Seasonality and daily weather conditions in relation to myocardial infarction and sudden cardiac death in Olmsted County, Minnesota, 1979 to 2002.

OBJECTIVES: We assessed the relationship of season and weather types with myocardial infarction (MI) and sudden cardiac death (SCD) in a geographically defined population, and tested the hypothesis that the increased risk in winter was related to weather. BACKGROUND: Winter peaks in coronary heart disease (CHD) have been documented. Yet, it is uncertain if seasonality exists for both incident events and deaths, and the role of weather conditions is not clear. METHODS: The daily occurrence of incident MI and SCD in Olmsted County was examined with data from the National Weather Service. Poisson regression models were used to assess the relative risks (RRs) associated with season and climatic variables. Subsequent analysis stratified SCD into those with and without antecedent CHD (unexpected SCD). RESULTS: Between 1979 and 2002, 2,676 MI and 2,066 SCD occurred. The age-, gender-, and year-adjusted RR of SCD, but not of MI, was increased in winter versus summer (1.17, 95% confidence interval [CI] 1.03 to 1.32) and in low temperatures (1.20, 95% CI 1.07 to 1.35, for temperatures below 0 degrees C vs. 18 degrees C to 30 degrees C). These associations were stronger for unexpected SCD than for SCD with prior CHD (p < 0.05). After adjustment for all climatic variables, low temperature was associated with a large increase in the risk of unexpected SCD (RR = 1.38, 95% CI 1.10 to 1.73), while the association with winter declined (RR = 1.06, 95% CI 0.83 to 1.35). CONCLUSIONS: These data suggest that the winter peak in SCD can be accounted for by daily weather.     

Transforming growth factor beta (TGF-beta), a potent inhibitor of erythropoiesis: neutralizing TGF-beta antibodies show erythropoietin as a potent stimulator of murine burst-forming unit erythroid colony formation in the absence of a burst-promoting activity

Transforming growth factor beta (TGF-beta) is a bifunctional regulator of the growth of myeloid progenitors and is here demonstrated to directly inhibit the growth of primitive erythroid progenitors by 95% to 100% regardless of the cytokines stimulating growth. Autocrine TGF- beta production of primitive hematopoietic progenitors has previously been reported. In the present study, a neutralizing TGF-beta antibody (anti-TGF-beta) added to serum-containing cultures, resulted in a 3-, 4- , and 25-fold increase in burst-forming unit erythroid (BFU-E) colony formation in response to interleukin-4 (IL-4) plus erythropoietin (Epo), SCF plus Epo, and IL-11 plus Epo, respectively. The growth of BFU-E progenitors has been suggested to require a burst-promoting activity in addition to Epo. Accordingly, we observed no BFU-E colony formation in serum-containing cultures in response to Epo alone. In contrast, 50 BFU-E colonies were formed when anti-TGF-beta was included in the culture. In serum-free cultures, Epo also stimulated BFU-E colony formation in the absence of other cytokines, whereas anti-TGF- beta had no effect on the number of colonies formed. Quantitation of TGF-beta 1 in serum by an enzyme-linked immunosorbent assay method showed predominantly the presence of precursor (latent) TGF-beta 1, but also showed active TGF-beta 1 at a concentration sufficient to potently inhibit erythroid colony formation. Thus, neutralization of active TGF- beta 1 in serum shows that Epo alone is sufficient to stimulate the growth of murine BFU-E progenitors.     

The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years

OBJECTIVE: It is hypothesized that the systemic inflammation associated with rheumatoid arthritis (RA) promotes an increased risk of cardiovascular (CV) morbidity and mortality. We examined the risk and determinants of congestive heart failure (CHF) in patients with RA. METHODS: We assembled a population-based, retrospective incidence cohort from among all individuals living in Rochester, Minnesota, in whom RA (defined according to the American College of Rheumatology 1987 criteria) was first diagnosed between 1955 and 1995, and an age- and sex-matched non-RA cohort. After excluding patients in whom CHF occurred before the RA index date, all subjects were followed up until either death, incident CHF (defined according to the Framingham Heart Study criteria), migration from the county, or until January 1, 2001. Detailed information from the complete medical records (including all inpatient and outpatient care provided by all local providers) regarding RA, ischemic heart disease, and traditional CV risk factors was collected. Cox models were used to estimate the effect of RA on the development of CHF, adjusting for CV risk factors and/or ischemic heart disease. RESULTS: The study population included 575 patients with RA and 583 subjects without RA. The CHF incidence rates were 1.99 and 1.16 cases per 100 person-years in patients with RA and in non-RA subjects, respectively (rate ratio 1.7, 95% confidence interval [95% CI] 1.3-2.1). After 30 years of followup, the cumulative incidence of CHF was 34.0% in patients with RA and 25.2% in non-RA subjects (P< 0.001). RA conferred a significant excess risk of CHF (hazard ratio [HR] 1.87, 95% CI 1.47-2.39) after adjusting for demographics, ischemic heart disease, and CV risk factors. The risk was higher among patients with RA who were rheumatoid factor (RF) positive (HR 2.59, 95% CI 1.95-3.43) than among those who were RF negative (HR 1.28, 95% CI 0.93-1.78). CONCLUSION: Compared with persons without RA, patients with RA have twice the risk of developing CHF. This excess risk is not explained by traditional CV risk factors and/or clinical ischemic heart disease.     

Fluorescent in vivo tracking of hematopoietic cells. Part I. Technical considerations

We report a new technology for in vivo tracking of hematopoietic cells, using fluorescent lipophilic probes. Because the probe is irreversibly bound in the lipids of the cell membrane; substantial numbers of dye molecules can be incorporated per cell and thus substantial signal to noise can be achieved. Although this technology can be used for all hematopoietic cells, these first findings are reported on red blood cells (RBCs) owing to the importance of the membrane to RBC function and integrity. We demonstrated that labeling 10% of the RBCs of a rabbit and reinjecting them into the animal makes possible the tracking of these cells at various times after injection. Furthermore, the labeling appears not to affect in vivo cell lifetime or cellular volume changes in response to hypotonic shock. The single cell fluorescence intensity of the labeled RBCs remains relatively constant for 60 days, and an immune response appears not to be generated against labeled cells. That labeled RBCs have lifetime kinetics in vivo, as shown in other studies, indicates that the membranes are functioning normally and are unaltered by the labeling technology. The technology we present is also applicable to white blood cells, bone marrow, and platelets.     

Heterozygous Mutations in Natriuretic Peptide Receptor‐B (NPR2) Gene as a Cause of Short Stature

Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor‐B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss‐of‐function mutations in short individuals and one gain‐of‐function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.     

End-Stage Renal Disease and Mortality Outcomes Across Different Glomerulonephropathies in a Large Diverse US Population

Objective

To compare renal function decline, incident end-stage renal disease (ESRD), and mortality among patients with 5 common glomerular diseases in a large diverse population.

Potent and nontoxic antisense oligonucleotides containing locked nucleic acids

Insufficient efficacy and/or specificity of antisense oligonucleotides limit their in vivo usefulness. We demonstrate here that a high-affinity DNA analog, locked nucleic acid (LNA), confers several desired properties to antisense agents. Unlike DNA, LNA/DNA copolymers were not degraded readily in blood serum and cell extracts. However, like DNA, the LNA/DNA copolymers were capable of activating RNase H, an important antisense mechanism of action. In contrast to phosphorothioate-containing oligonucleotides, isosequential LNA analogs did not cause detectable toxic reactions in rat brain. LNA/DNA copolymers exhibited potent antisense activity on assay systems as disparate as a G-protein-coupled receptor in living rat brain and an Escherichia coli reporter gene. LNA-containing oligonucleotides will likely be useful for many antisense applications.     

Fractures of the neuro-cranium: sensitivity and specificity of post-mortem computed tomography compared with autopsy

Post–mortem computed tomography (PMCT) is a routine tool in many forensic pathology departments as it is fast and non-destructive and allows less gruesome visualization than photographs, and the images are indefinitely storable. Several studies investigated congruence between PMCT and autopsy for skull fracture but registered only the presence or absence of fracture systems. The objective of this study was to determine location-specific sensitivity and specificity of PMCT for individual fracture lines in blunt force head trauma. Accurate 3D models based on PMCT data with all fracture lines visible are important for future studies on fractures, applying finite element analysis (FEA). We retrospectively sampled adult cases from 2013 to 2019 with skull fracture mentioned in the autopsy report. PMCT was on a Siemens 64-slice scanner and autopsy according to international guidelines. The location and direction of all fracture lines at autopsy and at de novo interpretation of scans were registered and compared. Ninety-nine cases with 4809 individual findings were included. Age ranged from 18 to 100 years. The overall sensitivity was 0.58, and specificity was 0.91. For individual locations, sensitivity ranged from 0.24 to 0.85, and specificity ranged from 0.73 to 1.00. Intra-observer agreement was 0.74, and inter-observer agreement ranged from 0.43 to 0.58. In conclusion, PMCT is suited for detection of fracture systems, but not for detection of all individual fracture lines. Our results differed from the existing literature due to the methodological choices of registering individual fracture lines. Future studies utilising FEA must supplement PMCT with autopsy data.

     

Diagnostic value of ascitic fluid cholesterol levels in the prediction of malignancy

In a prospective study abdominal paracentesis with ascitic fluid aspiration was performed in 54 consecutive patients with ascites of unknown cause. The ascitic fluid was examined cytologically and bacteriologically. The total cholesterol concentration was measured with an enzymatic colorimetric method. Malignant disease was diagnosed in 34 patients. Two of them had both malignant disease and liver cirrhosis and were excluded. Seventeen patients had liver cirrhosis, one had acute pancreatitis, and two had decompensated heart disease. The diagnostic value of an ascitic cholesterol concentration greater than 1.2 mmol/l in terms of predicting malignant disease was 87.5% (95% confidence limits, 71.0-96.5). The predictive value of an ascitic cholesterol concentration less than or equal to 1.2 mmol/l in terms of benign disease was 80.0% (95% confidence limits, 56.3-94.3). It is concluded that ascitic cholesterol measurement is a valuable supplement to cytologic examination in distinguishing between ascites of malignant and benign origin.     

Sympathetic reflex control of skeletal muscle blood flow in patients with congestive heart failure: evidence for beta-adrenergic circulatory control

Mechanisms controlling forearm muscle vascular resistance (FMVR) during postural changes were investigated in seven patients with severe congestive heart failure (CHF) and in seven control subjects with unimpaired left ventricular function. Relative brachioradial muscle blood flow was determined by the local 133Xe-washout technique. Unloading of baroreceptors with use of 45 degree upright tilt was comparably obtained in the patients with CHF and control subjects. Control subjects had substantially increased FMVR and heart rate to maintain arterial pressure whereas patients with CHF had decreased FMVR by 51 +/- 11% (mean +/- SEM, p less than .02) and had no increase in heart rate despite a fall in arterial pressure during upright tilt. The autoregulatory and local vasoconstrictor reflex responsiveness during postural changes in forearm vascular pressures were intact in both groups. Further investigations were carried out in the patients with CHF. The left axillary nerve plexus was blocked by local anesthesia in the seven patients. No alterations in forearm vascular pressures were observed. This blockade preserved the local regulation of FMVR but reversed the vasodilator response to upright tilt as FMVR increased by 30 +/- 7% (p less than .02). Blockade of central neural impulses to this limb combined with brachial arterial infusions of phentolamine completely abolished the humoral vasoconstriction in the tilted position. Infusions of propranolol to the contralateral brachial artery that did not affect baseline values of heart rate, arterial pressure, or the local reflex regulation of FMVR reversed the abnormal vasodilator response to upright tilt as FMVR increased by 42 +/- 12% (p less than .02). Despite augmented baseline values, forearm venous but not arterial plasma levels of epinephrine increased in the tilted position, as did arterial rather than venous plasma concentrations of norepinephrine in these patients. The results suggest a beta-adrenergic reflex mechanism elicited by spinal or supraspinal neural impulses and probably modulating a cotransmitter release in the patients with CHF.