p21(WAF1/Cip1) is not involved in kainic acid-induced apoptosis in murine cerebellar granule cells

Kainic acid (KA) treatment induced neuronal death and apoptosis in murine cerebellar granule cells (CGNs) cultures from both wild-type and knockout p21(-/-) mice. There was not statistically significant difference in the percentage of neuronal apoptosis among strains. KA-induced neurotoxicity was prevented in the presence of NBQX (20 microM) and GYKI 52446 (20 microM), but not by z-VAD-fmk, suggesting that caspases are not involved in the apoptotic process. Data suggest that p21(WAF/Cip) was unable to modulate KA-induced apoptosis in murine CGNs.     

Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates

Proprotein convertase substilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein (LDL) receptor (LDLR) and thereby increases serum LDL-cholesterol (LDL-C). We have developed a humanized monoclonal antibody that recognizes the LDLR binding domain of PCSK9. This antibody, J16, and its precursor mouse antibody, J10, potently inhibit PCSK9 binding to the LDLR extracellular domain and PCSK9-mediated down-regulation of LDLR in vitro. In vivo, J10 effectively reduces serum cholesterol in C57BL/6 mice fed normal chow. J16 reduces LDL-C in healthy and diet-induced hypercholesterolemic cynomologous monkeys, but does not significantly affect high-density lipoprotein-cholesterol. Furthermore, J16 greatly lowered LDL-C in hypercholesterolemic monkeys treated with the HMG-CoA reductase inhibitor simvastatin. Our data demonstrate that anti-PCSK9 antibody is a promising LDL-C-lowering agent that is both efficacious and potentially additive to current therapies.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

CD14 and CD169 expression in human lymph nodes and spleen: specific expansion of CD14+CD169- monocyte-derived cells in diffuse large B-cell lymphomas

The mononuclear phagocyte system of human lymphoid tissue comprises macrophages and dendritic cells (DCs). The heterogeneity of the non-DC mononuclear phagocyte population in human lymphoid tissue has been little addressed. Here, we studied the expression of 2 monocyte-derived markers, CD14 and CD169 (sialoadhesin), in reactive human lymphoid tissue as well as in a series of 51 B-cell lymphomas by immunohistochemistry on paraffin-embedded tissue. We confirmed that lymph node sinusoidal monocyte-derived cells were the only population staining for CD169. Although most sinusoidal histiocytes also expressed CD14, monocyte-derived cells with phagocytosis such as erythrophagocytosis, anthracosis, or tingible bodies macrophage lacked CD14 and CD169. Among B-cell lymphomas, splenic marginal zone lymphoma was the only one associated with an expansion of the CD14(+)CD169(+) cells in the cords. With respect to nodal B-cell lymphomas, CD14(+) cells were rare among B-chronic lymphocytic leukemia, follicular lymphoma (FL), mantle cell lymphoma (MCL). However, strikingly, we found a strong expansion of CD14(+)CD169(-) cells in numerous diffuse large B-cell lymphomas (DLBCLs), except in cases associated with numerous mitoses, apoptotic bodies, and tingible bodies macrophages. When cultivated in granulocyte/macrophage colony stimulating factor/interleukin 4, DLBCL purified CD14(+) cells differentiate into plasmacytoid cells, expressing DC-specific intercellular adhesion molecule 3-grabbing nonintegrin, suggesting dendritic cell differentiation potential. Our observation fits well with the lymph node and host response cluster signatures described in the gene profiling signatures of DLBCL. However, the role of this CD14(+) population that may constitute a microenvironment-related marker of this subgroup of DLBCL remains to be determined.     

Hypertrophic cardiomyopathy in mucopolysaccharidoses: Regression after bone marrow transplantation

Summary Mucopolysaccharide storage disease (MPS) presents clinically with a broad spectrum of abnormalities, among which cardiovascular involvement has been described.The echocardiographic findings have recently been reported for the various types of MPS. Among these, asymmetric septal hypertrophy (ASH) has been documented.We present a case of a 9-year-old girl suffering from type I MPS, atypical variant, with echocardiographic signs of ASH. She was given a bone marrow transplant after which the hypertrophic cardiomyopathy regressed.     

Influence of talc dose on extrapleural talc dissemination after talc pleurodesis

This study was designed to ascertain, in a rabbit model, extrapleural talc deposition and the related inflammatory response after talc slurry pleurodesis with two clinical doses, 200 and 50 mg/kg. Histopathologic evaluations revealed that whereas numerous rabbits receiving a high dose had talc in the ipsilateral (70%) and contralateral (55%) lung, mediastinum (90%), pericardium (30%), and liver (25%), a small number of animals treated with a low dose showed talc in the ipsilateral lung (10%) and mediastinum (20%) and none in the contralateral lung, pericardium, or liver. Hematologic and immunocytochemical analyses showed that a systemic inflammatory response develops shortly after pleurodesis with a high talc dose involving massive accumulation of neutrophils and macrophages in lung tissue. Zymography also revealed that the pulmonary expression of matrix metalloproteinases 2 and 9 was up-regulated in both lungs in a dose-dependent manner soon after talc instillation. Furthermore, microscopic examination of lung specimens revealed that the higher the dose of talc, the greater the development of both fibrotic visceral pleural thickening and foreign-body granulomas. These findings show pleurodesis with a high talc dose to be associated with an increased risk of extrapleural talc deposition, which may originate undesirable acute and chronic inflammatory responses.     

Postoperative cognitive dysfunction in middle-aged patients

BACKGROUND: Postoperative cognitive dysfunction (POCD) after noncardiac surgery is strongly associated with increasing age in elderly patients; middle-aged patients (aged 40-60 yr) may be expected to have a lower incidence, although subjective complaints are frequent. METHODS: The authors compared the changes in neuropsychological test results at 1 week and 3 months in patients aged 40-60 yr, using a battery of neuropsychological tests, with those of age-matched control subjects using Z-score analysis. They assessed risk factors and associations of POCD with measures of subjective cognitive function, depression, and activities of daily living. RESULTS: At 7 days, cognitive dysfunction as defined was present in 19.2% (confidence interval [CI], 15.7-23.1) of the patients and in 4.0% (CI, 1.6-8.0) of control subjects (P < 0.001). After 3 months, the incidence was 6.2% (CI, 4.1-8.9) in patients and 4.1% (CI, 1.7-8.4) in control subjects (not significant). POCD at 7 days was associated with supplementary epidural analgesia and reported avoidance of alcohol consumption. At 3 months, 29% of patients had subjective symptoms of POCD, and this finding was associated with depression. Early POCD was associated with reports of lower activity scores at 3 months. CONCLUSIONS: Postoperative cognitive dysfunction occurs frequently but resolves by 3 months after surgery. It may be associated with decreased activity during this period. Subjective report overestimates the incidence of POCD. Patients may be helped by recognition that the problem is genuine and reassured that it is likely to be transient.     

Glial expression of small heat shock proteins following an excitotoxic lesion in the immature rat brain

Heat shock proteins (HSPs) are chaperones induced under pathological conditions and involved in protein stabilization and cellular protection. In this study, we have evaluated the expression pattern of the glial cell-related HSP27, HSP32, and HSP47 following an excitotoxic lesion in the immature rat brain. Postnatal day 9 rats received an intracortical injection of N-methyl-D-aspartate and tissue was processed immunohistochemically for HSPs and double labeling using astroglial and microglial markers. HSP expression was quantified by image analysis. Excitotoxic damage caused primary cortical degeneration and secondary damage in the corresponding thalamus. In the injured cortex, reactive microglia/macrophages expressed HSP32 from 10 h until 14 days postlesion (PL), showing maximal levels at days 3-5. In parallel, most cortical reactive astrocytes showed expression of HSP47 from 10 h until 14 days PL and a population of them also displayed HSP27 labeling from 1 day PL. In addition, some cortical reactive astrocytes showed a temporary expression of HSP32 at day 1. In general, astroglial HSP expression in the cortex achieved maximal levels at days 3-5 PL. In the damaged thalamus, HSP32 was not significantly induced, but reactive astrocytes expressed HSP47 and some of them also HSP27. Thalamic astroglial HSP induction was transient, peaked at 5 days PL and reached basal levels by day 14. The injury-induced expression of HSP32, HSP27, and HSP47 in glial cells may contribute to glial cell protection and adaptation to damage, therefore playing an important role in the evolution of the glial response and the excitotoxic lesion outcome. HSP32 may provide antioxidant protective mechanisms to microglia/macrophages, whereas HSP47 could contribute to extracellular matrix remodeling and HSP27 may stabilize the astroglial cytoskeleton and participate in astroglial antioxidant mechanisms.     

Disseminated retroperitoneal choriocarcinoma with open fistula to intestine. «Restitutio ad integrum» with chemotherapy alone

We hereby present a clinical case of a germinal tumour with a pulmonary and retroperitoneal dissemination in form of a great adenopathic mass that fistulizes into the duodenum, that obtained a complete resolution with chemotherapy.