Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention

Cardiovascular sequelae including diabetic cardiomyopathy constitute the major cause of death in diabetic patients. Although several factors may contribute to the development of this cardiomyopathy, the underlying molecular/cellular mechanisms leading to cardiac dysfunction are still partially understood. Recently, a novel paradigm for the role of the adipocytokine resistin in diabetes has emerged. Resistin has been proposed to be a link between obesity, insulin resistance and diabetes. Using microarray analysis, we have recently found that cardiomyocytes isolated from type 2 diabetic hearts express high levels of resistin. However, the function of resistin with respect to cardiac function is unknown. In this study we show that resistin is not only expressed in the heart, but also promotes cardiac hypertrophy. Adenovirus-mediated overexpression of resistin in cultured neonatal rat ventricular myocytes (NRVM) significantly increased sarcomere organization and cell size, increased protein synthesis and increased the expression of atrial natriuretic factor and β-myosin heavy chain. Overexpression of resistin in NRVM was also associated with activation of the mitogen-activated protein (MAP) kinases, ERK1/2 and p38, as well as increased Ser-636 phosphorylation of insulin receptor substrate-1 (IRS-1), indicating that IRS-1/MAPK pathway may be involved in the observed hypertrophic response. Overexpression of resistin in adult cultured cardiomyocytes significantly altered myocyte mechanics by depressing cell contractility as well as contraction and relaxation velocities. Intracellular Ca²⁺ measurements showed slower Ca²⁺ transients decay in resistin-transduced myocytes compared to controls, suggesting impaired cytoplasmic Ca²⁺ clearing or alterations in myofilament activation. We conclude that resistin overexpression alters cardiac contractility, confers to primary cardiomyocytes all the features of the hypertrophic phenotype and promotes cardiac hypertrophy possibly via the IRS-1/MAPK pathway.     

High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.     

N-Nitroso-N-methylurea elicits mammary cancer in resistant and sensitive rat strains

A single intravenous (i.v.) injection of the water-soluble mammary carcinogen N-nitroso-N-methylurea (NMU; 35 mg/kg of body weight) elicited cancer of the breast in young female rats of two strains in the following incidence: Long-Evans strain, 4%; Sprague-Dawley strain, 70%. In sisters of these rats, a set of 5 i.v. injections of NMU (35 mg/kg at biweekly intervals) evoked mammary carcinoma as follows: Long-Evans strain, 76%; Sprague-Dawley strain, 100%. In its effectiveness in evoking mammary cancer in Sprague-Dawley rats, the lipid-soluble mammary carcinogen 7,8,12-trimethylbenz[a]anthracene exceeded NMU in rapidity of development of cancer and in tumor yield.     

De novo subgaleal abscess

The authors report a case of spontaneous subgaleal abscess formation in a 62-year-old woman without antecedent trauma or injury. She presented with occipital scalp pain and swelling which rapidly became generalized two days following recovery from an upper respiratory infection. Diagnosis was based on radiological examination and aspiration of the subgaleal space, which yielded a purulent exudate with a pure growth of Streptococcus pyogenes. Initial management with incision, drainage and parenteral antimicrobial therapy was not successful. Operative exploration of the subgaleal space revealed extensive necrosis of the galea aponeurotica, and bone curettings revealed microscopic evidence compatible with osteomyelitis. Management with debridement and excision of all necrotic tissue plus prolonged parenteral antimicrobials was successful. Subgaleal abscess formation without an overlying wound or previous trauma has not been reported previously.     

Adult acquired antral web

Summary Gastric antral webs in adults have been considered to be either congenital or acquired lesions. We present the first radiographically documented progression from a normal antrum to the development of an antral ulcer followed by healing with web formation.In a single study we feel that irregularity of the web and deformity or eccentricity of the antrum favor an acquired rather than a congenital web. Obtaining prior radiographs as well as follow-up examinations may be the only way to prove associa tion with peptic disease.The figures shown are published with permission from the Armed Forces Institute of Pathology.     

Acute thrombocytopenic purpura in relation to the use of drugs

The relation of acute thrombocytopenic purpura (TP) to the use of drugs was investigated in a case-control study conducted in eastern Massachusetts, Rhode Island, and the Philadelphia region; 62 cases over the age of 16 years with acute onset and with a rapid recovery were compared with 2,625 hospital controls. After control for confounding by multiple logistic regression, use of the following drugs in the week before the onset of symptoms was significantly associated: trimethoprim/sulfamethoxazole (relative risk [RR] estimate, 124), quinidine/quinine (101), dipyridamole (14), sulfonylureas (4.8), and salicylates (2.6). The overall annual incidence of acute TP was estimated to be 18 cases per million population. The excess risks for the associated drugs were estimated to be 38 cases per million users of trimethoprim/sulfamethoxazole per week, 26 per million for quinidine/quinine, 3.9 per million for dipyridamole, 1.2 per million for sulfonylureas, and 0.4 per million for salicylates. Associations with sulfonamides, quinidine/quinine, sulfonylureas, and salicylates have been previously reported, but the present study has provided the first quantitative measures of the risk. The association with dipyridamole was unexpected. In general, despite large RRs, the incidence rates attributable to the drugs at issue (excess risks) were low, suggesting that TP is not an important consideration in the use of the various drugs.     

Successful donor cell engraftment in a recipient of bone marrow from a cadaveric donor

A 12-year-old male with acute lymphocytic leukemia received donor bone marrow from his histocompatible father whose marrow was harvested 40 minutes postmortem after he suffered a myocardial infarction. The marrow was stored in liquid nitrogen for 17 days prior to infusion into the recipient. Trypan blue viability was greater than 99% for the fresh marrow. Progenitor cell assays revealed that 20% of the CFU-MIX, 16% of the BFU-E, 10% of the CFU-E, and 17% of the CFU-GM were spared during the cryopreservation period. Posttransplantation, the recipient had a leukocyte count greater than 10(3)/microL by day 26. Southern blotting analysis documented the donor origin of the peripheral blood mononuclear cells and granulocytes isolated 46 days posttransplantation. Unfortunately, the patient died of complications relating to graft-v-host disease 67 days following transplantation. This case demonstrates the feasibility of cadaveric marrow as a source of donor cells and is the first reported case of documented leukocyte engraftment in a recipient of cadaveric marrow.     

Proarrhythmic and antiarrhythmic effects of intravenous prostacyclin in man

Prostacyclin (PGI2) has been shown to reduce the occurrenceof experimental ventricular arrhythmias. To assess potentialbeneficial effects in man, the electrophysiological action ofPG12 was studied in 16 non medicated patients. The protocolused in incremental pacing and programmed stimulation in theright atrium and ventricle. This protocol and measurement ofeffective refractory periods (ERP) were performed before andduring the injection of 2.5, 5 and 10 ng kg^–1 min^–1of PGI2. The atrial functional refractory period decreased significantly(P<0.05); PGI2 had no influence on the occurrence of induciblenon-sustained (NS) atrial tachycardias and was responsible forthe occurrence of 2 non-sustained atrial tachycardias in 8 patientswith inducible atrial echo beats under basal conditions. Thirteenpatients did not have inducible ventricular tachycardia ( VT)under basal conditions. Non-sustained VT was induced after PGI2in 4 of them but in only 1 of them after the administrationof propranolol. Three patients had inducible VT under basalconditions (1 non-sustained, 2 sustained VT). PG12 did not preventthe occurrence of VT (1 non-sustained, 1 sustained VT), exceptin 1 patient with ischaemic-related VT, who had non-sustainedVT after PGI2. In conclusion, PGI2 does not seem to have a cardiacantiarrhythmic effect and may increase the atrial and ventricularrepetitive response. This effect could be related to an increaseof adrenergic tone.