Efficacy, usability and sequence of operations of a workflow-integrated algorithm for basal-bolus insulin therapy in hospitalized type 2 diabetes patients.

AIMS: To evaluate glycaemic control and usability of a workflow-integrated algorithm for basal-bolus insulin therapy in a proof-of-concept study to develop a decision support system in hospitalized patients with type 2 diabetes. METHODS: In this ward-controlled study, 74 type 2 diabetes patients (24 female, age 68 ± 11 years, HbA1c 8.7 ± 2.4% and body mass index 30 ± 7) were assigned to either algorithm-based treatment with a basal-bolus insulin therapy or to standard glycaemic management. Algorithm performance was assessed by continuous glucose monitoring and staff's adherence to algorithm-calculated insulin dose. RESULTS: Average blood glucose levels (mmol/l) in the algorithm group were significantly reduced from 11.3 ± 3.6 (baseline) to 8.2 ± 1.8 (last 24 h) over a period of 7.5 ± 4.6 days (p < 0.001). The algorithm group had a significantly higher percentage of glucose levels in the ranges from 5.6 to 7.8 mmol/l (target range) and 3.9 to 10.0 mmol/l compared with the standard group (33 vs. 23% and 73 vs. 53%, both p < 0.001). Physicians' adherence to the algorithm-calculated total daily insulin dose was 95% and nurses' adherence to inject the algorithm-calculated basal and bolus insulin doses was high (98 and 93%, respectively). In the algorithm group, significantly more glucose values <3.9 mmol/l were detected in the afternoon relative to other times (p < 0.05), a finding mainly related to pronounced morning glucose excursions and requirements for corrective bolus insulin at lunch. CONCLUSIONS: The workflow-integrated algorithm for basal-bolus therapy was effective in establishing glycaemic control and was well accepted by medical staff. Our findings support the implementation of the algorithm in an electronic decision support system.

Localization and mRNA steady-state level of cellular fibronectin in rat liver undergoing a CCl4-induced acute damage or fibrosis.

In an attempt to investigate cellular fibronectin synthesis and deposition during acute liver damage and fibrogenesis, we used the presence of the additional type III-related ED-A domain of cellular fibronectin as a characteristic for distinguishing it from the plasma form. Using site-specific antibodies, we localized cellular fibronectin deposition in the necrotic pericentral areas of acutely damaged liver tissue after a single CCl4-gavage, whereas in control liver only trace amounts of cellular fibronectin were detectable along the sinusoids. Upon several CCl4-administrations leading to liver fibrosis, cellular fibronectin deposits were accumulated in the fibrotic septa. Northern blot hybridization using a cDNA representing part of the ED-A domain revealed that in liver tissue, in response to an acute intoxication, cellular fibronectin synthesis was initiated within the first 48 h after CCl4-gavage. By in situ hybridisation transcripts for cellular fibronectin were identified in the necrotic areas of acutely damaged tissue restricted to single, pericentrally located cells, whereas no cellular fibronectin mRNA was detectable in control liver. During fibrogenesis cellular fibronectin transcripts were shown to be synthesized in the immediate vicinity of septa. We conclude that upon acute or chronic intoxication, cellular fibronectin is a member of the accumulating biomatrix and is produced locally by mesenchymal liver cells.

Characterisation of two types of head activator receptor on hydra cells.

A head activator (HA) analogue is described which even at high concentrations does not lose its biological activity. By cross-linking two HA molecules over a C8 spacer, the conformation was sufficiently altered, such that self-inactivation of HA by dimerisation was prevented. In addition, the introduction of a tyrosine instead of phenylalanine in one of the two HA molecules allowed radioactive labelling with iodine. This HA bipeptide was used to investigate the effect of HA at different concentrations and as ligand for HA receptor characterisation. We found that low concentrations (0.1-10 pM) sufficed to stimulate interstitial cell mitosis, and that higher concentrations (10-1000 pM) were required for the determination of interstitial cells to nerve cells. Binding of the radioactive HA ligand to living hydra and to purified membrane fractions was saturable and specific. Binding was compatible with HA analogues with a stable monomeric conformation, but less well with dimerising HA and HA analogues. Scatchard and kinetic analyses revealed the presence of at least two types of binding site in the membrane fraction, one with a 'lower' affinity (Kd = 10(-9) M) and one with a 100-fold higher affinity (Kd = 10(-11) M). Autoradiography showed that interstitial cells were differentially labelled, suggesting that the number or types of HA receptors may vary depending on cell cycle status. A mutant of hydra with a multiheaded morphology contained 6-20-times more HA receptors per mg protein than other hydra species or mutants.

The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells.

Activated hepatic stellate cells (HSC) are thought to play a pivotal role in development of liver fibrosis which takes place in chronic liver diseases. Previous studies have shown that "activated" rat HSC undergo spontaneous apoptosis probably through the CD95/CD95L pathway. TGF-beta as well as TNF-alpha reduced spontaneous apoptosis and CD95L expression. The aim of this study was to investigate the possible mechanisms responsible for the spontaneous apoptosis and for the anti-apoptotic effect of TGF-beta and TNF-alpha on activated HSC. While bcl-2, bax, NFkappaB and p53 gene expression were spontaneously upregulated, bcl-xL and p21WAF1 gene expression decreased and IkappaB remained unchanged during the activation process in vitro. TGF-beta as well as TNF-alpha induced activation of NFKB and upregulated bcl-xL. The latter was inhibited by overexpression of IkappaB. By suppressing spontaneous apoptosis TGF-beta as well as TNF-alpha inhibited p53 gene expression while that of the p21WAF1 gene was increased. We conclude that TGF-beta as well as TNF-alpha may act as surviving factors for activated rat HSC not only through reduction of CD95L gene expression but also by upregulating the anti-apoptotic factors NFKB, bcl-xL and p21WAF1 and by downregulating the proapoptotic factor p53. The interaction with these factors may lead to the generation of new antifibrotic drugs.

Purification and characterization of the head-activator receptor from a multi-headed mutant of Chlorohydra viridissima.

In hydra the neuropeptide head activator (HA) is responsible for head-specific growth and differentiation processes. The effects of HA are mediated by high and low affinity receptors on hydra cells. In the current study HA receptors from a multi-headed mutant of Chlorohydra viridissima were solubilized from the membrane fraction using 1% Triton X-100 and 2.5 M urea. Scatchard analysis showed that the solubilized receptor had a Kd of 1.55 x 10(-9) M, indicating the low affinity subtype of the HA receptor. The solubilized receptor was purified by DMAE chromatography and subsequent affinity chromatography to homogeneity. SDS-PAGE revealed a single protein band with a molecular mass of 96 +/- 4 kDa. The native receptor eluted during gel filtration as a 113 kDa protein, and focussed with an isoelectric point of 4.8.

Decrease of platelet-endothelial cell adhesion molecule 1-gene-expression in inflammatory cells and in endothelial cells in the rat liver following CCl(4)-administration and in vitro after treatment with TNFalpha.

UNLABELLED: Platelet-endothelial cell adhesion molecule (PECAM-1), a member of the Ig superfamily is strongly expressed at endothelial cell-cell junctions, on most leukocytes and on monocytes. PECAM-1 has been implicated as a key mediator of the transendothelial migration of leukocytes and monocytes. To further define the physiological role of PECAM-1, we studied the modulation of PECAM-1-expression in a model of liver inflammation in both mononuclear cells (MCs) and sinusoidal endothelial cells (SECs). In normal rat liver sections, PECAM-1 immunohistology indicated a sinusoidal pattern similar to the ICAM-1 staining. Both, SECs, small and large MCs isolated from control rats express PECAM-1 as demonstrated by immunocytochemistry, flow cytometry, and Northern blot analysis. Immunohistochemical studies on liver sections from CCl(4)-treated animals indicated, that in the areas of necrosis 24-48 h after a single administration of the toxin, there was an accumulation of LFA-1-, ED1- (marker for rat monocytes) and ICAM-1-positive, but ED2-(marker for tissue macrophages)-negative inflammatory cells. Most of these cells were PECAM-1-negative. In situ hybridization indicated that there is no accumulation of PECAM-1 specific transcripts after CCl(4) treatment within the pericentral region. Immunocytology, flow cytometry, and Northern blot analysis of MCs and SECs isolated at different times after the administration of CCl(4) revealed a decrease of PECAM-1 gene expression in MCs and in SECs, whereas ICAM-1 expression increased. As TNFalpha has been shown to be upregulated early after CCl(4) administration, the influence of TNFalpha on PECAM-gene-expression was analyzed. TNFalpha treatment of cultured rat SECs and of small and large MCs from normal liver decreased PECAM-1 specific transcript level in parallel to the increase of ICAM-1 transcript level. CONCLUSIONS: Early production of TNFalpha after liver injury could induce an increased ICAM-1-expression and a decreased PECAM-1 expression, which might be essential for the transmigration of inflammatory cells into the parenchyma.

Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis.

Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.

Trypanosoma cruzi: presence of the two major phylogenetic lineages and of several lesser discrete typing units (DTUs) in Chile and Paraguay.

Multilocus enzyme electrophoresis (MLEE) of 99 Chilean and 11 Paraguayan stocks of Trypanosoma cruzi, the agent of Chagas disease, was performed for 22 variable genetic loci. As previously shown for this parasite in other geographic areas, a pattern of long-term clonal evolution of T. cruzi genotypes was inferred, both by strong departures of Hardy-Weinberg expectations and high linkage disequilibrium. The presence of the two major phylogenetic lineages that subdivide the species T. cruzi [Tibayrenc, M., 1995. Population genetics of parasitic protozoa and other microorganisms. In: Baker, J.R., Muller, R., Rollinson, D. (Eds.), Advances in Parasitology, vol. 36, Academic Press, New York, pp. 47-115; Souto, R.P., Fernandes, O., Macedo, A.M., Campbell, D.A., Zingales, B., 1996. DNA markers define two major phylogenetic lineages of Trypanosoma cruzi. Mol. Biochem. Parasitol. 83, 141-152], and of several lesser genetic subdivisions ('discrete typing units' or DTUs; Tibayrenc, M., 1998a. Genetic epidemiology of parasitic protozoa and other infectious agents: the need for an integrated approach. Int. J. Parasitol. 28 (1), 85-104; Tibayrenc, M., 1998b. Beyond strain typing and molecular epidemiology: integrated genetic epidemiology of infectious diseases. Parasitol. Today 14, 323-329; Tibayrenc, M., 1998c. Integrated genetic epidemiology of infectious diseases: the Chagas model. Mem. Inst. Oswaldo Cruz 93 (5), 577-580), was recorded in this region. Comparison between clonal populations in sylvatic and domestic transmission cycles of the disease in Chile strongly suggests that these two cycles are at least partially separated from one another.

Liver fibrosis and altered matrix synthesis.

Liver fibrosis represents the uniform response of liver to toxic, infectious or metabolic agents. The process leading to liver fibrosis resembles the process of wound healing, including the three phases following tissue injury: inflammation, synthesis of collagenous and noncollagenous extracellular matrix components, and tissue remodelling (scar formation). While a single liver tissue injury can be followed by an almost complete restitution ad integrum, the persistence of the original damaging noxa results in tissue damage. During the establishment of liver fibrosis, the basement membrane components collagen type IV, entactin and laminin increase and form a basement membrane-like structure within the space of Disse. The number of endothelial fenestrae of the sinusoids decreases. These changes of the sinusoids are called 'capillarization' because the altered structure of the sinusoids resembles that of capillaries. At the cellular level, origin of liver fibrogenesis is initiated by the damage of hepatocytes, resulting in the recruitment of inflammatory cells and platelets, and activation of Kupffer cells, with subsequent release of cytokines and growth factors. The hepatic stellate cells seem to be the primary target cells for these inflammatory stimuli, because during fibrogenesis, they undergo an activation process to a myofibroblast-like cell, which represents the major matrix-producing cell. Based on this pathophysiological mechanism, therapeutic methods are developed to inhibit matrix synthesis or stimulate matrix degradation. A number of substances are currently being tested that either neutralize fibrogenic stimuli and prevent the activation of hepatic stellate cells, or directly modulate the matrix metabolism. However, until now, the elimination of the hepatotoxins has been the sole therapeutic concept available for the treatment of liver fibrogenesis in humans.

[Ranking of color-coded duplex ultrasonography (CCDU) in the staging of breast tumors]. / Stellenwert der farbkodierten Duplexsonographie (FKDS) bei der Dignitätsbestimmung von Mammatumoren.

PURPOSE: of the study was to detect vessels indirectly in conspicuous focal findings of the breast by means of measurement of blood flow by using colour-coded duplex sonography (CCDS) and to examine whether additional criteria can be defined to determine the pathological relevance of breast tumours. MATERIALS AND METHODS: In a prospective study 149 patients were investigated, in whom either palpable breast lesions had been noticed or focal findings in imaging diagnostics. The perfusion in the focus and its surroundings (if present) was demonstrated and documented by means of CCDS. The investigation results were compared and contrasted with the histological findings after the operation. RESULTS: Indirect detection of the vessels depended on the size of the malignant tumours and was successful in 41.7% of cases with a tumour diameter of < or = 1 cm, in 90% of cases with a diameter of 1-2 cm and in 100% of cases with a diameter of > 2 cm. Carcinoma and metastases could be detected with a sensitivity of 87.5% and overall specificity of 56.9%. No typical perfusion pattern allowing appraisal of the pathologic relevance was seen. Postoperative scars did not show perfusion in any case. CONCLUSIONS: CCDS is of limited suitability only for determining the relevance of breast tumours, but provides additional diagnostic information especially on T1 tumours having a diameter between 1 and 2 cm. According to our results obtained so far, CCDS appears to be reliable and informative in differential diagnosis of tumour recurrence and an older scar.

Von Willebrand gene expression in damaged human liver.

BACKGROUND/AIMS: von Willebrand factor (vWf) is an adhesive glycoprotein known to play a role in hemostasis and in tissue injury. It is found in high levels in plasma of patients with acute hepatic failure and chronic liver disease. The aim of this study was to investigate the pattern of tissue vWf in acute liver failure in humans. METHODOLOGY: We studied vWf immunostaining and mRNA expression in the liver of three patients with fulminant liver failure, two patients with chronic liver disease, and two controls. PECAM-1 (CD31) immunostaining and mRNA expression were used as an additional endothelial marker. RESULTS: In chronic liver cirrhosis, vWf deposits were strongly detected at the scar-parenchyma interface. In fulminant hepatic failure, intense deposits were seen in tissue sections in the area of necrosis. A similar pattern of immunostaining was seen with PECAM-1. vWf transcripts were abundant in the liver of patients with chronic disease and minimally expressed in patients with acute hepatic failure and in controls. CONCLUSIONS: vWf is deposited within the liver sinusoids early after liver damage. The factor is only partially produced locally during the acute phase of the disease, but is overproduced in chronic disease states. These changes may suggest a role for vWf in liver injury and repair.

Dementia and driving.

Many European countries test cars, but not their drivers, as they age. There is evidence to suggest that human factors are more important than vehicular factors as causes of motor crashes. The elderly also are involved in more accidents per distance travelled than middle-aged drivers. As the UK relies on self-certification of health by drivers over the age of 70 years, we examined the driving practices of patients with dementia attending a Memory Clinic. Nearly one-fifth of 329 patients with documented dementia continued to drive after the onset of dementia, and impaired driving ability was noted in two-thirds of these. Their families experienced great difficulty in persuading patients to stop driving, and had to invoke outside help in many cases. Neuropsychological tests did not help to identify those who drove badly while activity of daily living scores were related to driving ability. These findings suggest that many patients with dementia drive in an unsafe fashion after the onset of the illness. The present system of self-certification of health by the elderly for driver-licensing purposes needs to be reassessed.

[Logopedic diagnosis and therapy in psychiatric treatment]. / Logopedická diagnostika a terapie u psychiatricky lécených osob.

The paper outlines real and potential possibilities of logopedic activities within the framework of psychiatric care. The account is based on the experience in clinical logopedics and work published abroad in the field of diagnosis and therapy. The author presents the results of comprehensive logopedic examinations as well as its possible perfection and the contribution of logopedic diagnosis to the differential diagnosis in psychiatry. The author also focuses attention on possible therapeutic action and areas attended for logopedic care. In the conclusion he emphasizes the importance and necessity to include the clinical logopedist in the psychiatric in-patient team and the necessity of close cooperation of ambulatory departments concerned with psychiatric and logopedic problems.

Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant.

BACKGROUND: Septic episodes in preterm infants recently have been reported to be associated with periventricular leukomalacia (PVL). The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers. AIMS: To evaluate risk factors for cystic PVL focussing on the influence of hypocarbia. STUDY DESIGN: Retrospective single centre case-control study. SUBJECTS: Preterm infants 24 to 35 weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls. OUTCOME MEASURES: Multivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations. RESULTS: Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, early-onset sepsis, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL. Multivariate analysis using a logistic regression model revealed early-onset sepsis and hypocarbia being significantly associated with PVL (p=.022 and .024, respectively). Lowest PaCO(2) values did not differ as did not the duration of hypocarbia, but the onset of hypocarbia was significantly later in PVL cases compared to controls (mean 26 vs. 15 h, p=.033). Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome. CONCLUSION: We found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL.

Respiratory insufficiency related to COPD accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies.

UNLABELLED: A number of esophageal cancer patients suffer from respiratory insufficiency due to the coexistence of chronic obstructive pulmonary disease (COPD). AIM: To test the hypothesis that COPD-related systemic hypoxemia may result in accelerated inflammation, malnutrition, and angiogenesis in esophageal cancer patients. METHODS: Serum levels of C-reactive protein (CRP), albumin, transferrin, interleukin-1, interleukin-6, interleukin-8, TNF-alpha, platelet-derived growth factor (PDGF-BB), and midkine and patient BMI and weight-loss rate were determined and compared with blood oxygenation status (pO(2), SaO(2)) in 35 esophageal cancer patients and 42 controls. RESULTS: The incidence of cachexia tended to be higher in patients with systemic hypoxemia (67% vs 40%, p = 0.169). Mean SaO(2) level was also significantly decreased in cachectic patients (90.3 vs 93.3%, p = 0.026) and pO(2) exhibited a similar trend (58.0 vs 63.4 mmHg, p = 0.120). Transferrin (234 vs 316 mg/dl, p = 0.005) and albumin (31.9 vs 37.1 mg/dl, p= 0.002) concentrations were reduced and CRP was elevated (129.9 vs 54.7 mg/l, p = 0.004) in hypoxemic patients and correlated with pO(2) (r = 0.47, p = 0.016; r= 0.48, p = 0.012; r = -0.37, p = 0.064) and SaO(2) (r = 0.52, p = 0.006; r = 0.53, p = 0.006; r = -0.40, p= 0.042). Interleukin-6 (9.97 vs 2.21 pg/ml, p = 0.005) and midkine (2101 vs 944 pg/ml, p < 0.001) were elevated and PDGF-BB was decreased (12.2 vs 17.3 pg x 10(-6)/PLT, p = 0.014) in hypoxemic compared with normoxemic patients. Interleukin-6 and midkine negatively correlated with pO(2) (r = -0.44, p = 0.016; r = -0.42, p = 0.011) and SaO(2) (r = -0.54, p = 0.003; r = -0.57, p < 0.0001) and PDGF-BB correlated positively (r = 0.53, p = 0.003; r = 0.44, p = 0.020). Interleukin-8 level was affected by pO(2) (r = -0.55, p = 0.015) and SaO(2) (r= -0.55, p = 0.018) only in hypoxemic patients. CONCLUSIONS: COPD-related systemic hypoxemia negatively affects the status of esophageal cancer patients by accelerating inflammation, under-nutrition, and angiogenesis.

Treatment of neonatal hyperbilirubinaemia with flumecinolone, a new enzyme inducing drug.

The effect of flumecinolone, a new drug with enzyme inductor properties, on non-haemolytic hyperbilirubinaemia of term and premature newborns has been investigated. Prophylactic treatment with the drug prevented the development of severe hyperbilirubinaemia. Alone or in combination with phototherapy, flumecinolone inhibited the steep rise of serum bilirubin in premature infants. A similar effect has been shown in term babies with haematomas. The new drug is void of all side-effects of phenobarbital.

Cognitive assessment of the medical patient.

Cognitive assessment is the clinical examination of higher mental functioning. A structured and logical approach leads the clinician to identify specific functional deficits and patterns of dysfunction. This allows accurate diagnosis, which is vital to identify treatable disorders and quantify the nature of decline in irreversible conditions. This article defines common terms in use, suggests a logical deductive procedure and discusses screening tools.

Platelet-endothelial cell adhesion molecule-1 gene expression in liver sinusoidal endothelial cells during liver injury and repair.

BACKGROUND/AIMS: Platelet-endothelial cell adhesion molecule (PECAM)-1 is suggested to be critical for transmigration processes. It is a matter of debate whether PECAM-1 is expressed in liver sinusoids and whether it is involved in liver inflammation. METHODS: Indirect immunostaining and in situ hybridization was used to analyze PECAM-1 gene expression in normal and diseased rat and human livers as well as in isolated rat sinusoidal endothelial cells (SECs), hepatic stellate cells and hepatocytes. At various time points after the administration of CCl4 (6 h, 24 h, 48 h, and 72 h), PECAM-1 gene expression was analyzed in livers and in SECs by immunostaining, and Northern blot analysis. RESULTS: In normal rat or human livers PECAM-1 immunoreactivity was detected along the sinusoids in a pattern similar to ICAM-1 staining. PECAM-1 specific transcripts were detected in freshly isolated and cultured SECs. After a single CCl4-administration, PECAM-1 immunoreactivity did not increase along the sinusoids in contrast to the early increase of ICAM-1. Northern blot analysis indicated that PECAM-1 expression in liver tissue and in isolated SECs does not increase after a single administration of CCl4, whereas ICAM-1 steady-state level increased after 6 h. In diseased human livers PECAM-1 was detectable along the sinusoids, within inflammatory infiltrates and within fibrotic septa. Neither in acutely nor chronically diseased human livers was an obvious increase of PECAM-1 immunoreactivity detectable. CONCLUSIONS: PECAM-1 is expressed by SECs. In contrast to ICAM-1, PECAM-1 transcript level is not enhanced during liver damage.