Muscle spindle alterations precede onset of sensorimotor deficits in Charcot-Marie-Tooth type 2E.

Charcot-Marie-Tooth (CMT) is the most common inherited peripheral neuropathy, affecting approximately 2.8 million people. The CMT leads to distal neuropathy that is characterized by reduced motor nerve conduction velocity, ataxia, muscle atrophy and sensory loss. We generated a mouse model of CMT type 2E (CMT2E) expressing human neurofilament light E396K (hNF-LE396K ), which develops decreased motor nerve conduction velocity, ataxia and muscle atrophy by 4 months of age. Symptomatic hNF-LE396K mice developed phenotypes that were consistent with proprioceptive sensory defects as well as reduced sensitivity to mechanical stimulation, while thermal sensitivity and auditory brainstem responses were unaltered. Progression from presymptomatic to symptomatic included a 50% loss of large diameter sensory axons within the fifth lumbar dorsal root of hNF-LE396K mice. Owing to proprioceptive deficits and loss of large diameter sensory axons, we analyzed muscle spindle morphology in presymptomatic and symptomatic hNF-LE396K and hNF-L control mice. Muscle spindle cross-sectional area and volume were reduced in all hNF-LE396K mice analyzed, suggesting that alterations in muscle spindle morphology occurred prior to the onset of typical CMT pathology. These data suggested that CMT2E pathology initiated in the muscle spindles altering the proprioceptive sensory system. Early sensory pathology in CMT2E could provide a unifying hypothesis for the convergence of pathology observed in CMT.

Breast cancer patients' clinical outcome measures are associated with Src kinase family member expression.

BACKGROUND: This study determined mRNA expression levels for Src kinase family (SFK) members in breast tissue specimens and assessed protein expression levels of prominent SFK members in invasive breast cancer to establish associations with clinical outcome. Ki67 was investigated to determine association between SFK members and proliferation. METHODS: The mRNA expression levels were assessed for eight SFK members by quantitative real-time PCR. Immunohistochemistry was performed for c-Src, Lyn, Lck and Ki67. RESULTS: mRNA expression was quantified in all tissue samples. SRC and LYN were the most highly expressed in malignant tissue. LCK was more highly expressed in oestrogen receptor (ER)-negative, compared with ER-positive tumours. High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival. Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival. Ki67 expression correlated with tumour grade and nuclear c-Src, but was not associated with survival. CONCLUSIONS: All eight SFK members were expressed in different breast tissues. Src kinase was highest expressed in breast cancer and had a negative impact on disease-specific survival. Membrane expression of Lck was associated with improved clinical outcome. High expression of Src kinase correlated with high proliferation.

Altered sirtuin expression is associated with node-positive breast cancer.

Sirtuins are genes implicated in cellular and organismal ageing. Consequently, they are speculated to be involved in diseases of ageing including cancer. Various cancers with widely differing prognosis have been shown to have differing and characteristic expression of these genes; however, the relationship between sirtuin expression and cancer progression is unclear. In order to correlate cancer progression and sirtuin expression, we have assessed sirtuin expression as a function of primary cell ageing and compared sirtuin expression in normal, 'nonmalignant' breast biopsies to breast cancer biopsies using real-time polymerase chain reaction (PCR). Levels of SIRT7 expression were significantly increased in breast cancer (P<0.0001). Increased levels of SIRT3 and SIRT7 transcription were also associated with node-positive breast cancer (P<0.05 and P<0.0001, respectively). This study has demonstrated differential sirtuin expression between nonmalignant and malignant breast tissue, with consequent diagnostic and therapeutic implications.

Randomised controlled trial of effect of fruit and vegetable consumption on plasma concentrations of lipids and antioxidants.

OBJECTIVES: To determine the extent to which plasma antioxidant concentrations in people with habitual low intake of fruit and vegetables respond to increased intakes of these foods. To examine whether advice to increase fruit and vegetables will result in reduction of concentrations of total and low density lipoprotein cholesterol. DESIGN: Randomised controlled trial in which intervention and control groups were followed up for eight weeks. The intervention group was asked to consume eight servings of fruit and vegetables a day. SETTING: Dunedin, New Zealand. SUBJECTS: Eighty seven subjects with normal lipid concentrations who ate three or fewer servings of fruit and vegetables daily. MAIN OUTCOME MEASURES: Plasma concentrations of vitamin C, retinol, alpha and beta carotene, alpha tocopherol, lipids, and lipoproteins. Dietary intake assessed with diet records over four days. RESULTS: The mean plasma vitamin C, alpha carotene, and beta carotene concentrations increased in parallel with increased dietary intake of fruit and vegetables in the intervention group. Concentrations of retinol, alpha tocopherol, lipids, and lipoproteins remained unchanged despite some increase in dietary vitamin E and a small reduction in saturated fat intake. CONCLUSIONS: Following a recommendation to increase fruit and vegetable consumption produces change in plasma concentrations of vitamin C, alpha carotene, and beta carotene likely to reduce incidence of cancer. More specific dietary advice to modify fat intake may be necessary to reduce the risk of cardiovascular disease mediated by lipoprotein and vitamin E.