Current insights into the German lipoprotein apheresis standard: PCSK9-inhibitors, lipoprotein apheresis or both?

According to current European guidelines, lipid lowering therapy for progressive cardiovascular disease including cardiovascular events has to be focused on a target level for LDL-C. In contrast for Lp(a) a threshold has to be defined with respect to the method of measurement. However, due to new lipid lowering drug developments like PCSK9-inhibitors (PCSK-9-I) a therapeutic algorithm for patients with severe hypercholesterolemia or isolated Lipoprotein(a)-hyperlipoproteinemia with progressive cardiovascular disease may be necessary to manage the use of PCSK9-I, lipoprotein apheresis (LA) or both. The therapeutic approach for patients with homozygous familial hypercholesterolemia is unambiguous: In addition to LA, in order to improve LDL-C reduction, PCSK9-I could be applied. In patients with heterozygous familial hypercholesterolemia, PCSK9-I is to be applied first. If in addition to a pronounced LDL-C elevation, cardiovascular complications exist or if imaging techniques documented atherosclerotic changes pre-disposing for a cardiovascular event while LDL-C reduction is insufficiently reduced (LDL-C > 100 mg/dl (2.6 mmol/l)), LA treatment should then be applied as last resort. In patients with elevated Lp(a) concentrations (Lp(a) > 60 mg/dl (>120 nmol/l)) and established cardiovascular disease, therapy should rely primarily on LA methods. If in addition to high Lp(a) levels insufficiently treated LDL-C concentrations (LDL-C > 100 mg/dl (2.6 mmol/l)) exist, in rare cases PCSK9-I can supplement the lipid lowering concept.

Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma.

Proliferation of fibrotic tissue (desmoplasia) is one of the hallmarks of several epithelial tumors including pancreatic adenocarcinoma. This tissue reaction may be deleterious or advantageous to the host or tumor. In a systematic analysis, we identified two growth factors expressed by human pancreatic carcinoma cells that are positively correlated with the ability to induce fibroblast proliferation both in vitro and in vivo, i.e., transforming growth factor (TGF)-beta1 and fibroblast growth factor-2. Here we demonstrate that the overexpression of TGF-beta1 induced up-regulation of matrix proteins and growth factors in the TGFbeta1-transfected pancreatic tumor cells. Furthermore, transfection of PANC-1 cells induces the same change in fibroblasts in either cocultivation experiments or when they are grown in conditioned medium from TGF-beta1-transfected PANC-1 cells. TGF-beta1-transfected pancreatic tumor cells induced a rich stroma after orthotopical transplantation in the nude mouse pancreas. The transfer of a single growth factor, TGF-beta1, conveys the ability to induce a fibroblast response similar to that seen in desmoplasia in human pancreatic adenocarcinoma. This effect cannot only be attributed to direct effects of TGF-beta1 but also results from the up-regulation of several other factors including collagen type I, connective tissue growth factor, and platelet-derived growth factor.

Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance.

PURPOSE: Mucins are important biomolecules that frequently display an altered expression under pathological conditions. In a search for a unique and reliable marker(s) specific for pancreatic adenocarcinoma, we investigated the expression of different MUC genes in pancreatic tumors and tumor cell lines, in chronic pancreatitis, and in the normal pancreas. EXPERIMENTAL DESIGN: Total RNA from 16 pancreatic tumors, 10 chronic pancreatitis tissues, 7 normal pancreas tissues, and 15 pancreatic tumor cell lines were analyzed by reverse transcription-PCR with primers specific for MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC6, and MUC7 genes and by RNA slot blot analyses. RESULTS: Our results revealed that of all of the mucins examined, only MUC4 displayed a differential expression that was specific for pancreatic adenocarcinoma. Indeed, a substantial number of tumor tissue samples (12 of 16) and tumor cell lines (11 of 15) expressed MUC4 mRNA, whereas samples from chronic pancreatitis (0 of 10) and the normal pancreas (0 of 7) tissues failed to exhibit any detectable level of this mucin. In contrast, no significant alteration was observed in the expression of the other mucins relative to that in the normal pancreas samples. CONCLUSIONS: Overall, this work demonstrates that pancreatic mucin MUC4 is a tumor-associated mucin. Furthermore, the present study introduces a novel avenue to discriminate between pancreatic adenocarcinoma and pancreatitis. Future investigations of the role played by MUC4 in pancreatic adenocarcinoma may prove to be useful in the formulation of strategies for the diagnosis and therapeutic treatment of this malignancy.

Genetic variants of the renin-angiotensin system and ambulatory blood pressure in essential hypertension.

OBJECTIVE: To examine whether the angiotensinogen M235T and angiotensin converting enzyme insertion/deletion (I/D) variants are related to the severity of hypertension in patients with established essential hypertension. DESIGN: A cross-sectional study. SETTING: The hypertension clinic of the Benjamin Franklin University Hospital, Free University of Berlin. PARTICIPANTS: Three hundred and forty-three consecutive Caucasian patients who presented with treated or untreated (n = 115) hypertension were enrolled into the study. Twenty-two patients were excluded from analysis because they had secondary hypertension. MAIN OUTCOME MEASURES: Angiotensinogen M235T and angiotensin-converting enzyme I/D genotypes, 24 h ambulatory blood pressure values, the number of antihypertensive medications administered and left ventricular dimensions assessed by two-dimensional echocardiography. RESULTS: Neither the angiotensinogen nor the angiotensin converting enzyme genotype was related significantly to the average ambulatory blood pressure and left ventricular dimensions in hypertensives. Furthermore, neither the number of antihypertensive medications administered to treated patients nor blood pressure levels in untreated patients (n = 115) differed significantly between the genotypic groups. CONCLUSIONS: These results do not support the hypothesis that the studied molecular variants of the renin-angiotensin system may represent clinically useful markers of the severity of hypertension in Caucasians with established essential hypertension.

Hpa II polymorphism of the atrial natriuretic peptide gene and the blood pressure response to salt intake in normotensive men.

OBJECTIVE: To test the hypothesis that the Hpa II variant of the atrial natriuretic peptide gene (ANP), which has been reported to be more common among black hypertensives than it is among normotensive controls, is related to the response of blood pressure to salt intake in normotensive Caucasians. METHODS: One hundred and three young (aged 19-35 years) male volunteers were fed a low-salt diet (20 mmol NaCl/day) for 2 weeks and a supplement of either 200 mmol NaCl/day (slow sodium) or placebo for 1 week each in a randomized double-blind cross-over order. Salt sensitivity was defined as a significant (P < 0.05) decrease in resting mean arterial blood pressure by > 3 mmHg under the low-salt diet. The genotype was determined by amplification of genomic DNA extracted from peripheral leukocytes and subsequent digestion of the amplicon with Hpa II restriction enzyme. RESULTS: According to the above definition, 27 subjects were salt sensitive. There were no significant differences in age, body-mass index and waist:hip ratio between the salt-sensitive and salt-resistant groups. Only salt-sensitive subjects displayed a significantly higher blood pressure under the high-salt diet (increase in mean arterial pressure 5.6 +/- 2.4 mmHg, P < 0.001). The prevalence of the ANP-Hpa II wild-type (w) allele did not differ between the salt-sensitive (qw = 1.0, qm = 0) and the salt-resistant group (qw = 0.96, qm = 0.04). Furthermore, the salt-induced response of blood pressure did not differ between homozygotes (ww) and heterozygotes (wm). CONCLUSIONS: Our findings do not support the hypothesis that the ANP-Hpa II polymorphism is a marker for salt sensitivity in young Caucasian normotensives.

Aldosterone synthase gene (CYP11B2) C-344T polymorphism in Caucasians from the Berlin Salt-Sensitivity Trial (BeSST).

OBJECTIVE: Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, the T allele of a polymorphism in the 5'-flanking region of the CYP11B2 gene (C-344T) has been reported to be more frequent in hypertensives than in normotensives, and has also been associated with increased plasma aldosterone levels. We therefore hypothesized that this variant may be related to increased blood-pressure response to dietary salt intake. SUBJECTS AND METHODS: We genotyped 1 63 young normotensive men recruited within the framework of the Berlin Salt-Sensitivity Trial (BeSST) for the CYP11B2 C-344T polymorphism. Subjects were characterized for family history of hypertension, plasma parameters of the renin-angiotensin-aldosterone system and blood-pressure response to a high (220 mmol/day) and low (20 mmol/day) salt diet RESULTS: The frequency of the -344T allele (0.45) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (CC, n = 55; CT, n = 71; TT, n = 37). There was a trend towards a higher frequency of the T allele in subjects with a positive family history of hypertension (0.48 versus 0.42), but the C-344T genotype was not related to blood pressure under either diet Furthermore, when subjects were classified into salt-sensitive and salt-resistant groups, allelic distribution did not differ between the two groups (qT = 0.43 versus qT = 0.45). While renin activity and plasma aldosterone levels were not related to genotype, plasma angiotensinogen was significantly higher in T-allele carriers under both the high (P = 0.02) and low (P = 0.008) salt diet. CONCLUSION: Our findings do not support the hypothesis that the C-344T polymorphism of the CYP11B2 gene is associated with salt sensitivity or increased activity of the renin-angiotensin system in young normotensive subjects. It is, therefore, unlikely that the C-344T polymorphism is a genetic marker for salt sensitivity in young normotensive Caucasian men.

The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus.

A missense mutation of the beta3-adrenergic receptor gene (ADRB3) resulting in a tryptophan/arginine exchange at position 64 (Trp64Arg polymorphism) has recently been associated with greater capacity to gain weight, a low resting metabolic rate, higher blood pressure, and an early onset of type 2 diabetes. These findings prompted us to examine the relationship between this mutation, blood pressure, and vascular complications in German patients with type 2 diabetes. White patients with type 2 diabetes mellitus (n = 417) were enrolled in the study. The Trp64Arg polymorphism of the ADRB3 gene was detected by polymerase chain amplification and subsequent restriction digest with BstN I. Stepwise logistic regression analysis of the entire study population revealed a significant interaction between gender and genotype (P = .019). We therefore performed separate analyses for men and women. There was a significant relationship between hypertension and the ADRB3 Trp64Arg variant in men (P = .015), but not in women. Furthermore, blood pressure levels in male patients with the minor allele had higher blood pressure levels (P < .05), despite a significantly greater number of antihypertensive medications (P = .01). There was no association between ADRB3 genotype and vascular complications in these patients. In conclusion, our data are compatible with a contribution of this genetic variant of ADRB3 to hypertension in male patients with type 2 diabetes. Further studies will be needed to determine the role of this polymorphism as a predictor of hypertension or vascular complications in patients with type 2 diabetes.

Pancreatic adenocarcinoma cell lines show variable susceptibility to TRAIL-mediated cell death.

BACKGROUND AND AIMS: Programmed cell death via the Fas receptor/Fas Ligand and DR4, DR5/TRAIL plays a major role in tumor escape and elimination mechanisms. It also promises to be an effective therapy alternative for aggressive tumors, as has been recently shown for colon, breast, and lung cancer cells. We attempted to clarify the role of these molecules in aggressivity of pancreatic carcinomas and to identify possible pathways as targets for therapy. METHODS: Five pancreatic cell lines were investigated for the expression of FasL/Fas, DcR3, DR4, DR5/TRAIL, DcR1, DcR2, and other death pathways related molecules such as Bax, bcl-xL, bcl-2, FADD, and caspase-3 by flow cytometry, immunoblotting, and RT/PCR, both semiquantitative and real time (TaqMan). The susceptibility of these cell lines to apoptosis mediated by recombinant TRAIL was investigated. The effect of therapeutic agents (gemcitabine) on their susceptibility to TRAIL induced apoptosis was studied as well. RESULTS: Pancreatic adenocarcinomas expressed high levels of apoptosis-inducing receptors and ligands. They showed differential susceptibility to cell death induced by TRAIL, despite expressing intact receptors and signaling machineries. Treatment with commonly used therapeutic agents did not augment their susceptibility to apoptosis. This could be explained by the fact that they expressed differentially high levels of decoy receptors, as well as molecules known as inhibitors of apoptosis. CONCLUSIONS: The data suggest that pancreatic carcinoma cells have developed different mechanisms to evade the immune system. One is the expression of nonfunctional receptors, decoy receptors, and molecules that block cell death, such as bcl2 and bcl-xL. The second is the expression of apoptosis-inducing ligands, such as TRAIL, that could induce cell death of immune cells. The success in treating malignant tumors by recombinant TRAIL might apply to some but not all pancreatic tumors because of their differential resistance to TRAIL-induced cell death.

Childhood enuresis. A comprehensive treatment program.

Enuresis is a common, often misunderstood, condition that affects millions of children in the United States. For most children with primary enuresis, preventing secondary psychological sequelae associated with guilt and shame is an important consideration in the decision whether or not to treat. Because the spontaneous resolution rate is 15 per cent per year, the older the child, the more important treatment becomes. It is important to distinguish primary from secondary enuresis, as most psychogenically induced enuresis is of secondary nature. A careful history can usually elicit the etiology, as well as the exacerbatory factors in both types of conditions, providing direction for treatment. Treatments include pharmacologic, behavioral, and psychotherapeutic. In some cases, surgical intervention of either a urologic or otolaryngologic nature is indicated. A multidimensional approach is often best, and we have described our program with its success rate. Treating the enuretic child can be frustrating, but is usually quite gratifying for the child, parents, and the clinician.

National estimates of mental health utilization and expenditures for children in 1998.

No recent national data on expenditures and utilization are available to provide a benchmark for reform of mental health systems for children and adolescents. The most recent estimates, from 1986, predate the dramatic growth of managed care. This study provides updated national estimates. Treatment expenditures are estimated to be $11.68 billion ($172 per child). Adolescents have the highest expenditures at $293 per child followed by $163 per child aged 6 to 11 and $35 per preschool-aged child. Outpatient services account for 57%, inpatient for 33%, and psychotropic medications for 9% of the total. Unlike earlier reports, outpatient care now accounts for the majority of expenditures. This finding replicates the differences between recent managed care data and earlier actuarial databases for privately insured adults and confirms the trend from inpatient toward outpatient care.

[Effect of interruption on the prognosis of children from the following pregnancy]. / Vliv interrupce na prognózu detí z následujícího tehotenství

PIP: An analysis of the rates of neonatal fatility was made for the 10th district of Prague. Statistics showed that 50% of all neonatal fatalities occurred in newborns under 1000 gm of weight and that 60% of these fatalities occurred in women with artificial interruption of pregnancy in their history. On the basis of these statistics, abortion is considered to be 1 of the factors involved in the inability of women to carry pregnancies to full term. Perinatal mortality was also found to be worse in this district of Prague as opposed to rural districts. It was assumed that this is due to the higher number of abortions performed in the urban areas.^ieng

[Intraductal papillary mucinous neoplasia: which findings support observation?]. / Intraduktal papillär muzinöse Neoplasie: Welche Befunde sprechen für Beobachtung?

On abdominal CT scans asymptomatic cystic lesions of the pancreas are accidentally detected in 1-2% of patients. Congenital cysts and pancreatic pseudocysts account for two thirds of these lesions. Pancreatic pseudocysts are a frequent complication of acute and chronic pancreatitis. Among resected cystic neoplasms serous cystic adenoma accounts for 30%, mucinous cystic neoplasms for 45% and intraductal papillary mucinous neoplasms for 25%. The diagnosis of a cystic pancreatic lesion is usually made by diagnostic imaging. Symptomatic lesions require definitive therapeutic treatment after appropriate diagnostic work-up. In the diagnosis of asymptomatic cystic lesions several factors are important, among them whether the cyst is connected to the pancreatic duct (as in IPMN and pseudocysts), the size of lesion (for treatment indications) and whether nodules form in the wall of the cyst (a sign of potential malignancy). EUS-guided fine needle aspiration of the cyst fluid adds to the discrimination between benign, premalignant and malignant cystic lesions. Measuring lipase activity, CEA, viscosity and mucin as well as cytology can help in differentiating cystic lesions. An algorithm is discussed for the differential diagnosis and for selection of the appropriate treatment for pancreatic cystic lesions, most of which never require surgery.