Progression and recovery of Parkinsonism in a chronic progressive MPTP-induction model in the marmoset without persistent molecular and cellular damage.

Chronic exposure to low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in marmoset monkeys was used to model the prodromal stage of Parkinson's disease (PD), and to investigate mechanisms underlying disease progression and recovery. Marmosets were subcutaneously injected with MPTP for a period of 12weeks, 0.5mg/kg once per week, and clinical signs of Parkinsonism, motor- and non-motor behaviors were recorded before, during and after exposure. In addition, postmortem immunohistochemistry and proteomics analysis were performed. MPTP-induced parkinsonian clinical symptoms increased in severity during exposure, and recovered after MPTP administration was ended. Postmortem analyses, after the recovery period, revealed no alteration of the number and sizes of tyrosine hydroxylase (TH)-positive dopamine (DA) neurons in the substantia nigra. Also levels of TH in putamen and caudate nucleus were unaltered, no differences were observed in DA, serotonin or nor-adrenalin levels in the caudate nucleus, and proteomics analysis revealed no global changes in protein expression in these brain areas between treatment groups. Our findings indicate that parkinsonian symptoms can occur without detectable damage at the cellular or molecular level. Moreover, we show that parkinsonian symptoms may be reversible when diagnosed and treated early.

Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences.

Genome-wide association studies have suggested a role for a genetic variation in the presynaptic gene PCLO in major depressive disorder (MDD). As with many complex traits, the PCLO variant has a small contribution to the overall heritability and the association does not always replicate. One variant (rs2522833, p.Ser4814Ala) is of particular interest given that it is a common, nonsynonymous exon variant near a calcium-sensing part of PCLO. It has been suggested that the molecular effects of such variations penetrate to a variable extent in the population due to phenotypic and genotypic heterogeneity at the population level. More robust effects may be exposed by studying such variations in isolation, in a more homogeneous context. We tested this idea by modeling PCLO variation in a mouse knock-in model expressing the Pclo(SA)(/)(SA) variant. In the highly homogeneous background of inbred mice, two functional effects of the SA-variation were observed at the cellular level: increased synaptic Piccolo levels, and 30% increased excitatory synaptic transmission in cultured neurons. Other aspects of Piccolo function were unaltered: calcium-dependent phospholipid binding, synapse formation in vitro, and synaptic accumulation of synaptic vesicles. Moreover, anxiety, cognition and depressive-like behavior were normal in Pclo(SA)(/)(SA) mice. We conclude that the PCLO p.Ser4814Ala missense variant produces mild cellular phenotypes, which do not translate into behavioral phenotypes. We propose a model explaining how (subtle) cellular phenotypes do not penetrate to the mouse behavioral level but, due to genetic and phenotypic heterogeneity and non-linearity, can produce association signals in human population studies.

Transcriptome analysis of the central nervous system of the mollusc Lymnaea stagnalis.

BACKGROUND: The freshwater snail Lymnaea stagnalis (L. stagnalis) has served as a successful model for studies in the field of Neuroscience. However, a serious drawback in the molecular analysis of the nervous system of L. stagnalis has been the lack of large-scale genomic or neuronal transcriptome information, thereby limiting the use of this unique model. RESULTS: In this study, we report 7,712 distinct EST sequences (median length: 847 nucleotides) of a normalized L. stagnalis central nervous system (CNS) cDNA library, resulting in the largest collection of L. stagnalis neuronal transcriptome data currently available. Approximately 42% of the cDNAs can be translated into more than 100 consecutive amino acids, indicating the high quality of the library. The annotated sequences contribute 12% of the predicted transcriptome size of 20,000. Surprisingly, approximately 37% of the L. stagnalis sequences only have a tBLASTx hit in the EST library of another snail species Aplysia californica (A. californica) even using a low stringency e-value cutoff at 0.01. Using the same cutoff, approximately 67% of the cDNAs have a BLAST hit in the NCBI non-redundant protein and nucleotide sequence databases (nr and nt), suggesting that one third of the sequences may be unique to L. stagnalis. Finally, using the same cutoff (0.01), more than half of the cDNA sequences (54%) do not have a hit in nematode, fruitfly or human genome data, suggesting that the L. stagnalis transcriptome is significantly different from these species as well. The cDNA sequences are enriched in the following gene ontology functional categories: protein binding, hydrolase, transferase, and catalytic enzymes. CONCLUSION: This study provides novel molecular insights into the transcriptome of an important molluscan model organism. Our findings will contribute to functional analyses in neurobiology, and comparative evolutionary biology. The L. stagnalis CNS EST database is available at http://www.Lymnaea.org/.

Depression and the lower risk for breast cancer development in middle-aged women: a prospective study.

BACKGROUND: Depression has been hypothesized to be potentially linked to an increased risk of breast cancer. Few studies have addressed this question using population-based cohorts and prospective designs, adjusting for known biomedical risk factors. This has been done in the present investigation. METHOD: Participants were 5191 women from a cohort of women born between 1941 and 1947 and living in the city of Eindhoven, The Netherlands. All women completed questionnaires regarding the presence of depressive symptoms (Edinburgh Depression Scale) and background (demographic, medical and lifestyle) variables. The questionnaire data were linked with the records of the Eindhoven Cancer Registry. These records provided data on breast cancer diagnoses, which took place up to 5 years after the questionnaire screening. RESULTS: Fifty-eight women (1.1%) were found to have developed breast cancer at least 2 years after the questionnaire screening. After controlling for 15 potential risk factors, of which family history of breast cancer, hypothyroidism and unilateral oophorectomy were significant predictors of breast cancer development, women with depressive symptoms had a lower risk of subsequent breast cancer (OR=0.29, 95% CI=0.09-0.92, P=0.04). CONCLUSIONS: Depressive complaints may be associated with a protective factor involved in the development of breast cancer. Some of the possible candidates for this factor are discussed.

Test characteristics of carbohydrate-deficient transferrin and gamma-glutamyltransferase in alcohol-using perimenopausal women.

BACKGROUND: The application of biochemical markers to detect heavy alcohol use in women has shown disappointing results until now. We evaluated carbohydrate-deficient transferrin (CDT) by the CDTect method and gamma-glutamyltransferase (GGT) in a large cohort of alcohol-using perimenopausal women studied primarily for osteoporosis. METHODS: CDT and GGT were measured in 431 women aged 46 to 54 years, who were selected from a large cohort (n = 8503) of pre-, peri-, and postmenopausal women. Their alcohol intake was known from questionnaires and face-to-face interviews. Three groups were constructed for statistical analysis: those drinking on average less than 7 alcoholic drinks per week (n = 103), those drinking 7 to 34 per week (n = 280), and those drinking at least 35 per week (n = 48). RESULTS: The mean values of CDT and GGT of the three groups increased with an increasing alcohol intake, but there was a poor correlation between CDT and GGT in the complete study group (r = 0.3). The specificities of CDT and GGT were comparable, 83% and 78%, respectively. The sensitivities for CDT and GGT were 30% and 50%, respectively. A logistic regression model could assign, overall, 77% of the women correctly in relation to their alcohol intake: 43% of the women drinking at least 35 drinks per week and 92% of the women drinking less than 7 drinks per week. CONCLUSIONS: The test characteristics of both GGT and CDT are not good enough to be used as biochemical markers for detecting heavy alcohol use in women. The use of a logistic regression model offers an advantage, because both numeric values of CDT and GGT are taken into account instead of arbitrary cutoff values.

Replantation of the radial side of the hand in the rhesus monkey: anatomical and functional aspects. A preliminary study to composite tissue allografting.

Before human hand transplantation can even be considered, an appropriate research model must be studied in a non-human primate. The first ray of the hand, augmented with a radial forearm flap, was chosen as a functional composite tissue graft. Four technically successful replantation of the radial unit have been carried out. One monkey died on the first post-operative day due to cardiac arrythmia. Normal wound healing occurred in the other three animals. In three monkeys, functional sensory and motor recovery was almost complete. The monkeys were able to pick up small particles of food with the index finger and thumb. It is suggested that this model could be used for allogeneic composite tissue transplantation in a non-human primate.

Allogeneic transplantation of the radial side of the hand in the rhesus monkey: I. Technical aspects.

Since allogeneic transplantation of extremities can only be considered if uneventful long-term survival and functional recovery can be achieved, a series of 12 transplantations of the radial side of the hand were performed in rhesus monkeys so that these factors could be assessed. The transplant incorporated the first ray of the hand in conjunction with the radial forearm flap. Graft survival times varied from 21 to 179 days. Ten of 12 transplants showed rejection. In 2 of the 10, rejection could be reversed. Immunosuppressive therapy consisted of cyclosporin A, prednisone, monoclonal antibodies, and preoperative third-party blood transfusions. Monitoring of the microcirculation of the allograft could not provide a predictive value for transplant rejection. The first clinical signs of sensory and motor function recovery were detected after an average of 42 and 44 days, respectively. Indefinite uneventful allograft survival could not be established. Major complications such as sepsis, shock, and lymphoma development leading to death were encountered. The model, however, is technically feasible, and the results for functional recovery under immunosuppression are promising.

A protective thermoplast splint for the forearm and hand in nonhuman primates.

A custom-made thermoplastic splint was developed for the protection of the upper extremity after experimental surgery. It was used in 39 cases for a duration of 12-79 days. Complications were minimal and transient. The cast was easy to make, in one piece and inexpensive. Frequent removal for wound inspection was simple. This splint provides a good immobilization and protection of the arm and hand in the nonhuman primate.

Wheelchair racing: effects of rim diameter and speed on physiology and technique.

Effects of different hand rim diameters in wheelchair racing were studied with respect to physiological and technique parameters at five speed levels (N = 8 wheelchair sportsmen). In each of five subsequent 15-min exercise tests on a treadmill, a different sized hand rim was mounted to the rear wheels (0.3, 0.35, 0.38, 0.47, 0.56 m). In each test, speed increased with 0.83 m.s-1 every 3 min, starting at 0.83 m.s-1 and ranging up to 4.17 m.s-1 (slope: 0.5 degrees). Cardiorespiratory responses (ventilation, oxygen cost, heart rate, respiratory exchange ratio, mechanical efficiency) and timing data (cycle time, push time, recovery time, push angle, and work per cycle) were obtained every 3rd min, together with the movement pattern of trunk and arm segments. Clear effects of rim diameter and speed were seen for the physiological parameters (P less than 0.05). In physiological terms, D5 appeared the least beneficial, followed by D4. Moreover, increasing rim diameter had a significant effect on movement pattern of the upper arm in the sagittal as well the frontal plane of motion. However, no timing effects were seen with changing rim diameter. On the other hand, timing parameters varied markedly with speed, whereas the segmental excursions of the upper limb did not show a "speed-effect". In general, small hand rims show lower cardiorespiratory responses. This may be related to the decreased segmental excursions of the upper limb and the lower linear hand velocity. Together with a low rolling and air drag, heart rate, and oxygen cost, these are important prerequisites in racing events.(ABSTRACT TRUNCATED AT 250 WORDS)