Rotating night shift work and menopausal age.

STUDY QUESTION: How are rotating night shift schedules associated with age at menopause among a large, national cohort of shift working nurses? SUMMARY ANSWER: Our findings suggest that working rotating night shifts with sufficient frequency may modestly accelerate reproductive senescence among women who may already be predisposed to earlier menopause. WHAT IS KNOWN ALREADY: Younger age at menopause has been associated with increased risk of adverse health outcomes, particularly those linked to reproduction. Night work has been associated with reproductive dysfunction, including disruption of menstrual cycle patterns. STUDY DESIGN, SIZE, DURATION: This cohort study was conducted among 80 840 women of the Nurses' Health Study 2 (NHS2), with prospective follow-up from 1991 through 2013. Loss-to-follow-up of the NHS2 is estimated to be <10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed the association between cumulative and current rotating night shift work and age at natural menopause over 22 years of follow-up (1991-2013). Cox proportional hazards models were used to estimate hazard ratios (HR) for menopause, adjusted for age, smoking status, body mass index, physical activity, alcohol consumption, reproductive factors and exogenous hormone use. MAIN RESULTS AND THE ROLE OF CHANCE: Over follow-up, 27 456 women (34%) reached natural menopause. Women who worked 20 or more months of rotating night shifts in the prior 2-year had an increased risk of earlier menopause (multivariable-adjusted (MV)-HR = 1.09, 95% CI: 1.02-1.16) compared to women without rotating night shift work. This risk was stronger among women undergoing menopause or otherwise censored under age 45 years (MV-HR = 1.25, 95% CI: 1.08-1.46), than it was for those continuing in the study when >45 years old (MV-HR = 1.05, 95% CI: 0.99-1.13). Working 10 or more years of cumulative rotating night work was also associated with higher risk of menopause among women reaching menopause under age 45 (MV-HR10-19 years = 1.22, 95% CI: 1.03-1.44; MV-HR≥20 years = 1.73, 95% CI: 0.90-3.35), though not over the age of 45 years (MV-HR10-19 years = 1.04, 95% CI: 0.99-1.10; MV-HR≥20 years = 1.01, 95% CI: 0.89-1.15). LIMITATIONS, REASONS FOR CAUTION: The degree to which observed effects of rotating night shifts on age at natural menopause are due to circadian disruption, rather than fatigue and stress associated with working more demanding schedules, is uncertain due to potential residual confounding by these factors. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess the effects of night work on menopausal timing among a larger national cohort of shift working women. Women already prone to earlier menopause may further truncate their reproductive lifetime by working schedules comprising day as well as night shifts. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Center for Disease Control and Prevention/The National Institute for Occupational Safety and Health Grant 5R01OH009803 (PI: Schernhammer E), as well as UM1 CA176726 from the National Institute of Health. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; and decision to submit the article for publication. The authors have no conflicts of interest.

Alcohol use and mental health symptoms in female firefighter recruits.

BACKGROUND: Limited research suggests that female firefighters report problem drinking at higher rates than the general population. AIMS: To identify longitudinal drinking patterns in female firefighters, make comparisons to male firefighters and examine problem drinking in relation to post-traumatic stress disorder (PTSD) and depression. METHODS: Study participants included 33 female and 289 male firefighter recruits, who were assessed over their first 3 years of fire service. RESULTS: Female firefighters consumed increasing numbers of drinks per week, with a median of 0.90 drinks per week at baseline, and 1.27 drinks in year 3. Female firefighters reported binge drinking at high rates, with nearly half binging at least once per year across all time points (44-74%). The percentage that reported binge drinking three or more times per month doubled over the course of the study (from 9% to 18%). Overall, males reported higher rates of binge drinking and a greater number of drinks per week; however, binge drinking rates among females increased over time and became comparable to rates of binge drinking among males. A greater percentage of female than male firefighters met the criteria for problem drinking by year 1. Problem drinking was associated with screening positive for PTSD at year 1 and depression at year 2, but not with occupational injury. CONCLUSIONS: Over time, female firefighters reported increasing amounts of drinking, more frequent binge drinking and more negative consequences from drinking. These findings along with existing literature indicate female firefighters change their drinking in the direction of their male counterparts.

Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry.

BACKGROUND: Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention. METHODS: Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status. RESULTS: High parity (≥3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk. CONCLUSIONS: Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients.

BACKGROUND: In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs. METHODS: Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival. RESULTS: In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4-7.4, P<10(-6)) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9-21.7, P<10(-17)), but was not associated with patient survival. Concordant results were obtained in Newfoundland. CONCLUSION: Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.

Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations.

BACKGROUND: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. METHODS: We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. RESULTS: For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. CONCLUSION: First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

Association of apolipoprotein E polymorphisms and dietary factors in colorectal cancer.

ApoE single nucleotide polymorphisms (SNPs) Cys112Arg (Epsilon-4), and Arg158Cys (Epsilon-2) have been implicated in cardiovascular and Alzheimer's disease, but their role in colorectal cancer (CRC) has not been extensively studied. We investigated whether ApoE polymorphisms alone or in combination with dietary factors selectively contribute to mismatch-repair (MMR) proficient (microsatellite stable/low or MSS/L) vs deficient (microsatellite unstable or MSI-H) CRCs. We carried out a case-control study with 906 CRC cases and 911 unaffected controls to examine the associations between ApoE polymorphisms and dietary factors and assessed their contribution to MSS/L and MSI-H CRCs. We used unconditional logistic regression to evaluate the associations between ApoE SNPs, tumour MSI status, and dietary factors after adjusting for age and sex. All statistical tests were two-sided. No significant differences in ApoE genotype frequencies were observed between CRC cases and unaffected controls. We observed that increased dietary intake of total fat, saturated fat, cholesterol, and red meat was significantly associated with CRC. Among non-ApoE4 carriers, 2-4 and >4 red meat servings/week were associated with developing MSS/L CRC (OR=1.51, 95% CI 1.10-2.07 and OR=1.80, 95% CI 1.30-2.48, respectively), whereas among ApoE4 allele carriers, four or more red meat servings/week were associated with MSI-H CRC (OR=4.62, 95% CI 1.20-17.77) when compared with the controls. ApoE isoforms modulate the risk of MSI-H and MSS/L CRCs among high red meat consumers.

Functional characterization of novel presenilin-2 variants identified in human breast cancers.

We identified in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2), a gene involved in familial Alzheimer's disease (FAD). The role of these alleles in FAD is unclear, but neither allele affected Abeta(42)/Abeta(40) ratio. However, both R62H and R71W alterations compromised PS-2 function in Notch signaling in Caenorhabditis elegans and cell growth inhibition in mouse embryonic fibroblasts, and these effects were dependent on gene dosage. We found that both alterations enhanced the degradation of the PS-2 full-length protein, indicating that they may have a loss-of function effect. The effect of the R71W alteration was noticeably stronger, and we observed an almost threefold higher frequency of this allele in breast cancer cases versus controls, but this difference did not reach statistical significance. Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer.

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

Mammographic densities and risk of breast cancer among subjects with a family history of this disease.

BACKGROUND: A family history of breast cancer is known to increase risk of the disease, but other genetic and environmental factors that modify this risk are likely to exist. One of these factors is mammographic density, and we have sought evidence that it is associated with increased risk of breast cancer among women with a family history of breast cancer. METHODS: We used data from a nested case-control study based on the Canadian National Breast Screening Study (NBSS). From 354 case patients with incident breast cancer detected at least 12 months after entry into the NBSS and 354 matched control subjects, we analyzed subjects who were identified as having a family history of breast cancer according to one of three, nonmutually exclusive, criteria. We compared the mammographic densities of case patients and control subjects by radiologic and computer-assisted methods of measurement. RESULTS: After adjustment for other risk factors for breast cancer, the relative risks (RRs) between the most and least extensive categories of breast density were as follows: For at least one first-degree relative with breast cancer, RR = 11.14 (95% confidence interval [CI] = 1.54-80.39); for at least two affected first- or second-degree relatives, RR = 2.57 (95% CI = 0.23-28.22); for at least one first- or second-degree relative with breast cancer, RR = 5.43 (95% CI = 1.85-15.88). CONCLUSIONS: These results suggest that mammographic density may be strongly associated with risk of breast cancer among women with a family history of the disease. Because mammographic densities can be modified by dietary and hormonal interventions, the results suggest potential approaches to the prevention of breast cancer in women with a family history of breast cancer.

Neutral protease inhibitors from human intervertebral disc and femoral head articular cartilage.

Assays of several proteases, incorporating guanidinium chloride extracts of human femoral head cartilage and intervertebral disc, demonstrated that both tissues contain inhibitors of certain serine proteases. Trypsin, chymotrypsin and a granule extract of human polymorphonuclear leukocytes containing elastase and cathepsin G activities, were inhibited by low molecular weight fractions prepared by Sephadex G-75 chromatography. Using a radioassay, it was further shown that these fractions inhibit proteolysis of cartilage proteoglycan. The inhibitor in intervertebral disc is concentrated in the nucleus pulposus, with a decreasing gradient to the periphery of the annulus fibrosus. It is proposed that these inhibitors confer at least partial protection against pathological proteolysis of the proteoglycans in human articular cartilage and nucleus pulposus.

New antibiotic resistance Loci in the ribosomal region of yeast mitochondrial DNA.

A large number of mitochondrial antibiotic-resistant mutants have been isolated following mutagenesis with manganese. These include several different phenotypic classes of mutants, as distinguished by cross-resistance patterns, that have been found to be allelic at cap1 or ery1; some have been found to be heteroallelic.--Seven chloramphenicol-resistant mutants have been identified that are nonallelic by recombination tests with the three loci (cap1, spi1 and ery1) previously identified in the ribosomal region. Four of these are allelic with each other and define a new locus, cap3; two others are allelic and define another new locus, cap2; the seventh maps at yet a different locus, cap4. One new spiramycin-resistant mutant has been identified that defines still another new locus, spi2. A variety of genetic techniques have been used to map these loci within the ribosomal region of the mitochondrial genome.-Manganese has been shown to be effective in inducing the mutation from omega(-) to omega(n) in many mutants that experience a simultaneous mutation at the closely linked cap1 locus. The omega(n) mutation has also been described in the cap4 mutant, and this locus has been shown to be more closely linked to omega than cap1 is to omega.

Variation of long-lived free radicals responsible for the EPR native signal in bone of aged or diseased human females and ovariectomized adult rats.

The purpose of this study was to gain insights into the variations seen in the electron paramagnetic resonance (EPR) spectroscopy of the native signals of teeth and bones used for retrospective dosimetry measurements. We determined that changes occur in the long-lived free radicals responsible for the native signal of cortical bone in aging or diseased human females and aged ovariectomized rats. This was done by measuring the magnitude of the broad (BC) and narrow (NC) components of the native EPR signal of bone following chemical extraction, aging, crushing and thermal annealing. Bone from the upper midshaft of femora of young (17-34 years old, n=5) and elderly (70-92 years old, n=18) females was examined. The results showed that the elderly women had significantly higher BC than the younger women (P<0.01). A similar interpretation was made of the data from an aging female rat osteoporosis model. The results for the NC signals were similar. Finally, dramatic decreases in both NC and BC signals were seen in HIV positive and uncontrolled diabetic (one each) patients indicating the need for studying this signal for a broad spectrum of metabolic disorders. Experiments were performed which strongly indicate that iron liganded with organic molecules is the source of the BC signal. Finally, the accuracy achieved in this study indicates that resolving the dosimetric signal (g=2.0018) should be improved by subtraction of the deconvoluted NC and BC signals from the original spectrum.

Macronutrient intake and change in mammographic density at menopause: results from a randomized trial.

To examine the effects of dietary fat intake on breast cancer risk, we are conducting a randomized trial of dietary intervention in women with extensive areas of radiologically dense breast tissue on mammography, a risk factor for breast cancer. Early results show that after 2 years on a low-fat, high-carbohydrate diet there is a significant reduction in area of density, particularly in women going through menopause. In women who went through menopause during the 2-year follow-up, the mean decreases in area of density and percentage of density in the intervention group were 11.0 cm2 and 11.0%, respectively, whereas the control group decreased 4.5 cm2 and 5.2%. The purpose of this analysis was to determine whether changes in intake of specific macronutrients could account for the observed reduction in breast density in these women. Differences between 2-year and baseline values of macronutrients (averaged over 3 nonconsecutive days of food intake) were calculated. We examined the effect of dietary variables, adjusted for changes in total calorie intake and weight and for family history of breast cancer, on changes in area of density and percentage of density using linear regression. Reduction in total or saturated fat intake or cholesterol intake was significantly associated with decreased dense area (p < or = .004). The most significant dietary variable associated with reduction in percentage of density was reduction in dietary cholesterol intake (P = 0.001), although reducing saturated fat intake was of borderline significance (P = 0.05). The effect of the membership in the intervention and control groups on change in area of density or percentage of density was reduced by models that included changes in intake of any fat, or cholesterol, or carbohydrates. The observation of an effect of diet at menopause on breast density, a marker of increased risk of breast cancer, may be an indication that exposures at this time have an enhanced effect on subsequent risk.

Pathophysiologic role of alpha 4 integrins in the lung.

Evidence for a central role for the integrins alpha 4 beta 1 and alpha 4 beta 7 in leukocyte pathophysiology is rapidly accumulating. Five distinct alpha 4 mAbs, each able to block alpha 4-dependent adhesion in vitro, show beneficial effects in vivo in six different species, and in a wide variety of organ systems, including colon, lung, skin, neural tissue, pancreas, peritoneum, and the vessel wall. In particular, a clear role for these integrins in lung pathophysiology is implied on the basis of in vivo studies in four different species. Although several issues remain to be resolved, including the relative importance of alpha 4 beta 1 and alpha 4 beta 7, and the relative roles of their counterligands, VCAM1, fibronectin, and MAdCAM, the data argue that alpha 4 integrins will likely be critical to both the normal physiology and pathology of the lung in man. To this end, we (Adams, Lin, Lobb, and Gill, unpublished data) and others have generated peptidomimetic small molecule antagonists of VLA4 based on the connecting segment 1 (CS1) peptide sequence of fibronectin that are potent blockers of integrin adhesive function in vitro and show efficacy in vivo. We have found that our inhibitors are excellent blockers of both murine contact hypersensitivity, and of the LPR and AHR in the sheep allergic airways model (Abraham, Lobb, Adams, and Gill, unpublished data), and are therefore possible candidates for clinical intervention in human asthma. The use of the VCAM-Ig fusion protein as a probe for high-affinity alpha 4 integrins has further enhanced our understanding of alpha 4 integrin function in the lung. While integrin upregulation in vitro has been observed many times, and high affinity (as opposed to avidity) of integrins seen in vitro in several systems, in vivo proof of integrin upregulation to a high-affinity state has been difficult to obtain in the absence of selective probes. Our data provide key information in this regard and strongly argue not only that integrin upregulation does indeed occur in vivo, but also that it is in fact obligatory for the leukocyte pathologies we have examined to date. Further studies are clearly warranted to further examine mechanisms of action, and to confirm and extend these studies, both with the alpha 4 integrins and with other integrin families. In summary, our studies of alpha 4 integrins continue to provide novel insights into the pathophysiology of integrin function and into future directions for drug discovery.

Standard lecithin/sphingomyelin and phosphatidylglycerol techniques compared with immunologic slide test.

A commercially available, rapid, technically simple, immunologic slide agglutination test for amniotic fluid (AF) phosphatidylglycerol has been compared with the lecithin/sphingomyelin (L:S) ratio and phosphatidylglycerol determined by thin-layer chromatography. The immunologic test lacks sensitivity when compared with phosphatidylglycerol measured by thin-layer chromatography, and both phosphatidylglycerol measurements are considerably less sensitive than the L:S ratio. The authors' results suggest that the immunologic test is probably useful as a screening test, but all negative results should be immediately followed up with an L:S ratio and phosphatidylglycerol measured by thin-layer chromatography.

Changes in median nerve somatosensory transmission and motor output following transient deafferentation of the radial nerve in humans.

OBJECTIVE: To determine if transient anaesthetic deafferentation of the radial nerve would lead to alterations in processing of early somatosensory evoked potentials (SEPs) from the median nerve or alter cortico-motor output to the median nerve innervated abductor pollicis brevis (APB) muscle. METHODS: Spinal, brainstem, and cortical SEPs to median nerve stimulation were recorded before, during and after ipsilateral radial nerve block with local anaesthesia. Motor evoked potentials (MEPs) and motor cortex output maps were recorded from the APB muscle. RESULTS: There were no significant changes to most early SEP peaks. The N30 peak, however, showed a significant increase in amplitude, which remained elevated throughout the anaesthetic period, returning to baseline once the anaesthetic had completely worn off. MEP amplitude of the median nerve innervated APB muscle was significantly decreased during the radial nerve blockade. There was also a significant alteration in the APB optimal site location, and a small but significant decrease in the silent period during the radial nerve blockade. CONCLUSIONS: Transient anaesthetic deafferentation of the radial nerve at the elbow leads to a rapid modulation of cortical processing of median nerve input and output. These changes suggest an overall decrease in motor cortex output to a median nerve innervated muscle not affected by the radial nerve block, occurring concomitantly with an increased amplitude of the median nerve generated N30 SEP peak, thought to represent processing in the supplementary motor area (SMA). Independent subcortical connections to the SMA are thought to contribute to the N30 response observed in this study. Unmasking of pre-existing but latent cortico-cortical and/or thalamo-cortical connections may be the mechanism underlying the cortical SEP increases observed following radial nerve deafferentation. SIGNIFICANCE: Transient deafferentation of the radial nerve, which supplies wrist and hand extensor muscles, has been shown to alter sensory processing from and motor output to the median nerve innervated thenar muscles.

Mammographic densities and breast cancer risk.

Variations between individuals in the radiographic appearance, or mammographic pattern, of the female breast arise because of differences in the relative amounts and X-ray attenuation characteristics of fat and connective and epithelial tissue. Studies using quantitative methods of assessment have consistently shown these variations to be strongly related to risk of breast cancer. Individuals with extensive areas of radiologically dense breast tissue on the mammogram have been found to have a risk of breast cancer that is four to six times higher than women with little or no density. In this paper, we propose a model for the relationship of mammographic densities to risk of breast cancer. We propose that the risk of breast cancer associated with mammographically dense breast tissue is due to the combined effects of two processes: cell proliferation (mitogenesis), induced by growth factors and sex hormones and influenced by reproductive risk factors for breast cancer; and damage to the DNA of dividing cells (mutagenesis) by mutagens generated by lipid peroxidation. We review the evidence that each of these processes is associated with mammographic densities and propose further work that we believe should be done to clarify these relationships.

Parental occupational exposure and the risk of testicular cancer in Ontario.

The incidence of germ cell testicular cancer is increasing, but its etiology remains largely unknown. Initiation may occur in a parental germ cell. In a case-control study in Ontario, jobs and industries of mothers (before and during pregnancy) and fathers (before pregnancy) of 343 case subjects and 524 control subjects were analyzed. Significantly increased risk was associated with fathers who were wood processors (odds ratio [OR] = 10.46; 95% confidence interval [CI], 1.20 to 91.14), metalworkers (OR = 3.28; 95% CI, 1.03 to 10.52), stationary engineers (OR = 1.05; 95% CI, 1.05 to 11.87), or employees of the food products (OR = 2.79; 95% CI, 1.34 to 5.79), metal products (OR = 5.77, 95% CI, 1.53 to 21.77), or food and beverage services (OR = 4.36; 95% CI, 1.50 to 12.63) industries. There was little evidence of risk associated with maternal employment. Paternal employment before conception in jobs related particularly to metal or food and beverages may be related to testicular cancer risk in sons.

Occupation and risk of germ cell testicular cancer by histologic type in Ontario.

Incidence of both major histologic subgroups of germ cell testicular cancer, seminoma and nonseminoma, is increasing, but the etiology is largely unknown. Occupational clusters have been observed. In a case-control study in Ontario with 495 incident cases and 974 population control subjects, jobs and industries were coded and analyzed. There is little evidence of occupational risk for all cases or for seminoma. Significantly increased risk of nonseminoma was associated with: miners (odds ratio [OR] = 12.39; 95% confidence interval [CI], 2.22 to 69.27), food and beverage processors (OR = 3.20; 95% CI, 1.39 to 7.35), utilities employees (OR = 3.15; 95% CI, 1.15 to 8.61), and other service workers (OR = 1.05; 95% CI, 1.05 to 4.56). Leather-industry employees had elevated risk of nonseminoma (OR = 4.60; 95% CI, 0.75 to 28.28) consistent with a leather tannery cluster. Increased risk of nonseminoma among some workers can be explained if an additional event is required for converting seminoma to nonseminoma.