Hippocampal cingulum white matter increases over time in young people at high genetic risk for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a strongly familial psychiatric disorder associated with white matter (WM) brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about WM trajectories in those at increased genetic risk. METHODS: Diffusion magnetic resonance imaging (dMRI) data were acquired at baseline and after two years in 91 unaffected individuals with a first-degree relative with bipolar disorder (HR), and 85 individuals with no family history of mental illness (CON). All participants were aged between 12 and 30 years at baseline. We examined longitudinal change in Fractional Anisotropy (FA) using tract-based spatial statistics (TBSS). RESULTS: Compared to the CON group, HR participants showed a significant increase in FA in the right cingulum (hippocampus) (CGH) over a two-year period (p < .05, FDR corrected). This effect was more pronounced in HR individuals without a lifetime diagnosis of a mood disorder than those with a mood disorder. LIMITATIONS: While our study is well powered to achieve the primary objectives, our sub-group analyses were under powered. CONCLUSIONS: In one of the very few longitudinal neuroimaging studies of young people at high risk for BD, this study reports novel evidence of atypical white matter development in HR individuals in a key cortico-limbic tract involved in emotion regulation. Our findings also suggest that this different white matter developmental trajectory may be stronger in HR individuals without affective psychopathology. As such, increases in FA in the right CGH of HR participants may be a biomarker of resilience to mood disorders.

A proof of concept for assessing emergency room use with primary care data and natural language processing.

OBJECTIVE: The objective of this study was to undertake a proof of concept that demonstrated the use of primary care data and natural language processing and term extraction to assess emergency room use. The study extracted biopsychosocial concepts from primary care free text and related them to inappropriate emergency room use through the use of odds ratios. METHODS: De-identified free text notes were extracted from a primary care clinic in Guelph, Ontario and analyzed with a software toolkit that incorporated General Architecture for Text Engineering (GATE) and MetaMap components for natural language processing and term extraction. RESULTS: Over 10 million concepts were extracted from 13,836 patient records. Codes found in at least 1% percent of the sample were regressed against inappropriate emergency room use. 77 codes fell within the realm of biopsychosocial, were very statistically significant (p < 0.001) and had an OR > 2.0. Thematically, these codes involved mental health and pain related concepts. CONCLUSIONS: Analyzed thematically, mental health issues and pain are important themes; we have concluded that pain and mental health problems are primary drivers for inappropriate emergency room use. Age and sex were not significant. This proof of concept demonstrates the feasibly of combining natural language processing and primary care data to analyze a system use question. As a first work it supports further research and could be applied to investigate other, more complex problems.

Chromosomal aberration and sister-chromatid exchange frequencies in peripheral blood lymphocytes of a large human population sample. II. Extension of age range.

We have previously reported on a cytogenetic-epidemiological study of chromosomal aberration and sister-chromatid exchange (SCE) frequencies in peripheral blood lymphocytes (PBL) of a cohort of 353 healthy employees of the Brookhaven National Laboratory (Bender et al., 1988). This sample has now been increased in order to extend the age range represented and, incidentally, the representation of non-white subjects. In total, the data now include chromosomal aberration information from 108,950 cells and SCE information from 25,397 cells from 613 samples from 493 subjects. Neither the mean frequencies of any of the chromosomal aberration types nor the mean frequency of SCE have changed notably through the addition of the new subjects and samples. The mean age at sampling of the population is now 43.1 years with a range of from 1.1 to 83.7 years. However, we still find no significant relationship of the frequency of any conventional aberration category to age with the single exception of the dicentric chromosome, which now shows a positive regression (p = 0.001). The raw mean SCE frequencies show a statistically significant increase with subject age, but when cigarette smoking status is taken into account, no significant age relationship is found. As with the earlier samples, neither aberration nor SCE frequencies was influenced by race. Mean SCE frequencies, measured in non-smokers, were about 5% higher in females than males. Only one aberration category, "supernumerary acentric fragment", was significantly related to sex. This "aberration", known to constitute early centromere separation of an X chromosome, is much more common in females than in males and, in the females, increases significantly with increasing subject age.

Chromosomal aberration and sister-chromatid exchange frequencies in peripheral blood lymphocytes of a large human population sample.

In order to assess the potential of cytogenetic determinations on peripheral blood lymphocytes as a means of monitoring human populations subject to low level occupational and environmental exposures to chemical mutagens and carcinogens, accurate baseline data are required. Accordingly, we have determined mean frequencies of chromosomal aberrations and of sister-chromatid exchanges, their variances, and the sources of this variance in a cohort of 353 healthy employees of the Brookhaven National Laboratory. A detailed protocol was adopted for blood sampling, lymphocyte culture, cytogenetic preparation and scoring in order to minimize variation from these potential sources. Scoring was divided between the Oak Ridge and the Brookhaven groups with duplicate scoring sufficient to evaluate and minimize the effect of any differences between laboratories or between individual scorers. In all, the data include 71,950 cells scored for chromosomal aberrations and 16,898 cells scored for sister-chromatid exchanges. The mean unadjusted frequency of sister-chromatid exchanges was 8.29 +/- 0.08/cell. As reported in other studies, cigarette smoking very significantly influenced sister-chromatid exchange frequencies; in our study the mean for smokers was 9.0 +/- 0.2, while that for non-smokers was 8.1 +/- 0.1/cell. The mean frequency was statistically higher in females than in males, regardless of smoking status. On the other hand, age of the subject did not significantly influence sister-chromatid exchange frequencies. Curiously, the subject's total white cell count did influence sister-chromatid exchange frequency. No other source of variation was found. The frequencies of chromosomal aberrations of all types were determined. The frequency of the most common unequivocal chromatid type, the chromatid deletion, was 0.81 +/- 0.05%, that of the most common unequivocal chromosome type, the dicentric, was 0.16 +/- 0.02%. No statistically significant influence was found of age or sex, nor of any other parameter tested, on the frequency of any chromosomal aberration type, with the single exception of long acentric fragments, often "supernumerary", believed to represent X chromosomes precociously separated at the centromere. Such fragments were significantly more frequent in samples from females than those from males, and showed a significant positive regression on age.

Evaluation of radiation-induced chromosomal aberrations in human peripheral blood lymphocytes in vitro: result of an IAEA-coordinated programme.

The results of an IAEA coordinated programme on radiation induced chromosomal aberrations in human peripheral blood lymphocytes in vitro are presented. In a master experiment, a whole blood sample from one donor was irradiated with 200 R of X-rays. Different fixation times from 46 to 82 h were used. The progression of cells into mitosis was monitored by BrdUrd incorporation. 14 investigators took part in the scoring of chromosomal aberrations. The main conclusions of this study are: (1) The mean frequencies of aberrations changed with fixation time. (2) The number of cells scored as aberrant by different laboratories was very similar, but there was variability in the number of aberrations scored per aberrant cell. (3) The differences in the frequencies of aberrations between laboratories were minimal when the scoring was restricted to the first major peak of mitotic activity and sufficient cells were scored. It is concluded that using controlled experimentals conditions, human peripheral blood lymphocytes can effectively be used as a reliable biological dosimeter for absorbed radiation dose.

The induction of chromosome-type aberrations in G1 by methyl methanesulfonate and 4-nitroquinoline-N,-oxide, and the non-requirement of an S-phase for their production.

Human lymphocytes were treated in G1 with 4-nitroquinoline-N-oxide (4NQO) and methyl methanesulfonate (MMS) and then incubated in the presence or absence of cytosine arabinoside (ara-C). There was an increase in aberration frequency in those cells incubated with ara-C compared with those treated with 4NQO or MMS alone. This increase was restricted to chromosome-type aberrations. When cells were treated in G2 with 4NQO and then incubated with ara-C until fixation, there was an increase in deletions compared with cells treated with 4NQO alone. No exchange aberrations were observed following any treatment even when deletion frequencies were high, as in the case with 4NQO plus ara-C treatment. These results suggest that ara-C can inhibit the repair of DNA damage induced by 4NQO and MMS that is converted into aberrations. They also show that the terms "S-dependent' and "S-independent' used to describe the modes of action of chemical clastogens are not valid.

The production of chromosome aberrations in various mammalian cells by triethylenemelamine.

The cytogenetic effects of triethylenemelamine (TEM) were studied using five different mammalian tissues. Treatments of 0.1 and 0.2 mg/kg TEM on differentiating mouse spermatogonia and bone marrow cells showed no significant differences in the frequency of chromosomal aberrations produced in these two tissues. At higher doses, however, the sensitivites of the two tissues appear to be different. The frequency of aberrations varies with time after treatment, with the greatest amount occurring at the latter fixation times. Results of an experiment on primary spermatocytes indicated a correlation between the frequency of chromosome aberrations and DNA replication. Human peripheral leukocytes were utilized in an attempt to clarify the cell-stage specificity of TEM-induced chromosome aberrations. Cultures were treated with TEM prior to PHA stimulation (G0), as well as various time intervals after stimulation (late G,1 S, and G2). The most sensitive stages of the cell cycle to aberration induction were later G1 and S, with chromatid aberrations the predominant type. A very low yield of chromosome damage was observed with the G0 and G1 treated stages. The experiments described tend to support the view that TEM is most effective at inducing aberrations when an intervening round of DNA replication has occurred.

A new M-type of group A streptococcus of clinical importance in pyoderma and pharyngitis.

A new M-type of group A streptococcus, provisionally designated type 65, is described. The vaccine and other initially isolated strains of this type attracted attention because of the T-agglutination reactions 2/25, not previously encountered among pyoderma streptococci. The investigations characterizing the strains as members of a new type were done with streptococci isolated from patients with pyoderma. However, type 65 was subsequently found to cause both pyoderma and acute pharyngitis. The T-2 agglutination reactions encountered with original members of this type, plus the cross-reactions later seen with type 65 antiserum and M-type 2 streptococci, prompted a comparison of this new type with M-type 2 streptococci, including those with the T-2 agglutination and others with the 8-25-Imp. 19 complex. The two M-antigens were clearly distinguished from one another in reciprocal bactericidal and precipitin tests with absorbed antisera. They were further distinguished in that all type 65 strains were opacity-factor (OF) negative, whereas type 2 streptococci were uniformly OF-positive. Most M-type 65 strains subsequently found in surveillance studies were shown to be members of the 8-25-Imp,19 T-complex. Type 65 is thus a newly described type which shares with M-types 55 and 57 a commom T-agglutination pattern and, like members of these types, fails to produce opacity factor. In our colleciton of strains, from both pyoderma and pharyngitis, shown to be members of the 8-25-Imp. 19 complex, and OF-negative, only type 65 has been identified to date. In contrast to types 55 and 57, the new type 65 does not appear to be of major importance in causing acute glomerulonephritis.