Early administration of captopril and nitroglycerin in combination after acute myocardial infarction: an invasive haemodynamic study

The combination of captopril and nitroglycerin early after acutemyocardial infarction (AMI) could lead to a dangerous decreasein blood pressure coronary perfusion. To evaluate the safetyaspects and haemodynamic effects of this combination, we studied36 first ‘Q wave’ thrombolysed anterior wall AMIpatients during the 24 h following the onset of symptoms. Afterwards, thrombolysis patients received a continuous infusionof nitroglycerin and were submitted to pulmonary artery catheterization.Those patients with mean arterial pressure (MAP) 70 mmHg, cardiacindex 2.21. min^–1.m^–2, and wedge pressure 10 mmHgwere included and randomized to receive 6.25 mg of captoprilevery 6 h on the first day and 12.5 mg qid on the second f MAP 70mmHg (group 1). A second group (group 2) received a placebo.Haemodynamic parameters were determined after 1, 6 and thenevery 6 h up to 48 h after basal measurements. Significant differenceswere observed only for the MAP and the rate-pressure product(reduction in group 1 values, P <0.05). However, MAP wasmaintained within acceptable limits. Our data support the factthat the combination of captopril and nitroglycerin in the earlyhours of a non-complicated anterior wall AMI is safe, and couldguarantee its use in large clinical trials to determine theeffects on left ventricle remodelling and survival after AMI.     

Dietary oleic acid is inversely associated with pancreatic cancer – Data from food diaries in a cohort study

Background

Dietary oleic acid may prevent pancreatic ductal adenocarcinoma (PDA) by reducing hyperinsulinaemia which can otherwise promote DNA damage and tumour growth. Results from previous epidemiological studies investigating oleic acid are inconsistent. This study aims to clarify the relationship between dietary oleic acid intake and the risk of developing PDA using nutritional information from food diaries plus published serum biomarker data from HbA1c.

Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid cell-specific monoclonal antibodies

Second or third chemotherapy-induced remissions in acute myelogenous leukemia (AML) are limited by early relapse of the leukemia. We developed monoclonal antibodies (MoAbs) that are cytotoxic to myeloid leukemia cells to treat bone marrow from these patients ex vivo for autologous transplantation. In this pilot study, bone marrow was harvested from ten patients with AML in remission, treated with one or two complement-fixing MoAbs, PM-81 and AML-2-23, which react with myeloid differentiation antigens, incubated with rabbit complement, and cryopreserved. These MoAbs were chosen because they have broad reactivity with AML cells but not with pluripotent progenitor cells. At the time of transplant, 6 patients were in second complete remission, 1 each was in third complete or partial remission, and 2 were in early first relapse. The patients were treated with cyclophosphamide (60 mg/kg a day for 2 days) and total body irradiation (200 cGy twice a day for 3 days) and given infusions of MoAb-treated bone marrow. Full bone marrow reconstitution was observed in eight patients; two patients did not recover platelets. Seven of the ten patients are surviving and disease-free at 21.0, 15.0, 13.0, 10.0, 6.0, 3.0, and 2.0 months posttransplant. Treating bone marrow with MoAbs to myeloid differentiation antigens does not interfere with pluripotential stem cell engraftment. Longer follow-up and a controlled study are necessary to prove that the apparent efficacy of this therapeutic approach in some patients is attributable to MoAb-mediated killing of leukemia cells.     

Crohn's Disease of the Colon

Using accepted diagnostic criteria we have selected, for study, 160 patients with Crohn's disease involving the colon. There is a remarkable discrepancy between the clinical diagnosis prior to or at the time of initial admission to this hospital and the diagnosis following definitive investigation and observation of the progression of disease.
The peak age incidence occurred in the second decode The colitis group showed a greater percentage of patients over 30 years of age. Although histopathology was not obtained in all patients, there appeared to be sparing of the ascending colon in a small percentage (9%) of patients with ileocolitis.
Comparison of the clinical features of granulomatous disease limited to the colon and granulomatous ileocolitis shows a significantly greater incidence of extraintestinal symptoms and overt bleeding in the former. Nausea, vomiting, subacute obstruction, abdominal mass and internal fistulas were substantially more common in ileocolitis but the difference was not statistically significant. In this series retroperitoneal abscess did not occur in patients with disease localized to the colon. In the 10 patients with ileocolitis who developed an abscess, however, the site of fistula was the colon in four patients. In one of these, the abscess was left-sided.     

Stem Cell Migration and Proliferation During Severe Anemia

The pluripotential stem cell (CFU) compartment of marrow and spleen wasevaluated in mice subjected to an intense erythroid stimulus associated withphenylhydrazine-induced anemia. Erythroid hyperplasia occurred in both marrow and spleen. CFU in the marrowgradually declined to approximately 50per cent of control levels (day 5) whiletheir numbers in the spleen increased(fourfold) by day 3 and were maintainedat this level for several days. Thesechanges in numbers of marrow andsplenic CFU were not associated withCFU proliferation. Thereafter, CFU inthe marrow, but not in the spleen, entered active cell cycle. The data suggestthat CFU migrate from marrow to spleenduring the demands of severe anemia.The induction of marrow CFU into cyclefurther suggests a negative feedback,which, perhaps through cell-cell interaction, maintains stem cells at a criticalcompartment size. The failure of splenicCFU to cycle may reflect the converseeffect, i.e. an inhibition on stem cell proliferation in the wake of an expandedstem cell pool.

Submitted on March 17, 1970 Revised on May 14, 1970 Accepted on June 9, 1970     

Factor V deficiency in Philadelphia-positive chronic myelogenous leukemia

Factor V deficiency has been identified in 8 of 8 patients 7--20 yr of age, with Philadelphia-positive (Ph1+) chronic myelogenous leukemia (CML). In these 8 patients, factor V deficiency was not due to hepatic dysfunction, factor V inhibitors, or disseminated intravascular coagulation. In 3 patients, factor V activity rose 10%--12% (0.10--0.12 U/ml) after the infusion of 28--31 ml/kg body weight of fresh frozen plasma (FFP). The rise persisted less than 14 hr. The mean measured postinfusion rise in factor V was 18% of the expected rise calculated from the volume of FFP infused in the patients' plasma volume. In 4 patients, a small transient rise in factor V activity occurred after splenectomy or plateletpheresis. Factor V deficiency was completely corrected after a marked reduction in bone marrow cellularity in 2 patients with Ph1+ CML treated with extensive chemotherapy, total body irradiation, and bone marrow transplantation. Factor V deficiency was retrospectively observed in 6 of 20 patients, ages 20--80 yr, with Ph1+ CML and 3 of 6 patients with other myeloproliferative disorders. The factor V deficiency appears to be associated with the large myeloid- megakaryocytic cell mass characteristic of CML and other myeloproliferative disorders.     

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.The endoplasmic reticulum (ER) takes center stage for protein production, redox regulation, calcium homeostasis, and cell death (1, 2). It follows that genetic or acquired ER dysfunction can trigger a variety of common diseases, including neurodegenerative diseases, metabolic disorders, and inflammatory bowel disease (3, 4). Breakdown in ER function is also associated with genetic disorders such as Wolfram syndrome (5–8). It is challenging to determine the exact effects of ER dysfunction on the fate of affected cells in common diseases with polygenic and multifactorial etiologies. In contrast, we reasoned that it should be possible to define the role of ER dysfunction in mechanistically homogenous patient populations, especially in rare diseases with a monogenic basis, such as Wolfram syndrome (9).Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy (7). Insulin-dependent diabetes usually occurs as the initial manifestation during the first decade of life, whereas the diagnosis of Wolfram syndrome is invariably later, with onset of symptoms in the second and ensuing decades (7, 10, 11). Two causative genes for this genetic disorder have been identified and named Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2) (12, 13). It has been shown that multiple mutations in the WFS1 gene, as well as a specific mutation in the WFS2 gene, lead to β cell death and neurodegeneration through ER and mitochondrial dysfunction (5, 6, 14–16). WFS1 gene variants are also associated with a risk of type 2 diabetes (17). Moreover, a specific WFS1 variant can cause autosomal dominant diabetes (18), raising the possibility that this rare disorder is relevant to common molecular mechanisms altered in diabetes and other human chronic diseases in which ER dysfunction is involved.Despite the underlying importance of ER malfunction in Wolfram syndrome, and the identification of WFS1 and WFS2 genes, a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we show that the calpain protease provides a mechanistic link between the ER and death of neurons and β cells in Wolfram syndrome.     

MOLECULAR IDENTIFICATION OF Bartonella henselae IN A SERONEGATIVE CAT SCRATCH DISEASE PATIENT WITH AIDS IN RIO DE JANEIRO, BRAZIL

Bartonella henselae is associated with a wide spectrum of clinical manifestations, including cat scratch disease, endocarditis and meningoencephalitis, in immunocompetent and immunocompromised patients. We report the first molecularly confirmed case of B. henselae infection in an AIDS patient in state of Rio de Janeiro, Brazil. Although DNA sequence of B. henselae has been detected by polymerase chain reaction in a lymph node biopsy, acute and convalescent sera were nonreactive.