A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene

Several candidate genes for non-insulin-dependent diabetes mellitus (NIDDM) map on chromosome 20, including the phosphoenolpyruvate carboxykinase gene (PCK1) and one of the maturity onset diabetes of the young genes (MODY1). Thus, we have investigated the entire long arm of chromosome 20. Linkage analyses were conducted in a total sample of 148 NIDDM families (301 NIDDM sib pairs) and in a subset of 42 early onset NIDDM families, where genetic components are likely to play a more important role (55 NIDDM sib pairs diagnosed at or before 45 years of age), using 10 highly polymorphic markers with an average map density of 7.5 cM. Using affected sib pair methods (two-point linkage and multipoint linkage analyses), significant results were obtained with the 20q13 region, in the vicinity of the PCK1 locus, only in the subset of 55 early onset NIDDM sib pairs (multipoint MLS = 2.74, P = 0.0004; MLS = 2.34, P = 0.0009 when using a conservative weighting procedure). Moreover, another region spanning the ribophorin II (RPNII, phospholipase C (PLC1) and adenosine deaminase (ADA) loci suggested linkage with NIDDM (multipoint MLS of 1.81 in all NIDDM sib pairs, P = 0.003; MLS = 1.31, P = 0.012 when using a conservative weighting procedure). Whereas our study suggests the location of a susceptibility locus for early onset NIDDM in the PCK1 gene region, further investigation in larger data sets is required to confirm these results and assess the role of other regions on chromosome 20q in human NIDDM.      

BRCA1 as tumor suppressor: lord without its RING?

BRCA1 is a tumor suppressor with critical roles in the maintenance of genomic stability. It encodes a large protein with an amino-terminal RING domain that possesses ubiquitin-ligase activity. Given the occurrence of numerous cancer-causing mutations within its RING domain, investigators have long suspected that BRCA1's ubiquitin ligase is important for its tumor suppression and DNA repair activities. Using genetically engineered mouse models, two recent studies shed light on this age-old hypothesis.     

Self-reported side effects of breast cancer treatment: a cross-sectional study of incidence, associations, and the influence of exercise

Purpose

Side effects as a result of breast cancer treatment may have a lasting detrimental impact on quality of life. Exercise has been shown to be an effective intervention in post-treatment care. This study aimed to gain a better understanding of breast cancer treatment-related side effects through identifying potential patient characteristic associations, including current levels of exercise.

Methods

Four hundred and thirty-two breast cancer patients completed an online survey covering their treatment and demographic background, current exercise levels, and self-reported treatment side effects. Side effects were considered in a binary logistic regression against age, surgery, currently undergoing treatment, and exercise levels to ascertain significant relationships (p < 0.05) and associative values (Odds Ratio).

Results

Lumpectomy patients were less likely to report aching muscles (OR 0.61, 95 % CI 0.39–0.96), hot flushes (OR 0.60, 95 % CI 0.38–0.96), and weight gain (OR 0.59, 95 % CI 0.38–0.92) than mastectomy patients. Women currently undergoing treatment were more likely to report hot flushes (OR 3.77, 95 % CI 2.34–6.08), aching muscles (OR 1.62, 95 % CI 1.02–2.57), and weight gain (OR 1.89, 95 % CI 1.19–2.99) than women finished treatment. Sedentary women were more likely to experience shoulder limitations (OR 1.77, 95 % CI 1.14–2.77), muscular chest wall pain (OR 1.69, 95 % CI 1.07–2.65), weight gain (OR 2.29, 95 % CI 1.44–3.64), lymphedema (OR 1.68, 95 % CI 1.04–2.71), and breathlessness (OR 2.30 95 % CI 1.35–3.92) than their physically active counterparts.

Conclusions

Patient characteristics may inform interventions to improve care post-breast cancer treatment. Sufficient levels of exercise were consistently associated fewer side effects and should be encouraged.     

Study of smell and reproductive organs in a mouse model for CHARGE syndrome

CHARGE syndrome is a multiple congenital anomaly syndrome characterised by Coloboma, Heart defects, Atresia of choanae, Retardation of growth and/or development, Genital hypoplasia, and Ear anomalies often associated with deafness. It is caused by heterozygous mutations in the CHD7 gene and shows a highly variable phenotype. Anosmia and hypogonadotropic hypogonadism occur in the majority of the CHARGE patients, but the underlying pathogenesis is unknown. Therefore, we studied the ability to smell and aspects of the reproductive system (reproductive performance, gonadotropin-releasing hormone (GnRH) neurons and anatomy of testes and uteri) in a mouse model for CHARGE syndrome, the whirligig mouse (Chd7^Whi/+). We showed that Chromodomain Helicase DNA-binding protein 7 (Chd7) is expressed in brain areas involved in olfaction and reproduction during embryonic development. We observed poorer performance in the smell test in adult Chd7^Whi/+ mice, secondary either to olfactory dysfunction or to balance disturbances. Olfactory bulb and reproductive organ abnormalities were observed in a proportion of Chd7^Whi/+ mice. Hypothalamic GnRH neurons were slightly reduced in Chd7^Whi/+ females and reproductive performance was slightly less in Chd7^Whi/+ mice. This study shows that the penetrance of anosmia and hypogonadotropic hypogonadism is lower in Chd7^Whi/+ mice than in CHARGE patients. Interestingly, many phenotypic features of the Chd7 mutation showed incomplete penetrance in our model mice, despite the use of inbred, genetically identical mice. This supports the theory that the extreme variability of the CHARGE phenotype in both humans and mice might be attributed to variations in the fetal microenvironment or to purely stochastic events.     

Blockade of excitatory synaptic transmission by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the hippocampus in vitro

Superfusion of hippocampal slices with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 2-5 microM) reversibly blocked the Schaffer collateral and mossy fibre excitatory postsynaptic potential (EPSP), while sparing the fast and slow gamma-aminobutyric acid (GABA)-mediated inhibition. Membrane potential, input resistance and spike accommodation were not altered. Inward currents induced by quisqualate were reduced to a greater extent by CNQX than those induced by kainate or N-methyl-D-aspartate. We suggest that CNQX may be a useful antagonist to study excitatory amino acid-mediated synaptic transmission.     

The antidepressant bupropion exerts alleviating properties in an ovariectomized osteoporotic rat model

Aim:

Depression is a risk factor for impaired bone mass and micro-architecture, but several antidepressants were found to increase the incidence of osteoporotic fractures. In the present study we used ovariectomized (OVX) rats as a model of osteoporosis to investigate the effects of the antidepressant bupropion on the femoral bones.

Methods:

OVX animals were treated with bupropion (30, 60 mg·kg⁻¹·d⁻¹) for six weeks. Bone turnover biomarkers (urinary DPD/Cr ratio, serum BALP, OC, TRAcP 5b, CTX and sRANKL levels) and inflammatory cytokines (TNF-α, IL-1β and IL-6) were determined using ELISA. Inductively coupled plasma mass spectroscopy (ICP-MS) was used to determine the femoral bone mineral concentrations. The cortical and trabecular morphometric parameters of femoral bones were determined using micro-CT scan and histopathology.

Results:

In OVX rats, the levels of bone turnover biomarkers and inflammatory cytokines were significantly elevated and femoral bone Ca²⁺ and PO₄³⁻ concentrations were significantly reduced. Moreover, cortical and trabecular morphometric parameters and histopathology of femoral bones were severely altered by ovariectomy. Bupropion dose-dependently inhibited the increases in bone turnover biomarkers and inflammatory cytokines. OVX rats treated with the high dose of bupropion showed normal mineral concentrations in femoral bones. The altered morphometric parameters and histopathology of femoral bones were markedly attenuated by the treatment.

Conclusion:

Bupropion exerts osteo-protective action in OVX rats through suppressing osteoclastogenesis-inducing factors and inflammation, which stabilize the osteoclasts and decrease bone matrix degradation or resorption.     

Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles

Large oncosomes (LO) are atypically large (1-10μm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrep^TM) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5^th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.     

Exercise bra discomfort is associated with insufficient exercise levels among Australian women treated for breast cancer

Purpose

Although participating in exercise is beneficial for breast cancer survivors, not being able to find a comfortable exercise bra can be a barrier to exercise. It is likely that side effects specific to breast cancer treatment exacerbate exercise bra discomfort. This study aimed to determine the relationship between patient characteristics, physical side effects, exercise bra discomfort and exercise behaviours.

Methods

Four hundred thirty-two breast cancer survivors completed an online survey related to their treatment and demographic background, current exercise levels, reported exercise bra discomfort and breast cancer treatment side effects. Patient characteristics and exercise levels were considered in a binary logistic regression against reporting bra discomfort to ascertain significant relationships (p?<?0.05) and predictive value (odds ratio). Pearson's chi-square statistics was used to determine significant relationships between reporting a side effect and exercise bra discomfort.

Results

Eight out of nine physical side effects were significantly related to reporting exercise bra discomfort. Reporting exercise bra discomfort was significantly related to not achieving a minimal recommended level of exercise.

Conclusions

This is the first study in the scientific literature that systematically links the reporting of exercise bra discomfort to not achieving recommended levels of exercise. This effect of bra discomfort on exercise was found after controlling for age, surgery type and current treatment among a large cohort of women treated for breast cancer. Furthermore, results from this study suggest that physical side effects, as a result of surgery and treatment associated with breast cancer, are linked to experiencing bra discomfort during exercise.