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Biomedical subjects

M Berger

Publications and source records attributed to M Berger.

At least 127 records · Page 7Linked to original sources

Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis.

Numerous studies have reported increased risks of hip, spine, and other fractures among people who had previous clinically diagnosed fractures, or who have radiographic evidence of vertebral fractures. However, there is some variability in the magnitudes of associations among studies. We summarized the literature and performed a statistical synthesis of the risk of future fracture, given a history of prior fracture. The strongest associations were observed between prior and subsequent vertebral fractures; women with preexisting vertebral fractures (identified at baseline by vertebral morphometry) had approximately 4 times greater risk of subsequent vertebral fractures than those without prior fractures. This risk increases with the number of prior vertebral fractures. Most studies reported relative risks of approximately 2 for other combinations of prior and future fracture sites (hip, spine, wrist, or any site). The confidence profile method was used to derive a single pooled estimate from the studies that provided sufficient data for other combinations of prior and subsequent fracture sites. Studies of peri- and postmenopausal women with prior fractures had 2.0 (95 % CI = 1.8, 2.1) times the risk of subsequent fracture compared with women without prior fractures. For other studies (including men and women of all ages), the risk was increased by 2.2 (1.9, 2.6) times. We conclude that history of prior fracture at any site is an important risk factor for future fractures. Patients with a history of prior fracture, therefore, should receive further evaluation for osteoporosis and fracture risk.

Aged↗

Insulin treatment with preprandial injections of regular insulin in middle-aged type 2 diabetic patients. A two years observational study.

AIMS: To describe effectivity and safety variables in Type 2 diabetic patients on preprandial regular insulin therapy before each main meal (supplementary insulin therapy SIT) during an observational period. METHODS: A group of 77 consecutive Type 2 diabetic patients in whom SIT was initiated at this department between January 1994 and March 1998 were subjected to a follow-up examination after a mean of two years during which time they were mainly cared for by their family physicians. RESULTS: For 86 % patients (n =66) the continuation of SIT was documented; in 41 % of them (n =27) a bed time injection of NPH insulin was added in order to adequately control fasting glycaemia. HbA1c had fallen from 9.3 +/-1.8 to 7.4 +/-1.7 %; no episode of major hypoglycaemia occurred; there was no statistically significant increase in body weight. CONCLUSIONS: This observational study describes favourable intermediate outcome parameters of effectivity and safety for prandial regular insulin therapy of Type 2 diabetic patients, such as lowering of HbA1c without occurrence of major hypoglycaemia and without weight gain. Controlled trials are needed to confirm the encouraging results from this pilot study.

Blood Glucose↗

Product of side-chain cleavage of cholesterol, isocaproaldehyde, is an endogenous specific substrate of mouse vas deferens protein, an aldose reductase-like protein in adrenocortical cells.

Mouse vas deferens protein (MVDP) is an aldose reductase-like protein that is highly expressed in the vas deferens and adrenal glands and whose physiological functions were unknown. We hereby describe the enzymatic characteristics of MVDP and its role in murine adrenocortical Y1 cells. The murine aldose reductase (AR) and MVDP cDNAs were expressed in bacteria to obtain recombinant proteins and to compare their enzymatic activities. Recombinant MVDP was functional and displayed kinetic properties distinct from those of murine AR toward various substrates, a preference for NADH, and insensitivity to AR inhibitors. For MVDP, isocaproaldehyde, a product of side-chain cleavage of cholesterol generated during steroidogenesis, is the best natural substrate identified so far. In Y1 cells, we found that NADH-linked isocaproaldehyde reductase (ICR) activity was much higher than NADPH-linked ICR activity and was not abolished by AR inhibitors. We demonstrate that in Y1 cells, forskolin-induced MVDP expression enhanced NADH-linked ICR activity by 5-6-fold, whereas no variation in ICR-linked NADPH activity was observed in the same experiment. In cells stably transfected with MVDP antisense cDNA, NADH-linked ICR activity was abolished even in the presence of forskolin, and the isocaproaldehyde toxicity was increased compared with that of intact Y1 cells, as measured by isocaproaldehyde LD(50). In Y1 cells transfected with MVDP antisense cDNA, forskolin-induced toxicity was abolished by aminoglutethimide. These results indicate that in adrenocortical cells, MVDP is responsible for detoxifying isocaproaldehyde generated by steroidogenesis.

Adrenal Cortex↗

Functional and molecular aspects of voltage-gated K+ channel beta subunits.

Voltage-gated potassium channels (Kv) of the Shaker-related superfamily are assembled from membrane-integrated alpha subunits and auxiliary beta subunits. The beta subunits may increase Kv channel surface expression and/or confer A-type behavior to noninactivating Kv channels in heterologous expression systems. The interaction of Kv alpha and Kv beta subunits depends on the presence or absence of several domains including the amino-terminal N-type inactivating and NIP domains and the Kv alpha and Kv beta binding domains. Loss of function of Kv beta 1.1 subunits leads to a reduction of A-type Kv channel activity in hippocampal and striatal neurons of knock-out mice. This reduction may be correlated with altered cognition and motor control in the knock-out mice.

Alternative Splicing↗

Effect of age on excess mortality in obesity.

CONTEXT: The effect of age on excess mortality from all causes associated with obesity is controversial. Few studies have investigated the association between body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), age, and mortality, with sufficient numbers of subjects at all levels of obesity. OBJECTIVE: To assess the effect of age on the excess mortality associated with all degrees of obesity. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 6193 obese patients with mean (SD) BMI of 36.6 (6.1) kg/m2 and mean (SD) age of 40.4 (12.9) years who had been referred to the obesity clinic of Heinrich-Heine University, Düsseldorf, Germany, between 1961 and 1994. Median follow-up time was 14.8 years. MAIN OUTCOME MEASURE: All-cause mortality through 1994 among 6053 patients for whom follow-up data were available (1028 deaths) analyzed as standardized mortality ratios (SMRs) using the male-female population of the geographic region (North Rhine Westphalia) as reference. RESULTS: The cohort was grouped into approximate quartiles according to age (18-29, 30-39, 40-49, and 50-74 years) and BMI (25 to <32, 32 to <36, 36 to <40, and > or =40 kg/m2) at baseline. The SMRs showed a significant excess mortality with an SMR for men of 1.67 (95% confidence interval, 1.51-1.85; P<.001) and an SMR for women of 1.45 (95% confidence interval, 1.34-1.57; P<.001). The excess mortality associated with obesity declined with age. For men, the SMRs of the 4 age groups were 2.46, 2.30, 1.99, and 1.31, respectively; for women, they were 1.81, 2.10, 1.70, and 1.26, respectively (Poisson trend test, P<.001). The SMRs increased with BMI but, within each BMI group, the SMRs decreased with age. The lowest SMRs (for men, 1.01; for women, 0.91) were obtained for patients older than 50 years with BMIs of 25 to less than 32 kg/m2. Thus, older men and women at a BMI range of 25 to less than 32 kg/m2 had no excess mortality. The highest SMRs (for men, 4.22; for women, 3.79) were calculated for the patients aged 18 to 29 years with a BMI of 40 kg/m2 or higher. CONCLUSIONS: In this large cohort of obese persons, risk of death increased with body weight, but obesity-related excess mortality declined with age at all levels of obesity.

Adult↗

Tissue-specific translational regulation of alternative rabbit 15-lipoxygenase mRNAs differing in their 3'-untranslated regions.

By screening a rabbit reticulocyte library, an alternative 15-LOX transcript of 3.6 kb (15-LOX mRNA2) was detected containing a 1019 nt longer 3'-untranslated region (UTR2) than the main 2.6 kb mRNA (15-LOX mRNA1). In anaemic animals, northern blotting showed that 15-LOX mRNA2 was predominantly expressed in non-erythroid tissues, whereas 15-LOX mRNA1 was exclusively expressed in red blood cells and bone marrow. The 15-LOX 3'-UTR2 mRNA2 contained a novel 8-fold repetitive CU-rich motif, 23 nt in length (DICE2). This motif is related but not identical to the 10-fold repetitive differentiation control element (DICE1) of 19 nt residing in the 15-LOX UTR1 mRNA1. DICE1 was shown to interact with human hnRNP proteins E1 and K, thereby inhibiting translation. From tissues expressing the long 15-LOX mRNA2, two to three unidentified polypeptides with molecular weights of 53-55 and 90-93 kDa which bound to DICE2 were isolated by RNA affinity chromatography. A 93 kDa protein from lung cytosol, which was selected by DICE2 binding, was able to suppress translational inhibition of 15-LOX mRNA2, but not of 15-LOX mRNA1, by hnRNP E1. A possible interaction between DICE1/DICE2 cis / trans factors in translational control of 15-LOX synthesis is discussed. Furthermore, the 3'-terminal part of the highly related rabbit leukocyte-type 12-LOX gene was analysed. Very similar repetitive CU-rich elements of the type DICE1 (20 repeats) and DICE2 (nine repeats) were found in the part corresponding to the 3'-UTR of the mRNA.

3' Untranslated Regions↗

Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2.

In response to environmental stress, the p53 phosphoprotein is stabilized and activated to inhibit cell growth. p53 stability and activity are negatively regulated by the murine double minute (Mdm2) oncoprotein in an autoregulatory feedback loop. The inhibitory effect of Mdm2 on p53 has to be tightly regulated for proper p53 activity. Phosphorylation is an important level of p53 regulation. In response to DNA damage, p53 is phosphorylated at several N-terminal serines. In this study we examined the role of Ser20, a potential phosphorylation site in human p53, in the regulation of p53 stability and function. Substitution of Ser20 by Ala (p53-Ala20) significantly increases the susceptibility of human p53 to negative regulation by Mdm2 in vivo, as measured by apoptosis and transcription activation assays. Mutation of Ser20 to Ala renders p53 less stable and more prone to Mdm2-mediated degradation. While the in vitro binding of p53 to Mdm2 is not increased by the Ala20 mutation, the same mutation results in a markedly enhanced binding in vivo. This is consistent with the conclusion that phosphorylation of Ser20 in vivo attenuates the binding of wild-type p53 to Mdm2. Peptides bearing non-phosphorylated Ser20 or Ala20 compete with p53 for Mdm2 binding, while a similar peptide with phosphorylated Ser20 does not. This implies a critical role for Ser20 in modulating the negative regulation of p53 by Mdm2, probably through phosphorylation-dependent inhibition of p53-Mdm2 interaction.

Amino Acid Sequence↗

c-Abl neutralizes the inhibitory effect of Mdm2 on p53.

Upon exposure to stress signals, the p53 tumor suppressor protein is stabilized and induces growth suppression. p53 activities are efficiently inhibited by the Mdm2 oncoprotein through an autoregulatory feedback loop. In addition, Mdm2 promotes p53 degradation, thereby terminating its growth inhibitory signal. Hence, p53 exerts its effects during the interval between p53 activation and the subsequent inhibition by Mdm2. Modulation of this interval by regulatory proteins may determine the extent and duration of p53 activity. Recent studies have shown that the c-Abl protein-tyrosine kinase binds p53 and enhances its transcriptional activity. Here we provide an explanation for the cooperation between these proteins. We demonstrate that c-Abl increases the expression level of the p53 protein. The enhanced expression is achieved by inhibiting Mdm2-mediated degradation of p53. This provides a likely mechanistic explanation for the findings that c-Abl overcomes the inhibitory effects of Mdm2 on p53-mediated transcriptional activation and apoptosis. These results suggest that c-Abl modulates the time window within which p53 remains active. The ability of c-Abl to neutralize the inhibitory effects of Mdm2 on p53 may be important for its growth inhibitory function.

Animals↗

Large-volume leukapheresis procedure for peripheral blood progenitor cell collection in children weighing 15 kg or less: efficacy and safety evaluation.

BACKGROUND: We update our experience on large-volume leukapheresis (LVL) in very small patients with malignancies. LVLs were performed with the aim of reducing the psychological impact of leukaphereses by reducing the number of procedures while collecting large numbers of cells. PROCEDURE: Seventeen LVLs were performed using a Cobe Spectra separator in 14 patients weighing < or = 15 kg. A median of 3.8 patient's blood volumes corresponding to 296 mL/kg (range, 202-565) of blood was processed per session of 190 minutes (120-279) duration. A femoral catheter was installed specially for collection for 88% LVL (vs. 35% for standard leukaphereses). A median volume of 16.9 mL/kg was collected with 5.4 x 10(8) MNC/kg (range, 0.6-16.3) and 8.2 x 10(6) CD34+ cells/kg (range, 1.3-31.7). RESULTS: No signs of complications due to citrate toxicity were encountered. No hypotensive or hypothermic episodes were observed. Platelet counts were significantly diminished after each procedure (median: -59%). When the extracorporal line was not primed with red blood cells (RBC), the difference between pre-LVL and post-LVL hemoglobin levels was significant with a median 32 g/L decrease. CONCLUSIONS: The LVL approach for peripheral blood progenitor cells (PBPC) collection in very small children may expose them to the risk of anemia and thrombocytopenia and an excess of special central line installation. The application of this technique in these patients should be reserved for special cases when a very large number of cells must be collected and should be performed by an experienced team.

Anemia↗

Expression of leukocyte-type 12-lipoxygenase and reticulocyte-type 15-lipoxygenase in rabbits.

From a rabbit reticulocyte library a full length cDNA was isolated which predicted a novel lipoxygenase (LOX) sharing 99% identical amino acids with the rabbit 15-lipoxygenase. HPLC product analysis of the bacterially expressed protein identified it as a leukocyte-type 12-lipoxygenase (1.12-LOX). This proves the co-expression of a 15-lipoxygenase and a 1.12-lipoxygenase in one mammalian species. Among the six amino acids that are different to rabbit 15-lipoxygenase, leucine 353 is shown to be the primary determinant for 12-positional specificity. In the 3'-untranslated region of the 12-LOX-mRNA a CU-rich, 20-fold repetitive element has been found, closely related to the differentiation control element (DICE) of the rabbit 15-LOX-mRNA which is organized by ten repeats of 19 bases. By genomic PCR the 3'-terminal part of the gene for the novel 12-lipoxygenase containing the introns 10-13 has been amplified and sequenced. The introns were very similar in length to the corresponding 15-lipoxygenase introns with 89% to 95% identical nucleotide sequences. By screening a rabbit reticulocyte library an alternative 15-lipoxygenase transcript of 3.6 kb has been detected containing a 1019 nucleotides longer 3'-untranslated region (UTR2) than the main 2.6 kb mRNA. The determination of the tissue distribution by Northern blotting showed that the 3.6 kb mRNA2 was only expressed in non-erythroid tissues, whereas the 2.6 kb mRNA1 was exclusively expressed in reticulocytes. The only cell type which has been found to express the 1.12-lipoxygenase abundantly are monocytes. The results indicate that the expression of 1.12-lipoxygenase and 15-lipoxygenase is highly regulated. The UTR2 of the 15-LOX-mRNA2 contained a novel eight-fold repetitive CU-rich motif of 23 bases length which is related but not identical to the DICE of 19 bases in the UTR1. The analysis of a genomic recombinant of the complete 9.0 kb Alox15 gene confirmed that UTR1 and UTR2 are not interrupted by an additional intron.

Alternative Splicing↗

[Management of mental health and primary care. Development and evaluation of a training program based on the PLISSIT approach].

Deficits in current approaches of psychosomatic and psychiatric education for general practitioners are reviewed. A skill-based training was developed in line with the four step counseling approach of the "PLISSIT" approach: The GP helps in first step ("permission") the patient to accept his problem and assesses informations about causing and maintaining factors of his symptomatology. In the second step he should provide information about the disorder and reverse misunderstanding and passivity (Limited Information). The GP's should develop preliminary strategies for change in the third step ("coping strategies", "symptom management", "special suggestions") and preparate the intensive phase of therapy as the last step. First results of the evaluation of the training program are presented demonstrate the effectiveness and acceptance of the education program.

Disease Management↗

How to preserve the antidepressive effect of sleep deprivation: A comparison of sleep phase advance and sleep phase delay.

Total sleep deprivation (TSD) leads to an immediate amelioration of depressed mood in approximately 70 % of patients with the melancholic subtype of depression. The clinical utility of this procedure is limited, as the improvement usually subsides after the next night of sleep. In the present study, 40 depressed inpatients, being free of psychoactive medication for at least 7 days and who had responded to a TSD were then distributed (according to a matched-pair design) to a sleep phase advance (SPA = time in bed scheduled from 1700-2400 hrs) or a sleep phase delay (SPD = time in bed from 0200-0700 hrs) with a succeeding shift back (for one hour in the SPA group per day) respectively shift forward (for 30 minutes in the SPD group per day), until the initial sleep phase (2300-0600 hrs) was reached after seven days again. Based on previous observations it was hypothesized that a phase advance of the sleep period should prevent responders to TSD from relapsing. Whereas 75% of the TSD responders were stabilized by the phase advanced condition and did not relapse over a period of seven days, only 40% of the patients in the phase delayed condition did not relapse. Polysomnography during the course of the study gave no evidence that the unusual sleep schedules caused prolonged sleep deprivation. Abnormalities of REM sleep persisted both in the clinical responders and non-responders after the sleep wake manipulation. It is concluded that the clinical effectiveness of TSD can be significantly improved by combining TSD with a following phase advance of the sleep period.

Adult↗

The concept of "sense of coherence" and the development of posttraumatic stress disorder in traffic accident victims.

According to the "sense of coherence" concept, those subjects who can give meaning to a traumatic event can comprehend what has happened and have a sense of manageability of the sequelae, are able to cope better with the traumatic event itself. In the present study, this concept was applied to traffic accident victims. Severely injured traffic accident victims were assessed a few days after the accident and at 6-month follow-up. At follow-up, patients filled in the 29-item version of the Sense of Coherence (SOC) self-rating scale. The results show that the SOC total score correlated negatively with the development of: (i) posttraumatic psychopathology; (ii) psychological disorders (i.e., posttraumatic stress disorder after the accident); and (iii) anxious cognitions. The personality trait of neuroticism correlated negatively and extraversion and frustration tolerance correlated positively with SOC total score. Previous hypotheses are supported by our findings.

Accidents, Traffic↗