Lars Brudin

Common Methylenetetrahydrofolate Reductase Gene Mutation Leads to Hyperhomocysteinemia but Not to Vascular Disease The Result of a Meta-Analysis

BACKGROUND The results of retrospective and prospective case-control studies have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and peripheral vascular disease. Recently, a mutation (677C-->T) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced folate-dependent enzyme activity and reduced remethylation of homocysteine to methionine. Mutant homozygotes (TT genotype) constitute approximately 12% of the white population and frequently have mildly elevated circulating homocysteine. Therefore, it seems likely that they would also be at increased risk of vascular disease. A number of studies have investigated this during the past 3 years, and the present article evaluates the results in a meta-analysis. METHODS AND RESULTS We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 micromol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37). CONCLUSIONS We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease.

Effects of influenza A virus infection on migrating mallard ducks.

The natural reservoir of influenza A virus is waterfowl, particularly dabbling ducks (genus Anas). Although it has long been assumed that waterfowl are asymptomatic carriers of the virus, a recent study found that low-pathogenic avian influenza (LPAI) infection in Bewicks swans (Cygnus columbianus bewickii) negatively affected stopover time, body mass and feeding behaviour. In the present study, we investigated whether LPAI infection incurred ecological or physiological costs to migratory mallards (Anas platyrhynchos) in terms of body mass loss and staging time, and whether such costs could influence the likelihood for long-distance dispersal of the avian influenza virus by individual ducks. During the autumn migrations of 2002–2007, we collected faecal samples (n=10 918) and biometric data from mallards captured and banded at Ottenby, a major staging site in a flyway connecting breeding and wintering areas of European waterfowl. Body mass was significantly lower in infected ducks than in uninfected ducks (mean difference almost 20 g over all groups), and the amount of virus shed by infected juveniles was negatively correlated with body mass. There was no general effect of infection on staging time, except for juveniles in September, in which birds that shed fewer viruses stayed shorter than birds that shed more viruses. LPAI infection did not affect speed or distance of subsequent migration. The data from recaptured individuals showed that the maximum duration of infection was on average 8.3 days (s.e. 0.5), with a mean minimum duration of virus shedding of only 3.1 days (s.e. 0.1). Shedding time decreased during the season, suggesting that mallards acquire transient immunity for LPAI infection. In conclusion, deteriorated body mass following infection was detected, but it remains to be seen whether this has more long-term fitness effects. The short virus shedding time suggests that individual mallards are less likely to spread the virus at continental or intercontinental scales.

Late Psychological Symptoms after Awareness among Consecutively Included Surgical Patients

Background:Awareness during general anesthesia can cause late psychological symptoms. Selection bias may have affected the results in previous retrospective studies. The authors used prospective consecutive collection to recruit patients with previous awareness. Methods:In a cohort of 2,681 consecutive patients scheduled to undergo general anesthesia, 98 considered themselves to have been aware during previous surgery. Six patients died before inclusion, and another 13 were excluded (4 cases of stoke or dementia, 7 declined to participate, and 2 could not be located). Seventy-nine patients were interviewed by telephone, and medical records were checked in uncertain cases. The interview followed a structured protocol, including seven late symptoms (anxiety, chronic fear, nightmares, flashbacks, indifference, loneliness, and lack of confidence in future life). Three persons independently assessed the interviews for classification, to determine whether awareness had occurred. Results:Four cases were performed using regional anesthesia, and another 29 were not considered as awareness by the assessors. Therefore, the final analyses included 46 patients. Twenty (43%) had experienced pain, and 30 (65%) described acute emotional reactions during the awareness episode. Fifteen (33%) patients had experienced late psychological symptoms afterward. In 6 of those cases, the symptoms lasted for more than 2 months, and 1 patient had a diagnosis of post–traumatic stress disorder. Acute emotional reactions were significantly related to late psychological symptoms (P < 0.05). Conclusion:The method for recruiting awareness cases in studies on late psychological symptoms may affect the result. The authors found fewer and milder problems, despite a similar degree of initial problems as in previous studies.

Applying the Nottingham Prognostic Index to a Swedish breast cancer population

The aim of this study was to assess the applicability of histopathological grading according to the protocol of Elston/Ellis and the Nottingham Prognostic Index (NPI) to a defined breast cancer population. The NPI is the sum of the individual scores concerning grade, tumour size, and lymph node status, each weighted according to regression coefficients of a Cox proportional hazard analysis and calculated for each individual breast cancer patient. 630 consecutive patients with invasive breast cancer diagnosed 1988–91 were retrospectively followed up and their tumours reviewed and graded. A Cox proportional hazard analysis was performed. Grade, lymph node status, and tumour size were statistically significant predictors of survival within the follow up period (median 7.2 years). Similar to NPI, a temporary index (Kalmar Prognostic Index, KPI) was derived and normalised to NPI for comparison (KPI(norm)). NPI and KPI(norm) gave similar prognostic power in spite of the differences of the patient populations from which the 2 indices were derived. Patients with NPI 4 or less had 0.66% breast cancer specific mortality during the follow up time. 14% of the patients with NPI 4.1–5 and 32% of those with an index sum 5.1–6 died from breast cancer during this time. Younger patients tended to have higher grade tumours. We advocate the common use of grade and the NPI in order to increase the comparability of groups of patients receiving different therapies.

Functional measurements based on feature tracking of cine magnetic resonance images identify left ventricular segments with myocardial scar

BackgroundThe aim of the study was to perform a feature tracking analysis on cine magnetic resonance (MR) images to elucidate if functional measurements of the motion of the left ventricular wall may detect scar defined with gadolinium enhanced MR.Myocardial contraction can be measured in terms of the velocity, displacement and local deformation (strain) of a particular myocardial segment. Contraction of the myocardial wall will be reduced in the presence of scar and as a consequence of reduced myocardial blood flow.MethodsThirty patients (3 women and 27 men) were selected based on the presence or absence of extensive scar in the anteroseptal area of the left ventricle. The patients were investigated in stable clinical condition, 4-8 weeks post ST-elevation myocardial infarction treated with percutaneous coronary intervention. Seventeen had a scar area >75% in at least one anteroseptal segment (scar) and thirteen had scar area <1% (non-scar). Velocity, displacement and strain were calculated in the longitudinal direction, tangential to the endocardial outline, and in the radial direction, perpendicular to the tangent.ResultsIn the scar patients, segments with scar showed lower functional measurements than remote segments. Radial measurements of velocity, displacement and strain performed better in terms of receiver-operator-characteristic curves (ROC) than the corresponding longitudinal measurements. The best area-under-curve was for radial strain, 0.89, where a cut-off value of 38.8% had 80% sensitivity and 86% specificity for the detection of a segment with scar area >50%. As a percentage of the mean, intraobserver variability was 16-14-26% for radial measurements of displacement-velocity-strain and corresponding interobserver variability was 13-12-18%.ConclusionFeature tracking analysis of cine-MR displays velocity, displacement and strain in the radial and longitudinal direction and may be used for the detection of transmural scar. The accuracy and repeatability of the radial functional measurements is satisfactory and global measures agree.

Gastrointestinal microcirculation and cardiopulmonary function during experimentally increased intra-abdominal pressure

Objectives:The aim of this study was to assess gastric, intestinal, and renal cortex microcirculation parallel with central hemodynamics and respiratory function during stepwise increase of intra-abdominal pressure (IAP). Design:Prospective, controlled animal study. Setting:Research laboratory, University Hospital. Subjects:Twenty-six anesthetized and mechanically ventilated pigs. Interventions:Following baseline registrations, CO2 peritoneum was inflated (n = 20) and IAP increased stepwise by 10 mm Hg at 10 mins intervals up to 50 mm Hg and subsequently exsufflated. Control animals (n = 6) were not insufflated with CO2. Measurements and Main Results:The microcirculation of gastric mucosa, small bowel mucosa, small bowel seromuscular layer, colon mucosa, colon seromuscular layer, and renal cortex were selectively studied at all pressure levels and after exsufflation using a four-channel laser Doppler flowmeter (Periflex 5000, Perimed). Central hemodynamic and respiratory function data were registered at each level and after exsufflation. Cardiac output decreased significantly at IAP levels above 10 mm Hg. The microcirculation of gastric mucosa, renal cortex and the seromuscular layer of small bowel and colon was significantly reduced with each increase of IAP. The microcirculation of the small bowel mucosa and colon mucosa was significantly less affected compared with the serosa (p < 0.01). Conclusions:Our animal model of low and high IAP by intraperitoneal CO2-insufflation worked well for studies of microcirculation, hemodynamics, and pulmonary function. During stepwise increases of pressure there were marked effects on global hemodynamics, respiratory function, and microcirculation. The results indicate that intestinal mucosal flow, especially small bowel mucosal flow, although reduced, seems better preserved in response to intra-abdominal hypertension caused by CO2-insufflation than other intra-abdominal microvascular beds.

A common methylenetetrahydrofolate reductase gene mutation and longevity

Homozygotes (TT genotype) for the C677T mutation in the gene of methylenetetrahydrofolate reductase (C677T/MTHFR mutation) constitute about 12% of the Caucasian population. They have mild hyperhomocysteinemia which is an established risk factor for cardiovascular disease. If the mutation is associated with premature death its prevalence is expected to be lower in the elderly than in the young. To test this we determined the C677T/MTHFR genotypes in 220 newborn and 222 elderly 80-108-year-old Swedes. In the newborn and elderly, the allele frequency, of the C677T/MTHFR mutation was 29.1 and 27.0% and the mutant homozygote frequency was 10.0 and 9.5%, respectively. In a meta analysis of the present and three previous studies including a total of 1388 elderly and 1415 younger subjects, the odds ratio (OR) representing the likelihood of the TT genotype to attain old age relative to the CC genotype was 0.87 (95% confidence interval (CI), 0.69-1.11) and relative to both the CC and CT genotypes was 0.83 (95% CI, 0.66-1.04). This finding does not suggest that the C677T/MTHFR mutation is a strong risk factor for diseases frequently leading to premature death.

Hepatocyte growth factor may accelerate healing in chronic leg ulcers: a pilot study

BACKGROUND : Hepatocyte growth factor (HGF) is a heparin-binding protein with mitogenic, motogenic and morphogenic activities for various cell types. The regenerative properties of HGF have been the object of several animal and in vitro studies in recent years. OBJECTIVE : To investigate the physiological and therapeutic effects of HGF on chronic leg ulcers. METHODS : HGF in gel form was locally applied, once daily for 7 days, to 15 of 19 chronic leg ulcers in 11 elderly patients. All patients had previously been treated by conventional methods and their leg ulcers had been in stable conditions for between 1 and 14 years. Any signs of allergy, discomfort or pain were reported daily. Microcirculation perfusion in the ulcers, compared to the intact contiguous skin, was determined by laser Doppler at the beginning of the study, after 1 week and again after 3 months (in seven patients). Ulcer size and characteristics were also documented. RESULTS : It was observed that microcirculatory perfusion, which might reflect the angiogenic effect of HGF, was statistically significantly correlated ( r = 0.94, p < 0.002) to ulcer area reduction in the treated ulcers. Excellent (84-100% area reduction) or partial healing (58-59%) was seen in eight out of 11 patients. No control group was included in this pilot study, which must be completed by proper control studies. CONCLUSION : This study suggests that HGF may heal chronic leg ulcers, possibly by improving the microcirculation. Proper control studies need to be performed.

Trends in number of consultations and antibiotic prescriptions for respiratory tract infections between 1999 and 2005 in primary healthcare in Kalmar County, Southern Sweden

Background. Respiratory tract infections (RTIs) comprise the most common indication for consulting a general practitioner and obtaining an antibiotic prescription. Objective. To study changes in the number of visits, diagnoses, and antibiotic prescriptions for RTI in primary healthcare during the period 1999–2005. Design. A retrospective, descriptive, population-based study of electronic patient records. Setting. County of Kalmar in southeastern Sweden. Patients. Patients visiting primary healthcare units in Kalmar County for an RTI between 1 July 1999 and 31 December 2005. Main outcome measures. RTI diagnoses, antibiotic prescriptions, age groups. Results. A total of 240 447 visits for RTI made between 1999 and 2005 were analysed. The yearly consultation rates for the diagnoses acute tonsillitis and AOM decreased by 12% and 10%, respectively (p = 0.001). Of all patients consulting for an RTI diagnosis, 45% received antibiotics. Of all prescribed antibiotics, 60% were for phenoxymethylpenicillin (PcV) and 18% doxycycline. Amoxicillin or amoxicillin + clavulanic acid was prescribed to a lesser extent. The proportion of patients obtaining an antibiotic prescription was almost constant over time (44–46%). The prescriptions of doxycycline showed increasing values (NS). The prescriptions of remaining antibiotics decreased significantly especially for patients up to middle age. Conclusion. This large population study, comprising more than six years of observations, showed the number of primary healthcare patients receiving an RTI diagnosis decreased during the period 1999–2005, but the proportion of patients receiving an antibiotic prescription remained the same. The large seasonal variations indicate a need for further interventions to decrease antibiotic use for RTIs.

The effect of neuromuscular block and noxious stimulation on hypnosis monitoring during sevoflurane anesthesia.

BACKGROUND:There are conflicting results on the influence of neuromuscular block (NMB) on the bispectral index (BIS). We investigated the influence of two degrees of NMB on BIS, Alaris auditory-evoked potential index (AAI), and the electromyogram (EMG) obtained with needle electrodes from the frontal and temporal muscles, immediately adjacent to the BIS-sensor. METHODS:Twenty patients were anesthetized with sevoflurane, titrated for 30 min to an end-tidal concentration of 1.2% (baseline). Rocuronium was infused to 50% (partial) and 95% (profound) depression of the first twitch in a train-of-four response, the order being randomly chosen. Noxious tetanic electrical stimulation was applied at four occasions: 1) at baseline (control measurement), 2 and 3) at each degree of NMB, and 4) after neostigmine reversal. BIS, AAI, and EMG were obtained 2 min before and 2 min after each noxious stimulation. RESULTS:Median BIS and AAI at baseline were 44 (39–50) and 15 (14–16), respectively. The two degrees of NMB did not affect BIS, AAI, and EMG before noxious stimulation. In contrast, profound NMB altered the BIS and AAI responses to noxious stimulation when compared with partial NMB, (BIS P = 0.01, AAI P < 0.01), after neostigmine reversal (BIS P < 0.01, AAI P = 0.01) and compared with baseline (BIS P = 0.08, AAI P = 0.02). No significant increase in EMG was found. CONCLUSION:BIS and AAI responses to noxious tetanic electrical stimulation are affected by the degree of NMB during sevoflurane anesthesia whereas NMB does not affect BIS or AAI in the absence of noxious stimulation.