The baromodulatory effect of gamma knife irradiation of the hypothalamus in the obese Zucker rat

OBJECTIVE: The aim of this study was to evaluate the effect on body weight set point over time of focused, subnecrotic doses of radiation via gamma knife (GK) to the hypothalamus of the genetically obese Zucker rat. METHODS: A total of 36 adolescent animals were used in this experiment and placed in 6 groups of 6. The genetically obese homozygous Zucker rat was used in 4 groups (n = 24) and received GK, subcutaneous cobalt protoporphyrin (CoPP), both treatments combined or sham treatment. The heterozygous lean Zucker rat was used in 2 control groups (n = 12) and received either GK or sham treatment. All animals were weighed at the beginning of the experiment and at weekly intervals for 34 weeks. GK irradiation was accomplished using a specially designed stereotactic frame and a total dose of 40 Gy was given to 2 nearby targets in the medial hypothalamus. The drug subgroups received weekly subcutaneous injections. All animals were housed in the same environment with unlimited access to food. RESULTS: There were no significant differences in weight between the lean GK and sham groups. For the obese cohort, beginning at week 7 and throughout the remainder of the experiment, there were significant and sustained reductions in weight set point for animals that received GK (p < 0.05) and CoPP (p < 0.05) compared to sham-treated animals. Curiously, there was no statistical difference between the combined treatment and sham subgroups, though there was a trend toward weight reduction (p < 0.10). With the exception of one animal in the obese GK cohort in which there was a small area of necrosis lateral to the target area, histopathological analysis failed to reveal any abnormalities. There were no gross behavioral abnormalities noted. CONCLUSION: Our experimental results suggest that a single dose of GK irradiation to the hypothalamus can produce sustained reduction in the weight set point without emaciation in adolescent animals. The effect of this treatment is comparable to a well-studied drug therapy with a metalloporphyrin. We hypothesize that this involves a resetting of the hypothalamic set point for body weight through an as yet uncharacterized neuromodulatory effect.     

Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy

Senataxin recently was identified as the mutated gene in ataxia-oculomotor apraxia 2, which is characterized by ataxia, oculomotor apraxia, and increased alpha-fetoprotein levels. In this study, we evaluated 24 ataxic patients from 10 French-Canadian families. All cases have a homogeneous phenotype consisting of a progressive ataxia appearing between 2 and 20 (mean age, 14.8) years of age with associated dysarthria, saccadic ocular pursuit, distal amyotrophy, sensory and motor neuropathy, and increased alpha-fetoprotein levels but absence of oculomotor apraxia. Linkage disequilibrium was observed with markers in the ataxia-oculomotor apraxia 2 locus on chromosome 9q34. We have identified four mutations in senataxin in the French-Canadian population including two novel missense mutations: the 5927T-->G mutation changes the leucine encoded by codon 1976 to an arginine in the helicase domain (L1976R), and the 193G-->A mutation changes a glutamic acid encoded by codon 65 into a lysine in the N-terminal domain of the protein (E65K). The common L1976R mutation is shared by 17 of 20 (85%) carrier chromosomes. The study of this large French-Canadian cohort better defines the phenotype of this ataxia and presents two novel mutations in senataxin including the more common founder mutation in the French-Canadian population.     

The epidemic of asbestos-related diseases in New Zealand

New Zealand is a small country with a big asbestos disease problem. The lack of action on warnings in the 1960s and 1970s has led to epidemics of mesothelioma and asbestosis, which can be clearly documented via the death and cancer registers. In addition, an uncertain number of lung cancers due to asbestos exposure has occurred. The epidemic started in the 1980s, and will eventually have cost the lives of at least 2000 to 3000 workers. Prevention against ongoing exposures from asbestos installed in buildings is essential, and another key issue for New Zealand is to ensure that fair workers' compensation is provided to all victims of asbestos diseases.     

Arterial stiffness is not improved in long-term use of estrogen

OBJECTIVE: The purpose of this study was to compare arterial stiffness in long-term users of estrogen who were postmenopausal, age-matched women who did not use estrogen, and women of fertile age. STUDY DESIGN: In this clinical cross-sectional study, carotid, femoral, and aortic stiffness (estimated as elastic modulus and stiffness beta index) were assessed by ultrasonic phase-locked echo-tracking in 17 women who were postmenopausal and who were treated with 17 beta-estradiol implants (mean age, 68.8 years; mean duration of treatment, 20 years), 17 age-matched (+/-1 year) untreated women, and 20 women in the fertile age period. RESULTS: Compared with women of fertile age, both postmenopausal groups had significantly higher stiffness elastic modulus and stiffness beta index (carotid, P <.001; femoral, P <.05; aorta, P <.001). However, for all 3 arteries, both stiffness indices were similar in estrogen users and nonusers and did not differ significantly. These results remained after an adjustment for systolic blood pressure, body mass index, and low-density lipoprotein cholesterol levels. CONCLUSION: These data indicate that the arterial stiffening that is related to aging/menopause is not substantially affected by long-term estrogen therapy.     

Incidence of femoral and tibial shaft fractures: Epidemiology 1950-1983 in Malmö, Sweden

We studied 362 fractures of the femur that had occurred during the years 1950-57 and 1973-83, and 849 fractures of the tibia that occurred during the the years 1950-55 and 1980-83. There was an increase in age-specific incidence over aged 60 years. The risk of low-energy femoral shaft fractures also had increased in elderly women. Both fracture types shifted their age- and sex-specific incidence in the direction of a fragility pattern. There was no in-crease in the incidence of tibial shaft fractures. Fracture type, site, and degree of displacement of the tibial fractures remained unchanged during the 30 years, i.e, they were predominantly distal, longitudinal fractures with moderate displacement.     

Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles

Due to their small size, nanoparticles have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technology. Despite the remarkable speed of development of nanoscience, relatively little is known about the interaction of nanoscale objects with living systems. In a biological fluid, proteins associate with nanoparticles, and the amount and presentation of the proteins on the surface of the particles leads to an in vivo response. Proteins compete for the nanoparticle "surface," leading to a protein "corona" that largely defines the biological identity of the particle. Thus, knowledge of rates, affinities, and stoichiometries of protein association with, and dissociation from, nanoparticles is important for understanding the nature of the particle surface seen by the functional machinery of cells. Here we develop approaches to study these parameters and apply them to plasma and simple model systems, albumin and fibrinogen. A series of copolymer nanoparticles are used with variation of size and composition (hydrophobicity). We show that isothermal titration calorimetry is suitable for studying the affinity and stoichiometry of protein binding to nanoparticles. We determine the rates of protein association and dissociation using surface plasmon resonance technology with nanoparticles that are thiol-linked to gold, and through size exclusion chromatography of protein-nanoparticle mixtures. This method is less perturbing than centrifugation, and is developed into a systematic methodology to isolate nanoparticle-associated proteins. The kinetic and equilibrium binding properties depend on protein identity as well as particle surface characteristics and size.     

Cellular injury and neuroinflammation in children with chronic intractable epilepsy

Objective  

To elucidate the presence and potential involvement of brain inflammation and cell death in neurological morbidity and intractable seizures in childhood epilepsy, we quantified cell death, astrocyte proliferation, microglial activation and cytokine release in brain tissue from patients who underwent epilepsy surgery.