Natural history and familial characteristics of isolated left ventricular non-compaction.

AIMS: Non-compaction of the left ventricle (LVNC) is a disorder of endomyocardial morphogenesis that results in multiple trabeculations in the left ventricular myocardium. The current literature suggests that LVNC in adults is rare and associated with a poor prognosis. Given that the disorder is present at birth and that several studies have reported asymptomatic familial disease in some patients, we hypothesized that there is a long pre-clinical phase of the disease. The aim of this study was to define the prognosis and familial incidence of LVNC. METHODS AND RESULTS: This study cohort comprised 45 patients (mean age at diagnosis 37 years) consecutively identified at a referral centre for cardiomyopathy over a 10-year period. Twenty-eight patients (62%) had dyspnoea at presentation; 41 (91%) an abnormal ECG; and 30 (66%) left ventricular dilatation and impaired systolic function. Nine patients (20%) had non-sustained ventricular tachycardia on 24 h Holter monitoring. Mean survival from death or transplantation was 97% at 46 months. There were three thromboembolic events in two patients (4%). On systematic family screening, 8 of 32 (25%) asymptomatic relatives had a range of echocardiographic abnormalities, including LVNC, LVNC with impaired systolic function, and left ventricular enlargement without LVNC. CONCLUSION: This study demonstrates that LVNC is associated with a better prognosis than previously reported. In patients with familial disease, relatives may have features consistent with dilated cardiomyopathy rather than LVNC.     

The effect of macrophage colony-stimulating factor on haemopoietic recovery after autologous bone marrow transplantation

Macrophage colony-stimulating factor (M-CSF) is active in the late stages of monocyte maturation, activates mature monocyte-macrophages and enhances their production of various other cytokines. We have examined the effects of a 21 d course of escalating doses of M-CSF purified from human urine (hM-CSF) on recovery following autologous bone marrow transplantation (ABMT) in 20 patients with malignant lymphomas. Four patients were treated at each dose level of 4, 8, 16, 32 and 64 x 10(6) U/m2/d and results compared to 46 concurrent controls. There was no significant difference in recovery to an absolute neutrophil count (ANC) of 0.5 x 10(9)/l (median 20 d in hM-CSF group versus 22 in controls) or in recovery of platelets to 50 x 10(9)/l (32 d versus 39 d, 0.05 less than P less than 0.1); hM-CSF patients received a median of 81 platelet units following ABMT (controls 112 units, P = NS). hM-CSF patients had a median of 5.5 d with fever greater than 37.5 degrees C (control 8, P = NS), received parenteral antibiotics for 14.5 d (control 17, P = NS) and had a 50% incidence of bacteraemia (control 48%). hM-CSF treated patients were discharged by a median of day 29 following transplantation (control 33, P less than 0.05). Platelet and neutrophil recovery correlated significantly with the number of marrow mononuclear cells (MNC) reinfused in the hM-CSF group (P = 0.05 and P = 0.014 respectively) but not in controls. Subgroup analysis showed that hM-CSF patients receiving greater than 2 x 10(8) MNC/kg body weight reached an ANC of 0.5 x 10(9)/l by a median of day 16.5 (control 18.5, NS), became platelet transfusion independent by day 17 (control 29, P less than 0.05) and reached a platelet count of 50 x 10(9)/l by day 21 (control 40, P less than 0.05). No significant toxicity attributable to hM-CSF treatment was seen. These results suggest that hM-CSF accelerates platelet recovery following ABMT and that relatively large marrow innocula are required to see this effect.     

Association of extent and infection of pancreatic necrosis with organ failure and death in acute necrotizing pancreatitis.

BACKGROUND & AIMS: Organ failure is the usual cause of death in acute necrotizing pancreatitis. Our objective was to study whether the extent and infection of pancreatic necrosis correlate with organ failure and mortality. METHODS: All consecutive patients with acute pancreatitis were prospectively studied. They underwent a detailed clinical and investigative evaluation. Pancreatic necrosis, diagnosed on a computed tomography scan, was graded as <30%, 30%-50%, and >50% necrosis and characterized as either sterile or infected. Logistic regression analysis was done to find out the association of the extent and infection of pancreatic necrosis with organ failure and mortality. RESULTS: Of 276 patients (mean age, 41.25 years; 172 men), 104 had pancreatic necrosis: 30 had <30% necrosis, 37 had 30%-50% necrosis, and 37 had >50% necrosis; 74 had sterile necrosis, and 30 had infected necrosis. Of them, 37 (35%) patients developed organ failure. Two significant factors were associated with the development of organ failure, the extent of necrosis (<30% necrosis vs 30%-50% necrosis: P = .03; odds ratio [OR], 5.82; 95% confidence interval [CI], 1.15-29.45; <30% necrosis vs >50% necrosis: P = .0004; OR, 18.86; 95% CI, 3.75-94.92) and infected pancreatic necrosis (P = .02; OR, 3.29; 95% CI, 1.17-9.24). The overall mortality was 22%. Infected pancreatic necrosis (P = .006; OR, 4.99; 95% CI, 1.56-16.02) and Acute Physiology, Age, and Chronic Healthy Evaluation II score (P = .004; OR, 1.28; 95% CI, 1.08-1.52) were 2 independent predictors of mortality. CONCLUSIONS: Extent of necrosis and infected pancreatic necrosis were associated with the development of organ failure in patients with acute necrotizing pancreatitis. Infected pancreatic necrosis was the most significant predictor of mortality.     

Novel role of lactosylceramide in vascular endothelial growth factor-mediated angiogenesis in human endothelial cells

Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with coronary heart disease, vascular complications in diabetes, inflammatory vascular diseases, and tumor metastasis. The mechanism of VEGF-driven angiogenesis involving glycosphingolipids such as lactosylceramide (LacCer), however, is not known. To demonstrate the involvement of LacCer in VEGF-induced angiogenesis, we used small interfering RNA (siRNA)-mediated silencing of LacCer synthase expression (GalT-V) in human umbilical vein endothelial cells. This gene silencing markedly inhibited VEGF-induced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and angiogenesis. Second, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of LacCer synthase and glucosylceramide synthase, that significantly mitigated VEGF-induced PECAM-1 expression and angiogenesis. Interestingly, these phenotypic changes were reversed by LacCer but not by structurally related compounds such as glucosylceramide, digalactosylceramide, and ceramide. In a human mesothelioma cell line (REN) that lacks the endogenous expression of PECAM-1, VEGF/LacCer failed to stimulate PECAM-1 expression and tube formation/angiogenesis. In REN cells expressing human PECAM-1 gene/protein, however, both VEGF and LacCer-induced PECAM-1 protein expression and tube formation/angiogenesis. In fact, VEGF-induced but not LacCer-induced angiogenesis was mitigated by SU-1498, a VEGF receptor tyrosine kinase inhibitor. Also, VEGF/LacCer-induced PECAM-1 expression and angiogenesis was mitigated by protein kinase C and phospholipase A2 inhibitors. These results indicate that LacCer generated in VEGF-treated endothelial cells may serve as an important signaling molecule for PECAM-1 expression and in angiogenesis. This finding and the reagents developed in our report may be useful as anti-angiogenic drugs for further studies in vitro and in vivo.     

Endotherapy for pain in chronic pancreatitis

Pain is the most distressing symptom of chronic pancreatitis. Although the pathogenesis of pain is still poorly understood, an increase in intraductal pressure may be the dominant factor. The management of pain can involve medical, endoscopic, neurolytic, and surgical therapies. Endotherapy includes pancreatic sphincterotomy, extraction of stones, placement of stent, and dilatation of strictures, sometimes preceded or followed by extracorporeal shock‐wave lithotripsy. Several studies have now shown that endotherapy provides partial or complete relief of pancreatic pain in a majority of patients with an acceptable frequency of early and late complications. Endotherapy should now graduate from an experimental form of treatment to a realistic treatment option in patients with chronic or relapsing pain, particularly in the setting of calcific chronic pancreatitis.     

Cigarette smoking exacerbates and its cessation ameliorates renal injury in type 2 diabetes

BACKGROUND: Patients with type 2 diabetes and macroalbuminuria generally experience progressive glomerular filtration rate (GFR) decline despite angiotensin-converting enzyme inhibition (ACEI) and blood pressure (BP) control but this therapy generally stabilizes GFR in those without macroalbuminuria. Cigarette smoking exacerbates GFR decline in patients with type 2 diabetes and macroalbuminuria despite ACEI and BP control; whether this therapy prevents nephropathy progression in nonmacroalbuminuric type 2 diabetic smokers is unknown. METHODS: We determined the course of urine excretion of indices of renal injury that distinguished patients with type 2 diabetes with and without macroalbuminuria but with normal plasma creatinine who were prospectively followed 6 months while receiving ACEI and BP control. We compared this course in nonsmokers and smokers with normo-, micro-, and macroalbuminuria (n = 157) and in response to smoking cessation in a separate cohort (n = 80) with microalbuminuria. RESULTS: Urine excretion of transforming growth factor beta-1 (UTGFbetaV) increased in macroalbuminuric but not in nonmacroalbuminuric nonsmokers and UTGFbetaV rate was higher in smokers than nonsmokers within each albuminuria group. In the separate microalbuminuric cohort, the rate of UTGFbetaV change for quitting smokers was not different from nonsmokers (0.093 versus -0.123 ng/g of creatine/week, P = not significant) but that for nonquitting smokers (0.970) was higher than nonsmokers (P = 0.017). CONCLUSIONS: Patients with type 2 diabetes who are at high risk compared with low risk for nephropathy progression have progressive renal injury as measured by increasing UTGFbetaV. Cigarette smoking exacerbates renal injury in type 2 diabetes despite BP control and ACEI, but its cessation in those with microalbuminuria ameliorates the progressive renal injury caused by continued smoking.