Total arthroplasty of the hip by fritted alumina prosthesis. Experimental study and 1st clinical applications.

A new material is proposed in total hip arthroplasty as a bearing component. The tolerance of dense ceramics was studied, as well as the anchorage of this material into bone. Physical, chemical and mechanical properties of the prosthesis were tested. Two hundred patients have already been operated on, but the follow-up is too short for any conclusion.

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity.

AIMS/HYPOTHESIS: Morbid obesity (BMI>40 kg/m(2)) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. METHODS: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6+/-7.4 kg/m(2)), 808 non-obese subjects (BMI<30 kg/m(2)) and 493 obese subjects (30< or =BMI<40 kg/m(2)). RESULTS: Two 5'-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a "low-level" haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5'-ACDC "low-level" haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals. CONCLUSIONS/INTERPRETATION: These data clarify the contribution of the 5'-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.

[Results of fine needle aspiration biopsy, frozen section diagnosis and definite histological results in thyroid pathology. Report of 163 cases]. / Analyse des résultats de la cytoponction, de l'examen histologique extemporané et définitif dans le traitement chirurgical de la pathologie thyroïdienne: à propos de 163 cas.

INTRODUCTION: In thyroid diseases, the place of fine needle aspiration biopsy still continues to be discussed: the sensibility and specificity vary greatly in the literature. Frozen section diagnosis is necessary to form a diagnostic strategy. The objective of this study was compare the results of fine needle aspiration biopsy, frozen section diagnosis, and definitive histologic results in a population of 163 patients and to draw conclusions about treatment. MATERIAL AND METHOD: From 1994 to 1999, 163 patients (132 females and, 31 males) undergoing thyroid surgery were included in this retrospective study, after a standard preoperative work-up. Those with a single palpable nodule and hypofixation on scintigraphy underwent fine needle aspiration before surgery. These results were compared with the definitive histologic results. RESULTS: A loboisthmectomy was performed in 88 cases (54%), a subtotal thyroidectomy in 34 cases (21%), and a total thyrodectomy in 41 cases (25%). In the latter group, an associated neck dissection was performed in 18 cases (11%); a frozen section diagnosis was obtained in all cases of thyroid nodules. This study demonstrated a single nodule in 97 cases (60%), multiple nodules in 27 cases (17%), multinodular goitre in 34 cases (21%), and 5 Basedow diseases (3%). Sixty-two cases (38%) of thyroid nodules underwent fine needle aspiration before surgery. In 25 cases (15%), definitive pathology showed a malignant lesion. The frozen section diagnosis had a sensitivity of 73% and a specificity of 99%, and the fine needle aspiration biopsy had a sensitivity of 40% and a specificity of 100%. CONCLUSION: The authors propose fine needle aspiration biopsy in the following cases: a single palpable nodule and hypofixation on scintigraphy or a surgical contra indication; and direct surgery in symptomatic thyroid disease or if there are one or several full nodules > 2 cm. In near future, these indications will be modified with the increasing reliability of fine needle aspiration biopsy.

Mutations in the glucokinase regulatory protein gene in 2p23 in obese French caucasians.

AIMS/HYPOTHESIS: Glucokinase regulatory protein (GKRP) controls the activity of glucokinase in liver but possibly also in some areas of the central nervous system, suggesting that it could play a role in body mass control. Its gene is located in a region (2p21-23) linked to serum leptin levels. Our goal was to investigate whether mutations in the GKRP gene were associated with obesity. METHODS: Mutations were sought in the GKRP gene of 57 patients from the families of the French genome-wide scan for obesity that contributed most to the positive LOD score with 2p21-23. The identified mutations were further sought in 720 unrelated obese individuals and 384 individuals of normal weight and their effect on the properties of recombinant GKRP were investigated. RESULTS: The most frequent mutation (Pro446Leu) had a similar allele frequency in the obese (0.63) and normal weight (0.64) subjects and did not affect the properties of GKRP. Similarly, no effect on the properties of GKRP was observed with Arg590Tyr, found in 10 out of 720 obese subjects and in 2 out of 384 control subjects (p=0.18). Mutation Arg227Stop was found in one obese family and in 1 out of 384 control subjects and led to an insoluble protein. Mutation Arg518Gln, replacing a conserved residue, led to a marked decrease in the affinity of GKRP for both fructose 6-phosphate and fructose 1-phosphate and to a destabilization of GKRP. However, this mutation did not co-segregate with obesity in the single family in which it was found. CONCLUSIONS/INTERPRETATION: Mutations that affect the properties of GKRP are found in the French population, but they do not seem to account for the linkage between the 2p23 locus and quantitative markers of obesity.

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease.

Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a -499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the -499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

[Otosclerosis surgical techniques and results in 150 patients]. / Otospongiose: techniques chirurgicales et résultats. A propos de 150 cases.

OBJECTIVES: To analyze outcome after otosclerosis surgery with stamedeotomy with blood clot sealing. PATIENTS AND METHODS: Otosclerosis surgery was performed in 150 adult patients between 1997 and 1999 by five surgical teams (70% of the procedures were performed by senior surgeons) and followed for 18 months. Stapedotomy was carried out under general anesthesia with an intrameatal approach in 96% of the cases. Stapedotomy (n=120, 80%) was performed with a drill in 141 cases and by laser in 9 (6%). Ninety percent of the Teflon prostheses had a 0.4 mm diameter and a 4.5 mm length. The footplate opening was sealed with blood clots. Venous interposition (n=30, 20%) was performed in the event of partial or total stapedectomy which occurred in spite of an initial stapedotomy attempt. RESULTS: The preoperative air-bone gap (ABG) was 32 +/- 10.3 dB. The gain in air conduction was 25 +/- 11.7 dB with 75% of the patients having more than 15 dB gain. The ABG was 10 +/- 5.4 dB with 73% of the patients having less than 5 dB gain. The interaural difference was 0.5 +/- 14.1 dB and the bone conduction (BC) variation was 1 +/- 7.5 dB. Functional failures were related to significant intralabyrinthine bleeding and revision procedure. The following factors had not effect on outcome: i) stapedotomy versus partial or total stapedectomy, footplate opening sealed by clots or vein, ii) diameter of the stapedotomy and/or the prosthesis, iii) surgical procedure performed by a junior surgeon. CONCLUSION: Sealing the stapedotomy opening with blood clots appears to provide reliable and reproducible functional outcome that remains stable over time. In this study, changing from partial to total stapedectomy with vein interposition did not modify the functional outcome.

Rapid SNP allele frequency determination in genomic DNA pools by pyrosequencing.

Individual genotyping of single nucleotide polymorphisms (SNPs) remains expensive, especially for linkage disequilibrium mapping strategies involving high-throughput SNP genotyping. On one hand, current methods may suit scientific and laboratory needs in regard to accuracy, reproducibility/robustness, and large-scale application. On the other hand, a cheaper and less time-consuming alternative to individual genotyping is the use of SNP allelefrequencies determined in DNA pools. We have developed an accurate and reproducible protocol for allele frequency determination using Pyrosequencing technology in large genomic DNA pools (374 individuals). The measured correlation (R2) in large DNA pools was 0.980. In the context of disease-associated SNPs studies, we compared the allele frequencies between the disease (e.g., type 2 diabetes and obesity) and control groups detected by either individual genotyping or Pyrosequencing of DNA pools. In large pools, the variation between the two methods was 1.5 +/- 0.9%. It may be concluded that the allele frequency determination protocol could reliably detect over 4% differences between populations. The method is economical in regard to amounts of DNA, PCR, and primer extension reagents required. Furthermore, it allows the rapid determination of allelefrequency differences in case/control groups for association studies and susceptibility gene discovery in complex diseases.

Prevalence of the missense mutation Gly574Ser in the hepatocyte nuclear factor-1alpha in Africans with diabetes.

BACKGROUND: Clinical presentation and natural history of diabetes are somewhat different in Black Africans compared to Caucasians. This peculiar disease course could be at least partly related to a specific genetic profile that has not been studied in this population. METHODS: Medical backgrounds, anthropometric and biologic parameters were obtained from 69 diabetic subjects in Dakar, Senegal, in 1998. Blood anti GAD and Islet Cell Antibodies were studied, using RIA and immunofluorescence assay. The HNF-1alpha gene was sequenced searching the Gly574Ser mutation, previously described in MODY 3. RESULTS: Among these 69 diabetic patients, 11 (16%) were found to have the G574S mutation affecting the HNF-1alpha. These 11 patients carrying the mutation were compared respectively with the 58 non carriers. Mean age (57.5 yr. +/- 11 vs 51.1 yr. +/- 15) and duration of diabetes (11.9 vs 6.7 yr), were similar in the two groups. BMI was not different in patients with the mutation (26.3 vs 23.3, p=0.06). Metabolic control (Glycosylated hemoglobin) was poor in the two groups (9.5% vs 9.2%). Chronic complications were equally found in the patients, but no mutation carrier had macroangiopathy. None of the anti GAD positive or ICA positive patients had the mutation. CONCLUSIONS: The HNF-1alpha Gly574Ser mutation was found in 16% of cases in a 69 diabetic patients group in Senegal. Diabetes was as severe as in non carriers of mutation. This mutation has been implicated in atypical diabetes of Afro-American children. The study confirms its prevalence in Africans with diabetes.

Mutation screening of the urocortin gene: identification of new single nucleotide polymorphisms and association studies with obesity in French Caucasians.

A linkage between obesity-related phenotypes and the 2p21-23 locus has been reported previously. The urocortin (UCN) gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. We localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin levels (LOD score, 1.34; P = 0.006) and between D2S2247 and the z-score of body mass index (LOD score, 1.829; P = 0.0019). The gene was screened for SNPs in 96 obese patients. Four new variants were established. Two single nucleotide polymorphisms were located in the promoter (-535 A-->G, -286 G-->A), one in intron 1 (+31 C-->G), and one in the 3'-untranslated region (+34 C-->T). Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the two frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. Thus, our analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, they do not represent a major cause of obesity.

[Middle ear adenoma: report of two cases and review of the literature]. / Adénome bénin de l'oreille moyenne: a propos de deux cas.

INTRODUCTION: Middle ear adenoma is an uncommon tumor. We report two cases and review the relevant literature concerning this rare entity. MATERIAL AND METHODS: Two patients with a middle ear adenoma were operated on in our department. Pre- and postoperative data concerning clinical examination, audiometry, and radiology were obtained. Information concerning intraoperative observations and the pathological examination were also gathered. RESULTS AND DISCUSSION: The diagnosis of middle ear adenomas is based on clinical, radiological, and pathological confrontation. The microscopic examination should be combined with histochemical and immuno-histochemical methods in order to evidence the glandular and neuroendocrin components of these lesions. CONCLUSION: Today, classified as a benign epithelial tumor, the middle ear adenoma is associated with an excellent prognosis provided total excision.

Genetics of pathways regulating body weight in the development of obesity in humans.

Although rapid globalization of the Westernized way of life is responsible for the large rise in the number of obesity cases (about 1 billion individuals are now overweight or frankly obese), obesity is a typical common multifactorial disease in that environmental and genetic factors interact, resulting in a disease state. There is strong evidence for a genetic component to human obesity: e.g., the familial clustering (the relative risk among siblings being 3-7) and the high concordance of body composition in monozygotic twins. However, the role of genetic factors in many human obesities (referred to as "common obesity" in this review) is complex, being determined by interaction of several genes (polygenic), each of which may have relatively small effects (i.e., they are "susceptibility" genes and work in combination with each other as well as with environmental factors such as nutrients, physical activity, and smoking).

Genetics of human obesity.

Obesity is a multifactorial condition. Environmental risk factors related to a sedentary life-style and unlimited access to food apply constant pressure in subjects with a genetic predisposition to gain weight. The fact that genetic defects can result in human obesity has been unequivocally established over the past 3 years with the identification of the genetic defects responsible for different monogenic forms of human obesity: the leptin, leptin receptor, pro-opiomelanocortin, pro-hormone convertase-1 and melanocortin-4 receptor genes. The common forms of obesity are, however, polygenic. The examination of specific genes for involvement in the susceptibility to common obesity has not yet yielded convincing results. Approaches involving the candidate genes and the positional cloning of major obesity-linked regions (state-of-the-art future prospects) will be discussed.

Routine mutation screening of HNF-1alpha and GCK genes in MODY diagnosis: how effective are the techniques of DHPLC and direct sequencing used in combination?

AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor (HNF)-1alpha and glucokinase (GCK) genes are the major causes of monogenic forms of Type II (non-insulin-dependent) diabetes mellitus (Maturity-Onset Diabetes of the Young subtypes, MODY). We evaluated the effectiveness of fluorescent single-strand conformation polymorphism (F-SSCP), denaturing high-performance liquid chromatography (DHPLC) and sequencing based mutation detection in the molecular diagnosis of MODY. Our goal is to identify a rapid, efficient and cost effective mutation detection method for the molecular diagnosis of MODY and other human genetic disorders. METHODS: We evaluated the accuracy of DHPLC in screening for MODY 2 and 3 mutations. In addition, we compared the sensitivity, specificity, cost, handling time and analysis time of fluorescent single-strand conformation polymorphism, denaturing high-performance liquid chromatography and direct sequencing screening methods. RESULTS: Denaturing high-performance liquid chromatography is a recently developed method for mutation detection. It is cost effective, powerful and reliable and quite suitable for 22 out of the 24 fragments required for MODY 2 and 3 testing. However, exons 1 and 7 of the HNF-1alpha gene are very polymorphic and so direct sequencing is faster as well as more efficient and reliable. CONCLUSION/INTERPRETATION: Our results suggest that combining denaturing high-performance liquid chromatography and direct sequencing is a good approach for the routine detection of HNF-1alpha and GCK mutations in MODY families. Denaturing high-performance liquid chromatography appears to be a powerful tool in genetic testing and the method could be applied to the molecular diagnosis of other human genetic diseases.

Use of and attitudes about alternative and complementary therapies among outpatients and physicians at a municipal hospital.

OBJECTIVES: To survey outpatients and physicians about their use of, knowledge of, and interest in alternative therapies. DESIGN: Anonymous self-administered survey. SETTINGS/LOCATION: Outpatient clinics at a major municipal medical center. SUBJECTS: Outpatients visiting clinics and staff physicians. INTERVENTIONS: Patient survey about overall use of 7 categories and 19 types of alternative therapies, and their desire to have specific therapies offered at the institution. Survey to physicians about whether their patients used the same categories and types of alternative therapies, whether they provided or recommended their use, and their interest in having them available at the institution. OUTCOME MEASURES: Frequency of use of different alternative therapies by gender and race. Frequency of patient use of alternative therapies according to their physicians and frequency of physicians who provide or recommend alternative therapies. RESULTS: A total of 567 outpatients completed questionnaires during the survey week. When given a list of alternative therapies, 85% of patients acknowledged use of one or more alternative therapies. When Diet/Nutrition was excluded, 42% reported use of alternative therapies. No differences in overall use were seen by age, sex, or race; but when Diet/Nutrition was excluded, women were more likely to use alternative therapies, and use of Manual Healing and Herbal Medicine differed by race. Of the 85 responding physicians, 86% reported that their ambulatory patients used alternative therapies. Similar proportions (35%-38%) of patients and physicians wanted Manual Healing and Mind/Body Control therapies to be available. CONCLUSIONS: Frequency of use of alternative therapies was high, and similar according to patients and physicians. Overall use did not differ by gender and race, except when Diet/Nutrition was excluded. Patients and physicians had similar interests in having alternative therapies provided, and both were hampered by lack of information about many therapies.

The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes.

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.

A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals.

To compare intravenous (iv) ceftriaxone and penicillin G as therapy for neurosyphilis, blood and CSF were collected before and 14-26 weeks after therapy from 30 subjects infected with human immunodeficiency virus (HIV)-1 who had (1) rapid plasma reagin (RPR) test titers >/=1&rcolon;16, (2) reactive serum treponemal tests, and (3) either reactive CSF-Venereal Disease Research Laboratory (VDRL) tests or CSF abnormalities: (a) CSF WBC values >/=20/microL or (b) CSF protein values >/=50 mg/dL. At baseline, more ceftriaxone recipients had skin symptoms and signs (6 [43%] of 14 vs. 1 [6%] of 16; P=.03), and more penicillin recipients had a history of neurosyphilis (7 [44%] of 16 vs. 1 [7%] of 14; P=.04). There was no difference in the proportion of subjects in each group whose CSF measures improved. Significantly more ceftriaxone recipients had a decline in serum RPR titers (8 [80%] of 10 vs. 2 [13%] of 15; P=. 003), even after controlling for baseline RPR titer, skin symptoms and signs, or prior neurosyphilis were controlled for. Differences in the 2 groups limit comparisons between them. However, iv ceftriaxone may be an alternative to penicillin for treatment of HIV-infected patients with neurosyphilis and concomitant early syphilis.

Anticipation in schizophrenia and bipolar disorder controlling for an information bias.

Anticipation was investigated in schizophrenia (SZ) and bipolar disorder (BP) while addressing several biases in 18 large families (154 subjects) from Eastern Québec densely affected by SZ, BP, or both over three generations. In particular, we controlled for an information bias using a measure of quality and quantity of clinical information (QOI) concerning the subjects' illness. Otherwise, spurious anticipation could have arisen because we found that QOI varied with the generations as well as with the severity of illness. Although anticipation was investigated separately for SZ and BP, both disorders were also included in one analysis that tested anticipation under the unitary hypothesis that the SZ and the BP spectrums represent a continuum of severity of the same disease. Age of onset (AOO) and five indices of severity were tested for anticipation. Two statistics were used: the difference in the mean AOO or severity between two successive generations, and the mean difference in parent-offspring pairs (POP). The study led to four main findings: 1) the choice of the statistics greatly influenced the results, POP yielding systematically greater biased estimates; 2) for SZ and BP, the evidence for anticipation with the five severity indices vanished after controlling for QOI; 3) as regards AOO a decrease of 8.6 years, p = 0.0001, and 5.3 years, p = 0.009 in AOO was found for SZ between Generations 1-2, and 2-3, respectively, despite controlling for QOI and addressing all biases; and 4) conversely for BP, anticipation with AOO may be due to censoring. Findings suggest that future anticipation studies should also control for QOI. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:61-68, 2000.