Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo

To determine the stability of beta-amyloid peptide (Abeta) and the glial and neuronal changes induced by Abeta in the CNS in vivo, we made single injections of fibrillar Abeta (fAbeta), soluble Abeta (sAbeta), or vehicle into the rat striatum. Injected fAbeta is stable in vivo for at least 30 d after injection, whereas sAbeta is primarily cleared within 1 d. After injection of fAbeta, microglia phagocytize fAbeta aggregates, whereas nearby astrocytes form a virtual wall between fAbeta-containing microglia and the surrounding neuropil. Similar glial changes are not observed after sAbeta injection. Microglia and astrocytes near the injected fAbeta show a significant increase in inducible nitric oxide synthase (iNOS) expression compared with that seen with sAbeta or vehicle injection. Injection of fAbeta but not sAbeta or vehicle induces a significant loss of parvalbumin- and neuronal nitric oxide synthase-immunoreactive neurons, whereas the number of calbindin-immunoreactive neurons remains unchanged. These data demonstrate that fAbeta is remarkably stable in the CNS in vivo and suggest that fAbeta neurotoxicity is mediated in large part by factors released from activated microglia and astrocytes, as opposed to direct interaction between Abeta fibrils and neurons.     

Short-term exposure to JP-8 jet fuel results in long-term immunotoxicity

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and decreased sensorimotor speed. The United States Air Force has decided to implement the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Exposure to potential environment toxicants such as JP-8 may have significant effects on host physiology. Previous studies in mice have shown that short-term, low concentration JP-8 exposure had significant effects on the immune system; e.g., decreased viable immune cell numbers, decreased immune organ weights, and loss on immune function that persisted for extended periods of time (i.e., up to 4 weeks post-exposure). Previous studies have shown that JP-8 induced pulmonary dysfunction was associated with a decrease in levels of the neuropeptide substance P (SP) in lung lavage fluids. It was found that administration of aerosolized SP was able to protect exposed animals from such JP-8 induced pulmonary changes. In the current study, aerosolized SP was analyzed for its effects on JP-i induced immunotoxicity in exposed mice. It was observed that SP administration could protect JP-8 exposed animals from losses of viable immune cell numbers, but not losses in immune organ weights. Further, exposure of animals to SP inhibitors generally increased the immunotoxicity of JP-8 exposure. SP appeared to act on all immune cell populations equally as analyzed by flow cytometry, as no one immune cell population appeared to be preferentially protected by SP. Also, SP administration was capable of protecting JP-8 exposed animals from loss of immune function at all concentrations of JP-8 utilized (250-2500 mg/m3). Significantly, SP only needed to be administered for 15 minutes after JP-8 exposure, and was active at both 1 microM and 1 nM concentrations. Thus, SP administration appears to be a relatively simple and efficient means to reverse the immunotoxicity due to hydrocarbon exposure.     

Sexual functioning after treatment for testicular cancer: comparison of treatment modalities

BACKGROUND: This retrospective study evaluates changes in sexual functioning after treatment for testicular cancer and investigates whether there is a relationship with different treatment modalities. METHODS: A self-reported questionnaire was sent to 337 men who had been treated for testicular cancer at the University Hospital Groningen between 1977 and 1994. Medical information was obtained from the patient records. RESULTS: A response was received from 287 men (85%); 264 patients were included in this study (78%). The mean patient age at follow-up was 37.7 years (range, 17-71 years). The mean follow-up period was 6.7 years (range, 0.25-18 years). Decrease in sexual functions was reported by 40% of patients (decrease in libido: 19%; arousal: 12% erection: 12.5%; orgasm: 19%; and ejaculation: 26%). Moreover, 23.5% of patients responding reported decreased sexual activity and 12.5% were dissatisfied with their sexual functioning. Patients with Stage II-IV nonseminoma who had been treated with polychemotherapy (PCT) with or without resection of residual retroperitoneal tumor mass (RRRTM) (PCT +/- RRRTM) reported a significantly sharper decrease in sexual functioning than patients who had been followed with a wait-and-see policy (W & S) (Stage I nonseminoma patients). It was noteworthy that patients treated by PCT alone reported more sharply decreased sexual functioning than patients treated by PCT + RRRTM. Patients treated by radiotherapy (Stage I-IIA seminoma) did not report findings significantly different from the W & S group. CONCLUSIONS: Testicular cancer patients are at risk for reduced sexual functioning, especially when treated by chemotherapy, with or without resection of residual tumor. Although chemotherapy may influence somatic aspects of sexual functioning, it appears that psychologic factors arising from the confrontation with testicular cancer play a strongly mediating (if not determining) role.     

Interaction of the renin-angiotensin system, bradykinin and sympathetic nerves with cholinergic transmission in the rat isolated trachea

1. The present study was undertaken to investigate the interaction of the renin-angiotensin system (RAS), bradykinin and the sympathetic nervous system with cholinergic transmission in the rat airways. Experiments were performed on epithelium-intact and epithelium-denuded preparations of rat isolated trachea which had been incubated with [3H]-choline to incorporate [3H]-acetylcholine into the cholinergic transmitter stores. Tracheal preparations were subjected to electrical field stimulation (trains of 1 ms pulses, 5 Hz, 15 V) and the stimulation-induced (S-I) efflux taken as an index of transmitter acetylcholine release. 2. In both epithelium-intact and epithelium-denuded tracheal preparations, the alpha 2-adrenoceptor agonist UK14304 (0.1 and 1 microM) inhibited the S-I efflux, in a concentration-dependent manner. The inhibition of S-I efflux produced by UK14304 (1 microM) was antagonized by the selective alpha 2-adrenoceptor antagonist idazoxan (0.3 microM). Idazoxan (0.3 microM) alone had no effect on the S-I efflux. 3. Angiotensin II (0.1 and 1 microM) was without effect on the S-I efflux in either epithelium-intact or epithelium-denuded tracheal preparations. When angiotensin-converting enzyme was inhibited by perindoprilat (10 microM), angiotensin II (1 microM) was also without effect on the S-I efflux. Similarly, in the presence of idazoxan (0.3 microM), to block prejunctional alpha 2-adrenoceptors, angiotensin II (0.1 and 1 microM) did not alter the S-I efflux. When added alone, perindoprilat (10 microM) did not alter the S-I efflux. 4. In epithelium-denuded preparations, bradykinin (0.01-1 microM) inhibited the S-I efflux. In epithelium-intact preparations, there was also a tendency for bradykinin (0.1 and 1 microM) to inhibit the S-I efflux but this was not statistically significant. However, when angiotensin-converting enzyme and neutral endopeptidase were inhibited by perindoprilat (10 microM) and phosphoramidon (1 microM), respectively, bradykinin (1 microM) significantly inhibited the S-I efflux in epithelium-intact preparations as well as in epithelium-denuded preparations. The inhibition of the S-I efflux produced by bradykinin, in the combined presence of perindoprilat (10 microM) and phosphoramidon (1 microM), was unaffected by the additional presence of the cyclo-oxygenase inhibitor indomethacin (10 microM) and/or the nitric oxide synthase inhibitor NG-nitro-L-arginine (100 microM), in either epithelium-intact or epithelium-denuded preparations. 5. In conclusion, the findings of the present study suggest that airway parasympathetic nerves are endowed with alpha 2-adrenoceptors which subserve inhibition of transmitter acetylcholine release. Under the present conditions, however, transmitter acetylcholine release is not subject to transneuronal modulation by noradrenaline released from adjacent sympathetic nerves in the airways. Moreover, angiotensin II and perindoprilat do not appear to modulate acetylcholine release from parasympathetic nerves of the airways. In contrast, bradykinin inhibits acetylcholine release from airway parasympathetic nerves but this action of bradykinin is limited by the activity of epithelial angiotensin-converting enzyme and/or neutral endopeptidase. The inhibitory action of bradykinin on cholinergic transmission in the airways does not appear to involve the liberation of prostaglandins or nitric oxide.     

Private health insurance coverage and disability among older Americans

OBJECTIVES: This study examines the relationship between the lack of private supplemental health insurance coverage and the development of disability among adults aged 65 and older. METHODS: Data are from the baseline and six follow-up waves of the Duke Established Populations for Epidemiologic Studies of the Elderly survey (N = 4,000). Discrete-time hazard models were used to estimate the impact of insurance coverage and other risk factors on the incidence of disability among those unimpaired at baseline. RESULTS: Controlling for education, income, and other potential confounders, the odds of developing disability were 35-49% higher among those without private coverage. Insurance coverage also statistically explained part of the increased risk of disability among low-income persons. DISCUSSION: The results indicate that changes in health insurance coverage as well as in individual behaviors may be needed to reduce disability generally and disability among the socioeconomically disadvantaged, in particular.     

HLA-B27 does not affect invasion of arthritogenic bacteria into human cells

OBJECTIVE: To investigate the effect of HLA-B27 expression on entry of Salmonella typhimurium and Yersinia enterocolitica into human cells. METHODS: We performed standard bacterial invasion assays with S. typhimurium and Y enterocolitica to analyze isogenic pairs of HeLa (epithelial), U937 (promonocyte), C1R (B lymphocyte), and Jurkat (T lymphocyte) human cell lines and their respective HLA-B27 transfectants. Invasion of peripheral blood derived T lymphocytes, monocytes, and B lymphocytes/dendritic cell fraction (corresponding to peripheral blood cells depleted of monocytes and T lymphocytes) from patients with ankylosing spondylitis and healthy donors was also analyzed. The percentage of internalized bacteria was quantified, and the differences between HLA-B27 positive and negative samples were compared. RESULTS: The percentages of intracellular S. typhimurium and Y enterocolitica in HeLa, U937, and C1R with or without B27 were not statistically different (independent t test). We also found that the percentage of internalized bacteria did not differ significantly between HLA-B27 positive and negative samples in the different populations of peripheral blood derived cells. CONCLUSION: The presence of HLA-B27 on the surface of human cells does not alter the degree of bacterial invasion into either cultured human cell lines or peripheral blood derived human cells, and the influence of HLA-B27 expression on bacterial invasion should not be implicated in the pathogenesis of reactive arthritis related to Salmonella and Yersinia.     

Optimizing sound features for cortical neurons

The brain's cerebral cortex decomposes visual images into information about oriented edges, direction and velocity information, and color. How does the cortex decompose perceived sounds? A reverse correlation technique demonstrates that neurons in the primary auditory cortex of the awake primate have complex patterns of sound-feature selectivity that indicate sensitivity to stimulus edges in frequency or in time, stimulus transitions in frequency or intensity, and feature conjunctions. This allows the creation of classes of stimuli matched to the processing characteristics of auditory cortical neurons. Stimuli designed for a particular neuron's preferred feature pattern can drive that neuron with higher sustained firing rates than have typically been recorded with simple stimuli. These data suggest that the cortex decomposes an auditory scene into component parts using a feature-processing system reminiscent of that used for the cortical decomposition of visual images.