MKK4 and metastasis suppression: a marriage of signal transduction and metastasis research

MAP kinase kinase 4 (MKK4) is a member of the stress-activated protein kinase (SAPK) signaling cascade and is involved in the regulation of many cellular processes. We have recently demonstrated a functional role for MKK4 in the suppression of metastases. In this review, we discuss the established cellular and biochemical functions of MKK4, as well as a new function for MKK4 as a metastasis suppressor gene. Because of the importance of signaling studies to this translational work, a detailed example of the strategy and tools that can be employed to define the biochemical mechanism of MKK4-mediated metastasis suppression is presented. Finally, the potential therapeutic utility of these findings is discussed.     

Incidence of risk factors in parents with acute myocardial infarction at young age and in their children

INTRODUCTION: The preliminaries of the cardiovascular diseases can be traced back to the childhood. The authors tried to find relationship between parents with early onset myocardial infarction (AMI) and incidence of risk factors for ischemic heart disease in their children as compared to respective data for families with no incidence of myocardial infarction. METHODS: The study population consisted of 38 persons with early onset AMI myocardial infarction (age < 55 y) and their 66 children, and 38 adult control subjects and their 33 children. In each person arterial blood pressure, body weight, body height, waist circumference were recorded and body mass index (BMI: kg/m2) was calculated. Eating habits and life style practices were recorded in a questionnaire in the case of each participant. Laboratory variables were determined in the blood sera as follows, glucose, triglycerides (Tg), total cholesterol (T-C), HDL-cholesterol, LDL-cholesterol, apolipoprotein-A, apolipoprotein-B, and lipoprotein (a). The atherogenic index (LDL-C/HDL-C) (LDL-cholesterol/HDL-cholesterol) was also calculated. STATISTICAL EVALUATION: Data were evaluated statistically using the SPSS for Windows 9. RESULTS: According to the mean BMI values all groups of parents belonged to the overweight category. The mean cholesterol levels of all adults were in the borderline high category. In males with early onset myocardial infarction sera concentrations of HDL-cholesterol and apolipoprotein-A were significantly lower, whereas triglyceride and atherogenic index were significantly higher than respective data for control parents. In all groups of parents, fasting mean serum glucose concentrations were higher than the reference value, serum total-cholesterol concentrations were in the borderline high category. In the daughter of the parents with early onset myocardial infarction had a higher atherogenic index than that of controls. Eating habits did not essentially differ between case vs. control families. Consumption of milk, dairy products, fruit and vegetables was insufficient in each group. Incidences of smoking for parents and children were 55% and 35% in the myocardial infarction group and 44% and 37% in the control group, respectively. Physical activity was completely insufficient in each group studied. CONCLUSION: Since no considerable differences were seen between the case vs control families in the parameters tested, therefore it is presumed that the offspring born to parents with or without early onset myocardial infarction are at equal risk to develop cardiovascular diseases unless lifestyle practices are profoundly changed.     

CT halo sign in pulmonary metastases from mucinous adenocarcinoma of the pancreas

The CT halo sign was first described in immunocompromised patients with invasive pulmonary aspergillosis. Although the halo sign was originally thought to be specific for invasive pulmonary aspergillosis, it has been reported in a wide variety of pulmonary abnormalities in both immununocompromised and immunocompetent patients. We report a case of mucinous adenocarcinoma of the pancreas metastatic to the lungs in which there were multiple pulmonary nodules showing the halo sign. This case further illustrates the nonspecific nature of the CT halo sign and the need to consider malignancy as a cause in immunocompetent patients.     

A comparative study of hemorheological parameters in transient ischemic attack and acute ischemic stroke patients: possible predictive value

A complete neurological and laboratory assessment was made of 31 transient ischemic attack (TIA) and 33 acute ischemic stroke patients. Laboratory parameters were compared with 33 age- and sex-matched controls. Erythrocyte deformability was characterised by determining the relative cell transit time (RCTT) with a St. George filtrometer. Plasma viscosity was measured with a Haake microviscosimeter. In comparison with controls, fibrinogen content, erythrocyte sedimentation rate (ESR), platelet and leukocyte count, erythrocyte RCTT and plasma viscosity were found to be significantly higher in stroke patients. In TIA patients the elevation of these values was not significant with the exception of platelet count. Our results suggest that the hemorheological alterations observed in TIA and stroke are largely non-specific findings and associated with the atherosclerotic disease of patients. The significant elevation of leukocytes, fibrinogen and plasma viscosity in acute stroke versus TIA probably reflects the systemic acute phase response of organism to cerebral infarction.     

Calcium distribution in the vessel wall and intima-media thickness of the human carotid arteries

Increased common carotid artery (CCA) intima-media thickness (IMT) measured by B-mode ultrasound is an early marker of the atherosclerotic process. Arterial calcification is not clearly understood. Using the particle-induced X-ray emission (PIXE) method, we have looked for the location in the artery wall where calcium accumulated in the early phase of atherosclerosis. Twelve segments of CCAs of deceased stroke patients were investigated. In-vivo, carotid duplex ultrasound was performed with bilateral CCA IMT measurement at plaque-free sections. During autopsy, segments of carotid arteries were collected and filled under pressure with a stained histologic embedding material. The frozen arteries were cut into 60-microm-thick slices. Calcium distribution maps from the segments of arteries were determined by PIXE method. IMT measured by ultrasound and calcium distribution maps measured by PIXE were compared. In our cross-sectional study, using the PIXE analysis and ultrasound images, we could demonstrate early calcium accumulation in the media layer. Our results have also shown a significant relationship between calcium content of distributional maps measured by PIXE analysis and corresponding IMT on B-mode ultrasound images of human CCAs.     

Ventriculosubgaleal shunt in the treatment of posthemorrhagic and postinfectious hydrocephalus of premature infants

Purpose

The aim of the study was to compare the characteristics of ventriculosubgaleal shunts during the clinical course of posthemorrhagic and postinfectious hydrocephalus in the neonatal period.

Patients and methods

The study comprised 102 premature babies in whom subgaleal shunt was consecutively inserted between 2006 and 2011. Seventy-two patients had posthemorrhagic hydrocephalus (mean gestational age 27.3?±?2.1 weeks, mean birth weight 1,036.9?±?327.7 g, mean age at insertion 51.4?±?56.2 days) and 30 patients were operated postinfectiously (27.5?±?2.2 weeks, 1,064.7 g?±?310.7 g, 115.9?±?47.8 days).

Results

The mean survival of subgaleal shunts was 87.9 days for the posthemorrhagic group and 75.6 days for the postinfectious group. Only six infants (8.3 %) did not need ventriculoperitoneal shunts later, all posthemorrhagic. There were meaningful differences between two groups with regard to ventriculosubgaleal shunt-related infections (8.3 % in posthemorrhagic versus 20.0 % in postinfectious) and shunt revision rate (6.9 % in posthemorrhagic versus 13.3 % in postinfectious), but these were not statistically significant. The need of ventriculoscopic procedures was notably more frequent in postinfectious group (1.4 versus 23.3 %).

Conclusion

In premature infants with ventriculomegaly, the subgaleal shunt is an effective temporary diversion tool. The complications were less with posthemorrhagic than with postinfectious hydrocephalus. With previous severe infections of prematures, the risk for complications regarding infection and obstruction will be 2.75 and 2.06 (odds ratios) times higher and more frequent need of ventriculoscopic procedures should be considered (odds ratio 21.6).     

Fenestration of the middle cerebral artery and aneurysm at the site of the fenestration

Abstract

The authors report the case of a patient who presented a ruptured aneurysm of the anterior communicating artery and an unruptured aneurysm of the middle cerebral artery arising at the site of a fenestration of the MCA. The fenestration was undiagnosed on the preoperative angiogram but discovered during the surgery carried out for clipping of the aneurysms. In the literature, cases of fenestration of the MCA are sporadically reported and are incidental findings; an aneurysm may be associated on an artery other than the fenestrated MCA; an aneurysm arising at the site of the MCA fenestration is a very rare occurrence.     

Angiogenic profile of uveal melanoma

Uveal melanoma develops in one of the most capillary-rich tissues of the body and is disseminated hematogenously. Knowledge of the nature and the spatiotemporal expression of angiogenic factors in uveal melanoma is essential to the development of new treatment strategies, especially with regard to improving survival. In this study, we measured the angiogenic potential of several angiogenic factors in different uveal melanoma cell lines, in an in vivo model, and in primary tumor material from patients with melanoma. Most uveal melanoma cell lines expressed vascular endothelial growth factor (VEGF)-A (isoforms 121, 165, 189), VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF) to various extents. The expression of VEGF-A 121 was always higher than that of the other VEGF-A isoforms, suggesting that VEGF-A 121 is the most abundant VEGF-A isoform. All experimentally induced tumors expressed VEGF-A, VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF). Similarly, significant amounts of mRNA for VEGF-B, VEGF-C, VEGF-D, and b-FGF were detected in uveal melanoma material from patients. In contrast, VEGF-A mRNA (121, 165, 189) was low (9/28) or not detectable in the tumor samples. The synthesis of VEGF-A 165 and b-FGF protein by various cell lines was measured by enzyme-linked immunosorbent assay (ELISA). Most uveal melanoma cell lines, but not normal melanocytes, strongly synthesized and secreted VEGF-A 165 and b-FGF during cell culture. Our data suggest that the expression of (lymph) angiogenic factors may play a causal role in the angiogenesis and progression of uveal melanoma and distant metastasis.     

Muscarine receptor types mediating autoinhibition of acetylcholine release and sphincter contraction in the guinea-pig iris

Summary The potencies of several muscarine receptor antagonists in blocking either the autoinhibition of acetylcholine release or the muscarinic contraction of the sphincter muscle upon acetylcholine release were investigated in the guinea-pig iris. The agonist at pre- or postjunctional muscarine receptors was acetylcholine released upon field stimulation (5.5 Hz, 2 min) of the irides preloaded with ¹⁴C-choline. The stimulation-evoked ¹⁴C-overflow was doubled in the presence of atropine 0.1 mol/l but unaffected by the agonist (±)-methacholine (50 mol/l). Thus, under the present stimulation conditions, the autoinhibition of acetylcholine release on the guinea-pig iris cholinergic nerves was nearly maximally activated. Isotonic contractions of the irides upon field stimulation consisted of a rapid, atropine (0.1 mol/l). peak phase followed by a sustained contraction which involved a cholinergic and a non-cholinergic stimulation of the sphincter muscle. The M₂-selective antagonists methoctramine (10 mol/l) and gallamine (100 µmol/l). increased both the ¹⁴Goverflow and the peak contractions evoked by field stimulation. In contrast, the M₃-selective antagonist hexahydrosiladifenidol (0.1–10 mol/l) failed to affect the evoked ¹⁴C-release but concentration-dependently (1–10 mol/l) reduced the iris contractions. Pirenzepine (10 mol/l) enhanced the evoked ¹⁴C-overflow and inhibited the peak contractions (0.1–10 mol/l; maximal effect at 10 mol/l). The low potency of the antagonist at both receptor sites indicates that an M₁ muscarine receptor is not involved. The results are consistent with the idea of M₂ muscarine receptors mediating autoinhibition of acetylcholine release in the guinea-pig iris and M₃-like receptors inducing the contraction of the sphincter muscle. Send offprint requests to I. T. Bognar at the above address