can be excluded as a candidate gene in our mouse mutation and, where we have investigated, it is normal in human familial MND.

Animals↗
PubMed1999

Cost and morbidity associated with antibiotic prophylaxis in the ICU.

BACKGROUND: Although the high cost and inappropriate use of antibiotics have been documented before, we are not aware of any data on nonsurgical site infectious morbidity associated with prolonged courses of prophylactic antibiotics (PA). STUDY DESIGN: Data regarding antibiotic orders were collected using a custom designed microbiology database in the Surgical Intensive Care Unit of a teaching hospital from October 1, 1995 through April 30, 1997. The database was retrospectively reviewed. The cost of PA in excess of 1 day was calculated. Frequency of bacteremia and line infections were compared in patients receiving 1 day or less of PA versus more than 4 days of PA. RESULTS: Sixty-one percent of PA orders were continued for more than 1 day. Cost of PA beyond 1 day totaled $44,893. Bacteremia and line infection were more frequent in the patients receiving more than 4 days of PA. CONCLUSIONS: There was poor compliance with the protocol of stopping PA at 24 hours. The cost of noncompliance was $44,893. There were more bacteremias and line infections in patients with duration of PA of more than 4 days.

Anti-Bacterial Agents↗
PubMed1999

The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia.

Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

Amino Acid Sequence↗
PubMed1999

The prognostic significance of a history of systemic hypertension in patients randomised to either placebo or ramipril following acute myocardial infarction: evidence from the AIRE study. Acute Infarction Ramipril Efficacy.

BACKGROUND: After acute myocardial infarction (AMI), patients with a history of arterial hypertension (AH) have a worse prognosis than normotensives. Whether this adverse risk is beneficially modulated by treatment with angiotensin-converting enzyme (ACE) inhibitors is unknown. We evaluated the prognostic value of antecedent hypertension in post-AMI patients given ACE inhibitor therapy. METHODS: We analysed retrospectively data from the AIRE study (randomised, placebo-controlled trial of ramipril in 2006 post-AMI patients with clinical heart failure). A history of AH was present in 28% of the patients. We examined the prognostic value of antecedent hypertension separately among placebo and ramipril treated patients and also the effect of ramipril on clinical outcomes according to whether or not a history of AH was present. RESULTS: Antecedent hypertension was a significant indicator of adverse prognosis in the placebo (P) treated patients (Hazard Ratio 1.49, 95% Confidence Intervals 1.13 to 1.97, P = 0.005) but not in the ramipril (R) treated patients (1.17, 0.84 to 1.61, P = 0.34). A similar pattern was observed for the risks of sudden death (P: 1.75, 1.21 to 2.54, P = 0.003; R: 1.34, 0.86 to 2.07, P = 0.18) and severe/resistant heart failure (P: 1.48, 1.08 to 2.03, P = 0.014; R: 1.18, 0.83 to 1.68, P = 0.37). Treatment with ramipril reduced the all-cause mortality risk in both hypertensive (0.63, 0.44 to 0.89, P = 0.009) and normotensive patients (0.78, 0.61 to 0.99, P = 0.041). CONCLUSION: Antecedent hypertension is not a significant prognosticator in patients with AMI and clinical heart failure given ACE inhibitor therapy.

Aged↗
PubMed1999

Novel, starch-like polysaccharides are synthesized by an unbound form of granule-bound starch synthase in glycogen-accumulating mutants of Chlamydomonas reinhardtii.

In vascular plants, mutations leading to a defect in debranching enzyme lead to the simultaneous synthesis of glycogen-like material and normal starch. In Chlamydomonas reinhardtii comparable defects lead to the replacement of starch by phytoglycogen. Therefore, debranching was proposed to define a mandatory step for starch biosynthesis. We now report the characterization of small amounts of an insoluble, amylose-like material found in the mutant algae. This novel, starch-like material was shown to be entirely dependent on the presence of granule-bound starch synthase (GBSSI), the enzyme responsible for amylose synthesis in plants. However, enzyme activity assays, solubilization of proteins from the granule, and western blots all failed to detect GBSSI within the insoluble polysaccharide matrix. The glycogen-like polysaccharides produced in the absence of GBSSI were proved to be qualitatively and quantitatively identical to those produced in its presence. Therefore, we propose that GBSSI requires the presence of crystalline amylopectin for granule binding and that the synthesis of amylose-like material can proceed at low levels without the binding of GBSSI to the polysaccharide matrix. Our results confirm that amylopectin synthesis is completely blocked in debranching-enzyme-defective mutants of C. reinhardtii.

Amylopectin↗