A voxel-by-voxel parametric fMRI study of motor mental rotation: hemispheric specialization and gender differences in neural processing efficiency

Differences between men and women in brain size, cognitive performance and lateralization of brain activation have been perennial and controversial issues. Here we show that in a motor mental rotation task where women and men performed equally well, the slope of the functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) signal per degree of mental rotation was overall 2.4× higher in men than in women. This was attributed to the much more inefficient engagement (i.e. higher slopes) of the right hemisphere by men (mainly the frontal lobe). These findings indicate that women process information much more efficiently than men, which could offset smaller brain size.     

Antigenic variation among bovine enteric coronaviruses (BECV) and bovine respiratory coronaviruses (BRCV) detected using monoclonal antibodies

Summary.  Bovine coronavirus (BCV) causes neonatal calf diarrhea (CD) and is associated with winter dysentery (WD) in adult dairy cattle. It can also be isolated from the respiratory tracts of cattle entering feedlots. Monoclonal antibodies (MAbs) specific for the hemagglutinin esterase (HE) and spike (S) surface proteins of 2 bovine enteric coronavirus (BECV) strains and two bovine respiratory coronavirus (BRCV) strains were tested against 6 BECV strains and 6 recently isolated BRCV strains, in order to characterize the antigenicity of BCV strains with varied tissue tropisms. All MAbs had high immunofluorescence (IF) titers against BECV and BRCV strains, indicative of conserved cross-reactive epitopes. In hemagglutination inhibition (HI) tests, the S-MAbs were more broadly reactive than HE-MAbs. The BRCV and CD MAbs were more broadly reactive in HI than the WD MAbs. The HA activity of the Mebus vaccine CD strain was not inhibited by any of the MAbs tested. The HI activity of BRCV strain R6 was unique among the 6 BRCV isolates. In virus neutralization assays, MAbs to the BRCV strain R4 neutralized all 6 BECV strains tested. Antigenic variation exists among both BECV and BRCV strains, but it cannot be attributed soley to the clinical origin of the strain. Received February 9, 1998/Accepted July 22, 1999     

Familial gastric cancer: overview and guidelines for management

Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germline E-cadherin/CDH1 mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germline E-cadherin/CDH1 mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.     

Human sperm DNA integrity assessed by the Comet and ELISA assays.

DNA integrity in sperm is essential for the accurate transmission of genetic information and therefore the maintenance of good health in future generations. The ELISA and Comet assays, two techniques that detect DNA damage in cells, are compared in this study of DNA integrity in human sperm. Both techniques rely on alkaline unwinding for the release of single strands of DNA from the nucleus. The ELISA detects single strands immunochemically whereas the Comet assay measures single strands drawn out by electrophoresis, stained with ethidium bromide and quantified by image analysis. The two techniques, both modified for use with sperm, detect similar levels of baseline DNA damage along with similar dose-dependent patterns of induced damage by X-ray irradiation at 10 and 30 Gy (P < 0.05). The assays are also comparable in the detection of a significant protective effect by ascorbic acid (300 and 600 microM) and alpha-tocopherol (30 and 60 microM) on DNA integrity, both at baseline levels and following X-ray irradiation (p < 0.01). The advantages and disadvantages of each technique are discussed.     

Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer

Background

Although in vitro breast cancer models have demonstrated a role for protein kinase C (PKC) α and δ isoforms in endocrine insensitivity and resistance respectively, there is currently little clinical evidence to support these observations.

Aims

To define the pattern of PKC α and δ expression using breast cancer cell lines, with and without endocrine resistance, and also breast cancer samples, where expression can be correlated with clinicopathological and endocrine therapy outcome data.

Methods

PKC isoform expression was examined in tamoxifen responsive, oestrogen receptor positive (ER⁺), ER⁺ acquired tamoxifen resistant (TAM‐R) and oestrogen receptor negative (ER⁻) cell lines by western blotting and immunocytochemical analysis. PKC isoform expression was then examined by immunohistochemistry in archival breast cancer specimens from primary breast cancer patients with known clinical outcome in relation to endocrine response and survival on therapy.

Results

ER⁺ breast cancer cell lines expressed considerable PKC‐δ but barely detectable levels of PKC‐α, whereas ER⁻ cell lines expressed PKC‐α but little PKC‐δ. ER⁺ acquired TAM‐R cell lines expressed substantial levels of both PKC‐α and δ. In clinical samples, high PKC‐δ expression correlated to endocrine responsiveness whereas PKC‐α expression correlated to ER negativity. PKC‐δ was an independent predictor of duration of response to therapy. Patients showing a PKC‐δ⁺/PKC‐α⁻ phenotype had a six times longer endocrine response than patients with the PKC‐δ⁺/ PKC‐α⁺ phenotype (equating to tamoxifen resistance in vitro).

Conclusions

Levels of PKC‐α and δ expression appear to be indicative of response to anti‐oestrogen therapy and could be useful in predicting a patient''s suitability for endocrine therapy.Anti‐hormone therapies such as tamoxifen are widely used to treat breast cancer patients.¹ A small but significant number of patients receiving tamoxifen however will not respond or will develop resistance.^2,3 Many mechanisms have been suggested which may play a role in tamoxifen resistance but the mechanisms have not yet been fully elucidated.^4,5,6,7 Although rapid progress is being made in understanding the biology of oestrogen receptor (ER) function, the only predictive markers for endocrine therapy that currently yield sufficient levels of evidence to be recommended for routine practice, are ER and progesterone receptors, and to a lesser extent HER‐2 status.¹ Better ways of predicting which patients are suitable for endocrine therapy would prove useful in the fight against breast cancer. Expression of the signal transduction molecule, protein kinase C (PKC) is increased in breast cancer models of poor prognosis; for example, ER⁻ cell lines express significantly more PKC than ER⁺ cell lines.^8,9 However, multiple isoforms of PKC exist, with variation in their expression profile and mechanism of activation.^10,11,12 We have previously shown that ER⁺ MCF‐7 cell lines have high PKC‐δ and low PKC‐α expression, whereas ER⁻ MDA‐MB‐231 cells have high PKC‐α and low PKC‐δ expression. A wealth of literature now support these observations^13,14,15,16 linking PKC‐α expression to loss of ER expression and adverse cellular features,^13,15 and there is also emerging data that PKC‐δ expression can relate to loss of endocrine sensitivity in vitro.¹⁷ These studies did not however investigate the effect of PKC‐δ expression on clinical outcome. Moreover, a recent clinical study showed PKC‐α to be decreased in advanced breast cancer samples,¹⁸ suggesting that laboratory observations may not translate to the clinic.We have therefore established cell line models of tamoxifen resistance,^19,20 and used these models and well‐characterised clinical specimens^21,22 with known response to endocrine therapy, to study PKC expression. We have shown that PKC‐α and δ may prove useful in predicting whether patients will respond or not to endocrine therapy.     

The Symptoms of Trauma Scale (SOTS): Psychometric evaluation and gender differences with adults diagnosed with serious mental illness

A new clinician rating measure, the Symptoms of Trauma Scale (SOTS), was administered to adult psychiatric outpatients (46 men, 47 women) with severe mental illness who reported a history of trauma exposure and had recently been discharged from inpatient psychiatric treatment. SOTS composite severity scores for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, posttraumatic stress disorder (PTSD), complex PTSD (cPTSD), and total PTSD/cPTSD severity had acceptable internal consistency reliability. SOTS scores’ construct and convergent validity was supported by correlations with self-report measures of childhood and adult trauma history and PTSD, dissociation, and anger symptoms. For men, SOTS scores were associated with childhood sexual and emotional abuse and self-reported anger problems, whereas for women SOTS scores were most consistently and strongly associated with childhood family adversity and self-reported PTSD symptoms. Results provide preliminary support for the reliability and validity of the SOTS with adults with severe mental illness and suggest directions for replication, measure refinement, and research on gender differences.     

2p15-p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders

Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder - Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (P<0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P(FDR))=1.29 × 10(-5)), the AGRE cohort (P(FDR)=0.0011) and the combined families (P(FDR)=2.34 × 10(-9)). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 × 10(-7) and 6.07 × 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 × 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P(FDR)=2.63 × 10(-11)) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values <0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.     

Investigating transmission of Mycobacterium bovis in the United Kingdom in 2005 to 2008

Due to an increase in bovine tuberculosis in cattle in the United Kingdom, we investigated the characteristics of Mycobacterium bovis infection in humans and assessed whether extensive transmission of M. bovis between humans has occurred. A cross-sectional study linking demographic, clinical, and DNA fingerprinting (using 15-locus mycobacterial interspersed repetitive-unit-variable-number tandem-repeat [MIRU-VNTR] typing) data on cases reported between 2005 and 2008 was undertaken. A total of 129 cases of M. bovis infection in humans were reported over the period, with a decrease in annual incidence from 0.065 to 0.047 cases per 100,000 persons. Most patients were born pre-1960, before widespread pasteurization was introduced (73%), were of white ethnicity (83%), and were born in the United Kingdom (76%). A total of 102 patients (79%) had MIRU-VNTR typing data. A total of 31 of 69 complete MIRU-VNTR profiles formed eight distinct clusters. The overall clustering proportion determined using the n - 1 method was 33%. The largest cluster, comprising 12 cases, was indistinguishable from a previously reported West Midlands outbreak strain cluster and included those cases. This cluster was heterogeneous, having characteristics supporting recent zoonotic and human-to-human transmission as well as reactivation of latent disease. Seven other, smaller clusters identified had demographics supporting recrudescence rather than recent infection. A total of 33 patients had incomplete MIRU-VNTR profiles, of which 11 may have yielded 2 to 6 further small clusters if typed to completion. The incidence of M. bovis in humans in the United Kingdom remains low, and the epidemiology is predominantly that of reactivated disease.     

CD94 is essential for NK cell-mediated resistance to a lethal viral disease

It is well established that natural killer (NK) cells confer resistance to many viral diseases, but in only a few instances the molecular mechanisms whereby NK cells recognize virus-infected cells are known. Here we show that CD94, a molecule preferentially expressed by NK cells, is essential for the resistance of C57BL/6 mice to mousepox, a disease caused by the Orthopoxvirus ectromelia virus. Ectromelia virus-infected cells expressing the major histocompatibility complex (MHC) class Ib molecule Qa-1(b) are specifically recognized by the activating receptor formed by CD94 and NKG2E. Because CD94-NKG2 receptors and their ligands are highly conserved in rodents and humans, a similar mechanism may exist during human infections with the smallpox and monkeypox viruses, which are highly homologous to ectromelia virus.