Polyglutamine aggregation in Huntington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation.

AIMS: Polyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease-specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone-mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the polyQ disease spinocerebellar ataxia type 3 (SCA3) suggested a distinct pattern of protein aggregation and PQC dysregulation. METHODS: To corroborate these findings we have investigated immunohistochemically stained 5 µm sections from different brain areas of Huntington's disease (HD) and SCA3 patients. RESULTS: Irrespective of disease and brain region, we observed peri- and intranuclear polyQ protein aggregates. A subset of neurones with intranuclear inclusions bodies exhibited signs of proteasomal dysfunction, up-regulation of HSPA1A and re-distribution of DNAJB1. The extent of the observed effects varied depending on brain area and disease protein. CONCLUSIONS: Our results suggest a common sequence, in which formation of cytoplasmic and nuclear inclusions precede proteasomal impairment and induction of the cellular stress response. Clearly, impairment of the PQC is not the primary cause for inclusion formation, but rather a consequence that might contribute to neuronal dysfunction and death. Notably, the inclusion pathology is not directly correlated to the severity of the degeneration in different areas, implying that different populations of neurones respond to polyQ aggregation with varying efficacy and that protein aggregation outside the neuronal perikaryon (e.g. axonal aggregates) or other effects of polyQ aggregation, which are more difficult to visualize, may contribute to neurodegeneration.

Needle stick injuries among nurses in sub-Saharan Africa.

OBJECTIVES: Despite a heavy burden of HIV/AIDS and other blood borne infections, few studies have investigated needle stick injuries in sub-Saharan Africa. We conducted a cross-sectional study at Mulago national referral hospital in Kampala, Uganda, to assess the occurrence and risk factors of needle stick injuries among nurses and midwives. METHODS: A total of 526 nurses and midwives involved in the direct day-to-day management of patients answered a questionnaire inquiring about occurrence of needle stick injuries and about potential predictors, including work experience, work load, working habits, training, and risk behaviour. RESULTS: A 57% of the nurses and midwives had experienced at least one needle stick injury in the last year. Only 18% had not experienced any such injury in their entire career. The rate of needle stick injuries was 4.2 per person-year. Multiple logistic regression analysis showed that the most important risk factor for needle stick injuries was lack of training on such injuries (OR 5.72, 95% CI 3.41-9.62). Other important risk factors included working for more than 40 h/week (OR 1.90, 95% CI 1.20-3.31), recapping needles most of the time (OR 1.78, 95% CI 1.11-2.86), and not using gloves when handling needles (OR 1.91, 95% CI 1.10-3.32). CONCLUSIONS: The study showed a high rate of needle stick injuries among nurses and midwives working in Uganda. The strongest predictor for needle stick injuries was lack of training. Other important risk factors were related to long working hours, working habits, and experience.

A new animal model of venous thrombosis in rats with low flow conditions in the venous blood stream.

The aims of the present investigation were to develop a new venous thrombosis animal model with low flow conditions in the venous blood stream and then evaluate this model for testing new anticoagulants. In this model, the vena cava of rats was narrowed with a Doppler flow probe, blood flow velocity continuously recorded and thrombus formation initiated by thromboplastin infusion. Sixty-five minutes following thromboplastin infusion the animals were sacrificed and the following parameters measured: thrombus wet weight, fibrinopeptide A (FpA), activated partial thromboplastin time and platelet number. The new model was evaluated with aspirin, a PGI2 mimetic, heparin and a soluble thrombomodulin analogue. Without thromboplastin infusion no thrombus formation or reduction of blood flow was observed. Controls receiving thromboplastin infusion developed a thrombus, blood flow was arrested, platelet number decreased and FpA was elevated. In contrast, animals pretreated with anticoagulants maintained a residual flow, while thrombus weight, thrombocytopenia and FpA elevation were reduced. The antiplatelet agents were not effective. This study demonstrates that, under low flow conditions, only a combination of blood flow reduction with a hypercoagulable state results in venous thrombus formation. This improved model of venous thrombosis more closely resembles the clinical situation and is applicable for testing anticoagulants.

Metal cluster chemistry: Structure and stereochemistry in the polynuclear rhodium hydrides H(n)Rh(n)[P(OR)(3)](2n).

Crystallographic analyses of x-ray and neutron diffraction data have provided a definitive structural representation of {HRh[P(O-i-C(3)H(7))(3)](2)}(2) and {HRh[P(OCH(3))(3)](2)}(3). These polynuclear hydrides are generated from square planar H(2)Rh[P(OR)(3)](2) units by edge (hydrogen atom) sharing and by vertex (hydrogen atom) sharing to form the dimeric and trimeric structures, respectively. The square-planar units are held together through four-center and three-center two-electron Rh-H-Rh bonds in the dimer and trimer, respectively. The dimer and trimer molecules each add one molecule of hydrogen to form H[(i-C(3)H(7)O)(3)P](2)RhH(3)Rh [P(O-i-C(3)H(7))(3)](2) and H(5)Rh(3)[P(OCH(3))(3)](6), respectively. NMR spectral information has served to define the stereochemical features of these polyhydrides. The significance of this chemistry in the metal cluster-metal surface analogy is described.