[Facial palsy: diagnosis and management by primary care physicians]. / Paralysie faciale: diagnostic et prise en charge par le médecin de premier recours.

The incidence of facial palsy is about 50/100000/year, i.e. 210 cases/year in Geneva. Clinicians can be puzzled by it, because it encompasses aetiologies with very diverse prognoses. Most patients suffer from Bell palsy that evolves favourably. Some, however, suffer from diseases such as meningitis, HIV infection, Lyme's disease, CVA, that require fast identification because of their severity and of the need for specific treatments. This article proposes an algorithm for pragmatic and evidence-based management of facial palsy.

Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes.

Paraoxonase was identified as a genetic risk factor for cardiovascular disease (CVD) in recent studies focusing on a polymorphism affecting position 191. A second polymorphism of the paraoxonase gene affects position 54 and involves a methionine (M allele) to leucine (L allele) change. It was investigated in diabetic patients (n = 408) with and without vascular disease. There were highly significant differences in plasma concentrations and activities of paraoxonase between genotypes defined by the 54 polymorphism: MMAA, MLAA, LLAA; protein, 65.3+/-18.0, 77.9+/-18.0, 93.5+/-26.0 microg/ml; P < 0.0001: activity (phenylacetate), 48.6+/-13.5, 64.1+/-14.5, 68.1+/-13.0 U/ml; P < 0.0001. The 191 variant had little impact on paraoxonase concentrations. Homozygosity for the L allele was an independent risk factor for CVD (odds ratio 1.98 (1.07-3.83); P = 0.031). A linkage disequilibrium (P < 0.0001) was apparent between the mutations giving rise to leucine and arginine at positions 54 and 191, respectively. The study underlines that susceptibility to CVD correlates with high activity paraoxonase alleles. The 54 polymorphism would appear to be of central importance to paraoxonase function by virtue of its association with modulated concentrations. The latter could explain the association between both the 54 and 191 polymorphisms and CVD.

Abnormal regulation of hepatic glucose output in maturity-onset diabetes of the young caused by a specific mutation of the glucokinase gene.

A subtype of maturity-onset diabetes of the young (MODY) is caused by mutations of the glucokinase gene, an enzyme expressed in pancreatic beta-cells and the liver. To assess the consequences of a functional alteration of glucokinase at the level of the liver, endogenous (hepatic) glucose production and glucose cycling (an indirect assessment of hepatic glucokinase activity) were measured with 2-2H glucose and 6,6-2H glucose in patients who developed MODY because of the V203A mutation of glucokinase, and in control subjects at similar levels of glycemia. Measurements were performed in the postabsorptive state and after ingestion of 13C-labeled glucose. In the postabsorptive state, MODY patients had normal glucose production (10.9 +/- 1.3 vs. 11.3 +/- 0.6 micromol x kg(-1) x min(-1)) but decreased glucose cycling (0.6 +/- 0.3 vs. 1.5 +/- 0.3 micromol x kg(-1) x min(-1); P < 0.05) when compared with control subjects. However, at plasma glucose and insulin levels similar to those observed in MODY patients, control subjects' glucose production was markedly lower (3.2 +/- 1.5 micromol x kg(-1) x min(-1). After glucose ingestion, endogenous glucose production was reduced by only 29% in MODY patients compared with 80% in control subjects at a similar level of hyperglycemia (P < 0.05). This suggests that the V203A mutation of glucokinase results in decreased activity of glucokinase in liver cells. Thus endogenous glucose production is inadequately inhibited by hyperglycemia in MODY patients, possibly as a result of impaired hepatic glucokinase activity. These alterations contribute to the pathogenesis of hyperglycemia.

Glucose utilization and production in patients with maturity-onset diabetes of the young caused by a mutation of the hepatocyte nuclear factor-1alpha gene.

Mutations of the hepatocyte nuclear factor (HNF)-1alpha gene cause impaired insulin secretion and hyperglycemia in patients with maturity-onset diabetes of the young (MODY)3. Whether these mutations also affect glucose metabolism in tissues other than the beta-cell has not yet been documented. We therefore assessed, in five MODY3 patients and a dozen healthy control subjects, insulin secretion, oxidative and nonoxidative glucose disposal, and glucose production during a two-step hyperglycemic clamp and a euglycemic hyperinsulinemic (0.4 mU x kg(-1) x min(-1)) clamp. Compared with healthy control subjects, MODY3 patients had higher fasting plasma glucose (+100%) but similar rates of fasting glucose production and oxidation. Both the early and late phases of insulin secretion were virtually abolished during the hyperglycemic clamp, and glucose production was suppressed by only 43% in MODY3 patients vs. 100% in healthy control subjects. The rate of glucose infusion required to produce a 5 mmol/l increase above basal glycemia was reduced by 30%, net nonoxidative glucose disposal (which is equal to net glycogen deposition) was inhibited by 39%, and net carbohydrate oxidation during hyperglycemia was 25% lower in MODY3 patients compared with control subjects. Insulin-stimulated glucose utilization and oxidation measured during the hyperinsulinemic clamp (at approximately 200 pmol/l insulin) were identical in MODY3 patients and in healthy control subjects, indicating that peripheral insulin sensitivity was not altered. Suppression of endogenous glucose production was, however, mildly impaired. It is concluded that MODY3 patients have severely depressed glucose-induced insulin secretion. The development of hyperglycemia in these patients appears to be caused by a decreased stimulation of glucose utilization, oxidation, and nonoxidative glucose disposal as well as by a blunted suppression of endogenous glucose output. These phenomena are essentially secondary to insulinopenia, whereas insulin sensitivity remains intact.

Diagnostic heterogeneity of diabetes in lean young adults: classification based on immunological and genetic parameters.

The aim of our study was to investigate the relative prevalence of the different forms of diabetes in young adults and their respective clinical characteristics. Included were 51 nonobese patients (BMI < 27 kg/m2) with diabetes diagnosed before age 40, excluding typical IDDM. Each patient was subjected to screening for glucokinase gene (MODY2) and mitochondrial DNA (at nucleotide 3243) mutations, to HLA class II genotyping, and screening for the presence of islet cell antibodies (ICAs) and anti-GAD antibodies. Informative families were analyzed for linkage of diabetes to chromosome 12q (MODY3). Based on clinical criteria, patients were subdivided into MODY (n = 19) and non-MODY (n = 32). In the MODY group, we identified three patients with MODY2, one with the 3243 mitochondrial mutation, and another with autoimmune diabetes. One of the five MODY families available for linkage study was shown to have MODY3. In the non-MODY group, we found five patients with autoimmune diabetes and one with MODY2. No clinical parameter was helpful to classify patients in one of these subclasses of diabetes; however, the glucagon-stimulated C-peptide was useful to discriminate between MODY2 patients and the others. In conclusion, young and lean non-insulin-dependent diabetic patients constitute a very heterogeneous group, although they present similar clinical characteristics. The clinical distinction of MODY and non-MODY patients allows correct classification in, at most, 75% of the patients and thus is not sufficient to predict clinical course. However, immunological and genetic parameters allowed us to classify only 25% of the patients in specific diagnostic classes.

Insulin, but not glucose lowering corrects the hyperglucagonemia and increased proglucagon messenger ribonucleic acid levels observed in insulinopenic diabetes.

The factors that regulate glucagon biosynthesis and proglucagon gene expression are poorly defined. We previously reported that insulin inhibits proglucagon gene expression in vitro. In vivo, however, the effects of insulin on the regulation of the proglucagon gene have been controversial. Furthermore, whether glucose plays any role alone or in conjunction with insulin on proglucagon gene expression is unknown. We investigated the consequences of insulinopenic diabetes on glucagon gene expression in the endocrine pancreas and intestine and whether insulin and/or glucose could correct the observed abnormalities. We show here that in the first 3 days after induction of hyperglycemia by streptozotocin, rats have levels of plasma glucagon and proglucagon messenger RNA comparable to those of normoglycemic controls despite hyperglycemia. With more prolonged diabetes, plasma glucagon and proglucagon messenger RNA levels increase; this increase is corrected by insulin treatment, but not by phloridzin despite normalization of the glycemia by both treatments. Proglucagon gene expression exhibits the same regulatory response to glucose and insulin in both pancreas and ileum. We conclude that insulin tonically inhibits proglucagon gene expression in the pancreas and ileum and that glucose plays a minor, if any, role in this regulation.

[Swiss journey through the clinical and genetic characteristics of diabetes in young patients]. / Voyage helvétique à travers les caractéristiques cliniques et génétiques du diabète du sujet jeune.

The aim of this study is to understand better the genetic causes of type II diabetes and the phenotypic consequences of the genetic changes. We first investigated the relative prevalence of the different forms of diabetes in young adults and their clinical features. 51 non-obese patients were identified in whom diabetes had been diagnosed before age 40; cases of typical insulin-dependent type I diabetes were excluded. A search for mutations of the glucokinase and HNF-1 alpha genes and for mitochondrial DNA was made, anti-islet and anti-GAD antibodies were determined and HLA class II genotyping was performed. Patients were subdivided on clinical grounds into a MODY (maturity onset diabetes of the young) group (n = 19) and a non-MODY group (n = 32). MODY is a form of diabetes which has an autosomal dominant inheritance for which 3 genes have already been implicated (MODY1, HNF-4 gene; MODY2, glucokinase gene, and MODY3, HNF-1 alpha gene). In the MODY group we identified 3 patients with MODY2, 1 with MODY3, 1 with the 3243 mitochondrial mutation and a further patient with autoimmune diabetes. In the non-MODY group we found 5 patients with autoimmune diabetes and 1 with MODY2. No clinical parameter was helpful in classifying patients in one of these subclasses of diabetes; however, glucagon stimulated C-peptide was useful in discriminating between MODY2 patients and the others. Young and lean non-insulin-dependent diabetic patients thus constitute a very heterogeneous group, though presenting similar clinical features. In the second study we analyzed hepatic glucose metabolism in patients with a mutation of the glucokinase gene expressed in both liver and islet beta cells. We found that endogenous glucose production is inadequately inhibited by hyperglycemia, a fact which contributes to the pathogenesis of hyperglycemia in these patients.

Unusual association: Streptococcus bovis tricuspid endocarditis with atrial-septal aneurysm and patent foramen ovale.

Streptococcus bovis endocarditis is a frequent cause of streptococcal endocarditis and is associated with colonic tumours. The tricuspid valve is very rarely affected and its involvement is a complication which can lead to a less favourable outcome. We report the seventh case of tricuspid valve endocarditis due to S. bovis, and the first, to our knowledge, to be associated with an atrial-septal aneurysm and a patent foramen ovale. The underlying medical conditions and predisposing factors for development of tricuspid valve endocarditis are described and interesting new echocardiographic data are presented. The current guidelines on antibiotic therapy for S. bovis tricuspid valve endocarditis are reviewed.

Penicilliosis marneffei infection in AIDS.

Penicillium marneffei infection has emerged as a new potential indicator disease for AIDS in Southeast Asia. We report two additional cases of P. marneffei infection in patients infected with HIV who had traveled to endemic areas and review the mucocutaneous features of previously reported cases. Our two patients had many of the typical features associated with invasive infection: fever, weight loss, anemia, lymphadenopathy, hepatomegaly, pulmonary and gastrointestinal symptoms, as well as skin manifestations such as papular molluscum contagiosum-like lesions and oral lesions. Knowledge of cutaneous signs is important for prompt diagnosis of P. marneffei infection and institution of life-saving therapy with antifungal agents.

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. Recent studies have shown that mutations in the two functionally related transcription factors, hepatocyte nuclear factor 4 alpha (HNF-4alpha) and hepatocyte nuclear factor 1 alpha (HNF-1alpha) are associated with the MODY1 and MODY3 forms of diabetes respectively, whereas mutations in the enzyme glucokinase are the cause of the MODY2 form. We have examined 10 unrelated Caucasian families in which MODY/NIDDM co-segregated with markers for MODY3 for mutations in the HNF-1alpha gene (TCF1). Ten different mutations were observed in these families, all of which co-segregated with diabetes. There were no obvious relationships between the nature of the mutations observed (i.e. frameshift, nonsense, or missense) or their location in the gene with clinical features of diabetes (age at onset, severity) in these families. The mechanisms by which mutations in the HNF-1alpha gene cause diabetes mellitus are unclear but might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes that play a key role in normal pancreatic beta cell function.