Experimental Studies with Methylhydrazine Derivatives

Natulan (Procarbazine) is a methylhydrazine derivative which in animal experiments inhibits a series of transplantable tumours. The Walker carcinoma is markedly affected. Even well established Walker tumours disappear completely under Natulan treatment. Tumour tissue is replaced by fibrous tissue. Natulan does not act selectively on neoplastic tissue, it also depresses the growth of other rapidly proliferating tissues such as the bone marrow. As regards the mechanism of action the following data are known: Natulan lowers the mitotic index by prolonging the interphase and hindering the cell from entering into mitosis. In Ehrlich ascites tumour cells chromatid breaks were observed. Natulan depolymerizes deoxyribonucleic acid (DNA) in vitro. In vivo the synthesis of DNA is inhibited. Furthermore alkylation of purine bases has been demonstrated. All these mechanisms may be responsible for the cytotoxic effect of methylhydrazine derivatives. Natulan does not possess cross-resistance towards other cytotoxic agents. This phenomenon is a further proof of its particular mechanism of actio

Protein Kinase Cα Puts the Handcuffs on Epidermal Keratinocyte Proliferation

As the predominant cellular receptor for phorbol esters, protein kinase C (PKC) is assumed to play a role in epidermal carcinogenesis. Nevertheless, determining its exact role in keratinocytes has been difficult because of the existence of multiple PKC isoforms and the inherent weaknesses in methodologies used to investigate their function. In this issue, Jerome-Morais et al. describe their use of multiple in vitro, in situ, overexpression, and knockdown approaches to demonstrate that PKCα induces keratinocyte growth arrest

One Person, How Many Votes? Measuring Prison Malapportionment

“One-person, one-vote” is a fundamental principle of democracy. In practice, however, vote distribution among population groups is often less than equal. Even in established democracies, prison malapportionment—the distribution of legislative seats by counting incarcerated people in their prisons’ districts rather than their home districts—is one example of a practice that distorts voter representation. Prison malapportionment allows less populous districts that house prisons to maximize their voting power at the expense of more densely populated districts from which many incarcerated people previously lived. While there has been significant scholarship on the causes and effects of prison malapportionment, there is no standard method for quantifying the level of distortion that results from the phenomenon. As such, no comparative study of prison malapportionment exists in the international context. This Article presents a method to measure malapportionment that isolates the deviation from “one-person, one-vote” that arises specifically from prison malapportionment. This formula, “PMAL,” facilitates comparative analysis of prison malapportionment among various jurisdictions. It also aids in predicting and evaluating the success of reform efforts

A Hypothesis Concerning a Potential Involvement of Ceramide in Apoptosis and Acantholysis Induced by Pemphigus Autoantibodies

Autoimmune diseases affect more than 50 million Americans, resulting in significant healthcare costs. Most autoimmune diseases occur sporadically; however, endemic pemphigus foliaceus (EPF) is an autoimmune skin disease localized to specific geographic loci. EPF, and the related diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are characterized by skin lesions and autoantibodies to molecules found on epidermal keratinocytes. A variant of EPF in patients from El Bagre, Colombia, South America, has recently been reported to be distinct from previously described loci in Brazil and Tunisia epidemiologically and immunologically. As in PF and EPF, El Bagre EPF patients exhibit autoantibodies towards desmoglein-1, a cell adhesion molecule critical for maintaining epidermal integrity. An association of El Bagre EPF with sun exposure has been detected, and ultraviolet irradiation also exacerbates symptoms in PV, PF and EPF. Our hypothesis is that: (1) the autoantibodies generate pathology through an alteration in ceramide metabolism in targeted keratinocytes, resulting in apoptosis and/or cell death and acantholysis, but only when the cell's ability to metabolize ceramide is exceeded, and (2) apoptosis in response to this altered ceramide metabolism is initiated and/or exacerbated by other agents that increase ceramide levels, such as cytokines, ultraviolet irradiation, and senescence

Zinc accumulation and utilisation by wine yeasts

The present study has focused on the accumulation of zinc by wine yeast strains of Saccharomyces cerevisiae during fermentation of both grape juice and chemically defined medium with different carbohydrates and at varying levels of zinc. The results have shown that zinc accumulation by wine yeast was very rapid with all zinc being removed from the medium by yeast cells within the first two hours. Zinc uptake was stimulated by the presence of sucrose. Zinc affected fermentation progress at defined levels, with optimal concentrations at 1.5–2.5 ppm, depending on yeast strain and zinc bioavailability. The bioavailability of metal ions in grape must and the roles of metals in wine yeast physiology are aspects poorly understood by enologists. In brewing, it has long been recognized that malt wort may be zinc deficient and brewers often carry out zinc supplementations to avoid sluggish and incomplete fermentations. In winemaking, zinc levels in grape musts may be compromised depending on the bioavailability of zinc ions in vineyard soils as well as treatments with fertilizers and fungicides during grape growing. As a consequence, sub-optimal zinc levels in grape musts may negatively influence the fermentative performance of yeasts. We believe that optimization of metal ion bioavailability will improve yeast fermentation performance in industrial processes and this study addresses some issues relating to zinc in enology

8-Cl-Adenosine enhances 1,25-dihydroxyvitamin D(3)-induced growth inhibition without affecting 1,25-dihydroxyvitamin D(3)-stimulated differentiation of primary mouse epidermal keratinocytes

BACKGROUND: Epidermal keratinocytes continuously proliferate and differentiate to form the mechanical and water permeability barrier that makes terrestrial life possible. In certain skin diseases, these processes become dysregulated, resulting in abnormal barrier formation. In particular, skin diseases such as psoriasis, actinic keratosis and basal and squamous cell carcinomas are characterized by hyperproliferation and aberrant or absent differentiation of epidermal keratinocytes. We previously demonstrated that 8-Cl-adenosine (8-Cl-Ado) can induce keratinocyte growth arrest without inducing differentiation. RESULTS: To determine if this agent might be useful in treating hyperproliferative skin disorders, we investigated whether 8-Cl-Ado could enhance the ability of 1,25-dihydroxyvitamin D(3 )[1,25(OH)(2)D(3)], a known keratinocyte differentiating agent and a clinical treatment for psoriasis, to inhibit keratinocyte growth. We found that low concentrations of 8-Cl-Ado and 1,25(OH)(2)D(3 )appeared to act additively to reduce proliferation of primary mouse epidermal keratinocytes. However, another agent (transforming growth factor-beta) that triggers growth arrest without inducing differentiation also coincidentally inhibits differentiation elicited by other agents; inhibition of differentiation is suboptimal for treating skin disorders, as differentiation is often already reduced. Thus, we determined whether 8-Cl-Ado also decreased keratinocyte differentiation induced by 1,25(OH)(2)D(3), as measured using the early and late differentiation markers, keratin 1 protein levels and transglutaminase activity, respectively. 8-Cl-Ado did not affect 1,25(OH)(2)D(3)-stimulated keratin 1 protein expression or transglutaminase activity. CONCLUSIONS: Our results suggest that 8-Cl-Ado might be useful in combination with differentiating agents for the treatment of hyperproliferative disorders of the skin

Is the ebb of asthma due to the decline of allergic asthma? A prospective consultation-based study by the Swiss Sentinel Surveillance Network, 1999-2005

Objective. There are conflicting views on time trends of asthma and atopy during the last 10-15 years. Additional confusion is caused by the term of asthma which is a unifying name for different phenotypes. Asthma has been a topic for investigation to the Swiss Sentinel Surveillance Network (SSSN) since 1989. The objective of the actual study was to determine the influence of the allergic and non-allergic components of asthma on time trends from 1999 to 2005. Methods. Primary care physicians participating in the SSSN were guided by diagnostic criteria for asthma. Rates of asthma episodes per 1000 consultations were calculated for all, for first and subsequent asthma episodes and for allergic and non-allergic asthma. Allergic asthma was defined as asthmatic manifestations in conjunction with eczema and/or hay fever. The smoothed time trend and its 95% confidence intervals were determined using generalized additive models with a loess smoother adjusting for seasonality. Results. Consultations for allergic asthma have decreased between 1999 and 2005. Looking at different age groups, asthma associated with hay fever was reported with decreasing frequency in all age groups, whereas when associated with eczema, the other used marker of allergic asthma, slightly increased among young children. Conclusions. The decrease of consultations for asthma is most probably due to the allergic component of asthma. Diagnostic shift over time and ready available medications probably contributed to this phenomenon. Our findings indicate a real decline of allergic asthma. Practice recommendations. Consultations for asthma have decreased over recent years. The decrease of consultations for asthma is most probably due to the allergic component of asthma. Diagnostic shift over time and available medications probably contributed to this phenomenon. Strength of Recommendation Taxonomy (SORT) rating: strength of recommendation = C, level of evidence = 

Sickness certification in primary care - the physician's role.

Sickness certification is a routine task of primary care (PC) physicians which has an impact on patients' health, the health care system and the economy. As sickness certification is poorly studied, we quantified sickness certification and explored qualitatively the sickness certification process by Swiss PC physicians. PC physicians participating in the Swiss Sentinel Surveillance Network (SSSN) recorded the frequency and duration of absence from work of each related consultation and certificate during 2005. Patients' age and gender, reason for sick leave, psychosocial cofactors, problems at the workplace, type of employment, type of occupation, duration of absence (weeks) and type of certificate were registered. Physicians' views on the procedure and their suggestions for change were gathered before and after the study by means of a questionnaire containing four open-ended questions. Of the 223 SSSN physicians 73% participated. A total of 24,676 forms issued by 150 physicians were analysed. An average of four certificates was issued per 100 consultations; somewhat fewer by internists than by general practitioners and less in rural areas than urban areas. Psychosocial or work-related factors were mentioned in 20% of the certificates and were more often associated with longer absences from work. These factors were seen as inseparable from the somatic factors. Recommendations for change included the prolongation of self declaration time, a uniform declaration form, availability of an authority to which complex cases can be referred and the use of case management models. Sickness certificates were issued in 4% of GP consultations. This task has been assessed by physicians as part of their function. The certification process should be improved through better coordination and communication between all parties involved: patients, employers, insurers, physicians and politicians