Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease

<p>Abstract</p> <p>Backgound</p> <p>No disease modifying treatment currently exists for Huntington's disease (HD), a fatal neurodegenerative disorder characterized by the formation of amyloid-like aggregates of the mutated huntingtin protein. Curcumin is a naturally occurring polyphenolic compound with Congo red-like amyloid binding properties and the ability to cross the blood brain barrier. CAG140 mice, a knock-in (KI) mouse model of HD, display abnormal aggregates of mutant huntingtin and striatal transcriptional deficits, as well as early motor, cognitive and affective abnormalities, many months prior to exhibiting spontaneous gait deficits, decreased striatal volume, and neuronal loss. We have examined the ability of life-long dietary curcumin to improve the early pathological phenotype of CAG140 mice.</p> <p>Results</p> <p>KI mice fed a curcumin-containing diet since conception showed decreased huntingtin aggregates and increased striatal DARPP-32 and D1 receptor mRNAs, as well as an amelioration of rearing deficits. However, similar to other antioxidants, curcumin impaired rotarod behavior in both WT and KI mice and climbing in WT mice. These behavioral effects were also noted in WT C57Bl/6 J mice exposed to the same curcumin regime as adults. However, neither locomotor function, behavioral despair, muscle strength or food utilization were affected by curcumin in this latter study. The clinical significance of curcumin's impairment of motor performance in mice remains unclear because curcumin has an excellent blood chemistry and adverse event safety profile, even in the elderly and in patients with Alzheimer's disease.</p> <p>Conclusion</p> <p>Together with this clinical experience, the improvement in several transgene-dependent parameters by curcumin in our study supports a net beneficial effect of dietary curcumin in HD.</p

An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility

Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a three-generation Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5′ untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)–stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility.</p

Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential 15O-water (H2 15O) and 18F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals. These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia

Erros medicamentosos em unidade de terapia intensiva neonatal Medication errors in a neonatal intensive care unit

OBJETIVO: Determinar a incidência e o tipo de erros médicos em uma unidade de terapia intensiva neonatal e a relação entre o erro e o estado clínico do paciente. MÉTODOS: Revisamos os prontuários médicos, durante os primeiros 7 dias de hospitalização, de todos os recém-nascidos de alto risco admitidos por um período de 3 meses. RESULTADOS: Setenta e três pacientes foram admitidos durante o período de estudo. A média de peso de nascimento foi de 2.140 g (640-5.020 g), e a idade gestacional média foi de 34 semanas (25-40 semanas). Dos 73 prontuários analisados, 40 (55%) apresentaram um ou mais erros. Um total de 365 dias de hospitalização foi analisado, e 95 erros médicos foram detectados (um erro por 3,9 dias de hospitalização). O erro mais freqüente esteve associado com uso de medicamentos (84,2%). Uso de procedimentos terapêuticos (medicamentos, fototerapia, etc.) sem prescrição adequada no prontuário do paciente (erro de comissão) representou 7,4% dos erros, e a incidência de erros de omissão foi de 8,4%. A incidência de erros médicos foi significativamente maior em recém-nascidos com idade gestacional menor. CONCLUSÕES: A incidência de erros no cuidado de recém-nascidos de alto risco é elevada. Deve-se incentivar estratégias para melhorar a educação de profissionais da saúde envolvidos no cuidado e o desenvolvimento da cultura local, divulgando algoritmos claros e acessíveis para orientar o comportamento quando há ocorrência de erros.<br>OBJECTIVE: To determine the incidence and type of medical errors in a newborn intensive care unit and the relationship between the error and the patient's clinical status. METHODS: We reviewed the medical charts, during the first 7 days of hospitalization, of all high-risk newborn infants admitted for a period of 3 months. RESULTS: Seventy-three patients were admitted during the study period. Their mean birth weight was 2,140 g (640-5,020 g) and mean gestational age was 34 weeks (25-40 weeks). Of 73 medical charts analyzed, 40 (55%) had one or more errors. A total of 365 days of hospitalization was analyzed and 95 medical errors were detected (one error per 3.9 days of hospitalization). The most frequent error was associated with medication use (84.2%). Use of therapeutic procedures (drugs, phototherapy, etc.) without proper prescription in the patient's chart (commission error) accounted for 7.4% of the errors, and incidence of omission errors was 8.4%. Incidence of medical errors was significantly higher in newborn infants with lower gestational age. CONCLUSION: Incidence of errors in the care of high-risk newborn infants is elevated. Strategies to improve education of health professionals involved in the care and development of local culture by disseminating clear, accessible algorithms to guide behavior when errors occur must be encouraged

Levodopa-induced abnormal involuntary movements correlate with altered permeability of the blood-brain-barrier in the basal ganglia

Chronic levodopa treatment leads to the appearance of dyskinesia in the majority of Parkinson's disease patients. Neurovascular dysregulation in putaminal and pallidal regions is thought to be an underlying feature of this complication of treatment. We used microPET to study unilaterally lesioned 6-hydroxydopamine rats that developed levodopa-induced abnormal involuntary movements (AIMs) after three weeks of drug treatment. Animals were scanned with [15O]-labeled water and [18F]-fluorodeoxyglucose, to map regional cerebral blood flow and glucose metabolism, and with [11C]-isoaminobutyric acid (AIB), to assess blood-brain-barrier (BBB) permeability, following separate injections of levodopa or saline. Multitracer scan data were acquired in each animal before initiating levodopa treatment, and again following the period of daily drug administration. Significant dissociation of vasomotor and metabolic levodopa responses was seen in the striatum/globus pallidus (GP) of the lesioned hemisphere. These changes were accompanied by nearby increases in [11C]-AIB uptake in the ipsilateral GP, which correlated with AIMs scores. Histopathological analysis revealed high levels of microvascular nestin immunoreactivity in the same region. The findings demonstrate that regional flow-metabolism dissociation and increased BBB permeability are simultaneously induced by levodopa within areas of active microvascular remodeling, and that such changes correlate with the severity of dyskinesia