Formal and Informal Discrimination Against Women At Work: The Role of Gender Stereotypes

When asked to think about a hostile environment for women in the workplace, many of us would first envision overt instances of sexual harassment or blatant employment discrimination. These associations are certainly not astonishing: even in an age in which these behaviors are denounced and in large part illegal, such organizational misconduct seems almost commonplace. There have been many high-profile allegations of discrimination leveled against organizations within the last several years (Morris, Bonamici & Neering, 2005). For example, Morgan Stanley’s investment banking business recently paid out $54 million to over 300 female employees who claim to have been denied pay and promotions equal to those received by their male colleagues. Additionally, 1.6 million women who are currently, or were formerly, employed at Wal-Mart are eligible to participate in what is poised to become the largest-ever civil rights lawsuit: like the women of Morgan Stanley, they claim to have been victims of sex discrimination (Greenhouse, 2004). In fact, according to statistics from the Equal Employment Opportunity Commission, there has been no systematic decline over the last 12 years in the number of discrimination lawsuits filed, or the amount of monetary damages awarded to the plaintiffs of these suits (Equal Employment Opportunity Commission, 2004)

Fascicle localisation within peripheral nerves through evoked activity recordings: A comparison between electrical impedance tomography and multi-electrode arrays

BACKGROUND: The lack of understanding of fascicular organisation in peripheral nerves limits the potential of vagus nerve stimulation therapy. Two promising methods may be employed to identify the functional anatomy of fascicles within the nerve: fast neural electrical impedance tomography (EIT), and penetrating multi-electrode arrays (MEA). These could provide a means to image the compound action potential within fascicles in the nerve. NEW METHOD: We compared the ability to localise fascicle activity between silicon shanks (SS) and carbon fibre (CF) multi-electrode arrays and fast neural EIT, with micro-computed tomography (MicroCT) as an independent reference. Fast neural EIT in peripheral nerves was only recently developed and MEA technology has been used only sparingly in nerves and not for source localisation. Assessment was performed in rat sciatic nerves while evoking neural activity in the tibial and peroneal fascicles. RESULTS: Recorded compound action potentials were larger with CF compared to SS (∼700μV vs ∼300μV); however, background noise was greater (6.3μV vs 1.7μV) leading to lower SNR. Maximum spatial discrimination between Centres-of-Mass of fascicular activity was achieved by fast neural EIT (402±30μm) and CF MEA (414±123μm), with no statistical difference between MicroCT (625±17μm) and CF (p>0.05) and between CF and EIT (p>0.05). Compared to CF MEAs, SS MEAs had a lower discrimination power (103±51μm, p<0.05). COMPARISON WITH EXISTING METHODS: EIT and CF MEAs showed localisation power closest to MicroCT. Silicon MEAs adopted in this study failed to discriminate fascicle location. Re-design of probe geometry may improve results. CONCLUSIONS: Nerve EIT is an accurate tool for assessment of fascicular position within nerves. Accuracy of EIT and CF MEA is similar to the reference method. We give technical recommendations for performing multi-electrode recordings in nerves

Substance Misuse Education for Physicians: Why Older People are Important.

This perspective article focuses on the need for training and education for undergraduate medical students on substance-related disorders, and describes initiatives undertaken in the United Kingdom (UK), Netherlands, United States (US), and Norway to develop the skills, knowledge, and attitudes needed by future doctors to treat patients adequately. In addition, we stress that in postgraduate training, further steps should be taken to develop Addiction Medicine as a specialized and transverse medical domain. Alcohol use disorder is a growing public health problem in the geriatric population, and one that is likely to continue to increase as the baby boomer generation ages. Prescription drug misuse is a major concern, and nicotine misuse remains problematic in a substantial minority. Thus, Addiction Medicine training should address the problems for this specific population. In recent years, several countries have started an Addiction Medicine specialty. Although addiction psychiatry has been a subspecialty in the UK and US for more than 20 years, in most countries it has been a more recent development. Additional courses on addiction should be integrated into the curriculum at both undergraduate and postgraduate levels, as well as form part of the continuous training of other medical specialists. It is recommended that further research and mapping of what is currently taught in medical programs be undertaken, so as to enhance medical education in addiction and improve treatment services

A live attenuated RSV vaccine, process development studies

Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children. A vaccine to prevent the high burden of disease caused by RSV is urgently needed, but not available. A live attenuated respiratory syncytial virus (RSV) vaccine for intranasal delivery is currently under development at Intravacc. The vaccine concept comprises a live Glycoprotein-complemented RSVΔG virus. This G-RSVΔG virus is generated by proliferation of an RSVΔG on G-expressing Vero cells. The vaccine thus contains virus particles that have the G-protein on their surface but not in their RNA genomes. This recombinant virus is highly attenuated compared to wild type RSV and therefore presents a live attenuated vaccine candidate for RSV infection. A vaccine production process has been setup for the production of Phase I clinical lots. In short, the production process steps are: cell and virus culture, clarification, continuous flow density gradient ultracentrifugation, ultra/diafiltration, filling and lyophilization. An example of process development is the design of the cell and virus culture method. Using the statistical design of experiment approach the virus culture has been optimized to both virus yield and harvest quality. As RSV is a filamentous virus, the optimization of harvest quality with respect to purification opportunities is pivotal. This DoE was done at lab-scale bioreactors (2-L) and the chosen conditions were successfully scaled-up to 50-L single use bioreactors. Preparation of preclinical and clinical lots is done at this scale. The pre-clinical studies were successful. In the cotton rat model, the G-RSVΔG vaccine is safe, immunogenic and protects against challenge with wild type RSV. The following step, a clinical Phase I study, is planned

The Regulation of Skeletal Muscle Protein Turnover During the Progression of Cancer Cachexia in the \u3cem\u3eApc\u3csup\u3eMin/+\u3c/sup\u3e\u3c/em\u3e Mouse

Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The Apc(Min/+) mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the Apc(Min/+) mouse is not known. Cachexia progression was studied in Apc(Min/+) mice that were either weight stable (WS) or had initial (≤5%), intermediate (6-19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process

A KRT71 Loss-of-Function Variant Results in Inner Root Sheath Dysplasia and Recessive Congenital Hypotrichosis of Hereford Cattle

Genodermatoses, such as heritable skin disorders, mostly represent Mendelian conditions. Congenital hypotrichosis (HY) characterize a condition of being born with less hair than normal. The purpose of this study was to characterize the clinicopathological phenotype of a breed-specific non-syndromic form of HY in Hereford cattle and to identify the causative genetic variant for this recessive disorder. Affected calves showed a very short, fine, wooly, kinky and curly coat over all parts of the body, with a major expression in the ears, the inner part of the limbs, and in the thoracic-abdominal region. Histopathology showed a severely altered morphology of the inner root sheath (IRS) of the hair follicle with abnormal Huxley and Henle’s layers and severely dysplastic hair shafts. A genome-wide association study revealed an association signal on chromosome 5. Homozygosity mapping in a subset of cases refined the HY locus to a 690 kb critical interval encompassing a cluster of type II keratin encoding genes. Protein-coding exons of six positional candidate genes with known hair or hair follicle function were re-sequenced. This revealed a protein-changing variant in the KRT71 gene that encodes a type II keratin specifically expressed in the IRS of the hair follicle (c.281delTGTGCCCA; p.Met94AsnfsX14). Besides obvious phenocopies, a perfect concordance between the presence of this most likely pathogenic loss-of-function variant located in the head domain of KRT71 and the HY phenotype was found. This recessive KRT71-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002114-9913)

Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases

Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and rheumatoid arthritis (RA) are chronic inflammatory diseases in which abnormalities of B cell function play a central role. Although it is widely accepted that autoimmune B cells are hyperactive in vivo, a full understanding of their functional status in AID has not been delineated. Here, we present a detailed analysis of the functional capabilities of AID B cells and dissect the mechanisms underlying altered B cell function. Upon BCR activation, decreased spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk) phosphorylation was noted in AID memory B cells combined with constitutive co-localization of CD22 and protein tyrosine phosphatase (PTP) non-receptor type 6 (SHP-1) along with hyporesponsiveness to TLR9 signaling, a Syk-dependent response. Similar BCR hyporesponsiveness was also noted specifically in SLE CD27- B cells together with increased PTP activities and increased transcripts for PTPN2, PTPN11, PTPN22, PTPRC, and PTPRO in SLE B cells. Additional studies revealed that repetitive BCR stimulation of normal B cells can induce BCR hyporesponsiveness and that tissue-resident memory B cells from AID patients also exhibited decreased responsiveness immediately ex vivo, suggesting that the hyporesponsive status can be acquired by repeated exposure to autoantigen(s) in vivo. Functional studies to overcome B cell hyporesponsiveness revealed that CD40 co-stimulation increased BCR signaling, induced proliferation, and downregulated PTP expression (PTPN2, PTPN22, and receptor-type PTPs). The data support the conclusion that hyporesponsiveness of AID and especially SLE B cells results from chronic in vivo stimulation through the BCR without T cell help mediated by CD40-CD154 interaction and is manifested by decreased phosphorylation of BCR-related proximal signaling molecules and increased PTPs. The hyporesponsiveness of AID B cells is similar to a form of functional anergy

MLPH Genotype—Melanin Phenotype Correlation in Dilute Dogs

Coat color dilution in dogs is a specific pigmentation phenotype caused by a defective transport of melanosomes leading to large clumps of pigment. It is inherited as a Mendelian autosomal recessive trait and may be accompanied by hair loss, the so-called color dilution alopecia (CDA), or black hair follicular dysplasia (BHFD). We previously identified the noncoding c.-22G>A transition in the melanophilin gene (MLPH) as a candidate causative mutation for the dilute phenotype. We have now extended our study and genotyped 935 dogs from 20 breeds segregating for dilute coat color. The dilute-associated A allele segregates in many different breeds suggesting an old mutation event. We also investigated skin biopsies of dogs suspected of having either CDA or BHFD, and our data clearly indicate that the dilute mutation is required but not sufficient to develop clinical signs of the disease. The risk to develop CDA/BHFD seems to be breed specific. Interestingly, 22 out of 29 dogs with clinical signs of CDA/BHFD have clumped melanin in the epidermis, the follicular epithelium, and the hair shafts, whereas in dilute dogs without clinical disease, clumped melanin is only found in the follicular epithelium and the hair shafts but not in the epidermi