Active, artificial hair cells for biomimetic sound detection based on active cantilever technology.

We aim at building and studying artificial hair cells (AHC) based on MEMS technology to understand the extraordinary sound perception of the human ear and build a sensor system with similar properties. These perception properties, i.e. detecting six orders of sound pressure level and simultaneously frequency differences of only 3-5 Hz, are obtained mainly due to the sophisticated biological sensors in the inner ear, called hair cells, which convert the acoustic waves into electric signals. They amplify weak inputs and compress larger ones, known as compressive nonlinearity, thus enabling this impressive dynamic range, typically not captured by current engineering solutions. We tackle this demand by building artificial hair cells on the basis of smart, self-actuated and self-sensing mechanical resonator beams with suitable actuation feedback. Thereby, we take advantage of the fact that the compressive nonlinearity arises naturally in dynamical systems tuned to a bifurcation point. This tuning is achieved by an appropriate feedback loop inspired by physiological models. Initial results on the detection properties of a single AHC will be shown demonstrating amplification and a decreased width of the resonance peak.

Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study.

AIMS/HYPOTHESIS: The aim of this cohort study was to investigate the risk of malignant neoplasms and mortality in patients with diabetes treated either with human insulin or with one of three insulin analogues. METHODS: Data were provided by the largest German statutory health insurance fund (time-frame: January 1998 to June 2005 inclusive), on patients without known malignant disease who had received first-time therapy for diabetes mellitus exclusively with human insulin, aspart, lispro or glargine. The primary outcome was the diagnosis of a malignant neoplasm. Data were analysed by multiple Cox regression models adjusting for potential confounders. RESULTS: A total of 127,031 patients were included, with a mean follow-up time of 1.63 (median 1.41, maximum 4.41) years. A positive association between cancer incidence and insulin dose was found for all insulin types. Because patients receiving combined therapy with insulin analogues and human insulin were excluded, the mean daily dose was much lower for glargine than for human insulin, and a slightly lower cancer incidence in the glargine group was found. After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p < 0.0001): the adjusted HR was 1.09 (95% CI 1.00 to 1.19) for a daily dose of 10 IU, 1.19 (95% CI 1.10 to 1.30) for a daily dose of 30 IU, and 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU. No increased risk was found for aspart (p = 0.30) or lispro (p = 0.96) compared with human insulin. CONCLUSIONS/INTERPRETATION: Considering the overall relationship between insulin dose and cancer, and the lower dose with glargine, the cancer incidence with glargine was higher than expected compared with human insulin. Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients. Prospective long-term studies are needed to further evaluate the safety of insulin analogues, especially glargine.

[Integrated therapy approach in the inpatient rehabilitation of women and men with total gastrectomy for stomach carcinoma]. / Integrativer Therapieansatz in der stationären Rehabilitation von Frauen und Männern mit totaler Gastrektomie wegen Magenkarzinom.

On the basis of the documented course of 83 in-patient rehabilitation procedures in 28 female and 55 male patients who had undergone total gastrectomy due to cancer of the stomach, "objective" and "subjective" data were analyzed and correlated within an integrative treatment concept in order for one, to obtain as rehabilitation-specific a description as possible of how patients cope with the conditions resulting from their illness, and for the other, to contribute to furthering a multidisciplinary treatment concept, uniting the medical and psychosocial lines of approach. "Objective" data, i.e., data based on therapist assessments, inter alia include laboratory and other measures, diagnostic and therapeutic interventions and their gradings, sociomedical and psychosocial parameters, Karnofsky index, as well as Edinburgh Rehabilitation Status scores, while "subjective" ones, i.e., data based on the patients' own estimates, included symptom scores and judgements relative to treatment course and the so-called therapeutic environment. Findings are presented in detail for both planes (i.e., "objective" and "subjective" parameters) and discussed in light of pertinent literature. In particular the "missing" (yet perhaps expected) correlations among these planes are considered indicative of an urgent need for inclusion of the patient's behaviour and experience in the rehabilitative-therapeutic process. The partially surprising gender differences found are discussed with a view to behavioural patterns that might be conducive to coping with the malignant disease and its sequelae, an integrative treatment approach found to be of utmost importance, in particular in terms of the (therapeutic) relationship with self and others.

[The course of inpatient rehabilitation in gastrointestinal and metabolic diseases under increasing integration of behavior and experience]. / Verlaufsbeschreibung stationärer Rehabilitation bei Verdauungs- und Stoffwechselkrankheiten unter zunehmender Integration von Verhalten und Erleben.

Starting out from the thesis that behaviour and felt experience, i.e., the patient's "subjective world", have considerable influence on chronic diseases and their consequences in the gastrointestinal field, a "basic course documentation"-based comparison has been carried out of the courses of 4-week in-patient rehabilitation programmes designed to increasingly incorporate interventions directed at this area; the study population had consisted of two groups of patients (n = 688 each) without any significant differences concerning age and sex distribution admitted during the summer terms of 1990 (Group A) and 1991 (Group B), respectively. This documentation (in DBASE IV format) compiles (anonymized) patient data at an "objective" level on the one hand, i.e. basic data (such as diagnoses, age, sex), results obtained by the Edinburgh Rehabilitation Status Scale (ERSS), risk behaviour, and scope of interventions both in the organ-medical and physical therapy fields and in the area of "instruction, motivation, support, group work, and creativity" (designed to achieve integration of behaviour and felt experience); on the other hand, at "subjective level", it comprises the patient's own judgements relative to the treatment regimen and its environment, with subsequent correlational analysis of the data obtained (using the SPSSPC statistical package). As had been expected, correlations have on the one hand been stated at the "objective" level between an increased share of more "serious" conditions (ICD) in 1990 as compared to 1991 and higher ERSS scores (i.e., increased impact of disease consequences), greater organ-medical care intensity, and frequency of incapacity for work; on the other hand, at "subjective" level, strong linkages were found among the item ratings for general sense of improvement, specific and general therapy, as well as so-called "therapeutic environment". When the two levels are linked, the sense of improvement, as expected, is found to correlate negatively with the ERSS, but positively with the scope of the interventions designed to foster integration of behaviour and felt experience. The judgements given for quality of care provided relative to the patient's self-reported primary disorder and for general medical care correlate positively both with the scope of diagnostic/therapeutic organ-medical interventions and integration-focussed ones, which, at least from the patient's perspective, hence exercise an ascertainable, essential effect in the therapeutic setting of in-patient rehabilitation in gastrointestinal and metabolic diseases.

Identification of patients at high risk for colorectal carcinoma from biopsy studies of the apparently normal colorectal mucosa. A multivariate analysis.

A number of phenotypic abnormalities of the colorectal mucosa which appears normal have been described to be biomarkers of cancer development. To improve their sensitivity and specificity, we simultaneously determined 10 morphological and histochemical parameters in biopsies from the colonoscopically normal mucosa of the descending colon, sigmoid, and rectum. The results were analysed by multivariate statistical methods. We tested the discriminating power of proliferative, morphometric, enzyme and mucin histochemical parameters from 80 patients either at average risk (controls), with an increased risk for colorectal carcinoma (high-risk), or with a manifest carcinoma. The following parameters were investigated: number of mitotic figures per crypt, crypt length, apical, medial and basal crypt diameter, crypt surface, activity of succinate dehydrogenase (EC 1.3.99.1), activity of acid beta-galactosidase (EC 3.2.1.23), sulpho- and sialomucin contents. Univariate statistical analyses revealed that crypt length, crypt diameter and crypt surface were significantly increased in the high-risk group, the carcinoma carriers having intermediate values between average-risk and high-risk patients. In a two-group discriminant analysis, high-risk or carcinoma patients could be separated from average-risk patients with a sensitivity of 92.9% and a specificity of 100%. When the analysis was repeated for three groups (carcinoma carriers separated from high-risk patients), sensitivity and specificity were 100% for each group. We conclude that identification of patients at risk for colorectal carcinoma is possible from the normal-appearing left colonic and rectal mucosa by morphometric and cytochemical analysis of biopsies.

Characterization of stereomicroscopically identified preneoplastic lesions during dimethylhydrazine-induced colonic carcinogenesis.

Preneoplastic mucosal changes were studied at six different time-points during dimethylhydrazine (DMH)-induced colorectal carcinogenesis in the rat. After 40 weeks of treatment, seven of 10 animals were bearing a total of 11 colorectal adenocarcinomas. The crypt cell production rate in the normal mucosa of DMH-treated animals was greatly increased in the left colon and rectum and further rose with the duration of the experiment. Focal disturbances of the mucosal architecture could be detected as early as 4 weeks after the initiation of DMH-treatment using a stereomicroscope. Their incidence was greatest in the left colon and rectum and increased strongly with the duration of carcinogen exposure. Characterization of these mucosal alterations, by means of conventional histology, morphometry after microdissection, cell kinetics, mucin histochemistry and quantitative enzyme histochemistry performed with serial sections, revealed mild epithelial dysplasia, a considerable elongation and dilatation of the crypts and a marked increase of the crypt cell production, including a shift of the main proliferative compartment from the basal to the medial crypt segment as well as the occurrence of mitotic figures in the luminal epithelium. In affected crypts, the goblet cells completely lacked sulphomucins and exclusively contained sialomucins. The activities of the enzymes diaminopeptidase IV (brush-border), succinate dehydrogenase (mitochondria) and acid beta-galactosidase (lysosomes) were markedly reduced. We conclude that these early mucosal alterations are indeed preneoplastic lesions and indicate the existence of the adenoma-carcinoma sequence in this animal model.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the lectin-binding pattern of PNA-agglutinin and UEA1 during the DMH-induced carcinogenesis in the normal appearing colonic mucosa of the rat.

The purpose of this study was the investigation of changes in the lectin-binding pattern prior to tumour formation in an experimental model. Female Wistar rats were treated with 1,2-dimethylhydrazine (DMH). After 4, 8, 16, 24, 32 and 40 weeks of treatment the lectin-binding-pattern of the colonic mucosa appearing morphologically normal was examined at the caecum, proximal colon, distal colon and rectum, using FITC-conjugated Peanut-agglutinin (PNA) and Ulex europaeus-agglutinin1 (UEA1). In contradistinction to what has been reported earlier by other authors, PNA did not indicate constant cancer-associated mucin changes. In addition, there was no difference in the UEA1-binding between the control animals and the DMH-treated rats. Thus, in the rat there is no specific PNA- and UEA1-binding pattern during tumour induction in the gut.

[Incidence of endemic sprue in Berlin (West). A retrospective study based on biopsy findings]. / Inzidenz der einheimischen Sprue in Berlin (West). Eine retrospektive Untersuchung anhand bioptischer Befunde.

The incidence of celiac disease in Berlin (West) during the years 1979-1984 has been studied retrospectively by investigating the records of the local Pathological Institutes, which examine small intestinal biopsies, for the occurrence of abnormal specimens typical of celiac disease (group 1) or consistent with the diagnosis of celiac disease (group 2). Group 1 exhibited a constant average incidence of 0.74 per 100,000 inhabitants per year, while group 2 showed a small increase between 1979 and 1984, averaging 1.03 per 100,000 inhabitants per year. Classified according to age the highest incidence was seen in the 0-5 year-olds, namely 8.04 in group 1 and 10.00 in group 2. For those children born and examined during the period of investigation the values ranged between 15.8 and 64.7 per 100,000 births. Girls, with an average frequency of 1:1919 births were more often affected than boys, who averaged 1:4219 births. These figures obtained in Berlin (West) indicate only the lower ranges of incidences and will have to be further supplemented by a prospective study.

The intestinal monoxygenase enzyme system in DMH-induced rat colonic carcinogenesis.

Four enzymes of the microsomal mixed function oxidase system were studied in two different segments of each the small and large intestine and in the liver of untreated female Wistar rats. In order to test a possible induction of this enzyme system, due to the application of the colonic carcinogen N,N-dimethyl hydrazine, three of these enzymes were determined in the same intestinal segments, in the liver and, in addition, in the kidney after 4 and 8 weeks of DMH-treatment (weekly s.c. injections of 20 mg DMH/kg b.w.). In the untreated rats, the four enzymes under investigation revealed significantly higher specific activities in the liver and in the jejunum than in the ileum and colon. In the DMH-treated animals, liver AHH-activity was decreased after 4 and 8 weeks when compared with the EDTA-treated controls; so was the AHH in the jejunum and in the ileum after 8 weeks. Liver EOD was only decreased after 4 weeks and had normalized after 8 weeks, being diminished, however, in the jejunum at that time. UDP-GT-activity was not altered at all. No alterations of the investigated enzyme activities could be demonstrated either in the colonic segments or in the kidney. These findings indicate that a local induction of the mixed function oxidase system is not likely to be responsible for the organotropism of the DMH-induced colonic carcinogenesis.

Effects of biliary diversion to the ileum on the in situ disaccharidase activities of duodenal and ileal mucosa in the rat: a study on enzyme kinetics in tissue sections.

In order to study the influence of biliary secretions on the in situ kinetic data of brush border disaccharidases in relation to small intestinal villus-crypt architecture, an anastomosis was constructed between the common bile duct, which had been divided before its entrance into the pancreatic head, and the ileum in adult female Wistar rats. Simple attachment of the terminal ileum to the liver hilum was performed in the controls. Six weeks after the operation, tissue sections were prepared from duodenum and ileum of biliary-diverted and control animals (n = 5 in each group) and examined by section biochemistry and morphometry. In both groups the apparent Vmax values of neutral alpha-glucosidase and lactase/beta-glucosidase, measured at the villus base and at its apex, and the villus height were decreased from the duodenum towards the distal ileum. After biliary diversion to the ileum, an increase in villus height ensued in this segment, and the increasing gradient of glucosidase activity towards the villus apex, as seen in the ileum of the controls, was no longer detectable. In the duodenum, however, villus height remained unaltered and the in situ activity of the disaccharidases was increased at both villus sites when compared with the controls. The results indicate different effects of bile on mucosal morphology and function in the proximal and distal small intestine.

Segmental variations in the surface architecture of the normal rat colonic mucosa.

A microdissection technique used previously in the small intestine has been adapted for the rat colon in order to determine morphometric data and to calculate surface parameters in various proximal and distal segments (caecum, ascending and descending colon, rectum) of normal colonic mucosa. From the caecum to the rectum there was a gradual significant decrease in the diameter of the middle portions of the crypts, in the number of crypts per unit area and the inner intestinal circumference, as well as in the total mucosal surface per mm intestinal length and the surface of all crypts per unit area. However, there was an increase in the surface of the lining epithelium between the crypts from the caecum to the rectum. These findings are of importance when interpreting alterations in colonic function in terms of segmental changes in the mucosal architecture.

The adaptive response of disaccharidase activities at different sites along the villus epithelium after proximal intestinal resection in the rat. A microdensitometric study of enzyme kinetics.

The "in situ" kinetic constants (app. Km and Vmax) of brush border neutral alpha-glucosidase (EC 3.2.1.20) and lactase/beta-glucosidase (EC 3.2.1.21) were determined 4,6 (only alpha-glucosidase), and 12 days after 60% proximal intestinal resection in rat ileum at the villus base and the transition zone between middle and upper villus third by use of a quantitative biochemical analysis of enzymes in tissue sections (section biochemistry). Sham-operated rats served as controls, and the kinetic data (means per rat, time and villus position) were compared (n = 4 animals in each experimental group) first by an overall factorial analysis of variance and thereafter in detail using nonparametric test procedures. Both enzyme activities exhibited a differential response: No changes of lactase/beta-glucosidase kinetics, but a significant decrease in both Vmax- and Km-values of neutral alpha-glucosidase, which was already fully expressed on day 4 after resection and confined to the apical villus region still implying a basoapical increase of Vmax and thus maintaining the normal activity gradient on a lower level. In conclusion, a complex pattern of enzymatic adaptation to proximal intestinal resection ensues in the hyperplastic ileal mucosa which cannot be explained simply in terms of the hypothesis of cellular immaturity.

Adaptative response of alpha- and beta-glucosidase kinetics along the villi of rat self-filling jejunal blind loops.

Four and 12 days after the construction of self-filling jejunal blind loops in the rat, the apparent Km- and Vmax-values of lactase/beta-glucosidase and neutral alpha-glucosidase were determined by in-situ quantitative enzyme histochemistry, and changes in the villus-crypt architecture of the mucosa were examined by microdissection. The results were compared with corresponding data from sham-operated controls. The kinetics data were obtained from the base and the transition zone between medium and apical villus third by the use of a microdensitometric technique. The apparent Vmax of lactase/beta-glucosidase is significantly smaller than in the control rats at both measuring sites of the villi and even decreases from day 4 to day 12. The apparent Vmax of neural alpha-glucosidase is not affected, and thus the same increase in enzyme activity along the villi as in the controls is observed. The apparent Km of this enzyme, however, is already significantly increased on day 4 at both villus positions in the blind loops. A pronounced increase in villus surface area is detected in the blind loops as a result of an increase in crypt cell proliferation. The results indicate that enzymatic adaptation in the self-filling blind loops of rat jejunum exhibits different patterns for brush border alpha- and beta-glucosidases and is at least in part accomplished independently of the pronounced mucosal transformation occurring in this experimental condition.

Kinetic properties of neutral alpha-glucosidase in the atrophic mucosa of self-emptying blind loops of rat jejunum: a microdensitometric study at two different villus sites.

The in situ kinetic constants of neutral alpha- glucosidase were determined in the atrophic jejunal mucosa of self-emptying blind loops and in corresponding jejunal segments of control rats, using a quantitative histochemical technique. The apparent maximum velosity (Vmax) and km values were calculated from absorbance measurements of an azo dye-deposit formed in the brush border membrane at the villus base and at the transition zone between the middle and upper one-third of the villus. In the controls a significant increase of apparent Vmax and substrate affinity (decrease of apparent Km) was obtained, corresponding to enterocyte maturation along the villi. The mucosal atrophy in self-emptying blind loops was accompanied by a significant decrease of apparent Vmax of neutral alpha-glucosidase at both representative villus sites, but the substrate affinity was increased at both sites. The results indicate that alpha-glucosidase activity was reduced when measured at the cellular level of two representative villus sites in the atrophic jejunal mucosa, possibly due to the absence of substrate-effected enzyme induction. The decrease on hydrolytic enzyme activity was not matched by a compensatory increase in substrate affinity.

Effects of aromatic retinoid on non-keratinizing (intestinal) epithelium: biochemical and morphological studies.

Doses of 3 mg/kg Ro 10-9359 (in arachis oil) were daily administered to adult female Wistar rats by gastric tube for a period of 10 days. Control animals received corresponding quantities of arachis oil only. The body weight of all rats was registered daily. Samples of jejunum and ileum were processed for quantitative histochemical analysis of neutral alpha-glucosidase kinetics and for three-dimensional evaluation of the mucosal architecture. In addition, mucosal scrapings were prepared from these intestinal segments, and the specific sucrase activity was determined. For each animal data were pooled and analyzed by Wilcoxon (Wn) test. Body weight and all registered parameters in the jejunum of treated animals remained unchanged as compared to the controls. In the ileum, however, we found under aromatic retinoid an increase of sucrase activity (P = 0.02) and of mucosal surface per unit serosal area (P less than 0.05). The hydrolytic activity of neutral alpha-glucosidase (Vmax) showed a clear trend to increase at both the villus base and apex, whereas the apparent substrate affinity (Km) remained unaltered. Our results show that, in closes of 3 mg/kg/day, aromatic retinoid induces (1) an increase in mucosal surface area, apparently due to hyperproliferation of the absorptive epithelium in ileum, which could facilitate its absorptive capacity and (2) an increase of specific sucrase activity, which could result in an enhanced carbohydrate assimilation. These findings indicate that Ro 10-9359 in addition to its effects on keratinizing epithelia exerts a distinct influence on the structure and function of the intestinal epithelium.

Early changes in brush border disaccharidase kinetics in rat jejunum following subcutaneous administration of tetraiodothyronine: a quantitative histochemical study on villi revealing normal morphology.

In order to test the influence of thyroid hormones on small intestine function, adult female Wistar rats were injected daily with either 100 microgram/100 g body weight tetraiodothyronine or placebo. After 12 days, jejunal segments were removed and processed for morphometric analysis of mucosal architecture and quantitative histochemical determinations of the apparent Km- and Vmax-values of lactase/beta-glucosidase and neutral alpha-glucosidase at constant basal and apical measuring positions along the villi. The villus-crypt-architecture was the same in both experimental groups. At the cellular level, however, application of tetraiodothyronine resulted in a marked decrease in the apparent Vmax of lactase/beta-glucosidase at both villus positions, maintaining the normal activity gradient along the villi. In comparison with the controls, a less pronounced but significant reduction in activity was also demonstrated for the neutral alpha-glucosidase. Substrate affinity, however, was only increased for this enzyme, the apparent Km of lactase/beta-glucosidase not being affected by the hormone. The results indicate a direct effect of tetraiodothyronine on jejunal brush border disaccharidases of the rat. The alternative mechanism, an effect mediated by an altered enterocyte turnover is unlikely to occur.