Is the factor XIII 34Val/Leu polymorphism a protective factor for cerebrovascular disease?

A frequent polymorphism in the factor XIII (FXIII) A-subunit gene, leading to a Val to Leu amino acid exchange at position 34, suggested to affect clot stability, has been associated with a decreased risk for venous thromboembolism and myocardial infarction. Its role in the development of stroke is still under investigation. Ninety-four patients with primary arterial intracerebral haemorrhage (mean age +/- standard deviation: 69 +/- 14 years; 48 men, 46 women), 718 patients with ischaemic stroke (63 +/- 14 years; 395 men, 323 women) and 369 healthy control subjects (59 +/- 14 years; 299 men, 170 women) were analysed for FXIII Val34Leu. No differences in genotype distribution between all three groups were observed. Also, no significant differences in the genotype distribution were found between subgroups of patients stratified according to age, sex, aetiology, history of hypertension, antiplatelet or anticoagulant medication and other vascular risk factors. In contrast to previously reported findings in smaller collectives, our data suggest that an association of the FXIII Val34Leu polymorphism with a decreased risk of ischaemic stroke or an increased risk of intracerebral haemorrhage is highly unlikely. Thus, screening for the FXIII Val34Leu polymorphism will not contribute significantly to the risk prediction of cerebrovascular disease.     

A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation

Light stimuli produce graded hyperpolarizations of the photoreceptor plasma membrane and an associated decrease in a voltagegated calcium channel conductance that mediates release of glutamate neurotransmitter. The Ca(v)1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the poreforming subunit of the Ca(v)1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2). The molecular mechanism of the pathology underlying the CSNB2 phenotype remains to be established. Recent clinical investigations of a New Zealand family found a severe visual disorder that has some clinical similarities to, but is clearly distinct from, CSNB2. Here, we report investigations into the molecular mechanism of the pathology of this condition. Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745. The I745T CACNA1F allele produced a remarkable approximately -30-mV shift in the voltage dependence of Ca(v)1.4 channel activation and significantly slower inactivation kinetics in an expression system. These findings imply that substitution of this wild-type residue in transmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Ca(v)1.4 channel activity is likely to cause the unusual phenotype.     

Domestication quantitative trait loci in Triticum dicoccoides,the progenitor of wheat

Wild emmer wheat, Triticum dicoccoides, is the progenitor of modern tetraploid and hexaploid cultivated wheats. Our objective was to map domestication-related quantitative trait loci (QTL) in T. dicoccoides. The studied traits include brittle rachis, heading date, plant height, grain size, yield, and yield components. Our mapping population was derived from a cross between T. dicoccoides and Triticum durum. Approximately 70 domestication QTL effects were detected, nonrandomly distributed among and along chromosomes. Seven domestication syndrome factors were proposed, each affecting 5-11 traits. We showed: (i) clustering and strong effects of some QTLs; (ii) remarkable genomic association of strong domestication-related QTLs with gene-rich regions; and (iii) unexpected predominance of QTL effects in the A genome. The A genome of wheat may have played a more important role than the B genome during domestication evolution. The cryptic beneficial alleles at specific QTLs derived from T. dicoccoides may contribute to wheat and cereal improvement.     

High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study

High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches.     

Structural differences between the chromatin of procyclic Trypanosoma brucei brucei and of higher eukaryotes as probed by immobilized trypsin.

Soluble chromatin of Trypanosoma brucei brucei procyclic culture forms was submitted to digestion with free or immobilized trypsin. Digestion with trypsin in salt solutions of low and high ionic strengths generated characteristic sets of limit histone peptides. After incubation of chromatin with immobilized trypsin in a solution of low ionic strength, histones were not degraded, whereas a selective proteolysis occurred at 50 mM NaCl. Histones a and d, which correspond to H3 and H4 of higher eukaryotes, were rapidly attacked. Histones b and c, the counterparts of H2A and H2B, were more resistant. The results indicated that probably the basic N-terminal tails of the proteins a and d are located on the surface of the core particle. The location of d on the surface differs from the internal one proposed for histone H4. The salt-induced increase of susceptibility of histones to proteolysis reflects structural changes of T.b. brucei chromatin, which may result in partial chromatin compaction.     

Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden

Left ventricular (LV) diastolic dysfunction is prevalent in the community. Current assessment of diastolic function can be complex, involving Doppler evaluation of an array of hemodynamic data. The relation between left atrial (LA) volume and diastolic function, and between LA volume and cardiovascular risk and disease burden are not well known. In the present prospective study of 140 adults, mean age 58 ± 19 years, referred for a clinically-indicated echocardiogram and in sinus rhythm, with no history of atrial arrhythmias or valvular heart disease, we determined the LA volume, LV diastolic function status, cardiovascular risk score (based on age, gender, history of systemic hypertension, diabetes mellitus, hyperlipidemia, and smoking), and cardiovascular disease burden (based on confirmed vascular disease, congestive heart failure, and transient ischemic attack or stroke). LA volume was found to correlate positively with age, body surface area, cardiovascular risk score, LV end-diastolic and end-systolic dimensions, LV mass, diastolic function grade, tissue Doppler E/E′, tricuspid regurgitation velocity, and negatively with LV ejection fraction (all p <0.006). In a multivariate clinical model, LA volume indexed to body surface area (indexed LA volume) was independently associated with cardiovascular risk score (p <0.001), congestive heart failure (p = 0.014), vascular disease (p = 0.012), transient ischemic attack or stroke (p = 0.021), and history of smoking (p = 0.008). In a clinical and echocardiographic model, indexed LA volume was strongly associated with diastolic function grade (p <0.001), independent of LV ejection fraction, age, gender, and cardiovascular risk score. In patients without a history of atrial arrhythmias or valvular heart disease, LA volume expressed the severity of diastolic dysfunction and provided an index of cardiovascular risk and disease burden.     

Previous creatinine levels safely predict amantadine dose for influenza A outbreak control

BACKGROUND:

Amantadine, an antiviral agent, is the only drug currently approved in Canada for prophylaxis of influenza A virus infection. To minimize side effects, the amantadine dose is adjusted for age and estimated creatinine clearance (CrCl) based on plasma creatinine (Cr) levels. As amantadine is used more frequently for influenza A outbreak control in care facilities for elderly people, physicians are increasingly called on to prescribe it for residents and to consider the necessity of requesting plasma Cr levels.

OBJECTIVE:

To determine whether previous Cr levels are predictive in estimating current CrCl and safe amantadine dose determination.

DESIGN AND SETTING:

Residents'' charts were reviewed in two facilities in Vancouver, British Columbia. CrCl estimated using previous or current Cr results, current weight and age, as well as recommended amantadine doses based on Canadian National Advisory Committee on Immunization guidelines, were studied.

RESULTS:

165 charts with Cr results in March 1998 were included; 122 had results before March 1998, and 103 had Cr results after March 1998. Pearson''s correlation coefficient for CrCl estimated from current and previous Cr values was 0.929 for results less than six months previously, 0.974 for six to 12 months previously and 0.952 for 12 to 18 months previously. The same or a more conservative dose of amantadine was predicted in 92% of cases when using a Cr result taken within the previous year and in 76% of cases when using a Cr result taken 12 to 18 months previously.

CONCLUSION:

In long term care facilities, Cr levels measured up to 12 months previously can usually safely be used to estimate CrCl. Using previous Cr results permits advance preparation of doctor''s orders for amantadine prophylaxis and avoids repeating Cr testing on every resident when an outbreak occurs, reducing related staff time and cost.Key Words: Amantadine hydrochloride, Care facilities, Creatinine clearance, Influenza, Plasma creatinine, ProphylaxisInfluenza is a major infectious cause of death in the elderly, with institutionalized seniors particularly at high risk. Amantadine hydrochloride is the only drug approved in Canada for prophylaxis of influenza A virus infection. Because amantadine is used more frequently for influenza A outbreak control in long term care facilities (LTCFs), physicians are increasingly called on to prescribe it for residents and to consider the necessity of requesting plasma creatinine (Cr) levels to determine the appropriate amantadine dose.Amantadine is 70% to 90% effective in preventing illness caused by influenza A viruses (1), and reduces the severity and duration of influenza A illness if administered within 48 h of onset. About 5% to 10% of healthy young adults taking amantadine for prophylaxis report difficulty concentrating, insomnia, light-headedness and irritability. These side effects are usually mild and cease shortly after the prophylaxis is stopped but may be more frequent in the older population unless a reduced dosage is used. Serious side effects (eg, marked behavioural changes, delerium, hallucinations, agitation and seizures) have been associated with high plasma drug concentrations. Amantadine is excreted by the kidney unmetabolized. To avoid toxic levels, persons with impaired renal function should receive a lower dose. Creatinine clearance (CrCl) is used to reflect renal function and is estimated from Cr levels using the following formulas (2):Male CrCl (mL/min) = [(140 - age) x weight (kg)] / [serum creatinine (µmol/L) x 0.81]Female CrCl (mL/min) = 0.85 x male CrCl

The Role of Colonic Microbiota in Lactose Intolerance

In a previous study we observed a clear difference in lactose intolerance symptoms after a 25-g lactose load in two groups of persons with lactase nonpersistence and similar small intestinal lactase activity. From this observation we hypothesized a colon resistance factor. To identify this factor, the microbial composition of fecal samples of the two lactose intolerant groups (one with mild symptoms, n = 16, and one with diarrhea-predominant symptoms, n = 11) was compared using the fluorescent in situ hybridization technique. Large interindividual differences were found in the numbers of total bacteria and main groups of bacteria (CV: 0.65 and 0.64-0.82 respectively). The bacterial numbers were not significantly different between the two groups. A significant negative correlation, however, was found between the individual symptom scores of the intolerant persons and the numbers of total hybridizable bacteria (r(s) = -0.42, P = 0.03). The results suggest that an increased number of bacteria might contribute--by means of a higher fermentative capacity--to the reduction of lactose intolerance symptoms.     

A national survey of U.S. internists’ experiences with ethical dilemmas and ethics consultation

OBJECTIVE: To identify the ethical dilemmas that internists encounter, the strategies they use to address them, and the usefulness of ethics consultation. DESIGN: National telephone survey. SETTING: Doctors' offices. PARTICIPANTS: General internists, oncologists, and critical care/pulmonologists (N = 344, 64% response rate). MEASUREMENTS: Types of ethical dilemmas recently encountered and likelihood of requesting ethics consultation; satisfaction with resolution of ethical dilemmas with and without ethics consultation. RESULTS: Internists most commonly reported dilemmas regarding end-of-life decision making, patient autonomy, justice, and conflict resolution. General internists, oncologists, and critical care specialists reported participating in an average of 1.4, 1.3, and 4.1 consultations in the preceding 2 years, respectively (P <.0001). Physicians with the least ethics training had the least access to and participated in the fewest ethics consultations; 19% reported consultation was unavailable at their predominant practice site. Dilemmas about end-of-life decisions and patient autonomy were often referred for consultation, while dilemmas about justice, such as lack of insurance or limited resources, were rarely referred. While most physicians thought consultations yielded information that would be useful in dealing with future ethical dilemmas (72%), some hesitated to seek ethics consultation because they believed it was too time consuming (29%), might make the situation worse (15%), or that consultants were unqualified (11%). CONCLUSIONS: While most internists recall recent ethical dilemmas in their practices, those with the least preparation and experience have the least access to ethics consultation. Health care organizations should emphasize ethics educational activities to prepare physicians for handling ethical dilemmas on their own and should improve the accessibility and responsiveness of ethics consultation when needed.