Extreme self-monitoring, fear of hypoglycemia and obsessive-compulsive disorder in type 1 diabetes mellitus: when less is better

Background: Pre-existing psychological factors can strongly influence coping with type 1 diabetes mellitus and interfere with self-monitoring. Psychiatric disorders seem to be positively associated with poor metabolic control. We present a case of extreme compulsive blood testing due to obsessive fear of hypoglycemia in an adolescent with type 1 diabetes mellitus. Case report: Type 1 diabetes mellitus (anti GAD-antibodies 2624 U/l, norm < 9.5) was diagnosed in a boy aged 14.3 years [170 cm (+ 0.93 SDS), weight 50.5 kg (+ 0.05 SDS)]. Laboratory work-up showed no evidence for other autoimmune disease. Family and past medical history were unremarkable. Growth and developmental milestones were normal. Insulin-analog based basal-bolus regime was initiated, associated to standard diabetic education. Routine psychological evaluation performed at the onset of diabetes revealed intermittent anxiety and obsessivecompulsive traits. Accordingly, a close psychiatric follow-up was initiated for the patient and his family. An adequate metabolic control (HbA1c drop from >14 to 8%) was achieved within 3 months, attributed to residual =538;-cell function. In the following 6 months, HbA1c rose unexpectedly despite seemingly adequate adaptations of insulin doses. Obsessive fear of hypoglycemia leading to a severe compulsive behavior developed progressively with as many as 68 glycemia measurements per day (mean over 1 week). The patient reported that he could not bear leaving home with glycemia < 15 mmol/l, ending up with school eviction and severe intra-familial conflict. Despite intensive psychiatric outpatient support, HbA1c rose rapidly to >14% with glycemia-testing reaching peaks of 120 tests/day. The situation could only be discontinued through psychiatric hospitalization with intensive behavioral training. As a result, adequate metabolic balance was restored (HbA1c value: 7.1 %) with acceptable 10-15 daily glycemia measurements. Discussion: The association of overt psychiatric disorders to type 1 diabetes mellitus is very rare in the pediatric age group. It can lead to a pathological behavior with uncontrolled diabetes. Such exceptional situations require long-term admissions with specialized psychiatric care. Slow acceptation of a "less is better" principle in glycemia testing and amelioration of metabolic control are difficult to achieve.

Medical treatment of hypertension in Switzerland. The 2009 Swiss Hypertension Survey (SWISSHYPE).

OBJECTIVES: Despite a broad and efficient pharmacological antihypertensive armamentarium, blood pressure (BP) control is suboptimal and heterogeneous throughout Europe. Recent representative data from Switzerland are limited. The goal of the present survey was therefore to assess the actual control rate of high BP in Switzerland in accordance with current guidelines. The influence of risk factors, target organ damage and medication on BP levels and control was also evaluated.METHODS : A cross-sectional visit-based survey of ambulatory hypertensive patients was performed in 2009 in Switzerland. 281 randomly selected physicians provided data on 5 consecutive hypertensive patients attending their practices for BP follow-up. Data were anonymously collected on demographics, comorbidities and current medication, and BP was recorded. Subsequent modification of pharmacological antihypertensive therapy was assessed.RESULTS : Data from 1376 patients were available. Mean age was 65 +/- 12 years, 53.9% were male subjects. 26.4% had complicated hypertension. Overall, BP control (<140/90 mm Hg for uncomplicated and <130/80 mm Hg for complicated hypertension) was achieved in 48.9%. Compared to patients with complicated hypertension, BP control was better in patients with uncomplicated hypertension (59.4% vs. 19.2%, p < 0.001). As a monotherapy the most prescribed drug class were angiotensin receptor blockers (ARB, 41%), followed by angiotensin converting enzyme (ACE) inhibitors (21.5%), betablockers (20.8%) and calcium channel blockers (CCB, 10.8%). The most prescribed drug combinations were ARB + diuretic (30.1%) and ACE inhibitors + diuretic (15.3%). 46% were receiving a fixed drug combination. In only 32.7% of patients with uncontrolled hypertension was a change in drug therapy made.CONCLUSION : This representative survey on treated adult hypertensive patients shows that, compared to earlier reports, the control rate of hypertension has improved in Switzerland for uncomplicated but not for complicated, particularly diabetes-associated hypertension. ARBs and ACE inhibitors are the most prescribed antihypertensive drugs for monotherapy, whereas diuretics and ARBs were the most used for combination therapy.

L'hypertension chez les transplantés d'organes [Hypertension in solid organ transplants].

Hypertension is highly prevalent in transplantation and affects all type of organs. With the introduction of calcineurin inhibitors as immunosuppressive drugs, acute allograft rejection episodes have been significantly reduced and hence patient and allograft survival rates have dramatically improved. However, cardiovascular complications have become an important cause of morbidity and mortality. Treating cardiovascular risk factors such as diabetes, dyslipidemia and hypertension seems obvious, however in this population, there is little evidence for specific blood pressure targets, or for the best strategy to achieve blood pressure control. The aim of this article is to review the epidemiology and physiopathology of hypertension in transplant recipients as well as its clinical management.

Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).

Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.

siRNA-Mediated Knock-Down of P-Glycoprotein Expression Reveals Distinct Cellular Disposition of Anticancer Tyrosine Kinases Inhibitors.

Studies on the cellular disposition of targeted anticancer tyrosine kinases inhibitors (TKIs) have mostly focused on imatinib while the functional importance of P-glycoprotein (Pgp) the gene product of MDR1 remains controversial for more recent TKIs. By using RNA interference-mediated knockdown of MDR1, we have investigated and compared the specific functional consequence of Pgp on the cellular disposition of the major clinically in use TKIs imatinib, dasatinib, nilotinib, sunitinib and sorafenib. siRNA-mediated knockdown in K562/Dox cell lines provides a unique opportunity to dissect the specific contribution of Pgp to TKIs intracellular disposition. In these conditions, abrogating specifically Pgp-mediated efflux in vitro revealed the remarkable and statistically significant cellular accumulation of imatinib (difference in cellular levels between Pgp-expressing and silenced cells, at high and low incubation concentration, respectively: 6.1 and 6.6), dasatinib (4.9 and 5.6), sunitinib (3.7 and 7.3) and sorafenib (1.2 and 1.4), confirming that these TKIs are all substrates of Pgp. By contrast, no statistically significant difference in cellular disposition of nilotinib was observed as a result of MDR1 expression silencing (differences: 1.1 and 1.5) indicating that differential expression and/or function of Pgp is unlikely to affect nilotinib cellular disposition. This study enables for the first time a direct estimation of the specific contribution of one transporter among the various efflux and influx carriers involved in the cellular trafficking of these major TKIs in vitro. Knowledge on the distinct functional consequence of Pgp expression for these various TKIs cellular distribution is necessary to better appreciate the efficacy, toxicity, and potential drug-drug interactions of TKIs with other classes of therapeutic agents, at the systemic, tissular and cellular levels.

Type of alcoholic beverage and risk of head and neck cancer: a pooled analysis within the INHANCE Consortium

The authors pooled data from 15 case-control studies of head and neck cancer (9,107 cases, 14,219 controls) to investigate the independent associations with consumption of beer, wine, and liquor. In particular, they calculated associations with different measures of beverage consumption separately for subjects who drank beer only (858 cases, 986 controls), for liquor-only drinkers (499 cases, 527 controls), and for wine-only drinkers (1,021 cases, 2,460 controls), with alcohol never drinkers (1,124 cases, 3,487 controls) used as a common reference group. The authors observed similar associations with ethanol-standardized consumption frequency for beer-only drinkers (odds ratios (ORs) = 1.6, 1.9, 2.2, and 5.4 for < or =5, 6-15, 16-30, and >30 drinks per week, respectively; P(trend) < 0.0001) and liquor-only drinkers (ORs = 1.6, 1.5, 2.3, and 3.6; P < 0.0001). Among wine-only drinkers, the odds ratios for moderate levels of consumption frequency approached the null, whereas those for higher consumption levels were comparable to those of drinkers of other beverage types (ORs = 1.1, 1.2, 1.9, and 6.3; P < 0.0001). Study findings suggest that the relative risks of head and neck cancer for beer and liquor are comparable. The authors observed weaker associations with moderate wine consumption, although they cannot rule out confounding from diet and other lifestyle factors as an explanation for this finding. Given the presence of heterogeneity in study-specific results, their findings should be interpreted with caution.

Transient suppression of Shigella flexneri type 3 secretion by a protective O-antigen-specific monoclonal IgA.

Mucosal immunity to the enteric pathogen Shigella flexneri is mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag of S. flexneri serotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary for S. flexneri to gain entry into intestinal epithelial cells. IgAC5's effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5's effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag of S. flexneri partially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells. IMPORTANCE: Secretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by "immune exclusion," a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S-IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells.

The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice.

OBJECTIVE: The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. METHODS: The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. RESULTS: Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-^5; (TNF^5;) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNF^5; production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. CONCLUSIONS: These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

Preclinical evaluation of the immunogenicity of C-type HIV-1-based DNA and NYVAC vaccines in the Balb/C mouse model.

As part of a European initiative (EuroVacc), we report the design, construction, and immunogenicity of two HIV-1 vaccine candidates based on a clade C virus strain (CN54) representing the current major epidemic in Asia and parts of Africa. Open reading frames encoding an artificial 160-kDa GagPolNef (GPN) polyprotein and the external glycoprotein gp120 were fully RNA and codon optimized. A DNA vaccine (DNA-GPN and DNA-gp120, referred to as DNA-C), and a replication-deficient vaccinia virus encoding both reading frames (NYVAC-C), were assessed regarding immunogenicity in Balb/C mice. The intramuscular administration of both plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial T-cell responses against both antigens as well as Env-specific antibodies. Whereas low doses of NYVAC-C failed to induce specific CTL or antibodies, high doses generated cellular as well as humoral immune responses, but these did not reach the levels seen following DNA vaccination. The most potent immune responses were detectable using prime:boost protocols, regardless of whether DNA-C or NYVAC-C was used as the priming or boosting agent. These preclinical findings revealed the immunogenic response triggered by DNA-C and its enhancement by combining it with NYVAC-C, thus complementing the macaque preclinical and human phase I clinical studies of EuroVacc.

Type I osteogenesis imperfecta and multiple osteochondromas in the same child.

A male infant showed a humeral diaphysis fracture at 5 months of age and a distal tibial physis fracture at 2 years of age. A specialized consultant ruled out child abuse. This child had the characteristic features of type I osteogenesis imperfecta: blue sclerae, osseous fragility, and presumably autosomal dominant inheritance, as his father suffered from similar disorders. Later on, multiple painful osteochondromas were also found and some of these were surgically treated. The child's mother showed several peripheral osteochondromas. We describe the follow-up of this patient up to the age of 18 years. To our knowledge, the fortuitous association of these two inherited conditions has not been reported in medical literature.

Apparent stable-isotope heterogeneities in gangue carbonates of the Mississippi Valley-type Zn-Pb deposits of San-Vicente, Central Peru

The aim of the present communication is to emphasize that some variations of the measured delta(13)C and delta(18)O values are apparent, and due to analytical interferences caused by the presence of sulfur and organosulfur compounds in the analyzed carbonates. This is particularly relevant for isotopic studies on carbonate-hosted mineral deposits, where the nearly ubiquitous association of the host carbonates with organic matter and sulfides can certainly affect the metallogenetic interpretations. In this work two methods were used to overcome the disturbing effects of sulfides and organic matter: (1) sample pretreatment following the method proposed by Charef and Sheppard (1984), combining the oxidation of organic matter with sodium hypochlorite and trapping of the sulfur species with silver phosphate; and (2) laser-based microprobe extraction. Apparent isotopic variations in sparry dolomite from a single hand sample of zebra ore from the MVT Zn-Pb deposit, San Vicente, central Peru, are as large as 6 parts per thousand delta(13)C and 4 parts per thousand delta(18)O. These variations are reduced to several tenths of a per mil when the samples are pretreated. A careful examination of the effects of treatment with NaOCl and/or Ag3PO4 in relation to the concentration of sulfide inclusions indicates that the main disturbing effects for delta(13)C values are the presence of sulfur species and organic matter, whereas the delta(18)O values are mainly affected by the presence of sulfides. Fine- and medium-grained replacement carbonates from MVT and other sediment-hosted base metal deposits are potentially the most affected during isotope analysis, due to the common presence of organic matter and sulfides. Using in situ laser microprobe techniques, it is possible to determine isotopic variations at a sub-millimeter scale. Our results show that laser extraction analysis allows a more precise sampling of the carbonate minerals, and minimizes contamination of the sample with sulfides and to some extent with intergrown organic matter. However, there is an isotopic shift associated with the laser extraction technique, of the order of 0.5-1 parts per thousand for delta(13)C and delta(18)O values.

Surveillance of HIV type 1 drug resistance among naive patients from Venezuela.

We have studied 65 HIV-1-infected untreated patients recruited in Caracas, Venezuela with TCD4 counts > or =350/microl. The reverse transcriptase and protease sequences of the virus were sequenced, aligned with reference HIV-1 group M strains, and analyzed for drug resistance mutations. Most of the viruses were subtype B genotype in both the protease and RT genomic regions. Five of the 62 virus isolates successfully amplified showed evidence of recombination between protease and RT, with their protease region being non-B while their RT region was derived from subtype B. Four strains were found bearing resistance mutations either to NRTIs, NNRTIs, or PIs. The prevalence of HIV-1 isolates bearing resistance mutations was therefore above the 5% threshold of WHO.

Subclinical coronary and aortic atherosclerosis detected by magnetic resonance imaging in type 1 diabetes with and without diabetic nephropathy.

BACKGROUND: Patients with type 1 diabetes and nephropathy maintain an excess cardiovascular mortality compared with diabetic patients with normoalbuminuria. We sought to evaluate coronary and aortic atherosclerosis in a cohort of asymptomatic type 1 diabetic patients with and without diabetic nephropathy using cardiovascular magnetic resonance imaging. METHODS AND RESULTS: In a cross-sectional study, 136 subjects with long-standing type 1 diabetes without symptoms or history of cardiovascular disease, including 63 patients (46%) with nephropathy and 73 patients with normoalbuminuria, underwent cardiovascular magnetic resonance imaging. All subjects underwent cardiac exercise testing and noninvasive tests for peripheral artery disease and autonomic neuropathy. Coronary artery stenoses were identified in 10% of subjects with nephropathy (versus 0% with normoalbuminuria; P=0.007). Coronary plaque burden, expressed as right coronary artery mean wall thickness (1.7+/-0.3 versus 1.3+/-0.2 mm; P<0.001) and maximum right coronary artery wall thickness (2.2+/-0.5 versus 1.6+/-0.3 mm; P<0.001), was greater in subjects with nephropathy. The prevalence of thoracic (3% versus 0%; P=0.28) and abdominal aortic plaque (22% versus 16%; P=0.7) was similar in both groups. Subjects with and without abdominal aortic plaques had similar coronary plaque burden. CONCLUSIONS: In asymptomatic type 1 diabetes, cardiovascular magnetic resonance imaging reveals greater coronary plaque burden in subjects with nephropathy compared with those with normoalbuminuria.

Gene transfer of a soluble IL-1 type 2 receptor-Ig fusion protein improves cardiac allograft survival in rats.

OBJECTIVE: Interleukin-1 (IL-1) mediates ischemia-reperfusion injury and graft inflammation after heart transplantation. IL-1 affects target cells through two distinct types of transmembrane receptors, type-1 receptor (IL-1R1), which transduces the signal, and the non-signaling type-2 receptor (IL-1R2), which acts as a ligand sink that subtracts IL-1beta from IL-1R1. We analyzed the efficacy of adenovirus (Ad)-mediated gene transfer of a soluble IL-1R2-Ig fusion protein in delaying cardiac allograft rejection and the mechanisms underlying the protective effect. METHODS: IL-1 inhibition by IL-1R2-Ig was tested using an in vitro functional assay whereby endothelial cells preincubated with AdIL-1R2-Ig or control virus were stimulated with recombinant IL-1beta or tumor necrosis factor-alpha (TNF-alpha), and urokinase-type plasminogen activator (u-PA) induction was measured by zymography. AdIL-1R2-Ig was delivered to F344 rat donor hearts ex vivo, which were placed in the abdominal position in LEW hosts. Intragraft inflammatory cell infiltrates and proinflammatory cytokine expression were analyzed by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. RESULTS: IL-1R2-Ig specifically inhibited IL-1beta-induced u-PA responses in vitro. IL-1R2-Ig gene transfer reduced intragraft monocytes/macrophages and CD4(+) cell infiltrates (p<0.05), TNF-alpha and transforming growth factor-beta (TGF-beta) expression (p<0.05), and prolonged graft survival (15.6+/-5.7 vs 10.3+/-2.5 days with control vector and 10.1+/-2.1 days with buffer alone; p<0.01). AdIL-1R2-Ig combined with a subtherapeutic regimen of cyclosporin A (CsA) was superior to CsA alone (19.4+/-3.0 vs 15.9+/-1.8 days; p<0.05). CONCLUSIONS: Soluble IL-1 type-2 receptor gene transfer attenuates cardiac allograft rejection in a rat model. IL-1 inhibition may be useful as an adjuvant therapy in heart transplantation.

Quette place pour l'automesure glycémique dans la prise en charge du diabète de type 2 [Which role for self-monitoring of blood glucose in type 2 diabetes?]

There is a sustained controversy in the literature about the role and utility of self-monitoring of blood glucose (SMBG) in type 2 diabetes. The study results in this field do not provide really useful clues for the integration of SMBG in the follow-up of the individual patient, because they are based on a misconception of SMBG. It is studied as if it was a medical treatment whose effect on glycemic control is to be isolated. However, SMBG has no such intrinsic effect. It gains its purpose only as an inseparable component of a comprehensive and structured educational strategy. To be appropriate this strategy cannot be based on the health care professionals' view on diabetes only. It rather has to be tailored to the individual patient's needs through an ongoing process of shared reflection with him.