Sex and gender differences in Alzheimer's disease: current challenges and implications for clinical practice: Position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology.

Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

Ubiquitin-specific peptidase 2 as a potential link between microRNA-125b and psoriasis.

BACKGROUND: The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. miR-125b has previously been shown to be strongly associated with psoriasis, and presents as an obvious candidate for further investigation. OBJECTIVES: To elucidate the specific pathway and mechanism of interest in this association. METHODS: A three-step bioinformatical hypothesis-generation pipeline was performed to identify genes of interest. This pipeline was based on miR-125b binding, expression in psoriatic lesions and genome-wide association study-based evidence of involvement. The identified candidate gene was then carefully evaluated using luciferase binding assays, in vitro overexpression, small interfering RNA knock-down and downstream gene readouts. RESULTS: Based on our bioinformatical pipeline, ubiquitin-specific peptidase 2 was selected as a likely candidate for a mechanistic explanation for psoriasis association. After establishing a definite connection to miR-125b, we proceeded to show that modulation of nuclear factor kappa B-mediated inflammation is the likely mechanism through which this miRNA gene pair functioned. CONCLUSIONS: Shedding further light on the multifactorial causes of psoriasis is essential, if the goal is to progress towards finer control of therapeutic tools in disease management. Findings, such as the ones presented herein, are therefore necessary in order to achieve the future of personalized medicine.

Proteasome inhibition as a novel mechanism of the proapoptotic activity of γ-secretase inhibitor I in cutaneous T-cell lymphoma.

BACKGROUND: We have previously discovered that Notch1 is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL), and is required for survival of CTCL cell lines. Notch can be inhibited by γ-secretase inhibitors (GSIs), which differ widely in their ability to induce apoptosis in CTCL. OBJECTIVES: To investigate whether GSI-I, in addition to inhibiting Notch, induces apoptosis in CTCL by proteasome inhibition, as GSI-I is very potent and has structural similarity to the proteasome inhibitor MG-132. METHODS: Cell lines derived from CTCL (MyLa, SeAx, JK, Mac1 and Mac2a) were treated with GSI-I and two other proteasome inhibitors (MG-132 and bortezomib). The effects on cell viability, apoptosis and proteasome activity were measured, as was the impact on the prosurvival, nuclear factor κB (NF-κB) pathway. RESULTS: In CTCL, GSI-I had proteasome-blocking activity with a potency comparable to the proteasome inhibitors MG-132 and bortezomib. Proteasome inhibition was the main mechanism responsible for GSI-I-induced cell death, as tiron, a compound known to reverse the effect of MG-132, restored proteasome activity and largely abrogated the cytotoxic effect of GSI-I. Although inactivation of NF-κB is an important mechanism of action for proteasome inhibitors, we demonstrated an apparent activation of NF-κB. Furthermore, we showed that while the tumour suppressor protein p53 was induced during proteasome inhibition, it was dispensable for CTCL apoptosis, as both SeAx cells, which harbour p53 mutations that attenuate the apoptotic capacity, and HuT-78 cells, which have a deleted p53 gene, demonstrated potent apoptotic response. CONCLUSIONS: GSI-I represents an interesting drug with a dual mechanism of action comprising inhibition of both Notch and the proteasome.

Notch signalling in primary cutaneous CD30+ lymphoproliferative disorders: a new therapeutic approach?

BACKGROUND: The oncogenic potential of deregulated Notch signalling has been described in several haematopoietic malignancies. We have previously reported an increased expression of Notch1 in primary cutaneous CD30+ lymphoproliferative disorders, lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma (pcALCL). OBJECTIVES: To investigate the functional importance of Notch signalling in cell lines derived from pcALCL. METHODS: Cell lines derived from pcALCL (Mac1, Mac2a and JK) were treated with different γ-secretase inhibitors (GSIs) (GSI I, IX, XX and XXI). The effects of GSIs on cell viability, apoptosis and cell cycle progression were measured as well as the impact of GSI I on the known prosurvival pathway Akt-mTOR-FOXO3a. RESULTS: Notch family members were expressed in all investigated pcALCL cell lines. GSI I had a marked proapoptotic effect, but GSI IX, XX and XXI were much less potent. The GSI I-triggered apoptosis was preceded by an accumulation of cells in the G2/M, cyclin B1-controlled phase of the cell cycle accompanied by an increase in the cyclin-dependent kinase inhibitor, p21(WAF/Cip) . GSI I induced the nuclear translocation of proapoptotic FOXO3a, probably via an Akt-independent pathway. CONCLUSIONS: Notch signalling may be a future therapeutic target for the treatment of advanced pcALCL.

p-CREB-1 at Ser 133 is a potential marker for breast cancer.

OBJECTIVE: Dysregulation of numerous oncogenes and their downstream signaling pathways, among others in the signaling transduction molecule p-CREB-1 (p-cAMP responsive element binding protein-1), is an essential feature of different types of cancer. To investigate whether p-CREB-1 is also pivotal in tumorigenesis and metastogenesis of breast cancer, we conducted a prospective study with long-term follow-up on 96 patients with breast cancer. PATIENTS AND METHODS: Pathway array and tissue microarray (TMA) were used to detect the differential expression of CREB (cAMP-responsive element binding protein) and p-CREB-1 in breast cancer cells, breast cancer stem cells (BCSCs), human breast cancer tissues (BCTs), and adjacent normal tissues (ANTs). The associations between p-CREB-1 expression, clinicopathological variables, and survival rates of the patients were analyzed and calculated. RESULTS: Our results revealed that p-CREB-1 and CREB expression in cancerous cell lines and tissues were significantly upregulated compared with non-cancerous cell lines and tissues. Most statistically significant overexpression was detected in BCSCs (p<0.01). In TMA and immunohistochemical analyses, BCTs exhibited significantly higher expression of p-CREB-1 and CREB than ANTs (p<0.001). Clinicopathological variable and survival analysis revealed a correlation between high expression (++/+++) of p-CREB-1 and the presence of axillary lymph node metastasis (p<0.05) and poorer disease-free and overall survival. CONCLUSIONS: p-CREB-1 is a potential predictive and prognostic biomarker and a promising therapeutic target in breast cancer.

Oil extracts of herbal drugs--optimisation of the extraction parameters.

The plant constituents of fourty two olive oil extracts from chamomile flowers [Chamomilla recutita (L.) Rauschert] were analysed by means of GC, VIS-spectrometry, and HPLC in order to assess the effectiveness of the traditional extraction methods of the German Homoeopathic Pharmacopoeia (HAB 2008). The influence of the extraction temperature and the extraction period as well as the influence of stirring during the extraction period and of a pre-treatment of the herbal drug with ethanol 94% on the extraction efficiency was also studied. The results are presented in the form of transfer ratios with regard to the essential oil, the carotenoids, coumarins, flavonoids and the phenolcarboxylic acids.

To which countries do European psychiatric trainees want to move to and why?

BACKGROUND: There is a shortage of psychiatrists worldwide. Within Europe, psychiatric trainees can move between countries, which increases the problem in some countries and alleviates it in others. However, little is known about the reasons psychiatric trainees move to another country. METHODS: Survey of psychiatric trainees in 33 European countries, exploring how frequently psychiatric trainees have migrated or want to migrate, their reasons to stay and leave the country, and the countries where they come from and where they move to. A 61-item self-report questionnaire was developed, covering questions about their demographics, experiences of short-term mobility (from 3 months up to 1 year), experiences of long-term migration (of more than 1 year) and their attitudes towards migration. RESULTS: A total of 2281 psychiatric trainees in Europe participated in the survey, of which 72.0% have 'ever' considered to move to a different country in their future, 53.5% were considering it 'now', at the time of the survey, and 13.3% had already moved country. For these immigrant trainees, academic was the main reason they gave to move from their country of origin. For all trainees, the overall main reason for which they would leave was financial (34.4%), especially in those with lower (<500€) incomes (58.1%), whereas in those with higher (>2500€) incomes, personal reasons were paramount (44.5%). CONCLUSIONS: A high number of psychiatric trainees considered moving to another country, and their motivation largely reflects the substantial salary differences. These findings suggest tackling financial conditions and academic opportunities.

Essential oil polymorphism in finnish thymus species.

Chemical polymorphism concerning the essential oils of the genus THYMUS is a widespread phenomenon, especially in the northern species. The two Finnish species, T. SERPYLLUM ssp. SERPYLLUM and T. SERPYLLUM ssp. TANAENIS, turned out to form four different chemotypes each, with hedycaryol, germacra-1(10),5-dien-4-ol, germacra-1(10),4-dien-6-ol, linalool, and linalyl acetate as type-characterizing compounds. Otherwise the oils of the two subspecies were similar containing myrcene, TRANS-beta-ocimene, beta-caryophyllene, and germacrene D as the main terpene hydrocarbons. 1,8-Cineol and camphor represented another great portion in both oils. If Finland is regarded as an area of T. SERPYLLUM (s.l.), a total of six types of plants can be defined with regard to the essential oil chemistry only. Including the frequency of these six types at the four areas investigated, a certain gradient from the south to the north can be seen. A most interesting aspect is the fact that the most frequent, linalyl acetate containing chemotype of the northern Lapland has nearly the same oil composition as T. PRAECOX ssp. ARCTICUS in Island, Norway, and Greenland.

A comparative study of the in vitro antimicrobial activity of tea tree oils s.l. with special reference to the activity of beta-triketones.

The in vitro antibacterial and antifungal activities of Australian tea tree oil, cajuput oil, niaouli oil, kanuka oil and manuka oil as well as of a beta-triketone complex isolated from manuka oil were investigated in a constituent-oriented study. The compositions of the oils were analysed by capillary GLC and GLC-MS. The MICs for sixteen different microorganisms were determined applying the broth dilution method. Australian tea tree oil showed the best overall antimicrobial effect. The best inhibitory effects on Gram-positive bacteria and dermatophytes were achieved with manuka oil due to its beta-triketone content.

In vitro evaluation of the antibacterial activity of beta-triketones admixed to Melaleuca oils.

The in vitro antibacterial properties of mixtures of Australian tea tree oil and niaouli oil after adding the beta-triketone complex isolated from manuka oil were tested. MIC and MBC values for four different bacteria were determined applying the broth dilution method. Both Melaleuca oil mixtures showed good antimicrobial effects against Staphylococcus aureus and Moraxella catarrhalis, exceeding the effectiveness of myrtol, which is well established in the treatment of acute and chronic bronchitis and sinusitis. The death kinetics of S. aureus were determined to draw subtle comparisons between the mixtures. The kill rate data indicated that both Melaleuca oil mixtures achieved a complete kill within 240 min.