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W Berger

Publications and source records attributed to W Berger.

At least 19 recordsLinked to original sources

Modulation of soleus H-reflexes during gait in healthy children.

During locomotion spinal short latency reflexes are rhythmically modulated and depressed compared to rest. In adults this modulation is severely disturbed after bilateral spinal lesions indicating a role for supra-spinal control. Soleus reflex amplitudes are large in the stance phase and suppressed in the swing phase contributing to the reciprocal muscle activation pattern required for walking. In early childhood the EMG pattern during gait underlies an age-dependent process changing from co-contraction of agonists and antagonists to a reciprocal pattern at the age of 5-7 years. It is unknown whether at this stage apart from the EMG also reflexes are modulated, and if so, whether the reflex modulation is fully mature or still underlies an age-dependent development. This may give important information about the maturation of CNS structures involved in gait control. Soleus Hoffmann H-reflexes were investigated in 36 healthy children aged 7-16 years during treadmill walking at 1.2 km/h and 3.0 km/h. At 7 years old a rhythmic modulation similar to adults was observed. The H-reflex size during the stance phase decreased significantly with age while the maximum H-reflex (H (max)) at rest remained unchanged. At 3.0 km/h H-reflexes were significantly larger during the stance phase and smaller during the swing phase as compared to 1.2 km/h but the age-dependent suppression was observed at both walking velocities. In conclusion H-reflex modulation during gait is already present in young children but still underlies an age-dependent process independent of the walking velocity. The finding that the rhythmic part of the modulation is already present at the age of 7 years may indicate that the supra-spinal structures involved mature earlier than those involved in the tonic reflex depression. This may reflect an increasing supra-spinal control of spinal reflexes under functional conditions with maturation.

Adolescent↗

Cytokine gene polymorphisms and atopic disease in two European cohorts. (ECRHS-Basel and SAPALDIA).

BACKGROUND: Atopy and allergic phenotypes are biologically characterized by an imbalanced T helper cell response skewed towards a type 2 (TH2) immune response associated with elevated serum immunoglobulin E (IgE) levels. Polymorphisms in cytokine genes might modulate regulation of the TH1/TH2 balance. We thus aimed at reproducing our previous findings from a European study population on the association of various cytokine polymorphisms with self-reported hay fever as well as increased total and specific IgE levels in two comparable study populations. METHODS: Two prospective Caucasian cohorts were used. In the Basel center of the European Community Respiratory Health Survey (ECRHS, n = 418) ten distinct cytokine polymorphisms of putative functional relevance were genotyped. In the Swiss cohort Study on Air Pollution And Lung Disease In Adults (SAPALDIA, n = 6003) two cytokine polymorphisms were genotyped. The associations of these polymorphisms with atopy were estimated by covariance and logistic regression analysis. RESULTS: We confirmed IL4, IL10, IL6 and IL18 as candidate genes for atopic health outcomes. In the large, well-characterized SAPALDIA cohort the IL6(-174G>C) and IL18(-137G>C) polymorphisms were associated with circulating total IgE concentrations in subjects with hay fever. The IL18(-137G>C) polymorphism was also associated with the prevalence of hay fever. CONCLUSION: Comprehensive characterization of genetic variation in extended cytokine candidate gene regions is now needed. Large study networks must follow to investigate the association of risk patterns defined by genetic predisposing and environmental risk factors with specific atopic phenotypes.

Journal Article↗

In humans Ib facilitation depends on locomotion while suppression of Ib inhibition requires loading.

The role of force feedback during gait is still a matter of debate. From work on cats, it is known that input from Golgi tendon organs from triceps surae does produce Ib facilitation during locomotion instead of autogenic inhibition. In humans, Stephens and Yang (Stephens, M.J., Yang, J.F., 1996. Short latency, non-reciprocal group I inhibition is reduced during the stance phase of walking in humans. Brain Res. 743, 24-31) found that voluntary contraction results in a reduction of Ib inhibition. During gait, they even observed Ib facilitation in a subset of subjects. This raises the question whether the crucial elements involved in these changes are either loading of the leg or locomotion. To examine this question, Ib reflexes were investigated during sitting, lying supine, lying supine with 300 N pressure applied to the foot sole, standing, and a rhythmic loading and unloading task called "reduced" gait. Ib inhibition was obtained during sitting and lying supine. This inhibition was significantly reduced or disappeared during standing and when lying supine but loaded. During the stance phase of "reduced" gait, the inhibition disappeared in eight subjects, and even a facilitation was observed in six subjects. It is concluded that the decrease in Ib inhibition from gastrocnemius to soleus occurs during a load-bearing condition and does not require locomotion. In contrast, Ib facilitation requires locomotion at least in a rudimentary form.

Electromyography↗

Anticancer effects of zoledronic acid against human osteosarcoma cells.

Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N = 9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

The common G-allele of interleukin-18 single-nucleotide polymorphism is a genetic risk factor for atopic asthma. The SAPALDIA Cohort Study.

BACKGROUND: IL-18 is a pleiotrophic cytokine involved in both, T-helper type 1 (Th1) and Th2 differentiation. Recently genetic variants in the IL-18 gene have been associated with increased risk of atopy and asthma. OBJECTIVE: To examine the relationship of a genetic, haplotype-tagging promotor variant -137G/C in the IL-18 gene with atopic asthma in a large, well-characterized and population-based study of adults. METHODS: Prospective cohort study design was used to collect interview and biological measurement data at two examination time-points 11 years apart. Multivariate logistic regression analysis was used to assess the association of genotype with asthma and atopy. RESULTS: The G-allele of the IL-18 promotor variant (-137G/C) was associated with a markedly increased risk for the prevalence of physician-diagnosed asthma with concomitant skin reactivity to common allergens. Stratification of the asthma cases by skin reactivity to common allergens revealed an exclusive association of IL-18 -137 G-allele with an increased prevalence of atopic asthma (adjusted odds ratio (OR): 3.63; 95% confidence interval: (1.64-8.02) for GC or GG carriers vs. CC carriers), and no according association with asthma and concomitant negative skin reactivity (adjusted OR: 1.13; 0.66-1.94). The interaction between IL-18 -137G/C genotype and positive skin prick test was statistically significant (P=0.029). None of 74 incident asthma cases with atopy at baseline exhibited the CC genotype. CONCLUSION: Our results strongly suggest that this variant of the IL-18 gene is an important genetic determinant involved in the development of atopic asthma.

Adult↗

Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene encoding methyl CpG binding protein 2 (MeCP2). Recently, a new isoform of MeCP2 including exon 1 was identified. This new isoform is more abundantly expressed in brain than the isoform including exons 2-4. Very little is known about the phenotypes associated with mutations in exon 1 of MECP2 since only a limited number of RTT patients carrying such mutations have been identified so far. In this study, we screened a cohort of 20 girls with RTT for exon 1 mutations by sequencing and multiplex ligation-dependent probe amplification (MLPA). We identified one girl with a novel exon 1 mutation (c.30delCinsGA) by sequencing and three with genomic rearrangements by MLPA. Comparison of the phenotypes showed that the girls carrying a mutation or rearrangement encompassing exon 1 were more severely affected than the girls with rearrangements not affecting exon 1.

Adolescent↗

Economic evaluation of the impact of nicorandil in angina (IONA) trial.

OBJECTIVE: To estimate the net cost of adding nicorandil to usual treatment for patients with angina and to compare this with indicators of health benefit. DESIGN: Cost effectiveness analysis. SETTING: Based on results of the IONA (impact of nicorandil on angina) trial. PATIENTS: Patients with angina fulfilling the entry criteria for the IONA trial. INTERVENTIONS: In one arm of the trial nicorandil was added to existing antianginal treatment and compared with existing treatment alone. MAIN OUTCOME MEASURES: Costs were for use of hospital resources (for cardiovascular, cerebrovascular, and gastrointestinal reasons), nicorandil, and care after hospital discharge. Benefits were assessed in three ways: (1) IONA trial primary outcome (coronary heart disease (CHD) death, non-fatal myocardial infarction, or hospital admission for cardiac chest pain); (2) acute coronary syndrome (CHD death, non-fatal myocardial infarction, or unstable angina); and (3) event-free survivors at the end of the trial. RESULTS: The net cost for each additional IONA trial end point averted was -5 pounds sterling (-7 euros). The net cost for each case of acute coronary syndrome averted was -8 pounds sterling (-12 euros). The net cost for each event-free survivor was -5 pounds sterling (-7 euros). These figures are based on gastrointestinal events that were judged definitely or probably related to nicorandil. When all gastrointestinal events were included these three ratios rose to 567 pounds sterling (835 euros), 886 pounds sterling (1305 euros), and 516 pounds sterling (760 euros), respectively. CONCLUSIONS: A substantial amount of the additional cost of nicorandil is offset by reduced use of hospital services. The limited comparisons possible with other CHD interventions suggest that nicorandil compares favourably.

Angina Pectoris↗

A health economic model to determine the long-term costs and clinical outcomes of raising low HDL-cholesterol in the prevention of coronary heart disease.

OBJECTIVES: The aim of this study was to describe a health economic model developed to project lifetime clinical and cost outcomes of lipid-modifying interventions in patients not reaching target lipid levels and to assess the validity of the model. METHODS: The internet-based, computer simulation model is made up of two decision analytic sub-models, the first utilizing Monte Carlo simulation, and the second applying Markov modeling techniques. Monte Carlo simulation generates a baseline cohort for long-term simulation by assigning an individual lipid profile to each patient, and applying the treatment effects of interventions under investigation. The Markov model then estimates the long-term clinical (coronary heart disease events, life expectancy, and quality-adjusted life expectancy) and cost outcomes up to a lifetime horizon, based on risk equations from the Framingham study. Internal and external validation analyses were performed. RESULTS: The results of the model validation analyses, plotted against corresponding real-life values from Framingham, 4S, AFCAPS/TexCAPS, and a meta-analysis by Gordon et al., showed that the majority of values were close to the y = x line, which indicates a perfect fit. The R2 value was 0.9575 and the gradient of the regression line was 0.9329, both very close to the perfect fit (= 1). CONCLUSIONS: Validation analyses of the computer simulation model suggest the model is able to recreate the outcomes from published clinical studies and would be a valuable tool for the evaluation of new and existing therapy options for patients with persistent dyslipidemia.

Cholesterol, HDL↗

Cellular functions of vaults and their involvement in multidrug resistance.

Vaults are evolutionary highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. They are 41 x 73 nm in size and are composed of multiple copies of three proteins and small untranslated RNA (vRNA). The main component of vaults represents the 110 kDa major vault protein (MVP), whereas the two minor vault proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (VPARP) and the 240 kDa telomerase-associated protein-1 (TEP1). Vaults are abundantly present in the cytoplasm of eukaryotic cells and they were found to be associated with cytoskeletal elements as well as occasionally with the nuclear envelope. Vaults and MVP have been associated with several cellular processes which are also involved in cancer development like cell motility and differentiation. Due to the over-expression of MVP (also termed lung resistance-related protein or LRP) in several P-glycoprotein (P-gp)-negative chemoresistant cancer cell lines, vaults have been linked to multidrug resistance (MDR). Accordingly, high levels of MVP were found in tissues chronically exposed to xenobiotics. In addition, the expression of MVP correlated with the degree of malignancy in certain cancer types, suggesting a direct involvement in tumor development and/or progression. Based on the finding that MVP binds several phosphatases and kinases including PTEN, SHP-2 as well as Erk, evidence is accumulating that MVP might be involved in the regulation of important cell signalling pathways including the PI3K/Akt and the MAPK pathways. In this review we summarize the current knowledge concerning the vault particle and discuss its possible cellular functions, focusing on the role of vaults in chemotherapy resistance.

ATP Binding Cassette Transporter, Subfamily B↗

A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans.

Slow, rhythmic oscillations (<5 Hz) in the sleep electroencephalogram may be a sign of synaptic plasticity occurring during sleep. The oscillations, referred to as slow-wave activity (SWA), reflect sleep need and sleep intensity. The amount of SWA is homeostatically regulated. It is enhanced after sleep loss and declines during sleep. Animal studies suggested that sleep need is genetically controlled, yet the physiological mechanisms remain unknown. Here we show in humans that a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and SWA during sleep. In contrast, a distinct polymorphism of the adenosine A(2A) receptor gene, which was associated with interindividual differences in anxiety symptoms after caffeine intake in healthy volunteers, affects the electroencephalogram during sleep and wakefulness in a non-state-specific manner. Our findings indicate a direct role of adenosine in human sleep homeostasis. Moreover, our data suggest that genetic variability in the adenosinergic system contributes to the interindividual variability in brain electrical activity during sleep and wakefulness.

Adenosine Deaminase↗

Morphological variability and cell-wall deficiency in Mycobacterium tuberculosis 'heteroresistant' strains.

SETTING: Sofia State Hospital for Tuberculosis Treatment, Bulgaria. OBJECTIVE: To investigate the morphology of two 'heteroresistant' clinical isolates and one non-heteroresistant isolate, all isolated from newly diagnosed tuberculosis (TB) patients, as well as the reference strain H37Rv. Heteroresistant isolates contained clonally-related sensitive and drug-resistant organisms which could subsequently be separated using drug-containing primary cultures and had been isolated from patients originally diagnosed with susceptible TB by the 1% proportion method. Mycobacterial cultures were evaluated by transmission electron microscopy after 25 days of cultivation in Dubos broth. RESULTS: In contrast to H37Rv and the non-heteroresistant isolate, the bacterial populations in both heteroresistant isolates demonstrated distinct pleomorphic variability and coexistence of both classical and cell-wall deficient forms. Electron micrographs of mutants resistant to streptomycin and isoniazid showed predominance of atypical granular L-forms, which formed L-type colonies on Dubos agar. CONCLUSION: The L-form transformation processes, observed both in clinical heteroresistant isolates containing mixed populations of Mycobacterium tuberculosis organisms with different resistance gene genotypes and in the isolated resistant (mutant) clones, indicate a possible link between resistance and cell-wall deficient L-phase states and suggest one of the possible mechanisms by which resistant mutants are able to survive in vivo.

Antitubercular Agents↗

Heterocyclic complexes of ruthenium(III) induce apoptosis in colorectal carcinoma cells.

PURPOSE: The ruthenium complex salt indazolium trans-[tetrachlorobisindazole-ruthenate(III)] (KP1019) and the analogous sodium salt KP1339 are effective tumor-inhibiting drugs in experimental therapy of autochthonous colorectal carcinomas in rats. This paper examines the cell biological mechanisms underlying their antineoplastic effects. METHODS: Colorectal tumor cell lines were used to analyze uptake of the ruthenium(III) complexes into the cells and the mechanism as well as the efficacy of their cytotoxic effects. RESULTS: KP1019 and KP1339 are efficiently taken up into the cells: 100 microM ruthenium(III) complex in the growth medium led to the uptake of 120-160 ng ruthenium per 10(6) cells within 30 min. Uptake of KP418 was tenfold lower correlating with its lower cytotoxic efficiency. KP1019 and KP1339 induced apoptosis in SW480 and HT29 cells predominantly by the intrinsic mitochondrial pathway as indicated by loss of mitochondrial membrane potential. Correspondingly sensitivity of the cells paralleled expression of bcl(2) while it was only slightly affected by mutations in Ki-ras. CONCLUSIONS: Our data demonstrate that trans-[tetrachlorobisindazole-ruthenate(III)] complex salts are promising candidate drugs in the second-line treatment of colorectal cancers resistant to other cytostatic drugs and has been introduced into phase I clinical trials.

Apoptosis↗

Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A).

KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

The role of vision in maintaining heading direction: effects of changing gaze and optic flow on human gait.

How is heading direction maintained in human gait? This question was investigated with respect to the role of optic flow and in the context of different movement strategies. While walking on a treadmill the deviation from the ideal straight path was measured in terms of lateral sway induced by a lateral gaze shift (by looking at a moving visual target). The role of the focus of expansion (FOE) within a radially expanding optic flow pattern was investigated by varying its relative velocity of expansion from 0- to 4-fold (the equivalent of walking speed), thus increasing the perceptibility of FOE. If FOE was a relevant cue for maintaining heading direction, a reduction of lateral sway amplitude was expected with increasing flow velocity. The presence of a radially expanding flow pattern did not reduce lateral sway. Lateral sway was least when the visual background remained stable without any flow pattern. Increasing the velocity of the flow pattern resulted in an increase in lateral sway. If the relative velocity of the flow pattern was raised beyond that corresponding to walking speed, lateral sway amplitude approached the maximal values observed in the dark. In all experiments, sway amplitude increased linearly with the increasing excursion of the visual target. Different strategies to perform the gaze shift (eye or head turns) only resulted in minor differences in lateral sway amplitude. The results show that gaze shifts during locomotion induce lateral sway, which depends upon the presence, and characteristics, of background optic flow. Under the present conditions, the FOE within the flow field seems not to be a dominant cue to control heading. However, the systematic increase in lateral sway induced by high flow velocities indicates that motion parallax has an effect on heading during locomotion.

Adult↗

[Genetic causes of retinal degeneration].

Premature death of rod and cone photoreceptor cells in the human retina leads to severe visual handicaps in affected patients. The two most important groups of retinal dystrophies, macular degeneration and retinitis pigmentosa, differ in primary symptoms and disease progression. Macular degeneration starts in the central retina and progresses towards the periphery. In RP, photoreceptor cell death starts in the periphery and then proceeds to the central part of the retina. Molecular studies have revealed important new findings during the last decade. There are two important results to be emphasized: 1. The very same clinical symptoms can result from mutations in different genes. RP is a prominent example for this phenomenon. 2. Mutations in the same gene can result in different phenotypes. The correlation between genotype and phenotype is not essentially straight forward. This may indicate that other factors can influence the phenotypic consequences of mutations. Different X-linked retinal dystrophies represent excellent examples for these findings.

Adult↗

Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalised Anxiety Disorder--an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.

OBJECTIVE: An 8-week randomized, reference-controlled, double-blind, multi-centre clinical trial investigated Kava-Kava LI 150 in Generalized Anxiety Disorder (GAD; ICD-10: F41.1). METHOD: 129 out-patients received either 400 mg Kava LI 150, 10 mg Buspirone or 100 mg Opipramol daily for 8 weeks. At week 9, subjects were seen to check for symptoms of withdrawal or relapse. Primary outcome measures comprised the HAMA scale and the proportion of responders at week 8. Secondary measures were the Boerner Anxiety Scale (BOEAS), SAS, CGI, a self-rating scale for well-being (Bf-S), a sleep questionnaire (SF-B), a quality-of-life questionnaire (AL) and global judgements by investigator and patients. RESULTS: In 127 patients (ITT) no significant differences could be observed regarding all efficacy and safety measures. About 75% of patients were classified as responders (50% reduction of HAMA score) in each treatment group, about 60% achieved full remission. CONCLUSION: Kava-Kava LI150 is well tolerated and as effective as Buspirone and Opipramol in the acute treatment of out-patients suffering from GAD.

Adult↗

[Reduction of severe hypoglycemia by functional insulin therapy of type I diabetes mellitus].

Life style has to be adapted to insulin regimens in conventionally intensified insulin therapy. Functional insulin therapy (FIT) allows for flexible adjustments to changing insulin requirements. FIT is based on separating the substitution of basal, meal dependent and correction insulin by the patient. The patient has to acquire special knowledge. We here report longitudinal data of 183 patients out of 221 patients who have been educated by FIT outpatient programs in the years 1990 to 1996. The 3 month FIT education program consisted of sixteen hours in total. Five and a half hours were held in a whole day preparation seminar and the other seven hours in evening sessions each of 90 minutes duration. Prior to FIT education patients were treated by intensified conventional insulin therapy. Mean glycosylated hemoglobin prior to FIT education was 7.0% (normal range 3.7-5.6%). After FIT education glycosylated hemoglobin remained unchanged. However, the percentage of patients experiencing severe hypoglycemic episodes (stupor and coma) in a one year course was significantly reduced from 26% prior to FIT education to 14% after FIT education--hypoglycemic coma was reduced from 13% to 7% respectively. Thus, we can report that FIT reduces the risk of severe hypoglycemia. We believe that our data should stimulate the broad supply of FIT education programs available to diabetes patients in Switzerland.

Adult↗

[Functional insulin therapy: patient education and algorithms].

Functional insulin therapy is a teaching approach of intensified insulin therapy. Its aim is to transfer to the patient the decisional process and the management of its insulin treatment, this according to the various acts of everyday life, and particularly meals. The principles of functional insulin therapy, the pedagogic approach, the benefits observed in type 1 diabetic patients (better diabetes control, and particularly decrease in the number of severe hypoglycaemic events) are briefly described - Nevertheless, to apply this functional insulin therapy in practice, requires a specific teaching program preferably ambulatory in real everyday life conditions, and carried out by a staff highly qualified in diabetology.

Algorithms↗