Intraarticular sodium hyaluronate injections in the Pond-Nuki experimental model of osteoarthritis in dogs. II. Morphological findings

The effect of the intraarticular sodium hyaluronate (HA) injection on the osteoarthritic knee joint has been evaluated in dogs using an experimental model of osteoarthritis induced by sectioning the anterior cruciate ligament. Seven weeks after surgery, the damage, graded according to Mankin's scale, was significantly reduced in knee joints treated with HA from the second week postsurgery compared to untreated joints. When intraarticular HA therapy was initiated after the seventh week, osteoarthritis progression was still reduced compared to controls. Both morphology and morphometry showed a beneficial effect of HA on the cartilage response to the damage, as well as a clearcut inhibitory effect on the development of the fibroblastlike cell layer on the articular cartilage in untreated joints. The beneficial effects on the cartilage integrity and response to osteoarthritic damage might be related to a primary effect of HA on the cartilage surface. However, these effects do not exclude the possibility that, in addition, HA might act on the synovial membrane by limiting the synovial reaction.     

Striatal dopamine transporter binding in patients with Parkinson's disease and severe occupational hydrocarbon exposure

We used ¹²³I-Ioflupane SPECT to study striatal dopamine transporter (DAT) binding in 36 Parkinson's disease (PD) patients with history of severe occupational exposure to hydrocarbons. Data were compared with 38 PD patients without exposure history as well as healthy controls. Both PD cohorts showed significant striatal uptake decrements compared with controls. We found significantly lower values in the whole striatum of exposed compared with non-exposed patients (0.83 ± 0.25 vs. 1.05 ± 0.39; P  = 0.004), more pronounced in the putamen (0.61 ± 0.24 vs. 0.85 ± 0.42; P  = 0.004). We conclude that severe occupational exposure to hydrocarbons may modify disease course and ultimately accelerate nigro-striatal denervation.     

Astrocytes expressing Vitamin D‐activating enzyme identify Parkinson’s disease

IntroductionAstrocytes are involved in Parkinson''s disease (PD) where they could contribute to α‐Synuclein pathology but also to neuroprotection via α‐Synuclein clearance. The molecular signature underlying their dual role is still elusive. Given that vitamin D has been recently suggested to be protective in neurodegeneration, the aim of our study was to investigate astrocyte and neuron vitamin D pathway alterations and their correlation with α‐Synuclein aggregates (ie, oligomers and fibrils) in human brain obtained from PD patients.MethodsThe expression of vitamin D pathway components CYP27B1, CYP24A1, and VDR was examined in brains obtained from PD patients (Braak stage 6; n = 9) and control subjects (n = 4). We also exploited proximity ligation assay to identified toxic α‐Synuclein oligomers in human astrocytes.ResultsWe found that vitamin D‐activating enzyme CYP27B1 identified a subpopulation of astrocytes exclusively in PD patients. CYP27B1 positive astrocytes could display neuroprotective features as they sequester α‐Synuclein oligomers and are associated with Lewy body negative neurons.ConclusionThe presence of CYP27B1 astrocytes distinguishes PD patients and suggests their contribution to protect neurons and to ameliorate neuropathological traits.     

Tuberculosis,Fiji, 2002–2013

During 2002–2013, a total of 1,890 tuberculosis cases were recorded in Fiji. Notification rates per 100,000 population increased from 17.4 cases in 2002 to 28.4 in 2013. Older persons were most affected, but tuberculosis also increased sharply in persons 25–44 years of age.     

Novel membrane-bound GM-CSF vaccines for the treatment of cancer: generation and evaluation of mbGM-CSF mouse B16F10 melanoma cell vaccine

Cancer vaccines composed of tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) are currently being clinically evaluated. To enhance the immunogenicity of GM-CSF-secreting tumor cell vaccines, a novel approach expressing GM-CSF as a membrane-bound form (mbGM-CSF) on the tumor cell surface was investigated. The intent was to enhance antigen presentation by increasing interactions between the tumor cell lines in the vaccine and GM-CSF receptor positive antigen presenting cells (APC), notably the patient's Langerhans cells residing within the intradermal injection site. B16.F10 cells engineered to express either membrane-bound or secreted GM-CSF were compared in the B16.F10 mouse melanoma model. We observed that mbGM-CSF on the tumor cell surface retarded growth and induced protective immunity to subsequent wild-type tumor challenge more effectively than tumor cells secreting GM-CSF. Vaccination with irradiated mbGM-CSF B16.F10 also provided strong protection from wild-type tumor challenge, improved therapeutic effects against established tumors, and retarded lung metastases. These results demonstrate that mbGM-CSF B16.F10 cells can induce strong systemic immunity that protects against and therapeutically treats B16.F10 melanoma more effectively than analogous vaccines containing only secreted GM-CSF. These data warrant further development and clinical testing of mbGM-CSF tumor cell vaccines.     

Anthropometric indices of fat distribution and cardiometabolic risk in Parkinson's disease

Background &; aimsTo investigate the association between anthropometric indices of body fat distribution and cardiometabolic risk factors in a population of Parkinson’s disease (PD) patients.Methods &; resultsOne hundred and fifty-seven PD patients (57.3% males) were studied measuring: waist circumference (WC), waist-hip ratio (WHR), waist-to-height ratio (WtHR), body fat percentage (BF%) by impedance, fasting glucose, serum lipids. Information was collected also on diabetes, hypertension and metabolic syndrome (MetS). Increased cardiometabolic risk was defined by ≥2 MetS component traits other than abdominal adiposity. In the whole population, prevalence of overweight and obesity were 35.0% and 19.2%, respectively. However, prevalence of MetS and elevated cardiometabolic risk were 14.6% and 18.5%, respectively. Prevalence was similar between genders, with one exception: adverse fat distribution according to WC and WHR was more common in females (P < 0.001). Using a multivariable model (adjustments: age, smoking status and disease duration), indices were highly correlated with BF% in both genders. WC and WtHR were associated with the number of MetS criteria and elevated risk. The only cardiometabolic parameters associated with anthropometric indices were HDL in men and triglycerides in women. After adjusting also for BMI all the associations found with anthropometric indices disappeared.ConclusionsDespite their correlation with BF%, anthropometric indices of body fat distribution appear to poorly account for the reduced cardiometabolic risk of the PD patient. This finding suggests a low metabolic activity within the adipose tissue. The implications of fat distribution on the cardiometabolic risk of PD patients clearly deserves further investigation.     

Oral administration of growth hormone (GH)-releasing peptide stimulates GH secretion in normal men.

Intravenous infusions of the synthetic hexapeptide GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2; GHRP) specifically stimulate GH release in man. To determine whether orally administered GHRP stimulates GH secretion, 10 normal men received oral doses of placebo, 30, 100, and 300 micrograms/kg GHRP, and an iv injection of 1.0 micrograms/kg GHRP at weekly intervals in a single blind, randomized design. Serum GH concentrations were measured in blood samples obtained at 5-min intervals for 1 h (0700-0800 h) before and 4 h (0800-1200 h) after each dose. Mean (+/- SE) peak GH concentrations were 4.0 +/- 1.5, 5.2 +/- 1.6, 9.2 +/- 3.3, 18 +/- 3.7, and 26 +/- 5.6 micrograms/L for placebo; 30, 100, and 300 micrograms/kg oral GHRP; and 1 micrograms/kg iv GHRP, respectively; mean 4-h (0800-1200 h) integrated GH concentrations were 312 +/- 109, 406 +/- 159, 698 +/- 284, 1264 +/- 303, and 1443 +/- 298 min.micrograms/L, respectively. To analyze changes in the pulsatile pattern and amount of GH secretion after the administration of GHRP, a waveform-independent deconvolution method was used to estimate GH secretion rates. Variable increases in GH secretion after placebo and GHRP treatments were observed. Despite this variability, weighted least squares linear regression revealed that increasing doses of oral GHRP progressively stimulated GH secretion (P less than 0.005); similar relationships were observed for the peak GH concentration and 4-h integrated GH concentrations. The GH responses to oral GHRP (300 micrograms/kg) and iv GHRP (1 microgram/kg) were significantly greater than that to placebo (P less than 0.05) and were comparable in magnitude. Pairwise comparisons revealed that increases in GH concentrations and secretion rates after the 30 and 100 micrograms/kg oral doses of GHRP were not significantly different from those after placebo. The increase in GH secretion after GHRP treatment was accounted for entirely by an increase in the amplitude of GH secretory events, as no significant increase in the number of GH secretory pulses was observed. The onset and duration of action of GHRP were analyzed by a proportional hazards general linear regression model. Intravenous GHRP had a more rapid onset of action than all doses of oral GHRP (P less than 0.02). Increasing doses of oral GHRP resulted in earlier GH responses (P = 0.006). However, the duration of the GH response was similar for iv GHRP and all doses of oral GHRP, averaging 120-150 min.(ABSTRACT TRUNCATED AT 400 WORDS)     

The NIEHS Environmental Health Sciences Data Resource Portal: placing advanced technologies in service to vulnerable communities

BACKGROUND: Two devastating hurricanes ripped across the Gulf Coast of the United States during 2005. The effects of Hurricane Katrina were especially severe: the human and environmental health impacts on New Orleans, Louisiana, and other Gulf Coast communities will be felt for decades to come. The Federal Emergency Management Agency (FEMA) estimates that Katrina's destruction disrupted the lives of roughly 650,000 Americans. Over 1,300 people died. The projected economic costs for recovery and reconstruction are likely to exceed $125 billion. OBJECTIVES: The NIEHS (National Institute of Environmental Health Sciences) Portal aims to provide decision makers with the data, information, and the tools they need to a) monitor human and environmental health impacts of disasters; b) assess and reduce human exposures to contaminants; and c) develop science-based remediation, rebuilding, and repopulation strategies. METHODS: The NIEHS Portal combines advances in geographic information systems (GIS), data mining/integration, and visualization technologies through new forms of grid-based (distributed, web-accessible) cyberinfrastructure. RESULTS: The scale and complexity of the problems presented by Hurricane Katrina made it evident that no stakeholder alone could tackle them and that there is a need for greater collaboration. The NIEHS Portal provides a collaboration-enabling, information-laden base necessary to respond to environmental health concerns in the Gulf Coast region while advancing integrative multidisciplinary research. CONCLUSIONS: The NIEHS Portal is poised to serve as a national resource to track environmental hazards following natural and man-made disasters, focus medical and environmental response and recovery resources in areas of greatest need, and function as a test bed for technologies that will help advance environmental health sciences research into the modern scientific and computing era.     

'Senile' myeloma: a possible variant form of multiple myeloma

Fifty-four patients were recognized as having multiple myeloma after the coincidental finding of a serum and/or urine M component on agarose gel electrophoresis during a survey for monoclonal gammopathies of a large random hospital population sample over 70 yr of age. Analysis of the presenting features and the clinical characteristics revealed that about two-thirds of the myeloma patients over 80 yr were asymptomatic at the time of the discovery of their monoclonal gammopathy. Follow-up studies and serial evaluations of changes in the myeloma cell mass without chemotherapy showed a subset of the older patients exhibiting a distinct pattern of slow tumor growth. The results of the study would suggest the possible existence of a variant form in the advanced age group of myeloma patients. This 'senile' type of myeloma would appear to be characterized primarily by non-specific presenting features, a fairly symptom-poor status, and a relatively protracted and benign course without chemotherapy.     

Loss‐of‐Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association

The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs’ malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next‐generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild‐type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss‐of‐function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death.