Insulin-sensitizing antihyperglycaemic medications are associated with better outcome in patients with diabetes undergoing cardiac stress testing

Background: There are several treatment modalities available for diabetes; however, the effects of the different medications on coronary artery disease are less understood. The purpose of this study was to evaluate the correlation of insulin‐sensitizing therapy with the outcome of stress myocardial perfusion testing and to compare it with conventional therapy. Methods: Of 417 patients referred to stress testing for evaluation of chest pain, 222 were identified as being treated with conventional therapy only (insulin and insulin secretagogues) and 195 as being treated with insulin sensitizers (metformin and thiazolidinediones (TZD)). Multivariate logistic regression models were used to correct for confounding factors and to determine the independent relation between treatment type and stress‐test outcome. Results: Ischaemia, infarction and the composite outcome were less frequent in the insulin‐sensitizer group than in the conventional therapy group (odds ratio (OR) = 0.39, P = 0.025; OR = 0.32, P = 0.021 and OR = 0.38, P = 0.009, respectively). The subgroup analysis showed that treatment with metformin (n = 125) compared with conventional therapy was associated with less infarction or the composite outcome of ischaemia and/or ischaemia (OR = 0.18 (95% confidence interval (CI): 0.05–0.66), P = 0.010; OR = 0.34 (95%CI: 0.15–0.80), P = 0.014, respectively). Treatment with TZD (n = 43) was associated with a trend to less frequent ischaemia (OR = 0.18 (95%CI: 0.03–1.01), P = 0.051). Conclusion: The addition of insulin‐sensitizing medications to the conventional diabetes therapy or their sole use was associated with decreased coronary artery disease or its severity in patients with diabetes as determined by stress myocardial perfusion study. Randomized prospective trials will be necessary to prove this benefit.     

Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF

Recombinant human interleukin-5 (rhIL-5), in either liquid or semi- solid cultures, selectively induced eosinophil production from normal human bone marrow, with no activity on other cell lineages. The time course of eosinophil production induced by murine IL-5, rhIL-3, and rh granulocyte-macrophage colony stimulating factor (GMCSF) was similar to rhIL-5. The rate of eosinophil maturation in vitro was independent of the stimulating cytokine, mature eosinophils being produced after 4 to 5 weeks in liquid culture with each of these cytokines. The eosinophils produced in response to each cytokine were morphologically indistinguishable, and had the ultrastructural features of maturity except that the electron-dense material in the granules had not formed into crystalline cores. Neither rhIL-1 nor rhIL-6 alone, or in combination with rhIL-5 or rhIL-3, induced eosinophil differentiation or proliferation under the conditions used. rhIL-3 and rhGMCSF induced more eosinophil colonies than rhIL-5, rhIL-5 had an additive, not synergistic, effect on eosinophil colony production when combined with either rhIL-3 or rhGMCSF, suggesting that rhIL-5 stimulates a smaller and possibly different population of eosinophil progenitors. However, rhIL-5 induced the greatest eosinophil production in liquid cultures, suggesting that although it may act on a smaller population of precursors, it is able to stimulate more proliferative steps than either rhIL-3 or rhGMCSF.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Clinical and histopathological evaluation of the adrenal incidentaloma

Clinically silent adrenal masses (incidentaloma) are incidentally discovered lesions, when noninvasive imaging methods (USG, CT, MRI) are performed for reasons other than known or suspected adrenal disease. Most studies report on a prevalence of adrenal incidentaloma range between 1% and 10% in radiological series. Between 1994 and 1999 we observed in our Department 57 patients with incidentalomas of adrenal glands. After endocrinological evaluation silent Cushing's syndrome was found in 2 cases (3.5%). Fifty two patients were qualified for surgery. Adrenocortical adenoma was diagnosed in 73.1%; adrenocortical carcinoma in 7.7%; pheochromocytoma in 7.7% and less frequent adrenal lesions in 11.5%. All adrenal carcinomas and malignant pheochromocytomas (11.5%) were found in tumors with diameter over 4 cm.     

Clonal dysregulation of the antibody response to tetanus-toxoid after bone marrow transplantation

After bone marrow transplantation (BMT), a prolonged dysregulation of humoral immunity can be observed. In the present study, we investigated whether this is reflected in an abnormal production of specific antibodies (Ab) to the T-cell-dependent recall antigen tetanus-toxoid (TT). The study group consisted of children receiving transplants of an unmodified allogeneic graft and of adults receiving either a T-cell- depleted allogeneic or an unmodified autologous BM graft. Findings were compared with those in healthy controls. In pediatric graft recipients, who were routinely revaccinated early after BMT, the Ab response was quantitatively superior to that in adult graft recipients who did not receive early revaccination. In the majority of graft recipients, the time period after vaccination required to reach the peak level of antibodies was prolonged and the number of responding TT-specific B- cell clones was markedly decreased in comparison with controls. In controls, a low frequency of dominant B-cell clones may produce low quantities of homogeneous Ab components (H-Ab) against a heterogeneous background. However, in BM graft recipients, "overshooting" of Ab production by separate B-cell clones was observed, resulting in the development of H-Ab at a relatively high concentration. These abnormalities were present up to 10 years after BMT, irrespective of either the age of the recipient, the modulation of the graft, or the vaccination schedule used. It is hypothesized that the dysregulated Ab production is the consequence of activation of a restricted number of resting memory B cells, present in germinal centers, repopulating gradually after BMT. Our data show that routine revaccination early after BMT improves the humoral immune response. However, because of a clonally dysregulated Ab production, long-lasting qualitative defects may be present even after normalization of Ab titers.     

Overall hemodynamic pattern in coarctation of the abdominal aorta in conscious rats

This study was designed to examine the total body hemodynamics of abdominal aortic coarctation hypertension. The study quantitates both regional and organ blood flow and resistance in conscious rats both above and below an experimentally produced coarctation. The experimental group consisted of 10 male Sprague-Dawley rats with a mean pressure gradient of 68 mm Hg across the coarctation. This experimental group was compared with a group of eight control rats with no pressure gradient. Flow measurements were made with radioactively labeled microspheres 4 weeks after aortic constriction. This aortic coarctation produced an increase in cardiac index (22%) and total peripheral resistance (19%). Blood flow through tissues proximal to the coarctation was not different from control; vascular resistance was increased (31%). Flow through the tissues distal to the coarctation was increased (16%); vascular resistance was decreased (-22%). The upper carcass, diaphragm, and brain were the tissues most representative of flow above the coarctation, and the lower carcass and large intestine were the tissues most representative of flow below the coarctation. Coarctation of the aorta produced cardiac hypertrophy and increased microsphere shunting to the lungs.     

Effectiveness of aggressive management of dyslipidemia in a collaborative-care practice model

The Cardiovascular Risk Identification and Treatment Center was established in 1997, adopting a collaborative-care clinic model for the purpose of improving the management of high-risk patients with dyslipidemia. This was a retrospective analysis of 417 high-risk patients with ≥1 year of follow-up laboratory data. Analysis included changes in total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), non-HDL, triglycerides, and total cholesterol to HDL ratio; lipoprotein goal achievement; Framingham risk score; liver function; and cardiovascular events. At baseline, 66% of patients had coronary heart disease (CHD) or equivalent risk, 45% were not receiving dyslipidemia therapy, and 29% were on statin monotherapy. After 3 years in the program, 56% were receiving combination therapy, 41% were on monotherapy, and 2% were not on therapy. The 3 most common treatment regimens were statin plus niacin (36%), statin alone (22%), and niacin alone (14%). All lipoproteins improved from baseline (p <0.001). Overall, 62% to 74% of patients reached singular lipid goals and 35% achieved combined lipid goals. Patients with Framingham 10-year CHD risk of >20% were reduced from 6% to <1%. Only 29 patients (7.0%) had a cardiovascular event, including 5 (1.0%) who experienced a myocardial infarction. Aspartate aminotransferase/alanine transferase elevation >3 times normal occurred in 1% of patients. In conclusion, a collaborative-care practice model adopting individualized, aggressive pharmacologic and nonpharmacologic treatment strategies is highly effective in achieving lipid goals, is sustainable, and is safe. Furthermore, this approach yields reduced projected 10-year CHD risk. A low rate of cardiovascular events was observed.     

Antiidiotypic IgG crossreactive with Rh alloantibodies in red cell autoimmunity

IgG autoantibodies eluted from RBCs of antiglobulin positive normal blood donors contained at least two antibody populations, an IgG autoantibody (Ab 1), and an IgG population (Ab 2) that agglutinated RBCs coated with some Rh(D) alloantibodies. Eight of 24 autoantibody eluates tested agglutinated 3 of 10 anti-Rh(D) sensitized RBCs. The agglutinating activity was inhibited specifically by preincubation of the autoantibody eluate with the reactive anti-D. The reaction did not require the Fc domain of the anti-Rh(D), since autoantibody eluates agglutinated RBCs coated with F(ab')2 prepared from the reactive anti-D sera. These findings indicate that the RBCs of some antiglobulin- positive blood donors contain an immunoglobulin auto-antiidiotype (Ab 2) against the RBC autoantibody (Ab 1) which is demonstrable through its cross-reactivity with selected Rh(D) alloantibodies. Identification of auto-antiidiotypes in RBC autoimmunity lends support to the idiotype- antiidiotype network hypothesis of immune regulation and is consistent with the bizarre and complex serology of autoimmune hemolytic anemia. The absence of clinical hemolysis in antiglobulin-positive normal blood donors suggests that immunoglobulin idiotype-antiidiotype interactions may play a role in modulating the effects of RBC autoimmunity.     

Hemostatic plug formation in normal and von Willebrand pigs: the effect of the administration of cryoprecipitate and a monoclonal antibody to Willebrand factor

Hemostatic plug (HP) formation was investigated in the ear bleeding time incision in normal and von Willebrand pigs. HP volume was calculated by integrating the areas of serial sections. In normal pigs (n = 11), platelets immediately formed a layer on the surface of the cut channel. Platelet aggregates formed at the ends of transected vessels and gradually enlarged. Finally, all transected vessels were occluded by HP and bleeding stopped. In contrast, large HPs were formed in the incision in von Willebrand's disease (vWD) pigs (n = 4); these HPs did not cover the ends of the transected vessels, which continued to bleed, allowing the formation of large hemostatically ineffective platelet aggregates in the incision. Canals traversed these HPs, and bleeding from the open vessels may have continued through them. After infusion of cryoprecipitate into a vWD pig, the bleeding time shortened, and the morphological findings of the HPs were similar to those of normal pigs. In normal pigs (n = 3) infused with an anti- Willebrand factor monoclonal antibody, which prolonged the bleeding time, a large HP formed in the incision, similar to that observed in the vWD pig. The volume of the normal and vWD HPs increased with time. These in vivo findings suggest that Willebrand factor is involved in the localization of the HP to the damaged vessel and may also play a role in platelet-platelet interaction. A computerized morphometric technique was used for measuring the volume of the hemostatic plugs and the distance of sequential points on the perimeter of the HP from the center of selected bleeding vessels.