Altered expression patterns of clock gene mRNAs and clock proteins in human skin tumors

The majority of our genes may be regulated in a daily rhythm, including the genes for cell cycle control. Epidemiological and genetic evidences suggest that disruption of circadian timing mechanisms makes our cells more vulnerable to cancer formation. The aim of this study was to investigate the relationship between expression patterns of circadian clock genes (period homolog (per)1, per2, clock, and cry1) and tumor development by analyzing human skin biopsies of malignant melanoma and nonmalignant naevus tumors. We found that mRNA levels and nuclear immunopositivity for the investigated clock genes were reduced by 30–60 % in both melanoma and in naevus biopsies if compared with adjacent nontumorous samples. The alterations in melanoma presented significant associations with clinicopathological characteristics (e.g., Breslow thickness). Contrary to previous reports, the moderate decrease of per1 expression seen in malignant tissues could not be linked to malignant transformation itself; rather, it reflects only the alterations in tissue composition. In turn, clock expression was upregulated in nontumorous cells of melanoma biopsies but not in melanoma cells or naevus cells. As this gene (clock) is closely related to cellular metabolism, our data suggest its role in the impaired regulation of metabolism in malignant tumors. Our results present the first clinical evidence for a possible link between circadian clock genes and human skin tumorigenesis.     

A community-based trial of an online intimate partner violence CME program

BACKGROUND: There is a broad need to improve physician continuing medical education (CME) in the management of intimate partner violence (IPV). However, there are only a few examples of successful IPV CME programs, and none of these are suitable for widespread distribution. DESIGN: Randomized controlled trial beginning in September 2003 and ending in November 2004. Data were analyzed in 2005. SETTING/PARTICIPANTS: Fifty-two primary care physicians in small (fewer than eight physicians), community-based medical offices in Arizona and Missouri. INTERVENTION: Twenty-three physicians completed a minimum of 4 hours of an asynchronous, multi-media, interactive, case-based, online CME program that provided them flexibility in constructing their educational experience ("constructivism"). Control physicians received no CME. MAIN OUTCOME MEASURES: Scores on a standardized self-reported survey, composed of ten scales of IPV knowledge, attitudes, beliefs, and self-reported behaviors (KABB) administered before randomization and repeated at 6 and 12 months following the CME program. RESULTS: Use of the online CME program was associated with a significant improvement in eight of ten KABB outcomes, including physician self-efficacy and reported IPV management practices, over the study period. These measures did not improve in the control group. CONCLUSIONS: The Internet-based CME program was clearly effective in improving long-term individual educational outcomes, including self-reported IPV practices. This type of CME may be an effective and less costly alternative to live IPV training sessions and workshops.     

Radiation-Related Deregulation of TUBB3 and BRCA1/2 and Risk of Secondary Lung Cancer in Women With Breast Cancer

IntroductionBreast cancer survivors are at increased risk of developing unrelated primary cancers, particularly lung cancer. Evidence indicates that sex hormones as well as a deregulation of DNA-repair pathways may contribute to lung cancer onset. We investigated whether the hormone status and expression of markers involved in DNA repair (BRCA1/2, ERCC1, and P53R2), synthesis (TS and RRM1), and cell division (TUBB3) might be linked to lung cancer risk.Patients and MethodsThirty-seven breast cancer survivors with unrelated lung cancer and 84 control subjects comprising women with breast cancer (42/84) or lung cancer (42/84) were enrolled. Immunohistochemistry on tumor tissue was performed. Geometric mean ratio was used to assess the association of marker levels with patient groups.ResultsEstrogen receptor was expressed in approximately 90% of the breast cancer group but was negative in the majority of the lung cancer group, a result similar to the lung cancer control group. Likewise, ER isoform β was weakly expressed in the lung cancer group. Protein analysis of breast cancer versus control had a significantly lower expression of BRCA1, P53R2, and TUBB3. Likewise, a BRCA1 reduction was observed in the lung cancer group concomitant with a BRCA2 increase. Furthermore, BRCA2 and TUBB3 increased in ipsilateral lung cancer in women who had previously received radiotherapy for breast cancer.ConclusionThe decrease of DNA-repair proteins in breast cancer could make these women more susceptible to therapy-related cancer. The increase of BRCA2 and TUBB3 in lung cancer from patients who previously received radiotherapy for breast cancer might reflect a tissue response to exposure to ionizing radiation.     

Economic recession and first births in Europe: recession-induced postponement and recuperation of fertility in 14 European countries between 1970 and 2005

Objectives

The economic crisis that emerged after 2008 caused speculation about further postponement of fertility and a recession-induced baby-bust in countries affected by the economic downturn. This paper aims to disentangle short-term and long-term effects of economic context on entry into parenthood and explores variation of postponement and recuperation by age, gender, educational level and welfare state context.

Methods

Random-effects complementary log–log models including macro-level indicators are used to analyse longitudinal microdata on 12,121 first births to 20,736 individuals observed between 1970 and 2005.

Results

Adverse economic conditions and high unemployment significantly reduce first birth hazards among men and women below age 30, particularly among the higher educated. After age 30 economic context continues to affect first birth hazards of men, but not for women. Recuperation of fertility is further associated with access to labour markets and entry into cohabiting unions.

Conclusions

The continuing postponement of first births has clear medical consequences and implications for health policies. Preventive policies should take access to labour markets for younger generations into account as an important factor driving postponement.     

Course of cerebral lesions in a patient with periarteritis nodosa studied by magnetic resonance imaging

Summary The course is reported of a patient with periarteritis nodosa who initially presented with neurological symptoms. Multiple cerebral lesions were documented by the first magnetic resonance imaging (MRI) investigation. The majority of these had disappeared completely in the follow-up MRI studies. In contrast to neurological improvement the patient eventually died due to multiorgan failure. Postmortem histological examination revealed no pathological findings in the brain except one single necrotic area already known from MRI. Remissions of histological and angiographic alterations in periarteritis nodosa have been described as local healing leading to fibrosis and scarring. Our findings suggest that restitutio ad integrum may occur, at least in cerebral lesions.Abbreviations PAN panarteritis nodosa - MRI magnetic resonance imaging - CT computerized tomography - CNS central nervous system     

Protein kinase inhibitor as a potential candidate for epilepsy treatment

Purpose: Effects of the “VID‐82925” kinase inhibitor molecule were investigated both during the developing phase as well as during the stable phase of the focus with spontaneous recurrent seizures using the 4‐AP‐induced in vivo epilepsy model in anesthetized rats. Methods: In electrophysiologic experiments, VID‐82925 (0.85 mg/kg) was injected intravenously either before the induction (pretreatment) or after the development of the stable focus (treatment). Reference drugs carbamazepine (4.8 mg/kg) and levetiracetam (50 mg/kg) were employed using the same experimental paradigm. The antiepileptic effect of VID‐82925 was also compared to those of the broad‐spectrum gap junction channel blocker carbenoxolone (10 mm ). Key Findings: Pretreatment with VID‐82925 revealed an antiepileptogenic effect as it suppressed significantly the manifestation of the epileptiform activity not only during the developing phase, but also for a considerable long period during the stable phase of the focus. The current data do not allow us to differentiate an antiictal treatment effect from an antiepileptogenic effect of the compound during the stable phase of the focus. Treatment with VID‐82925 was also effective against ictogenesis during the stable phase of the focus. Pretreatment with levetiracetam failed to exert any antiepileptogenic effect. The antiepileptic effects of VID‐82925 and of the reference drugs on the epileptiform activity of the stable focus were comparable in intensity; however, the effect of VID‐82925 was 2–3 times longer. The effects of VID‐82925 and of carbenoxolone overlapped one another to some extent, suggesting that VID‐82925 may exert its effects at least partially through blocking of gap junctional communication. Significance: Our results indicate that inhibition of protein kinases may also provide an effective strategy for the development of a drug that is not only antiepileptic but also depresses the course of epileptogenesis.     

Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma

Medulloblastoma (MB) represents approximately 4% of adult brain tumours, and as such is a poorly studied disease. Although many adult MB are treated using paediatric MB protocols, the reported outcomes are inferior to those observed in children. It remains unclear whether biologic differences underlie these clinical observations. We investigated the molecular characteristics of 31 adult MB. Twelve and 19 adult MB were respectively examined using Affymetrix-HG-U133-plus-2.0-genechips and immunohistochemical analyses. 26/31 (84%) of adult MB examined by gene expression and/or immunohistochemical analysis showed evidence of sonic hedgehog (SHH) pathway activation. A comparison of adult and paediatric MB showed that most adult tumours cluster within the SHH-active subgroup of paediatric MB. The preponderance of SHH activity in adult MB tumours was also shown by positive SFRP1 immunostaining in 16/19 adult paraffin-embedded adult MB tumour blocks. A smaller proportion of adult tumours exhibited evidence of WNT pathway activation, as confirmed by nuclear β-catenin staining (9.7%; 3/31). Notably, we found PTCH1 gene mutation in 4/8 samples tested. Similar to children, adult MB has abnormalities in developmental signalling pathways including SHH and WNT. Importantly, we found a preponderance of SHH pathway activation amongst MB tumours in adults. This SHH signature does not appear to correlate with a long-term favourable outcome. Differences in molecular profiles exist between adult and paediatric SHH-driven MB and further investigations are needed to better characterize age-related molecular profiles in this subgroup.     

Adjunctive supragingival irrigation with acetylsalicyclic acid in periodontal supportive therapy

Abstract To assess the clinical efficacy of adjunctive supragingival irrigation with buffered 0.3% acetylsalicylic acid (ASA), 60 patients with periodontitis receiving supportive periodontal therapy were randomly assigned to 1 of 3 home regimens: (1)1 × daily adjunctive supragingival irrigation with 300 ml water immediately followed by 200 ml of buffered 0.3% ASA; (2) 1 × daily adjunctive supragingival irrigation with 500 ml water; or (3) normal oral hygiene alone. Clinical parameters were assessed at baseline and 6 months. Irrigator use was measured by timers built into the irrigator units. Results at 6 months showed that both supragingival irrigation with buffered 0.3% ASA and supragingival irrigation with water significantly reduced gingival index scores (median 0.1 and 0.35, respectively) and pocket probing depths (both median 0.26 mm) compared to the control group. In addition, irrigation with water resulted in a significant reduction in bleeding on probing (median 0.13), whereas irrigation with buffered 0.3% ASA had no significant effect on bleeding on probing compared to the control group. The clinical efficacy of irrigation with either ASA or water was found to be positively correlated to initial disease severity and irrigator use. Thus, frequent supragingival irrigation with either 0.3% ASA or water in addition to regular oral hygiene appears to be a beneficial adjunct to periodontal supportive therapy in patients with moderate to severe signs of periodontitis. However, the use of buffered 0.3% ASA as an irrigant does not seem to enhance the clinical efficacy of supragingival irrigation on periodontal health.