Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate

The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway. Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway. Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation. This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro‐cuneiform nucleus pathway could control axial posture whereas the pallido‐pedunculopontine nucleus pathway could modulate locomotion. © 2011 Movement Disorder Society     

A phase III trial of docetaxel-estramustine in high-risk localised prostate cancer: a planned analysis of response, toxicity and quality of life in the GETUG 12 trial

AimTo assess docetaxel–estramustine in patients with localised high-risk prostate cancer.Patients and methodsAfter staging pelvic lymph node dissection, patients with high-risk prostate cancer randomly received androgen deprivation therapy (ADT) (3 years) + DE (4 cycles of docetaxel 70 mg/m²/3 weeks + estramustine 10 mg/kg/d d1–5) or ADT alone. Local therapy was administered at 3 months.ResultsFour hundred and thirteen patients were accrued: T3–T4 (67%), Gleason score ⩾8 (42%), PSA >20 ng/mL (59%), pN+ (29%). In the chemotherapy arm, 94% of patients received the planned four cycles of docetaxel. Local treatment consisted of radiotherapy in 358 patients (87%) (median dose 74 Gy in both arms). ADT was given for 36 months in both arms. A PSA response (PSA ⩽0.2 ng/mL after 3 months of treatment) was obtained in 34% and 15% in the ADT + DE arm and in the ADT arm, respectively (p < 0.0001). Febrile neutropenia occurred in only 2%. Moderate to severe hot flashes occurred less often in the ADT + DE arm (2% versus 22%; p < 0.001). There was no toxicity-related death, no secondary leukaemia, and no excess second cancers. Chemotherapy had a negative impact on quality of life (global health status, p = 0.01; fatigue, p = 0.003; role functioning, p = 0.003; social functioning, p = 0.006) at 3 months but this effect disappeared at 1 year.ConclusionDocetaxel–estramustine can be combined safely with standard therapy in high-risk prostate cancer, with a promising PSA response rate and no negative impact on quality of life after 1 year. Long-term follow-up is required to assess the impact on relapse and survival.     

Relationship between iron status and dietary fruit and vegetables based on their vitamin C and fiber content

BACKGROUND: Dietary fruits and vegetables may enhance iron status because of their high vitamin C content. The potential association between iron status and intakes of specific fruits and vegetables, according to sex and menopausal status, must be investigated. OBJECTIVE: The objective was to assess the relation between dietary fruits, vegetables, and juices (FVJ) according to their vitamin C and fiber contents and serum ferritin and hemoglobin concentrations. DESIGN: A total of 4358 subjects, aged 35-60 y, of the Supplementation with Antioxidant Vitamins and Minerals (SU.VI.MAX) cohort were selected. Subjects had completed at least six 24-h-dietary records over 2 y. The relation between serum ferritin and hemoglobin, measured at inclusion, and dietary FVJ according to their vitamin C and fiber contents was assessed by multiple regression analysis. RESULTS: In premenopausal women, serum ferritin was positively associated with intakes of fiber-poor FVJ (up to 10% higher serum ferritin in the third tertile compared with the first tertile). In the whole sample, hemoglobin was positively associated with fruits, vitamin C-rich FVJ, FVJ ascorbic acid, and fiber-poor FVJ categories (up to 1.5 g/L higher hemoglobin concentration). CONCLUSIONS: Intakes of fiber-poor FVJ were associated with higher serum ferritin concentrations in premenopausal women and with higher hemoglobin concentrations in the whole sample. Our results suggest that the fiber content of fruits and vegetables influences iron stores in premenopausal women but has no influence in groups in whom nonheme-iron absorption is limited because of high iron stores. Other mechanisms are likely to be involved in the case of hemoglobin.     

Antitumorigenic effects of a mutant of the heparin affin regulatory peptide on the U87 MG glioblastoma cell line

Glioblastoma is the most common primary brain tumor in human adults. Since existing treatments are not effective enough, novel therapeutic targets must be sought. The heparin‐binding growth factor, heparin affin regulatory peptide (HARP), also known as pleiotrophin (PTN), could potentially represent such a target. We have previously shown that a mutant protein, HARPΔ111–136, which lacks HARP's C‐terminal 26 amino acids, acts as a dominant negative HARP effector by heterodimerizing with the wild‐type growth factor. The aim of our study was to evaluate the potential inhibitory activity of HARPΔ111–136 on the U87 MG human glioblastoma cell line. By overexpressing the truncated form of HARP in stably established clones of U87 MG cells, we observed an inhibition of proliferation under both anchorage‐dependent and anchorage‐independent conditions. We confirmed these results in an in vivo subcutaneous tumor xenograft model. In addition, we found that HARPΔ111–136 inhibited cell proliferation in a paracrine manner. Analysis of key cellular pathways revealed a decrease of cell adhesion in U87 MG cells that overexpressed the mutant protein, which could explain this inhibitory effect. A replication‐defective adenovirus model that encoded HARPΔ111–136 supported a putative antiproliferative role for the truncated protein in vitro and in vivo. Interestingly, HARPΔ111–136 was also able to abolish angiogenic activity in HUVEC proliferation and in a Matrigel plug assay. These results demonstrate that considering its antiproliferative and angiostatic effects, HARPΔ111–136 could be of great interest when used in conjunction with standard treatments.     

Modifications in dietary and alcohol intakes between before and after cancer diagnosis: Results from the prospective population‐based NutriNet‐Santé cohort

Postdiagnosis diet and alcohol consumption may be associated with cancer prognosis, recurrence and mortality. Our aim was to investigate food, nutrient and alcohol intake variations between before and after cancer diagnosis and their determinants in a prospective cohort. Subjects (n = 696) were incident cancer cases diagnosed in the NutriNet‐Santé cohort between 2009 and 2016. Food, nutrient and alcohol intakes were prospectively collected using repeated nonconsecutive 24‐hr dietary records since subjects' inclusion (i.e. an average of 2 y before diagnosis). Mean number of dietary records per subject was 5.9 before and 8.1 after diagnosis. All dietary data before and after diagnosis were compared by mixed models. Factors associated with the main dietary changes observed were also investigated using multivariable logistic regressions. We observed a decrease in intakes of vegetables (mean decrease in intake in patients who decreased their intake=‐102.4 ± 79.8 g/d), dairy products (–93.9 ± 82.8 g/d), meat/offal (–35.5 ± 27.8/d), soy products (–85.8 ± 104.1 g/d), sweetened soft drinks (–77.9 ± 95.4 g/d), and alcoholic drinks (–92.9 ± 119.9 g/d), and an increase in broths (42.1 ± 34.9 g/d) and fats/sauces (18.0 ± 13.4 g/d). We observed a decrease in energy intake (–377.2 ± 243.5 kcal/d) and in intakes of alcohol (–7.6 ± 9.4 g/d) proteins (–17.4 ± 12.5 g/d), and several vitamins (p < 0.05) and micronutrients (p < 0.05). Conversely, lipid (19.4 ± 14.6 g/d), SFA (9.3 ± 7.0 g/d), MUFA (8.3 ± 6.3 g/d) and vitamin E (3.9 ± 3.3 mg/d) intakes increased after diagnosis. This large prospective study suggests that cancer diagnosis is a key period for nutritional changes. It highlights some healthy behaviors such as a decrease in alcohol and sweetened drink consumption, but also less favorable trends, such as a decrease in vegetable consumption and in many vitamin and mineral intakes. These results provide insights to identify and target recommendations to put forward for better nutritional care of cancer survivors.