Investigating the longitudinal association between diabetes and anxiety: a systematic review and meta-analysis.

AIM: Previous research has indicated an association between diabetes and anxiety. However, no synthesis has determined the direction of this association. The aim of this study was to determine the longitudinal relationship between anxiety and diabetes. METHODS: We searched seven databases for studies examining the longitudinal relationship between anxiety and diabetes. Two independent reviewers screened studies from a population aged 16 or older that examined either anxiety as a risk factor for incident diabetes or diabetes as a risk factor for incident anxiety. Studies that met eligibility criteria were put forward for data extraction and meta-analysis. RESULTS: In total 14 studies (n = 1 760 800) that examined anxiety as a risk factor for incident diabetes and two (n = 88 109) that examined diabetes as a risk factor for incident anxiety were eligible for inclusion in the review. Only studies examining anxiety as a risk factor for incident diabetes were put forward for the meta-analysis. The least adjusted (unadjusted or adjusted for age only) estimate indicated a significant association between baseline anxiety with incident diabetes (odds ratio 1.47, 1.23-1.75). Furthermore, most-adjusted analyses indicated a significant association between baseline anxiety and incident diabetes. Included studies that examined diabetes to incident anxiety found no association. CONCLUSIONS: There was an association between baseline anxiety and incident diabetes. The results also indicate the need for more research to examine the direction of association from diabetes to incident anxiety. This work adds to the growing body of evidence that poor mental health increases the risk of developing diabetes.

Depression and risk of type 2 diabetes: the potential role of metabolic factors.

The aim of the present study was to evaluate the interaction between depressive symptoms and metabolic dysregulations as risk factors for type 2 diabetes. The sample comprised of 2525 adults who participated in a baseline and a follow-up assessment over a 4.5-year period in the Emotional Health and Wellbeing Study (EMHS) in Quebec, Canada. A two-way stratified sampling design was used, on the basis of the presence of depressive symptoms and metabolic dysregulation (obesity, elevated blood sugar, high blood pressure, high levels of triglycerides and decreased high-density lipoprotein). A total of 87 (3.5%) individuals developed diabetes. Participants with both depressive symptoms and metabolic dysregulation had the highest risk of diabetes (adjusted odds ratio=6.61, 95% confidence interval (CI): 4.86-9.01), compared with those without depressive symptoms and metabolic dysregulation (reference group). The risk of diabetes in individuals with depressive symptoms and without metabolic dysregulation did not differ from the reference group (adjusted odds ratio=1.28, 95% CI: 0.81-2.03), whereas the adjusted odds ratio for those with metabolic dysregulation and without depressive symptoms was 4.40 (95% CI: 3.42-5.67). The Synergy Index (SI=1.52; 95% CI: 1.07-2.17) suggested that the combined effect of depressive symptoms and metabolic dysregulation was greater than the sum of individual effects. An interaction between depression and metabolic dysregulation was also suggested by a structural equation model. Our study highlights the interaction between depressive symptoms and metabolic dysregulation as a risk factor for type 2 diabetes. Early identification, monitoring and a comprehensive management approach of both conditions might be an important diabetes prevention strategy.

Depressive symptoms and glycated hemoglobin A1c: a reciprocal relationship in a prospective cohort study.

BACKGROUND: The aim of this study was to evaluate the dynamic association between depressive symptoms and glycated hemoglobin A1c (HbA1c) levels using data from the English Longitudinal Study of Ageing (ELSA). METHOD: The sample was comprised of 2886 participants aged ⩾50 years who participated in three clinical assessments over an 8-year period (21% with prediabetes and 7% with diabetes at baseline). Structural equation models were used to address reciprocal associations between depressive symptoms and HbA1c levels and to evaluate the mediating effects of lifestyle-related behaviors and cardiometabolic factors. RESULTS: We found a reciprocal association between depressive symptoms and HbA1c levels: depressive symptoms at one assessment point predicted HbA1c levels at the next assessment point (standardized ß = 0.052) which in turn predicted depressive symptoms at the following assessment point (standardized ß = 0.051). Mediation analysis suggested that both lifestyle-related behaviors and cardiometabolic factors might mediate the association between depressive symptoms and HbA1c levels: depressive symptoms at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted HbA1c levels 4 years later. A similar association was observed for the other direction: HbA1c levels at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted depressive symptoms 4 years later. CONCLUSIONS: Our results suggest a dynamic relationship between depressive symptoms and HbA1c which might be mediated by both lifestyle and cardiometabolic factors. This has important implications for investigating the pathways which could link depressive symptoms and increased risk of diabetes.

Cyclical relationship between depressive symptoms and diabetes distress in people with Type 2 diabetes mellitus: results from the Montreal Evaluation of Diabetes Treatment Cohort Study.

AIMS: To determine if longitudinal cyclical relationships exist between depressive symptoms and diabetes distress in people with Type 2 diabetes mellitus. METHODS: Data were obtained from the Montreal Evaluation of Diabetes Treatment study, a cohort study of 1691 people with Type 2 diabetes mellitus. Depressive symptoms and diabetes distress, measured with the Patient Health Questionnaire and Diabetes Distress Scale, respectively, were assessed at baseline, 1 year and 2 years. A cross-lagged path model analysis with all autoregressive associations was used. Paths and indirect associations were examined. RESULTS: All paths in the model were significant. Depressive symptoms were positively associated with diabetes distress across consecutive time points and diabetes distress was positively associated with depressive symptoms across consecutive time points. The association between depressive symptoms at baseline and depressive symptoms at 2 years was mediated by both depressive symptoms and diabetes distress at 1 year. The association between diabetes distress at baseline and diabetes distress at 2 years was also mediated by both depressive symptoms and diabetes distress. CONCLUSIONS: Depressive symptoms and diabetes distress are cyclically related; results suggest that depressive symptoms influence diabetes distress, which, in turn, influences depressive symptoms. Although many studies focus on the differences between depressive symptoms and diabetes distress, the present study is the first to provide longitudinal evidence that these constructs are cyclically related.

Depressive symptoms and sleep problems as risk factors for heart disease: a prospective community study.

AIMS: The goals of the present study were to examine the associations between depressive symptoms, sleep problems and the risk of developing heart disease in a Canadian community sample. METHODS: Baseline data were from the CARTaGENE study, a community health survey of adults aged 40-69 years in Quebec, Canada. Incidence of heart disease was examined in N = 33 455 participants by linking survey data with administrative health insurance data. Incident heart disease was identified using the World Health Organization's International Classification of Diseases, 9th or 10th edition (ICD-9 and ICD-10) diagnostic codes for heart disease. Sleep problems were assessed with diagnostic codes for sleep disorders within the 2 years preceding the baseline assessment. Average sleep duration was assessed by self-report. Depressive symptoms were assessed with the nine-item Patient Health Questionnaire. RESULTS: In total, 2448 (7.3%) participants developed heart disease over an average follow-up period of 4.6 years. Compared to those without depressive symptoms and with no sleep disorders, those with elevated depressive symptoms and a sleep disorder (HR = 2.60, 95% CI 1.83-3.69), those with depressive symptoms alone (HR = 1.40, 95% CI 1.25-1.57) and those with sleep disorders alone (HR = 1.33, 95% CI 1.03-1.73) were more likely to develop heart disease. Test of additive interaction suggested a synergistic interaction between depressive symptoms and sleep disorders (synergy index = 2.17 [95% CI 1.01-4.64]). When sleep duration was considered, those with long sleep duration and elevated depressive symptoms were more likely to develop heart disease than those with long sleep alone (HR = 1.77, 95% CI 1.37-2.28; and HR = 1.16, 95% CI 0.99-1.36, respectively). CONCLUSIONS: Depression and diagnosed sleep disorders or long sleep duration are independent risk factors for heart disease and are associated with a stronger risk of heart disease when occurring together.

Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins.

More than 130 different mutations in the gap junction integral plasma membrane protein connexin32 (Cx32) have been linked to the human peripheral neuropathy X-linked Charcot-Marie-Tooth disease (CMTX). How these various mutants are processed by the cell and the mechanism(s) by which they cause CMTX are unknown. To address these issues, we have studied the intracellular transport, assembly, and degradation of three CMTX-linked Cx32 mutants stably expressed in PC12 cells. Each mutant had a distinct fate: E208K Cx32 appeared to be retained in the endoplasmic reticulum (ER), whereas both the E186K and R142W mutants were transported to perinuclear compartments from which they trafficked either to lysosomes (R142W Cx32) or back to the ER (E186K Cx32). Despite these differences, each mutant was soluble in nonionic detergent but unable to assemble into homomeric connexons. Degradation of both mutant and wild-type connexins was rapid (t(1/2) < 3 h) and took place at least in part in the ER by a process sensitive to proteasome inhibitors. The mutants studied are therefore unlikely to cause disease by accumulating in degradation-resistant aggregates but instead are efficiently cleared from the cell by quality control processes that prevent abnormal connexin molecules from traversing the secretory pathway.

Monitoring the efficacy of omega-3 supplementation on liver steatosis and carotid intima-media thickness: a pilot study.

PURPOSE: To determine the effects of omega-3 supplementation on liver fat and carotid intima-media thickness (IMT) and to assess accuracy of ultrasound (US) for grading liver steatosis. MATERIALS AND METHODS: In this one-way crossover pilot study, we assigned children with obesity and liver steatosis to receive 1.2 g daily of omega-3 supplementation vs. inactive sunflower oil for 24 or 12 weeks. Liver fat content was assessed by magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI) and US, and common carotid IMT by US. Statistical analysis included Chi-square, Student's t-tests, ANOVA tests and receiver operating characteristic (ROC) curves. RESULTS: Omega-3 supplementation was associated with a trend towards decrease in MRS-determined liver fat fraction (0.7% and 2.1% decrease in the 24-week and 12-week omega-3 group, respectively) compared with the sunflower oil group (1.0% increase). These changes were not significant, whether assessed by MRS (P = 0.508), MRI (P = 0.508) or US (P = 0.678). Using US, the area under the ROC curves were 0.964, 0.817 and 0.783 for distinguishing inferred steatosis grades 0 vs. 1-2-3, 0-1 vs. 2-3 and 0-1-2 vs. 3, respectively, indicating good accuracy of US-based fat grading. Omega-3 supplementation was associated with a decrease in US-determined IMT (0.05-mm decrease in the 24-week omega-3 group. A 0.015-mm increase was found in the 12-week omega-3 group, and a 0.007-mm decrease in the sunflower oil group (P = 0.003). CONCLUSION: Omega-3 supplementation had no significant effect on liver fat fraction, but led to carotid IMT decrease in children with obesity and liver steatosis.

3D reconstruction of the pelvis from bi-planar radiography.

3D personalized models are more and more requested for clinical and biomechanical studies. Techniques based on bi-planar X-rays present the advantage of a low radiation dose for the patient. However, up to now, such techniques have shown limited accuracy in the case of pelvis reconstruction. This study proposes and validates a method providing accurate 3D personalized model of the pelvis from bi-planar X-rays. The algorithm is based on the fast computation of an initial solution followed by local deformations based on 2D anatomical points and contours that are digitized in both radiographs. Results were close to CT-scan reconstructions (mean difference 1.6 mm and differences under 4.3 mm for 95% of the points). Moreover, 3D morphometry of the pelvis could be obtained with an accuracy of 5%. This technique provides 3D patient specific model with a low radiation dose.

Genetic markers, bone mineral density, and serum osteocalcin levels.

We evaluated five genetic markers for products that contribute to skeletal mineralization including the Sp1 polymorphism for type I collagen Ai (COLIA1), the vitamin D receptor (VDR) translation initiation site polymorphism, the promoter of the osteocalcin gene containing a C/T polymorphism, the estrogen receptor (ER) gene containing a TA repeat, and the polymorphic (AGC)n site in the androgen receptor. These markers were evaluated for their potential relationship with bone mineral density (BMD), measured by dual-energy X-ray densitometry, or its 3-year change. Additionally, potential associations of these genotypes and with baseline osteocalcin concentration or its 3-year change (assessed using radioimmunoassay) were evaluated. The study was conducted in 261 pre- and perimenopausal women of the Michigan Bone Health Study, a population-based longitudinal study of musculoskeletal characteristics and diseases. The polymorphic (AGC)n site in the androgen receptor showed a strong association with BMD of the femoral neck (FN) and lumbar spine and remained highly significant after adjusting for body mass index (BMI), oophorectomy/hysterectomy, oral contraceptive (OC) use and hormone replacement use (p < 0.001). The TA repeat at the 5' end of the ER gene was associated with total body calcium (p < 0.05) after adjusting for BMI, oophorectomy and hysterectomy, and OC use. The frequency of oophorectomy and hysterectomy within selected genotypes explained much of the statistically significant association of the ER genotypes with BMD of the FN and spine. There was no association of measures of BMD or bone turnover with the Sp1 polymorphism for COLIA1, the VDR translation initiation site polymorphism, or the C/T promoter polymorphism of the osteocalcin gene. These findings suggest that sex hormone genes may be important contributors to the variation in BMD among pre- and perimenopausal women.

Nonsense mutations in the COL1A1 gene preferentially reduce nuclear levels of mRNA but not hnRNA in osteogenesis imperfecta type I cell strains.

Osteogenesis imperfecta (OI) is a heterogeneous disorder of type I collagen resulting in varying degrees of severity. The mildest form of OI (Type I) is associated with bone fragility, normal or near normal stature and blue sclerae. All forms of OI are the result of mutations in COL1A1 or COL1A2, the genes that encode the proalpha1(I) and proalpha2(I) chains of type I collagen, respectively. Mutations identified in patients with OI type I lead to premature termination codons and allele-specific reductions of nuclear mRNA (termed nonsense-mediated mRNA decay or NMD), resulting in a COL1A1 null allele. In mammals, this process primarily effects RNA that co-purifies with the nuclear fraction of the cell. Using a semi-quantitative RT-PCR assay, we compare the relative amounts of normal and mutant transcripts in unprocessed hnRNA and mature mRNA isolated from the nuclear fraction of cells from 11 OI type I individuals with previously identified mutations distributed throughout the COL1A1 gene. While we detect about equal amounts of normal and mutant hnRNA from each cell strain, there is preferential reduction in the relative amount of mutant mRNA when compared to normal; only the cell strain with a mutation in the last exon escapes the major effects of NMD. Our data indicate that NMD targets mRNA rather than hnRNA for degradation, and that this occurs either during or after splicing but prior to cytoplasmic translation.

The role of the gap junction protein connexin32 in the pathogenesis of X-linked Charcot-Marie-Tooth disease.

Mutations in the gene encoding the gap junction protein connexin32 (Cx32; beta 1) cause the X-linked form of Charcot-Marie-Tooth disease (CMTX), a common form of inherited demyelinating neuropathy. Cx32 is localized to the paranodes and incisures of myelinating Schwann cells, and probably participates in the formation of gap junctions at these locations, thereby allowing the diffusion of ions and small molecules directly across the myelin sheath. In transfected cells different CMTX mutations have different effects on the ability of the mutant protein to form functional gap junctions; some mutant proteins cannot be detected within the cell, other mutant proteins accumulate within the cell but do not reach the cell membrane, while other mutants reach the cell membrane and some of these form functional gap junctions. In transgenic mice two mutants, R142W and 175 frameshift, have similar effects on protein trafficking as in transfected cells: the R142W mutant protein remains in the perinuclear region and does not reach the paranodes or incisures, and the 175 frameshift protein cannot be detected. Thus, different CMTX mutations have different effects on Cx32 protein, and these differences may help to explain the phenotypic differences seen in CMTX kindreds.

Mutagenicity of acridines in a reversion assay based on tetracycline resistance in plasmid pBR322 in Escherichia coli.

The mutagenicity of a series of acridine compounds was studied in an assay based on the reversion of mutations in the tetracycline-resistance gene (tet) of plasmid pBR322 in Escherichia coli. Mutations that restore the tetracycline-resistant phenotype were detected in tetracycline-sensitive strains carrying mutant plasmids. Mutations that revert by +2, +1, -1 and -2 frameshift mutations and by base-pair substitutions were used to analyze the mutagenicity of two simple acridines, two acridine mustards, and a nitroacridine. The simple acridines (9-aminoacridine and quinacrine) effectively induced -1 frameshifts and weakly induced +1 frameshifts. The acridine mustards (quinacrine mustard and ICR-191) were more potent inducers of -1 and +1 frameshifts than the simple acridines. Reactive acridines, including both the mustards and the nitroacridine Entozon, were effective inducers of -2 frameshifts but the simple acridines were not. The two classes of reactive acridines differed from one another, in that the mustards were better inducers of +1 frameshifts than Entozon, whereas Entozon was a particularly potent inducer of -2 frameshifts. None of the compounds induced +2 frameshifts, and the induction of base-pair substitutions was negligible. These results confirm and extend studies showing that adduct-forming acridines are stronger frameshift mutagens than simple intercalating acridines and that the acridines differ from one another not only in overall mutagenic potency but also in the prevalence of different classes of frameshift mutations.

[Student enrollment in Canadian medical schools, 1976-77]. / Etudiants inscrits aux facultés de médecine du Canada, 1976-77.

The 1976-77 statistical study of medical school enrollment by the Association of Canadian Medical Colleges shows that total enrollment in Canadian medical schools had increased 103.8% since 1960-61, although the rate of increase had decreased to almost zero by 1976-77. Women accounted for 30.3% of the total enrollment in 1976-77 (for all years of the course), which represents an increase of more than 550% in the 17-year period; for the 16 schools the proportion ranged between 23.9% and 43.8%. Enrollment of foreign students had decreased from 340 in 1966-67 to 90 (1.2%) in 1976-77; 71 of the 90 students were American. For the entire nation the mean number of medical students per 10 000 population was 3.1, but in British Columbia the figure was only 1.5. Of the Canadian and landed immigrant students 94.5% were attending medical school in their home province.

Monochromatic electromagnetic wavelets and the huygens principle.

For the first time, to our knowledge, optical diffraction is shown to be a wavelet transform with the electromagnetic wavelets. We show that the optical wavelets proposed by Onural [Opt. Lett. 18, 846 (1993)] are the Huygens wavelets under a Fresnel approximation, and the electromagnetic wavelets proposed by Kaiser [A Friendly Guide to Wavelets (Birkhauser, Boston, Mass., 1994)] reduce to Hyugens wavelets in the case of a monochromatic field.

Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I.

Osteogenesis imperfecta type I results from decreased production of structurally normal type I collagen as a result of a COL1A1 "null" allele. Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and cytoplasm of dermal fibroblasts from most affected subjects. Mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, could alter steady state levels of mRNA, and therefore lead to this phenotype. To determine the frequency of such mutations in OI type I cell strains, we used PCR amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis (DGGE) and SSCP, to screen the 5' untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. Forty unrelated probands with OI type I, in whom no causative mutation was known, were included in the study. No mutations were included in the study. No mutations were identified in either the TATAAA or CCAAAT boxes in any of the affected people. In addition, there was little evidence of sequence diversity among any of the 40 subjects. These data suggest that mutations in the COL1A1 promoter do not play a significant role in the aetiology of OI type I.

Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains.

Nonsense and frameshift mutations, which predict premature termination of translation, often cause a dramatic reduction in the amount of transcript from the mutant allele (nonsense-mediated mRNA decay). In some genes, these mutations also influence RNA splicing and induce skipping of the exon that contains the nonsense codon. To begin to dissect how premature termination alters the metabolism of RNA from the COL1A1 gene, we studied nonsense and frameshift mutations distributed over exons 11-49 of the gene. These mutations were originally identified in 10 unrelated families with osteogenesis imperfecta (OI) type 1. We observed marked reduction in steady-state amounts of mRNA from the mutant allele in both total cellular and nuclear RNA extracts of cells from affected individuals, suggesting that nonsense-mediated decay of COL1A1 RNA is a nuclear phenomenon. Position of the mutation within the gene did not influence this observation. None of the mutations induced skipping of either the exon containing the mutation or, for the frameshifts, the downstream exons with the new termination sites. Our data suggest that nonsense and frameshift mutations throughout most of the COL1A1 gene result in a null allele, which is associated with the predictable mild clinical phenotype, OI type 1.

Mammalian DNA mismatch repair.

DNA mismatch repair (MMR) is one of multiple replication, repair, and recombination processes that are required to maintain genomic stability in prokaryotes and eukaryotes. In the wake of the discoveries that hereditary nonpolyposis colorectal cancer (HNPCC) and other human cancers are associated with mutations in MMR genes, intensive efforts are under way to elucidate the biochemical functions of mammalian MutS and MutL homologs, and the consequences of defects in these genes. Genetic studies in cultured mammalian cells and mice are proving to be instrumental in defining the relationship between the functions of MMR in mutation and tumor avoidance. Furthermore, these approaches have raised awareness that MMR homologs contribute to DNA damage surveillance, transcription-coupled repair, and recombinogenic and meiotic processes.

Comparative mapping of canine and human proximal Xq and genetic analysis of canine X-linked severe combined immunodeficiency.

Parallel genetic analysis of animal and human genetic diseases can facilitate the identification and characterization of the causative gene defects. For example, canine X-linked severe combined immunodeficiency (SCID) is characterized by clinical, pathological, and immunological manifestations similar to the most common form of human SCID. To derive a canine syntenic map including genes that in humans are located in proximal Xq, near human X-linked SCID, poly(TG) polymorphisms were identified at the canine phosphoglycerate kinase (PGK) and choroideremia (CHM) loci. These plus a polymorphic poly(CAG) sequence in exon 1 of the canine androgen receptor gene (AR) were used to genotype members of the colony informative for X-linked SCID. No recombinations among SCIDX1, AR, PGK, or CHM were observed. Fluorescence in situ hybridization localized PGK and CHM to proximal Xq in the dog, in the same chromosomal location occupied by the human genes. Somatic cell hybrid analysis and methylation differences at AR demonstrated that female dogs carrying X-linked SCID have the same lymphocyte-limited skewed X-chromosome inactivation patterns as human carriers. These genetic and phenotypic findings provide evidence that mutations in the same gene, now identified as the gamma chain of the IL-2 receptor, cause canine and human X-linked SCID. This approach is an efficient method for comparative gene mapping and disease identification.

Altered trafficking of mutant connexin32.

We examined the cellular localization of nine different connexin32 (Cx32) mutants associated with X-linked Charcot-Marie-Tooth disease (CMTX) in communication-incompetent mammalian cells. Cx32 mRNA was made, but little or no protein was detected in one class of mutants. In another class of mutants, Cx32 protein was detectable in the cytoplasm and at the cell surface, where it appeared as plaques and punctate staining. Cx32 immunoreactivity in a third class of mutants was restricted to the cytoplasm, where it often colocalized with the Golgi apparatus. Our studies suggest that CMTX mutations have a predominant effect on the trafficking of Cx32 protein, resulting in a potentially toxic cytoplasmic accumulation of Cx32 in these cells. These results and evidence of cytoplasmic accumulation of other mutated myelin proteins suggest that diseases affecting myelinating cells may share a common pathophysiology.

Connexin32 and X-linked Charcot-Marie-Tooth disease.

Mutations in the gap junction gene connexin32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. More than 130 different mutations have been described, affecting all portions of the Cx32 protein. In transfected cells, the mutant Cx32 proteins encoded by some Cx32 mutations fall to reach the cell surface; other mutant proteins reach the cell surface, but only one of these forms functional gap junctions. In peripheral nerve, Cx32 is localized to incisures and paranodes, regions of noncompact myelin within the myelin sheath. This localization suggests that Cx32 forms "reflexive" gap junctions that allow ions and small molecules to diffuse directly across the myelin sheath, which is a thousandfold shorter distance than the circumferential pathway through the Schwann cell cytoplasm. Cx32 mutations may interrupt this shorter pathway or have other toxic effects, thereby injuring myelinating Schwann cells and their axons.