Methamphetamine sensitization attenuates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus.

Methamphetamine (MA) use is associated with activation of microglia and, at high doses, can induce neurotoxicity. Given the changes in the neuroinflammatory environment associated with MA, we investigated whether MA sensitization, a model of stimulant psychosis and an indicator of drug addiction, would interfere with the thermoregulatory and neuroinflammatory response to a subsequent peripheral immune stimulus. C57BL6/J mice were given either 1 mg/kg MA or saline i.p. once a day for 5 days to produce behavioral sensitization. Seventy-two hours following the last MA injection, 100 microg/kg LPS or saline was co-administered with 1 mg/kg MA or saline and blood and brains were collected. Here we report that while co-administration of LPS and MA did not affect the LPS-induced increase in central cytokine mRNA, mice sensitized to MA showed an attenuated central response to LPS. Interestingly, the peripheral response to LPS was not affected by MA sensitization. Plasma cytokines increased similarly in all groups after LPS. Further, c-Fos expression in the nucleus of the solitary tract did not differ between groups, suggesting that the periphery-to-brain immune signal is intact in MA-sensitized mice and that the deficit lies in the central cytokine compartment. We also show that MA sensitization decreased LPS- or acute MA-induced microglial Iba1 expression compared to non-sensitized mice. Taken together, these data show that MA sensitization interferes with the normal central immune response, preventing the CNS from efficiently responding to signals from the peripheral immune system.

Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation.

The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation in the periphery and brain, but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the present study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3-mo-old) and middle-aged (12-mo-old) wild-type (IL-10(+/+)) and IL-10-deficient (IL-10(-/-)) mice after intraperitoneal injection of lipopolysaccharide (LPS) or saline. No age-related differences were observed; therefore, data from the two ages were pooled and analyzed to determine effects of genotype and treatment. LPS treatment increased IL-1beta, IL-6, and TNFalpha mRNA in all brain areas examined in IL-10(+/+) and IL-10(-/-) mice, but to a greater extent and for a longer time in IL-10(-/-) mice. Plasma IL-1beta and IL-6 were increased similarly in IL-10(+/+) and IL-10(-/-) mice 4 h after LPS but remained elevated longer in IL-10(-/-) mice, whereas TNFalpha was higher in IL-10(-/-) mice throughout after LPS treatment. Motor performance and motor learning in IL-10(+/+) mice were not affected by LPS treatment; however, both were reduced in IL-10(-/-) mice treated with LPS compared with those treated with saline. Furthermore, although LPS reduced the time to fatigue in IL-10(+/+) and IL-10(-/-) mice, the effects were exacerbated in IL-10(-/-) mice. Thus the increased brain and peripheral inflammation induced by LPS in IL-10(-/-) mice was associated with increased coordination deficits and fatigue. These data suggest that IL-10 may inhibit motor deficits and fatigue associated with peripheral infections via its anti-inflammatory effects.

Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice.

Peripheral immune stimulation as well as certain types of psychological stress increases brain levels of inflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6 and tumor necrosis factor alpha (TNFalpha). We have demonstrated that aged mice show greater increases in central inflammatory cytokines, as well as greater cognitive deficits, compared to adults in response to peripheral lipopolysaccharide (LPS) administration. Because aged mice are typically more sensitive to systemic stressors such as LPS, and certain psychological stressors induce physiological responses similar to those that follow LPS, we hypothesized that aged mice would be more sensitive to the physiological and cognitive effects of mild stress than adult mice. Here, adult (3-5 months) and aged (22-23 months) male BALB/c mice were trained in the Morris water maze for 5 days. Mice were then exposed to a mild restraint stress of 30 min before being tested in a working memory version of the water maze over a 3-day period. On day 4 mice were stressed and then killed for collection of blood and brain. In a separate group of animals, mice were killed immediately after one, two or three 30 min restraint sessions and blood was collected for peripheral corticosterone and cytokine protein measurement, and brains were dissected for central cytokine mRNA measurement. Stress disrupted spatial working memory in both adult and aged mice but to a much greater extent in the aged mice. In addition, aged mice showed an increase in stress-induced expression of hippocampal IL-1beta mRNA and MHC class II protein compared to non-stressed controls while expression in adult mice was unaffected by stress. These data show that aged mice are more sensitive to both the cognitive and inflammatory effects of mild stress than are adult mice and suggest a possible role for IL-1beta.

LPS fever in old rats depends on the ambient temperature.

In earlier work, we found that following lipopolysaccharide (LPS) injection at an ambient temperature (Ta) of 23 degrees C, old rats developed blunted fevers compared with those of young rats. However, the old rats did become febrile if placed in a thermally graded alleyway: they spent more time in the warm end of the gradient and developed a significantly higher body temperature (Tb) than they did following saline injections. In the present experiments, we maintained old and young rats for 3 days at 20 or 31 degrees C (the Ta preferred by the old rats given LPS). After LPS (50 microg/kg ip), the young rats developed equivalent fevers at both Ta's. The old rats developed fevers that were equivalent to those of the young rats at 31 degrees C. At 20 degrees C, their fever was significantly lower. These results suggest that Ta plays a decisive role in the ability of old rats to mount febrile responses.

Examining the impact of administration medium on examine perceptions and attitudes.

The present study explored the impact of administration medium on examinees' affective reactions. The research compared managers' reactions with 3 versions of the Conflict Resolution Skills Assessment (J. B. Olson-Buchanan et al., 1998) that were identical in content but varied in terms of the level of technology used: a paper-and-pencil form, a written form administered by computer (i.e., a computerized page-turner), and a multimedia form administered by computer. Managers completing the multimedia assessment perceived the assessment as more face valid and had more positive attitudes, relative to managers who completed the other 2 assessments. Computerization, however, was not enough to make a difference; instead, it was the multimedia nature of the computer presentation that resulted in the most positive affective reactions. Study limitations and implications for research and practice are discussed.

Systematic investigation of physiological correlates of motion sickness induced by viewing an optokinetic rotating drum.

PURPOSE: This study investigated the physiological correlates of motion sickness provoked by viewing an optokinetic rotating drum. METHOD: A total of 52 subjects viewed an optokinetic rotating drum for 16 min. Subjective symptoms of motion sickness (SSMS) and ratings of over-all sickness were measured during the drum rotation. Electrogastrogram (EGG), electroencephalogram (EEG), electrocardiogram, and skin conductance were measured as physiological correlates of motion sickness. RESULTS: Analysis by Pearson's correlation showed that the subjects who had higher scores of SSMS during the drum rotation generated the following: a) a higher rating of over-all sickness (r = 0.76); b) a higher ratio of spectral power of EGG at 4-9 cycles per minute (cpm) between drum rotation and baseline periods (r = 0.63); c) a higher net percent increase of spectral power in the EEG frequency band 0.5-4 Hz between drum rotation and baseline periods on C3 (r = 0.29) and C4 (r = 0.31); d) a higher ratio of spectral power of EEG frequency band 0.5-4 Hz between drum rotation and baseline periods on C3 (r = 0.31); and e) a higher level of net increase in skin conductance from baseline to drum rotation (r = 0.30). CONCLUSION: The increase of EGG at 4-9 cpm activity, gastric tachyarrhythmia, is the most sensitive physiological index of the severity of symptoms of motion sickness.

Xeromammography.

Early detection of breast malignancy can insure more effective treatment and a more likely cure. The early detection of cancer of the breast has become the most vital factor in determining successful treatment, arresting the malignancy before it spreads to other organs. Women do not die from breast cancer--it is the cancer's invasion throughout the body and its affect on vital organ systems which ultimately kills the patient. It is, therefore, understandable why the earliest possible detection offers any woman the most favorable prognosis. Evaluation of the female breast using xeromammography techniques provides us with the technical capability of detecting breast cancer at the earliest and, in the majority of women, the most favorable stage. Using today's reduced dose techniques, any proposed risk, hypothetical or real, becomes insignificant.

Organochlorine contamination in shorebirds from Washington state and the significance for their falcon predators.

Arctic-breeding shorebirds collected in western Washington state during winter and spring, and a comparative sample collected in coastal California during the winter were analyzed for organochlorine contaminants to determine the potential impact of these residues on populations of peregrine falcons (Falco peregrinus) and merlins (F. columbarius) which prey upon shorebirds in western Washington. Dunlins (Calidris alpina), an important winter prey for falcons in western Washington, were collected between 1975 and 1981. During winter 1980-81, dunlins carried low organochlorine residues; DDE levels ranged from 0.01 to 1.2 ppm, and PCB levels ranged from 0.02 to 0.82 ppm (wet weight). Levels of other organochlorine contaminants (HCB, Chlordane compounds, Dieldrin, and Heptachlor Epoxide), analyzed in a subsample of dunlins, were consistently lower than DDE and PCB levels, and ranged from 0.001 to 0.22 ppm (wet weight). Dunlins in western Washington did not significantly increase their DDE or PCB burdens over the 1980-81 winter. A decline in DDE residues between 1978 and 1981 was noted, and declines in PCB residues from both 1975 and 1978 to 1980-81 were noted. Residues in other wintering shorebirds from western Washington were similar. Wintering sanderlings (Calidris alba) from California, revealed much higher DDE contamination than in Washington (up to 32 ppm, wet weight). Spring migrant shorebirds in western Washington contained both low and very high DDE residues (up to 417 ppm, wet weight). There is evidence suggesting these high DDE concentrations are accumulated along the Pacific coast of North America.

Association of chronic cystic mastopathy, xeromammographic patterns, and cancer.

The Breast Cancer Demonstration and Detection Project in Louisville (BCDDP-L) screened 10,128 women for cancer. From this screening, another project evolved wherein those patients diagnosed as having chronic cystic mastopathy (CCM) were followed over a 10-year period to evaluate any association between CCM and breast cancer. In all, 1396 breast biopsies were performed, with 165 cancers being diagnosed either on initial screening or during subsequent years. Three of these are excluded, since histopathologic slides could not be obtained for central review. Of this group, cancer was associated with CCM in 116 specimens and without CCM in 46 specimens. One subset of 355 patients with biopsy-proven CCM but no breast cancer was followed for 6 to 12 years, for a total of 2443.5 woman-years of observation. Within this subset, a total of only four cancers occurred (4 cancers/2443.5 woman-years for 0.00164 cancers/woman-years). This incidence is not significantly different from the expected value. However, an estimate is provided as to the power of the test that could be obtained from a larger sample size derived from other BCDDPs. This group of 355 women was sorted into subsets by establishing a matrix matching ten histopathologic subdivisions of CCM against six subdivisions of Wolfe's xeromammographic (XM) patterns. The numbers of cancers in each cell of this matrix is reported. The results found no concentration of these four cancers in this matrix.

The association of pathologic and mammographic characteristics of primary human breast cancers with "slow" and "fast" growth rates and with axillary lymph node metastases.

This article reports statistically significant associations existing between the clinical, mammographic and histopathologically classified properties of mammary cancers occurring in the population of 10,120 women screened in the BCDDP at the University of Louisville over a 5-year period and the propensity to grow "fast" and "slow" and metastasize or not metastasize to the axillary lymph nodes. Fast cancers, divided into two defined subsets as "fast 1" and "fast 2," are those surfacing in the intervals between mammograms. The faster cancers exhibited a significant absence of calcification, were discovered in younger patients and resulted in a shorter 5-year cumulative survival rate (fast 1 = 74 +/- 9% to slow = 94 +/- 4%). In addition to growth rates, another index of virulence in small cancers is the early appearance of metastases in the axillary lymph nodes. The absence of microscopic calcifications and the presence of lymphatic invasion around the primary cancer site were significantly associated with the presence of axillary metastases. Other factors associated with the occurrence of axillary metastases were a higher mitotic index, poor cellular differentiation and a larger size of cancer at diagnosis. The author's results confirm that interval surfacing cancers are biologically different and are not comparable to cancers discovered by scheduled screens. Cancers that metastasize to lymph nodes while very small have properties in common with these interval surfacing and, presumably, faster growing cancers.

Acute carcinoma of the breast.

The timely discovery of curable carcinoma through screening and early treatment is compromised by the existence of acute carcinoma with adverse properties. The existence of an acute carcinoma must be considered in planning and promoting any public health program for the control of carcinoma of the breast. These carcinomas will surface under any contemporarily available screening or detection program through no physician or patient error. These carcinomas have identifiable properties, and their occurrence should not be the basis of a malpractice suit, since their evolution is not presently preventable. The available data on actual doubling times obviously provide truncated distributions, since they contain no data on the faster subsets of carcinomas that surface in the intervals between screenings too quickly to permit measurement of size and calculation of DT (act).

Tumor growth, doubling times, and the inability of the radiologist to diagnose certain cancers.

In the absence of prevention, the control of breast cancer demands that it be discovered as soon as possible after it reaches threshold size, but before it disseminates. This optimal detection time is known as the "cancer control window." The actual doubling time of a cancer is a major determinant of the length of time available for effective discovery. Data are presented showing the enormous variance possible for this interval, ranging from very short times to extremely long times. With refined mammographic techniques and conscientious, aggressive mammographers, this threshold size continues to shrink and now approaches 2 mm. Many factors, however, continue to influence effective detection in this size range including cancer type, breast parenchymal density, proper applications of examination techniques, and the duration of the cancer control window for different cancers. Our own experience and review of the literature indicate that a certain percentage of cancers will be missed in the symptomatic and screened populations. With some adjustments of technique and interpretation and careful attention to them, many of these overlooked cancers can be recognized. However, data support the presence of a subset of acute breast cancers below threshold size at examination but that can grow to clinically detectable and symptomatic size within weeks to months of the breast evaluation showing no abnormality. These cancers will surface under any contemporarily available screening or detection program through no physician error. Under optimal conditions, this group of cancers can neither be prevented nor recognized and account for the inability of the radiologist to diagnose some breast cancers.

A clinicopathologic correlation of mammographic parenchymal patterns and associated risk factors for human mammary carcinoma.

The five-year screening experience for 10,131 asymptomatic women evaluated at the Louisville Breast Cancer Detection Demonstration Project (LBCDDP) disclosed 144 breast carcinomas in 1,209 patients (12%) aged 35 to 74 years in whom 904 biopsies and 305 aspirations were performed. This study included 44,711 high-quality xeromammograms (XM) prospectively classified by the modified Wolfe mammographic parenchymal patterns into low-risk (N(1), P(1)) versus high-risk (P(2), DY) groups, with expansion of the P(2) cohort into three additional categories. Using BMDP computer-program analysis, each XM pattern was collated with 21 nonneoplastic and 18 malignant pathologic variables and commonly associated risk factors. A separate analysis of epithelial proliferative and nonproliferative fibrocystic disease of the breast (FCDB) was performed. The histopathology for each biopsy, with distinction of FCDB and neoplasms, was analyzed with regard to the statistical probability of influencing the XM pattern. An average of 1.05 biopsies per patient were performed in women with findings suggestive of carcinoma at clinical and/or XM examinations. An equal distribution of the N(1), P(1), and P(2) DYXM patterns was observed in the 10,131 screenees. Of 8.5% of the screened population having biopsies, 623 were observed to have nonproliferative FCDB and 137, proliferative FCDB. For women 50 years of age or younger, these pathologic variables were seen more frequently in the P(2) DY patterns (p < 0.001), whereas no difference in XM pattern distribution was observed for the screenee 50 years of age or older for proliferative FCDB (p = 0.65). Sixteen percent of the biopsied/aspirated lesions were carcinomas, yielding a biopsy/cancer ratio of 6.25:1. These in situ and invasive neoplasms were more commonly (p < 0.04) observed in 55% of the P(2) (P(2f), P(2n), P(2c)) categories, while 64% of all cancers appeared more frequently in the P(2) DY subgroup (p <0.001), compared with this pattern in the screened population. An equal distribution frequency of the XM classification existed for screenees 50 years of age or older with cancer (p = 0.50), while screenees 35-49 years of age were more often observed to have the high-risk P(2), DY patterns (p <0.001). Analysis of 1,759 histologic characteristics in biopsies of 863 patients with FCDB revealed ductal and lobular hyperplastic lesions, sclerosing adenosis, or epithelial cyst(s) to be the major constituents of 64-69% of the high-risk P(2) (P(2f), P(2n), P(2c)) image (p < 0.001). These data suggest that XM parenchymal patterns observed in asymptomatic screenees incompletely correlate with known pathologic variables and risk factors. Additionally, benefit for recognition of these preinvasive proliferative pathologic factors and carcinomas appears restricted to the younger screenee. The clinical integration of these risk factors with XM patterns may allow preselection of patients deserving of frequent follow-up for breast cancer; however, these data do not support the contention that Wolfe XM patterns are predictors for screening strategies or that they decisively enhance patient management.

Selected prognostic variables for mammographic parenchymal patterns.

Conjecture exists about the influence of numerous risk-factors for breast cancer on mammographic parenchymal patterns. To allow more precise documentation of the common variables considered influential in alterations of breast parenchyma, we conducted a randomized retrospective analysis. Of 10,132 women participants in the Louisville Breast Cancer Detection Demonstration Project, every tenth participant was randomly selected for evaluation using SPSS statistical programming. Each accessioned patient had discriminant analysis for the risk factors of age, parity, age at birth of first child, family history, personal history, previous history of breast biopsy, and exogenous estrogen therapy. One-thousand-and-two women were examined for the significance of the selected prognostic variable association with Wolfe mammographic parenchymal patterns (WMPP). Each prognostic factor was tested by chi-square analysis for the low-risk pattern (N1P1) versus the high-risk pattern (P2DY). A high correlation existed between the age of patient and WMPP (P = 0.0002) in the subjects evaluated (50--85 years, mean 60). Similarly, a very significant correlation was evident between WMPP and parity (P = 0.0002), age at birth of first child (P = 0.0014), family history of breast cancer (P = 0.097), and history of previous breast biopsy (P = 0.0066). Little correlation existed between the Wolfe parenchymal pattern classification and a personal history of breast cancer (P = 0.7779) or the use of exogenous estrogens (P = 0.5776).

Association between the actual doubling times of primary breast cancer with histopathologic characteristics and Wolfe's parenchymal mammographic patterns.

This study identifies associations between the actual doubling time of primary mammary cancers with histopathologic characteristics and Wolfe's parenchymal mammographic patterns. Seventy microscopic criteria and Wolfe's mammographic parenchymal patterns were coded for 32 primary breast cancers on which actual volume doubling times were calculated from serial mammographic views of tumor nucleus shadows. Circumscribed cancer margin and papillary intraductal growth were associated with slow-growing breast cancers. More anaplastic nuclear grade was associated with faster-growing cancers. No association could be established between doubling time and parenchymal patterns as described by Wolfe.

Analysis of breast cancer screening in women younger than 50 years.

The five-year screening experience for 10,128 asymptomatic women whose conditions were evaluated at the Louisville Breast Cancer Detection Demonstration Project disclosed 163 breast carcinomas in women aged 35 to 74 years. Thirty-four percent of patients with proved carcinoma were younger than 50 years; 31% with infiltrating carcinoma had axillary metastases at the time of diagnosis. In younger patients, carcinomas disclosed at intervals between scheduled screenings were more commonly metatastic. Minimal breast cancer was more prevalent in the screened population (29%) than the unscreened population (less than 5%), and appeared with similar frequency in screenees of each age category. Screening women younger than 50 years allow earlier diagnosis and treatment of breast cancer in a favorable stage that is comparable with that noted in the older screenees.

The effects of exogenous estrogen replacement therapy of the breast: breast cancer risk and mammographic parenchymal patterns.

A retrospective pilot study was implemented to better define the potential carcinogenic role of conjugated equine estrogen (Premarin) on the breast, and the influence of these hormone analogues on proliferative and atrophic breast parenchyma as determined by high-quality serial xeromammograms. Four hundred and five postmenopausal (spontaneous and surgical) women (mean age 59.7 years) were group matched for the risk factors of age and parity. The dominant parenchymal pattern (N1P1P2DY) as disclosed mammographically was determined for each patient, who was then categorized into one of four groups: Group 1 Asymptomatic-no hormones, 124 patients; Group 2 Symptomatic-no hormones, 75 patients; Group 3 Asymptomatic-hormones; 152 patients; and Group 4 Symptomatic-hormones, 54 patients. Patients in Groups 3 and 4 were treated with therapeutic estrogens a minimum of 18 months (mean 79 months) and follow-up ranged from 39-344 months. In the entire series, 25 carcinomas (6.2%) were detected. In Group 3, five carcinomas (2.4%) were detected, but two cancers (1.0%) were found in symptomatic estrogen users. The occurrence of carcinoma in Group 2 was greater than the remaining categories; however, cancer risk was not statistically greater in any category with regard to hormone replacement therapy. Patients treated with therapeutic estrogens were observed to have an increase of 8.9% in the frequency of a more glandular (P2,DY) mammographic parenchymal pattern and this was noted to be within the range of interpretation error of the mammographer. This suggests a physiologic effect of therapeutic estrogens on atrophic breast parenchyma with conversion to a glandular, proliferative state. This study suggests that long-term replacement estrogen therapy for postmenopausal symptoms does not significantly alter mammographic parenchymal patterns and that the use of these compounds in therapeutic doses does not increase the risk of breast cancer.

Neurofibromatosis, hypertension, and renal artery aneurysms.

A case of bilateral renal artery stenosis and aneurysms in association with neurofibromatosis and hypertension is discussed and the literature is reviewed. In patients with neurofibromatosis and hypertension, the association of pheochromocytomas is well known. The association of renal of renal vascular lesions must also be recognized. In children with neurofibromatosis and hypertension, renal artery stenosis is far more common than pheochromocytoma. In adults aneurysms often accompany the renal artery stenosis. Laboratory studies, as well as most intravenous pyelograms, have been normal and, therefore, unreliable for screening. Angiography is essential in the investigation of hypertension in patients with neurofibromatosis.