Is QT interval a marker of subclinical atherosclerosis in nondiabetic subjects? The Insulin Resistance Atherosclerosis Study (IRAS).

BACKGROUND AND PURPOSE: We studied the relationship of heart rate-corrected QT interval with subclinical atherosclerosis, as determined by ultrasonographic measurement of carotid intima-media thickness (IMT) in nondiabetic subjects in the Insulin Resistance Atherosclerosis Study (IRAS). Prolonged heart rate-corrected QT interval is an unfavorable prognostic factor of cardiovascular morbidity and mortality, and QT interval prolongation may be the result of atherosclerosis. METHODS: B-mode ultrasound imaging of the carotid artery IMT was performed in a large, triethnic, nondiabetic population free of clinical coronary artery disease (n=912). QT interval was measured on resting electrocardiograms with use of a computer program and corrected for heart rate with standard equations. RESULTS: IMT of the common carotid artery correlated significantly with heart rate-corrected QT interval duration (r=0.15 for QT(60) and r=0.14 for QTc), whereas no relationship between IMT of the internal carotid artery and QT interval was found (r=-0.01). The association was somewhat stronger in women than in men. In a multiple regression analysis adjusting for demographic variables, the association of common carotid artery IMT to heart rate-corrected QT interval remained highly significant, but adjustment for cardiovascular risk factors weakened the relationship. CONCLUSIONS: We found a significant relation of heart rate-corrected QT interval to carotid atherosclerosis in nondiabetic subjects that was stronger in women and partly mediated by cardiovascular risk factors, including hypertension. QT interval may therefore serve as a marker for clinically undetected ("subclinical") atherosclerotic disease.     

Rheologic predictors of the severity of the painful sickle cell crisis

Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.     

Impaired gastric emptying and altered intragastric meal distribution in diabetes mellitus related to autonomic neuropathy?

Previous studies in diabetic patients suggested a relationship between delayed gastric emptying and increased ingesta retention in either proximal or distal stomach, but the determinants underlying these abnormalities remained obscure. We aimed at assessing the impact of cardiovascular autonomic neuropathy, blood glucose concentration, long-term glycemic control, and other factors in 34 type I and 43 type II diabetic patients (ages 21–67 and 34–81 years, respectively). Emptying was slower (P < 0.04) in type I diabetic patients than in 20 healthy control subjects (ages 23–63 years). Patients with autonomic neuropathy (N = 45) had slower gastric emptying (P < 0.02) and retained more in the distal stomach (P < 0.0001) than patients without neuropathy (N = 32). Multiple regression analyses revealed that slow emptying and increased distal retention were significantly associated with autonomic neuropathy (P < 0.043, P < 0.0002), whereas blood glucose, glycemic control, diabetes duration, age, and other factors had no discernible influence. Thus, both slow emptying and increased distal ingesta retention seem primarily referable to autonomic neuropathy.     

Sustained, retransplantable, multilineage engraftment of highly purified adult human bone marrow stem cells in vivo

Data from many laboratory and clinical investigations indicate that CD34+ cells comprise approximately 1% of human bone marrow (BM) mononuclear cells, including the progenitor cells of all the lymphohematopoietic lineages and lymphohematopoietic stem cells (stem cells). Because stem cells are an important but rare cell type in the CD34+ cell population, investigators have subdivided the CD34+ cell population to further enrich stem cells. The CD34+/CD38- cell subset comprises less than 10% of human CD34+ adult BM cells (equivalent to < 0.1% of marrow mononuclear cells), lacks lineage (lin) antigens, contains cells with in vitro replating capacity, and is predicted to be highly enriched for stem cells. The present investigation tested whether the CD34+/CD38- subset of adult human marrow generates human hematopoiesis after transfer to preimmune fetal sheep. CD34+/ CD38- cells purified from marrow using immunomagnetic microspheres or fluorescence-activated cell sorting generated easily detectable, long- term, multilineage human hematopoiesis in the human-fetal sheep in vivo model. In contrast, transfer of CD34+/CD38+ cells to preimmune fetal sheep generated only short-term human hematopoiesis, possibly suggesting that the CD34+/CD38+ cell population contains relatively early multipotent hematopoletic progenitor cells, but not stem cells. This work extends the prior in vitro evidence that the earliest cells in fetal and adult human marrow lack CD38 expression. In summary, the CD34+/ CD38- cell population has a high capacity for long-term multilineage hematopoietic engraftment, suggesting the presence of stem cells in this minor adult human marrow cell subset.     

Rupture of mitral chorda tendinea following blunt chest trauma

Acute mitral insufficiency, originated from rupture of mitral chordae tendineae secondary to nonpenetrating thoracic trauma, is an unusual condition. This diagnosis is difficult to establish because physical examination, electrocardiogram, and cardiac enzymes are neither sensitive nor specific. The diagnosis of rupture must be quickly established because this disorder may be fatal. This paper reports the case of a patient with acute mitral insufficiency secondary to a mitral valve chord rupture a week after a nonpenetrating thoracic trauma.     

Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow

In the course of ontogeny, the homing site for the hematopoietic stem cells (HSC) moves with certain predictability from the yolk sac to the liver/spleen and then to the marrow. The pattern of this migration has thus far been established mostly on a morphologic basis. To delineate further the course of this migration and to gain insight into its possible mechanism, we used in utero transplantation of allogeneic or xenogeneic HSC in preimmune sheep fetuses. Sex chromosome, type of hemoglobin, and species-specific surface markers were used to follow the path of transplanted cells in the fetus. Before the development of the bone marrow, transplanted HSC (liver- or marrow-derived) homed exclusively to the liver/spleen. With the development of marrow, around day 60 of gestation (term, 145 days), homing occurred also in the nascent marrow and by day 80 transplanted cells homed exclusively to the marrow. This suggests that there may be a hierarchy in homing sites, with those of the marrow having higher affinity than those of liver/spleen. Interestingly, despite a change in homing that was followed by the expansion of the marrow compartment of HSC (ie, HSC proliferation), these cells did not participate actively in blood cell formation during most of the prenatal period. Liver remained the major hematopoietic organ throughout the gestation. It was only during the perinatal period that this organ assumed the function of hematopoiesis from the liver. This lack of expression of HSC in fetal marrow can possibly be attributable to the immaturity of marrow stroma required for differentiation and maturation of progenitors and the orderly egress of mature cells into the blood stream. The availability of this model allows us to begin studies in the molecular mechanism of stem cell homing in vivo during ontogeny.     

Gastric emptying in Type II (non-insulin-dependent) diabetes mellitus before and after therapy readjustment: no influence of actual blood glucose concentration

Aims/hypothesis. Hyperglycaemia that is induced short-term slows gastric emptying in healthy subjects and patients with diabetes mellitus. Little information is available on the impact of longer-lasting, naturally occurring blood glucose increases and their reduction to euglycaemic values. We studied the relation between gastric emptying and pre-prandial and postprandial blood glucose concentrations in patients with Type II (non-insulin-dependent) diabetes mellitus and secondary failure to respond to oral hypoglycaemic treatment (a) before readjusting hypoglycaemic therapy and (b) 1 week thereafter.¶Methods. We studied 9 female and 1 male patient (age 60–78 years, BMI 21.9–32.5 kg/m², diabetes duration 3–33 years, HbA_{1 c} 8.8–13.2 %). Gastric emptying of a radiolabelled semisolid 1168 kJ meal was recorded scintigraphically.¶Results. Blood glucose concentration pre-prandial and postprandial was considerably lower subsequent to than before therapy readjustment in all patients (fasting, 7.9 mmol/l ± 1.5 SD vs 11.7 ± 1.7 mmol/l; 60 min postprandial, 11.7 ± 2.0 vs 15.4 ± 2.2 mmol/l). By contrast, gastric emptying was unchanged (residual radioactivity in stomach 50 min postprandial 65.7 ± 14.1 % vs 66.5 ± 12.9 %). There was no relation between emptying and either fasting blood glucose concentration or its postprandial increase.¶Conclusion/interpretation. The data do not support a major impact of actual, longer-lasting, naturally occurring blood glucose concentrations upon the rate of gastric emptying in patients with Type II diabetes. [Diabetologia (1999) 42: 1410–1412]     

Evaluating glucose-lowering treatment in older people with diabetes: Lessons from the IMPERIUM trial

Understanding the benefits and risks of treatments to be used by older individuals (≥65 years old) is critical for informed therapeutic decisions. Glucose-lowering therapy for older patients with diabetes should be tailored to suit their clinical condition, comorbidities and impaired functional status, including varying degrees of frailty. However, despite the rapidly growing population of older adults with diabetes, there are few dedicated clinical trials evaluating glucose-lowering treatment in older people. Conducting clinical trials in the older population poses multiple significant challenges. Despite the general agreement that individualizing treatment goals and avoiding hypoglycaemia is paramount for the therapy of older people with diabetes, there are conflicting perspectives on specific glycaemic targets that should be adopted and on use of specific drugs and treatment strategies. Assessment of functional status, frailty and comorbidities is not routinely performed in diabetes trials, contributing to insufficient characterization of older study participants. Moreover, significant operational barriers and problems make successful enrolment and completion of such studies difficult. In this review paper, we summarize the current guidelines and literature on conducting such trials, as well as the learnings from our own clinical trial (IMPERIUM) that assessed different glucose-lowering strategies in older people with type 2 diabetes. We discuss the importance of strategies to improve study design, enrolment and attrition. Apart from summarizing some practical advice to facilitate the successful conduct of studies, we highlight key gaps and needs that warrant further research.     

Orbital volume and surface after Le Fort III advancement in syndromic craniosynostosis

There are no quantitative standards for the volumetric measurements of the orbital cavity after Le Fort III advancement. Computed tomography (CT) scan images have given the opportunity to compare with accuracy the real anatomic changes and potentially the functional improvements that resulted after a surgical treatment.Three-dimensional CT scan images processed by DICOM files in Dolphin 3D Software were used to assess orbital volume and surface in 12 subjects affected by craniofacial syndromic malformations treated with Le Fort III advancement. The preoperative (T0) and postoperative (T1: 6 months after surgery) three-dimensional craniofacial CT scans of the subjects were collected and retrospectively analyzed. Image segmentation of the anatomic orbital cavity and the three-dimensional graphic rendering were done by using the Dolphin Imaging Plus 11.0 software.The orbital volume was increased after surgery, with statistical significance, from 22,267 to 22,706.3 mm(3) in the right eye and from 26,511 mm(3) to 26,256.4 mm(3) in the left eye. The surface of both bony orbits had an expansion, which is statistically significant. In conclusion, this study showed that the orbital advancement in white subjects after Le Fort III advancement was significant and produced a significant augmentation of the orbital volume and surface area with correction of the ocular bulb proptosis.     

Molecular pathology and genetics of pancreatic endocrine tumours

Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.