[Contribution of physical and rehabilitation medicine to primary care medicine]. / Apport de la médecine physique et de réadaptation à la médecine de premier recours.

Physical and rehabilitation medicine (PRM) is an independent medical specialty, little known in Switzerland. This specialty, strongly linked to the holistic approach of the International Classification of Functioning, will be increasingly solicited by the epidemiology of disability and the imperatives of "ageing better". Its skills in prescribing human and material resources for rehabilitation provide added value in terms of loss of autonomy. Based on a biopsychosocial model, PRM has a high role to play in prevention and primary healthcare, as well as in the management and prevention of the consequences of functionally limiting diseases. There are, however, financial (pricing) and demographic (lack of representation) obstacles to effective action on behalf of the population and the healthcare system.

La médecine physique et de réadaptation (MPR), discipline indépendante, est peu connue en Suisse. Cette spécialité, liée à l'approche holistique de la classification internationale du fonctionnement, sera de plus en plus sollicitée par l'épidémiologie du handicap et les impératifs du « vieillir mieux ¼. Ses compétences de prescription des moyens humains et matériels en réadaptation apportent une plus-value sur la perte d'autonomie. Basée sur un modèle biopsychosocial, la MPR trouve sa place dans la prévention et les soins de santé primaires ainsi que dans la prise en charge et la prévention des conséquences des maladies induisant une limitation fonctionnelle. Il existe toutefois des obstacles financiers (tarification) et démographiques (insuffisance de représentation) pour une action efficace au service de la population et du système de santé.

Specific detection of Treponema pallidum in clinical samples: validation of a qPCR assay combining two genomic targets.

OBJECTIVES: We evaluated a real-time quantitative PCR (qPCR) for detection of the Treponema pallidum (TP) genome in clinical samples through simultaneous detection of two genomic targets. METHODS: We performed qPCR with TaqMan technology using two TP genes, polA and tpp47, as targets, with an internal positive control. The qPCR assay was compared with syphilis diagnosis based on a combination of clinical examination, serological results and inhouse nested PCR (nPCR). Samples were analysed at the National Reference Center for STIs at Cochin Hospital in Paris. RESULTS: In total, from October 2010 to December 2016, 320 documented clinical samples (mucosal and cutaneous swabs) were collected from patients with or without syphilis attending STI centres in France. The qPCR had an overall sensitivity of 89% (95% CI 85.1% to 92.1%), a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 88% (95% CI 84.3% to 91.5%). The agreement between qPCR and nPCR results was 94% (κ=0.88, 95% CI 0.83 to 0.93). Calibration of the qPCR assay, by cloning both the polA and tpp47 genes, defined the detection threshold as 1 copy/µL of DNA elution. CONCLUSIONS: We validated a new qPCR for detecting the TP genome in clinical samples with excellent sensitivity and specificity. The cloning of polA and tpp47 genes for calibration would be interesting in the evaluation of bacterial loads in samples.

29Si Magic Angle Spinning Nuclear Magnetic Resonance, Fourier-Transform Infrared, and Monte Carlo Study of Synthetic Tetrasilicic Magnesium Mica Solid Solutions.

The parallel 29Si magic angle spinning nuclear magnetic resonance (MAS NMR) and Fourier-transform infrared study of synthetic micas made it possible to compare structural features of the tetrasilicic magnesium mica K(Mg2.5□0.5) Si4O10(OH)2 (TMM) and their K(Mg3)(Si3.5Mg0.5)O10(OH)2 (TMMA) and K(Mg3)(Si3.5Be0.5)O10(OH)2 (TMMB) derivatives. In the TMM mica, SiO4 tetrahedra are elongated in the plane ab and shortened along the c* direction with respect to those of the phlogopite (Phl) K(Mg3)(Si3Al)O10(OH)2. The substitution of Si4+ by R2+ (Mg2+ or Be2+) produces, besides the 29Si MAS NMR signal of Si (3Si) at -91.2 ppm, new components at -84.4 or -87.5 ppm that correspond to Si (2Si1Mg) or Si(2Si1Be) environments. Tetrahedral cation distributions in TMM/TMMA, TMM/TMMB solid solutions are investigated with respect to the TMM/Phl series by means of NMR and Monte Carlo simulations, concluding that divalent Mg2+ and Be2+ are further dispersed than trivalent Al3+ cations in tetrahedral sheets of micas. In three analyzed series, cation distributions display features between those of the homogeneous dispersion of charges of phlogopites and the maximum dispersion of charges of TMM derivatives. In three series, the location of charge deficits that compensate K+ cations changes from octahedral in TMM to tetrahedral sheets in phlogopite and TMMA and TMMB derivatives.

Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist.

Targeting cannabinoid 1 receptors (CB1R) with peripherally restricted antagonists (or inverse agonists) shows promise to improve metabolic disorders associated with obesity. In this context, we designed and synthetized JM-00266, a new CB1R blocker with limited blood-brain barrier (BBB) permeability. Pharmacokinetics were tested with SwissADME and in vivo in rodents after oral and intraperitoneal administration of JM-00266 in comparison with Rimonabant. In silico predictions indicated JM-00266 is a non-brain penetrant compound and this was confirmed by brain/plasma ratios and brain uptake index values. JM-00266 had no impact on food intake, anxiety-related behavior and body temperature suggesting an absence of central activity. cAMP assays performed in CB1R-transfected HEK293T/17 cells showed that the drug exhibited inverse agonist activity on CB1R. In addition, JM-00266 counteracted anandamide-induced gastroparesis indicating substantial peripheral activity. Acute administration of JM-00266 also improved glucose tolerance and insulin sensitivity in wild-type mice, but not in CB1R-/- mice. Furthermore, the accumulation of JM-00266 in adipose tissue was associated with an increase in lipolysis. In conclusion, JM-00266 or derivatives can be predicted as a new candidate for modulating peripheral endocannabinoid activity and improving obesity-related metabolic disorders.

Surveillance of Antibiotic Resistance Genes in Treponema Pallidum Subspecies Pallidum from Patients with Early Syphilis in France.

Benzathine penicillin G (BPG) is the reference treatment for early syphilis, but shortages have recently been reported, highlighting a need for the validation of alternative treatments. The aim of this study was to evaluate the genomic resistance of Treponema pallidum subspecies pallidum (TPA) to macrolides and doxycycline in France. Swabs from genital, anal, oral and cutaneous lesions were obtained from 146 patients with early syphilis in France. They were screened for mutations conferring resistance to macrolides and doxycycline by nested PCR and sequencing. Resistance to macrolides was detected in 85% of the isolates, but no point mutations conferring doxycycline resistance were detected. These findings confirm that, in France, resistance to macrolides is widespread. Moreover, we confirmed the absence of genomic resistance to doxycycline in the TPA strains. Therefore, doxycycline could be safely recommended as an alternative to BPG for the treatment of early syphilis.

Rapid Synthesis and Antiproliferative Properties of Polyazamacrocycle-Based Bi- and Tetra-Gold(I) Phosphine Dithiocarbamate Complexes.

A family of bi- and tetrametallic gold(I) phosphine dithiocarbamate complexes were synthesized, starting from cyclam and dimethylcyclam polyazamacrocycles, respectively, along with their monometallic gold(I) chloridophosphine precursors. Their antiproliferative properties were evaluated on two cancer cell lines (A549 and NSCLC-N6-L16). Most of the mono- and bimetallic complexes displayed strong activities and, in particular, one bimetallic derivative showed antiproliferative properties in the low micromolar range. Insights into the structure-activity relationships are given, along with determination of the thioredoxin reductase inhibition potential, two-photon imaging of the fluorescent derivatives, and evaluation of gold uptake.

A novel NEUROG3 mutation in neonatal diabetes associated with a neuro-intestinal syndrome.

Neonatal diabetes mellitus (NDM) is a rare form of non-autoimmune diabetes usually diagnosed in the first 6 months of life. Various genetic defects have been shown to cause NDM with diverse clinical presentations and variable severity. Among transcriptional factor genes associated with isolated or syndromic NDM, a few cases of homozygous mutations in the NEUROG3 gene have been reported, all mutated patients presenting with congenital malabsorptive diarrhea with or without diabetes at a variable age of onset from early life to childhood. Through a targeted next-generation sequencing assay for monogenic diabetes genes, we aimed to search for pathogenic deleterious mutation in a Turkish patient with NDM, severe malabsorptive diarrhea, neurointestinal dysplasia and other atypical features. In this patient, we identified a novel homozygous nonsense mutation (p.Q4*) in NEUROG3. The same biallelic mutation was found in another affected family member. Of note, the study proband presents with abnormalities of the intrahepatic biliary tract, thyroid gland and central nervous system, which has never been reported before in NEUROG3 mutation carriers. Our findings extend the usually described clinical features associated with NEUROG3 deficiency in humans, and question the extent to which a complete lack of NEUROG3 expression may affect pancreas endocrine function in humans.

Targets and teamwork: Understanding differences in pediatric diabetes centers treatment outcomes.

OBJECTIVE: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. RESEARCH DESIGN AND METHODS: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. RESULTS: Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. CONCLUSIONS: The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.

Revisiting autoimmune gastritis in children and adolescents with type 1 diabetes.

OBJECTIVE: Assess the frequency of anti-H+ /K+ adenosine triphosphatase (ATPase) autoantibodies (AAB) and symptoms of autoimmune gastritis in children and adolescents with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Anti-H+ /K+ ATPase AAB were measured in 402 children and adolescents (210 boys and 192 girls, 11.1 ± 4.5 years) treated for T1D (screened positive for ß-cell AAB), along with search of symptoms of anemia (hemoglobin, serum iron, and ferritin levels) and gastric pain. The AAB specific for thyroperoxydase, thyroglobulin, and transglutaminase were also measured. RESULTS: Anti-H+ /K+ ATPase AAB were present in 6.5% of children. Their frequency increased with age: 4% at 10 years, 10% at 15 years, and 20% at 20 years. Iron deficiency (45% vs 3.8%), iron deficiency anemia (36% vs 3.8%), antithyroid AAB (24% vs 9.7%), and family history of Graves' disease (25% vs 5.6%) were more frequent in patients with anti-H+ /K+ ATPase AAB. Two patients, a 13-year-old girl and a 11-year-old boy, experienced symptoms (iron deficiency anemia and epigastric pain) which led to diagnosis of autoimmune gastritis confirmed upon fibroscopy. Both showed high levels of anti-H+ /K+ ATPase AAB and atrophic gastritis. CONCLUSIONS: Autoimmune gastritis presents an age-dependent frequency in children and adolescents with T1D but is rarely symptomatic. Screening for anti-H+ /K+ ATPase AAB should thus target patients with iron deficiency, anemia, epigastralgia, autoimmune thyroiditis, or age over 15 years.

Diabetes knowledge in adolescents with type 1 diabetes and their parents and glycemic control.

OBJECTIVE: To evaluate diabetes knowledge and skills (DKS) in adolescents (>10 year) with type 1 diabetes (T1D) and their parents, and its effect on glycemic control. METHODS: A ready-to-use program and a standardized questionnaire comprising 50 true-false questions based on this program, were elaborated by a National Committee, to help dispensing education at diagnosis of T1D. The questionnaire was completed by 2933 T1D patients (49% girls, 51% boys; 14.1 ± 2.5 year), 2180 mothers and 798 fathers, in 115 pediatric centers. Associations between DKS score (number of correct answers), glycated hemoglobin (HbA1c) and sociofamilial characteristics were assessed. RESULTS: DKS score increased with age, and was higher in girls than in boys and in mothers than in fathers; it correlated strongly between adolescents and their own parents; it was higher when adolescents had previously participated in diabetes camp and when parents had higher academic levels. HbA1c decreased significantly with parents' higher DKS score and academic level, and when both parents lived together. Mean adolescent DKS score was significantly higher in patients with HbA1c below 8% or 8.5% than for patients with HbA1c above these thresholds. CONCLUSION: A large survey in T1D children and adolescents and their parents showed associations between DKS and glycemic control, and the major role of sociofamilial factors.

Insulin regimens, diabetes knowledge, quality of life, and HbA1c in children and adolescents with type 1 diabetes.

OBJECTIVES: To further describe the changes in insulin therapy regimens and hemoglobin A1c (HbA1c) in children and adolescents with type 1 diabetes, and their associations with diabetes knowledge and quality of life. RESEARCH DESIGN AND METHODS: The study included 4293 children and adolescents (12.9 ± 2.6 yr, diabetes >1 yr) attending AJD (Aide aux Jeunes Diabétiques) summer camps between 2009 and 2014. The distribution of insulin regimens and associations between HbA1c, therapeutic regimens, diabetes knowledge (AJD questionnaire), and Quality of Life (Ingersoll et Marrero, Hvidoere Study Group short version) were assessed. RESULTS: The percentage of youth treated with insulin pumps increased up to about 45%, basal bolus stabilized around 40%, and other regimens decreased majorly. HbA1c was higher with premixed insulins only regimens (9.05 ± 2.43%), but there was no difference between pump (8.12 ± 1.09%), basal bolus (8.32 ± 1.33%) and two to three injections (8.18 ± 1.28%). Mean HbA1c decreased by 0.014% per year. The percentage of HbA1c <7.5% increased by 1.5% per year, and the percentages of HbA1c >9% or >10% decreased by 4 and 5.5%, changes being greater with the pump. HbA1c was weakly associated with diabetes knowledge, and strongly with general health perception and perception about diabetes. CONCLUSION: The percentage of children and adolescents with the highest risk of complications decreased markedly. The distribution of HbA1c better depicts the glycemic control in a population than the mean or the percentage of patients reaching the target (7.5%). HbA1c was more strongly associated with general health perception than with therapeutic regimens and diabetes knowledge.

A unique CD8(+) T lymphocyte signature in pediatric type 1 diabetes.

Human type 1 diabetes results from a destructive auto-reactive immune response in which CD8(+) T lymphocytes play a critical role. Given the intense ongoing efforts to develop immune intervention to prevent and/or cure the disease, biomarkers suitable for prediction of disease risk and progress, as well as for monitoring of immunotherapy are required. We undertook separate multi-parameter analyses of single naïve and activated/memory CD8(+) T lymphocytes from pediatric and adult patients, with the objective of identifying cellular profiles associated with onset of type 1 diabetes. We observe global perturbations in gene and protein expression and in the abundance of T cell populations characterizing pediatric but not adult patients, relative to age-matched healthy individuals. Pediatric diabetes is associated with a unique population of CD8(+) T lymphocytes co-expressing effector (perforin, granzyme B) and regulatory (transforming growth factor ß, interleukin-10 receptor) molecules. This population persists after metabolic normalization and is especially abundant in children with high titers of auto-antibodies to glutamic acid decarboxylase and with elevated HbA1c values. These findings highlight striking differences between pediatric and adult type 1 diabetes, indicate prolonged large-scale perturbations in the CD8(+) T cell compartment in the former, and suggest that CD8(+)CD45RA(-) T cells co-expressing effector and regulatory factors are of interest as biomarkers in pediatric type 1 diabetes.

Bone imaging findings in genetic and acquired lipodystrophic syndromes: an imaging study of 24 cases.

OBJECTIVE: To describe the bone imaging features of lipodystrophies in the largest cohort ever published. MATERIALS AND METHODS: We retrospectively examined bone imaging data in 24 patients with lipodystrophic syndromes. Twenty-two had genetic lipodystrophy: 12/22 familial partial lipodystrophy (FPLD) and 10/22 congenital generalized lipodystrophy (CGL), 8 with AGPAT2-linked CGL1 and 2 with seipin-linked CGL2. Two patients had acquired generalized lipodystrophy (AGL) in a context of non-specific autoimmune disorders. Skeletal radiographs were available for all patients, with radiographic follow-up for two. Four patients with CGL1 underwent MRI, and two of them also underwent CT. RESULTS: Patients with FPLD showed non-specific degenerative radiographic abnormalities. Conversely, CGL patients showed three types of specific radiographic alterations: diffuse osteosclerosis (in 7 patients, 6 with CGL1 and 1 with CGL2), well-defined osteolytic lesions sparing the axial skeleton (7 CGL1 and 1 CGL2), and pseudo-osteopoikilosis (4 CGL1). Pseudo-osteopoikilosis was the sole bone abnormality observed in one of the two patients with AGL. Osteolytic lesions showed homogeneous low signal intensity (SI) on T1-weighted and high SI on T2-weighted MR images. Most of them were asymptomatic, although one osteolytic lesion resulted in a spontaneous knee fracture and secondary osteoarthritis in a patient with CGL1. MRI also showed diffuse fatty bone marrow alterations in patients with CGL1, with intermediate T1 and high T2 SI, notably in radiographically normal areas. CONCLUSIONS: The three types of peculiar imaging bone abnormalities observed in generalized lipodystrophic syndromes (diffuse osteosclerosis, lytic lesions and/or pseudo-osteopoikilosis) may help clinicians with an early diagnosis in pauci-symptomatic patients.

[Acute neurorehabilitation in neurooncology: Swiss Pilot Project and review of the litterature]. / Neurorééducation aiguë neuro-oncologique: projet pilote et revue de la literature.

New treatment modalities in oncology, radiation oncology and surgery have led to a significant improvement in life expectancy for cancer patients. Some will however develop severe neurologic deficits that will impact their quality of life. To limit this impact, it is essential to offer optimal neurorehabilitation. In this context, a pilot project of early and intensive neurorehabilitation for brain tumor patients has been set up. A collaboration between the teams of neurooncology, acute neurorehabilitation and neurosurgery from the CHUV and the Clinique La Lignière allows an intensive and direct neurorehabilitation following neurosurgery. This neuroreeducation has allowed 75% of the patients included in this program to return home.

Genetic diversity and trait genomic prediction in a pea diversity panel.

BACKGROUND: Pea (Pisum sativum L.), a major pulse crop grown for its protein-rich seeds, is an important component of agroecological cropping systems in diverse regions of the world. New breeding challenges imposed by global climate change and new regulations urge pea breeders to undertake more efficient methods of selection and better take advantage of the large genetic diversity present in the Pisum sativum genepool. Diversity studies conducted so far in pea used Simple Sequence Repeat (SSR) and Retrotransposon Based Insertion Polymorphism (RBIP) markers. Recently, SNP marker panels have been developed that will be useful for genetic diversity assessment and marker-assisted selection. RESULTS: A collection of diverse pea accessions, including landraces and cultivars of garden, field or fodder peas as well as wild peas was characterised at the molecular level using newly developed SNP markers, as well as SSR markers and RBIP markers. The three types of markers were used to describe the structure of the collection and revealed different pictures of the genetic diversity among the collection. SSR showed the fastest rate of evolution and RBIP the slowest rate of evolution, pointing to their contrasted mode of evolution. SNP markers were then used to predict phenotypes -the date of flowering (BegFlo), the number of seeds per plant (Nseed) and thousand seed weight (TSW)- that were recorded for the collection. Different statistical methods were tested including the LASSO (Least Absolute Shrinkage ans Selection Operator), PLS (Partial Least Squares), SPLS (Sparse Partial Least Squares), Bayes A, Bayes B and GBLUP (Genomic Best Linear Unbiased Prediction) methods and the structure of the collection was taken into account in the prediction. Despite a limited number of 331 markers used for prediction, TSW was reliably predicted. CONCLUSION: The development of marker assisted selection has not reached its full potential in pea until now. This paper shows that the high-throughput SNP arrays that are being developed will most probably allow for a more efficient selection in this species.

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

Time domain compressive beam forming of ultrasound signals.

Ultrasound imaging is a wide spread technique used in medical imaging as well as in non-destructive testing. The technique offers many advantages such as real-time imaging, good resolution, prompt acquisition, ease of use, and low cost compared to other techniques such as x-ray imaging. However, the maximum frame rate achievable is limited as several beams must be emitted to compute a single image. For each emitted beam, one must wait for the wave to propagate back and forth, thus imposing a limit to the frame rate. Several attempts have been made to use less beams while maintaining image quality. Although efficiently increasing the frame rate, these techniques still use several transmit beams. Compressive Sensing (CS), a universal data completion scheme based on convex optimization, has been successfully applied to a number of imaging modalities over the past few years. Using a priori knowledge of the signal, it can compute an image using less data allowing for shorter acquisition times. In this paper, it is shown that a valid CS framework can be derived from ultrasound propagation theory, and that this framework can be used to compute images of scatterers using only one plane wave as a transmit beam.

Using redundancy of round-trip ultrasound signal for non-continuous arrays: Application to gap and blockage compensation.

In ultrasound imaging, an array of elements is used to image a medium. If part of the array is blocked by an obstacle, or if the array is made from several sub-arrays separated by a gap, grating lobes appear and the image is degraded. The grating lobes are caused by missing spatial frequencies, corresponding to the blocked or non-existing elements. However, in an active imaging system, where elements are used both for transmitting and receiving, the round trip signal is redundant: different pairs of transmit and receive elements carry similar information. It is shown here that, if the gaps are smaller than the active sub-apertures, this redundancy can be used to compensate for the missing signals and recover full resolution. Three algorithms are proposed: one is based on a synthetic aperture method, a second one uses dual-apodization beamforming, and the third one is a radio frequency (RF) data based deconvolution. The algorithms are evaluated on simulated and experimental data sets. An application could be imaging through ribs with a large aperture.

Changes in insulin therapy regimens over 10 yr in children and adolescents with type 1 diabetes attending diabetes camps.

OBJECTIVE: To describe the changes in insulin therapy regimens of children and adolescents with type 1 diabetes over 10 yr and their correlation with hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS: The study included 7206 children and adolescents (age 12.8 ± 2.7 yr, more than 1 yr of diabetes duration) admitted in summer camps between 1998 and 2007 (707-896/yr). Based on injection times (breakfast, lunch, afternoon, dinner, bedtime) and insulin types (short, long and premixed; human or analog), 786 different therapeutic combinations were classified in six main types of regimens. The distribution of the different regimens and their correlation with HbA1c were evaluated as a function of year and age. RESULTS: Over 10 yr, basal bolus increased from 13 to 52% and the pump from <1 to 13%, regimens with two to three injections per day decreased from 50 to 25%, those with only premixed insulins from 33 to 7%, and diverse regimens from 9 to 1%. HbA1c was significantly higher with premixed insulin only, but there were no differences between the other regimens throughout the follow-up. Mean yearly HbA1c (8.21-8.45%) did not show any significant decrease, but the percentage of patients with HbA1c > 9 and 10% decreased significantly, in those treated with two to three injections and the pump, not with basal bolus or premixed only regimens. CONCLUSION: A major trend in intensifying insulin treatment in children and adolescents with type 1 diabetes was accompanied by modest improvements in HbA1c. No insulin regimen has shown any better results, except over premixed insulins.

Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors.

New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/ß and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines.