Covid-19 management by farmers and policymakers in Burkina Faso, Colombia and France: Lessons for climate action.

CONTEXT: During crises, adaptation or recovery measures or plans at local or national scales may not necessarily address longer-term or structural problems such as climate change mitigation. OBJECTIVE: This article describes farmers and policymakers' responses to mitigate the adverse effects of Covid-19 on the agricultural sector. We then assess the responses' possible effects on greenhouse gas (GHG) emissions. METHODS: The study is based on surveys conducted with farmers, traders, and extension staff in Burkina Faso, Colombia, and France, and literature. We used the Cool Farm Tool calculator to assess GHG emissions associated with fertilizer production, crop production and produce transportation to international markets for the three main cash crops in the three countries. RESULTS AND CONCLUSIONS: We identified contrasting responses by the agricultural sector mostly driven by changes in the consumption patterns at local or international levels. We also identified contrasting state responses to mitigate Covid-19. These responses at farm and policy scales led to similar trends in decreasing carbon dioxide (CO2) emissions across the studied countries. However, none of the studied countries linked Covid-19 response measures to long-term climate change mitigation actions. Therefore, an opportunity to sustain Covid-19 induced short-term decreases in GHG emissions was overlooked. SIGNIFICANCE: Analyzing the impacts that Covid-19 had on agricultural systems and the decision taken by policymakers to handle its direct and indirect effects can help society draw lessons on how to improve climate action.

[Lapeyronie disease's treatment]. / Traitement de la maladie de Lapeyronie.

Lapeyronie's disease occurs mostly in middle age men and consists in pain and bending or arching of the penis during erection. This could negatively impact quality of life. A good knowledge of the physiopathology is necessary to adapt the different treatment modalities.

Strong association between c-myb and oestrogen-receptor expression in human breast cancer.

Previous articles have reported that the c-myb proto-oncogene was activated in various types of tumours of the hematopoietic system suggesting that this gene plays a role in the development of these malignancies. However no studies of the c-myb gene have as yet been performed in solid primary tumours. In the present study we have analysed in breast cancer the c-myb gene with the aim to determine its involvement in tumour progression. Expression of the c-myb oncogene was analysed from 169 carcinoma specimens obtained from untreated patients with non-inflammatory breast cancer (NBC) (112 patients) and inflammatory breast cancer (IBC) (57 patients). A 3.5 kb c-myb transcript band was detected in 108 (64%) tumours. c-myb expression was found to be associated with good prognostic factors (lowest histopathologic grade (P = 0.01), oestrogen and progesterone receptor status (P less than 10(-4)) and pS2 gene expression (P less than 10(-4)) and negatively correlated with breast cancers of poorer prognosis, namely IBC (P = 0.03) and NBC with multiple involved nodes (P = 0.15). Other genes (c-myc, c-erbB2, c-fos and epidermal growth factor receptor) were also studied. The c-myb gene expression was found to be inversely correlated (P less than 0.03) with only c-erbB2 overexpression in NBC. When data were analysed with a logistic regression model using a stepwise procedure, c-myb expression was found to be associated only with the oestrogen receptor status (P less than 10(-4)). In conclusion, our data indicate that analysis of c-myb expression in breast cancer could allow the characterization of a new class of oestrogen-dependent tumours.

Degradation of fluorescent and radiolabelled sphingomyelins in intact cells by a non-lysosomal pathway.

The aim of the present study was to investigate the role of the entitled neutral, sphingomyelinase in the non-lysosomal pathway of sphingomyelin degradation by intact cells (Spence et al. (1983) J. Biol. Chem. 258, 8595-8600; Levade et al. (1991) J. Biol. Chem. 266, 13519-13529). The uptake and degradation of sphingomyelin by intact living cells was studied using cell lines exhibiting a wide range of activity levels of acid, lysosomal and neutral sphingomyelinases as determined in vitro on cell homogenates by their respective standard assays. For this purpose, neuroblastoma, skin fibroblasts, lymphoid and leukemic cell lines, some of them derived from patients with Niemann-Pick disease (deficient in the acid, lysosomal sphingomyelinase) were incubated with radioactive, [oleoyl-3H]sphingomyelin or fluorescent, pyrene-sulfonylaminoundecanoyl-sphingomyelin. Either compound was taken up by a pathway which was not receptor-mediated and hydrolyzed by all intact cells, including those derived from Niemann-Pick disease patients. Moreover, their degradation by the intact cells was not inhibited by treatment with chloroquine, indicating hydrolysis by a non-lysosomal sphingomyelinase. The intracellular sphingomyelin degradation rates showed no correlation with the activity of the 'classical' neutral sphingomyelinase as determined in vitro. In particular, fibroblasts derived from Niemann-Pick patients lacking the lysosomal sphingomyelinase, and having no detectable in vitro activity of the 'classical' neutral sphingomyelinase, were able to degrade the exogenously supplied sphingomyelins. Indeed, in vitro these cells were shown to exhibit neutral, magnesium- and dithiothreitol-dependent sphingomyelinase activities, that might contribute to the non-lysosomal pathway for sphingomyelin degradation to ceramide in intact cells.

Doxorubicin induces slow ceramide accumulation and late apoptosis in cultured adult rat ventricular myocytes.

OBJECTIVES: Anthracyclines cause apoptotic death in many cell types through activation of the ceramide pathway. We tested the hypothesis that doxorubicin induces cardiac myocyte apoptosis through ceramide generation. METHODS: Adult rat ventricular myocytes were grown in the presence of 10% fetal calf serum, and exposed to 0.5 microM doxorubicin (Dox) for 1 h on the day of cell isolation (day 0). We used the membrane-permeant ceramide analog C2-ceramide (C2-cer) to mimic the effects of endogenous ceramide and PDMP to induce endogenous ceramide accumulation. Apoptosis was assessed upon morphological criteria and DNA fragmentation by the TUNEL method and agarose gel electrophoresis. Ceramide concentration was assessed using the DAG kinase assay. RESULTS: Myocyte exposure to Dox was associated with cellular and nuclear alterations typical of apoptosis on day 7 but not on day 3. At day 7, the percentage of TUNEL-positive myocytes was markedly increased in Dox-treated cultures compared to control (Cl) cultures (82 +/- 3 vs. 12 +/- 1%, n = 7; p < 0.001); internucleosomal DNA fragmentation was confirmed by the observation of DNA ladders. These alterations were associated with an increase in the intracellular ceramide concentration (1715 +/- 243 vs. 785 +/- 99 pmol/mg prot, n = 5; p < 0.01), a phenomenon also detected on day 3 (731 +/- 59 vs. 259 +/- 37 pmol/mg prot, n = 5; p < 0.001). Incubation of myocytes at day 0 with 50 microM C2-cer induced rapid cell shrinkage and DNA fragmentation (45 +/- 3 vs. 10 +/- 1% TUNEL-positive myocytes on day 1 in C2-cer-treated and Cl cultures, respectively; n = 6, p < 0.001). Myocyte exposure to 10 microM PDMP for 7 days (n = 5), caused ceramide accumulation (1.7-fold increase vs. Cl, p < 0.01), and a marked increase in the percentage of TUNEL-positive myocytes (62 +/- 6 vs. 11 +/- 3% in Cl cultures, p < 0.001). Ventricles of rats injected intraperitoneally with a cumulative dose of 14 mg/kg Dox over a period of 2 weeks also showed an increased ceramide concentration 2 weeks later (11.01 +/- 0.64 vs. 5.24 +/- 0.88 pmol/mg prot, n = 6; p < 0.001). CONCLUSION: Our study confirms the existence of a functional ceramide pathway related to apoptosis in cardiac myocytes, and points to its possible involvement in doxorubicin-induced cardiomyopathy.

Detection of interaction involving identified genes: available study designs.

Advances in molecular genetic techniques have led to an increased ability to examine gene-environment interactions. Studies to detect gene-environment interactions are motivated by different situations, including 1) most identified cancer genes having associated lifetime risks less than 100% (i.e., incomplete penetrance), 2) hereditary factors that control the metabolism of carcinogens that may modulate risk of disease as hypothesized in pharmacogenetics, and 3) inconsistent associations across studies between a cancer and a suspected risk factor. The above situations and others have led to increased study of interaction between genetic and environmental factors. Less studied so far, but with increased potential for the future, is interaction between identified genes. Gene-gene interaction studies would also be motivated by the situations described above. Approaches to detect gene-environment and gene-gene interactions are reviewed. Available risk estimates, required types of subjects, and feasibility of the proposed study designs are discussed; efficiency and power for interaction assessment are summarized where available. In general, most designs allow for estimating risk associated with a genetic factor, environmental factor, and interaction effect. Although power and efficiency for detecting interactions have been assessed for specific situations in some of the methods, further investigations are needed to define the efficiency spectra of each design.

Familial relative risk of colorectal cancer: a population-based study.

This study aimed to assess the familial relative risk for colorectal cancer (CRC) and its variation according to age and gender. A population-based family study was carried out in France, from 1993 to 1998, including 761 families. Familial CRC risks were estimated from a cohort analysis of the relatives. No obvious decrease in CRC risk was found with increasing age, except when either the proband, or the relative, were in the youngest age class. The effect of the relatives' and probands' ages on the CRC risk differed according to their gender. The cumulative risk of CRC increased at an earlier age in male relatives of probands younger than 60 years of age, than in female relatives. This result suggests that mechanisms specific to females, possibly interacting with genetic factors, explain the difference in the cumulative risks between families with male and female probands.

Association between breast cancer and family malignancies.

In a case-control study, the relationship between a family history of cancer of the breast, ovary, colon, uterus or prostate and the risk of breast cancer was investigated. The data consisted of family histories from 495 breast cancer cases and 785 controls aged 20-56 years. A positive association was found between the occurrence of breast cancer and a history of breast cancer in the families of the subjects affected. This relationship increased linearly with both the degree of kinship of the affected relatives and with their number. The risk of breast cancer associated with other types of cancer in the family was not significantly different from unity.

The case-combined-control design was efficient in detecting gene-environment interactions.

OBJECTIVE: The interest in studying gene-environment (GxE) interaction is increasing for complex diseases. A design combining both related and unrelated controls (e.g., population-based and siblings) is proposed to increase the power to detect GxE interaction. STUDY DESIGN AND SETTING: We used simulations to assess the efficiency of the case-combined-control design relative to a classical case-control study under a variety of assumptions. RESULTS: The case-combined-control design appears more efficient and feasible than a classical case-control study for detecting interaction involving rare exposures and/or genetic factors. The number of available sibling controls per case and the frequencies of the risk factors are the most important parameters for determining relative efficiency. Relative efficiencies decrease as the frequency of the gene (G) increases. A positive correlation in exposure (E) between siblings decreases relative efficiency. CONCLUSIONS: Although the case-combined-control design may not be efficient for common genes with moderate effects, it appears to be a useful alternative in certain situations where classical approaches remain unrealistic.

Variations in the risk of breast cancer associated with a family history of breast cancer according to age at onset and reproductive factors.

In a case-control study of 495 breast cancer patients and 785 controls between 20 and 56 years of age, the risk of breast cancer associated with a family history of breast cancer was studied according to age and reproductive factors. The familial risk of breast cancer was not significantly modified by age at onset, age at menarche, number of children, age at first full-term pregnancy, menstrual cycle length or age at menopause. However, the familial risk significantly increased with the number of abortions (p < 0.05) and seemed to decrease after a natural menopause (p = 0.08). These results suggest that a familial predisposition to breast cancer exerts the same influence during the first six decades of life, except maybe when there are isolated or repeated events such as abortions or artificially imposed menopause, in which case the risk is apparently greater.

Use of relatives of cases as controls to identify risk factors when an interaction between environmental and genetic factors exists.

BACKGROUND: The difficulty in detecting relevant risk factors for chronic diseases (such as breast and colon cancer) may be due to heterogeneity in the populations of studied cases, and one source of heterogeneity may be differential genetic susceptibility predisposing to differential environmental sensitivity. METHODS: The purpose of this investigation is to determine whether the estimates of odds ratios are modified by using relatives as controls when risk factors interact with an underlying genetic factor. RESULTS: We demonstrate that using relative controls in matched case-control studies produces odds ratios different from population-based odds ratios. This difference is dependent on the amount of interaction between the genetic and environmental factors and on the genetic correlation between relatives. CONCLUSIONS: In the case of a common disease, the use of relatives as controls could be helpful in detecting interaction between an exposure and an underlying genetic factor when the genetic factor is common.

Oral contraceptives and breast cancer: a French case-control study.

The relationship between the risk of breast cancer and oral contraceptive use was investigated in a case-control study conducted in France between 1983 and 1987 in five public hospitals. Some 464 cases aged 25 to 56 years and 542 matched controls were interviewed about their history of the use of oral contraceptives (OC). Results are given for the entire population and for the subgroup of 358 and 379 premenopausal cases and controls. The multivariate relative risk estimate, for ever user, was 1.5 (p less than 0.01) in the whole group as well as in the premenopausal subgroup (p less than 0.02). However, there was no evidence that the effect varied appreciably according to duration of use, age at first use, use before first full-term pregnancy (FFTP) and time since first or last use. The risk was not altered for any particular brand of OC. We conclude that, because of the widespread attention given to the relationship between OC use and breast cancer, information bias might be responsible for part of the excess in risk observed among OC ever users.

PIP: The relationship between the risk of breast cancer and oral contraceptive (OC) use was investigated in a case-control study conducted in France between 1983-87 in 5 public hospitals. Some 464 cases ages 25-56 years and 542 matched controls were interviewed about their history of OC use. Results are provided for the entire population and for the subgroups of 358 and 379 premenopausal cases and controls. The multivariate relative risk estimate, for ever-use, was 1.5 (p0.01) in the entire group as well as in the premenopausal subgroup (p0.02). However, there was no evidence that the effect varied appreciably according to the duration of use, age at 1st use, use prior to 1st fullterm pregnancy, and time since 1st or last use. The risk was not altered for any particular OC brand. The authors conclude that because of the widespread attention given to the relationship between OC use and breast cancer, information bias might be responsible for a part of the excess of risk observed among OC ever-users.

Variation in the interaction between familial and reproductive factors on the risk of breast cancer according to age, menopausal status, and degree of familiality.

BACKGROUND: Studies have found that reproductive factors might have a variable effect on the occurrence of breast cancer (BC) according to the existence or not of a family history of BC. The effect of a family history of BC on the risk of BC may also vary according to the age at diagnosis and the degree of kinship. This may confound the relation between familial risk and reproductive factors. A combined analysis was performed to study the interaction between familial risk and reproductive factors according to degree of familiality, age at interview and menopausal status. METHODS: The present analysis included 2948 cases and 4170 controls in seven case-control studies from four countries. The combined relative risks were estimated using a Bayesian random-effects logistic regression model. RESULTS: The main effects of reproductive life factors on the risk of BC are in agreement with previous studies. Two-way interactions between subject's age or menopausal status and a family history of BC were not significant. Although the three-way interaction between age, familial risk and parity was not significant, familial risk seemed to be increased slightly for women with high parity compared with women with low parity in the older age group, and seemed to be slightly decreased for women with high parity compared with women with low parity in younger women. The subject's age also appeared to have an effect on the interaction between familial risk and the age at first childbirth (P = 0.1). CONCLUSIONS: A possible influence of reproductive and menstrual factors on familial risk of BC has been suggested previously and was also evident in the present study. Three-way interactions between age, family history and parity or age at first childbirth might exist and they merit further investigation.

[Estimation of individual breast cancer risk: relevance and limits of risk estimation models]. / Estimation du risque individuel de cancer du sein: intérêt et limites des modèles de calcul de risque.

Several risk estimation models for breast or ovarian cancers have been developed these last decades. All these models take into account the family history, with different levels of sophistication. Gail model was developed in 1989 taking into account the family history (0, 1 or > or = 2 affected relatives) and several environmental factors. In 1990, Claus model was the first to integrate explicit assumptions about genetic effects, assuming a single gene dominantly inherited occurring with a low frequency in the population. BRCAPRO model, posterior to the identification of BRCA1 and BRCA2, assumes a restricted transmission with only these two dominantly inherited genes. BOADICEA model adds the effect of a polygenic component to the effect of BRCA1 and BRCA2 to explain the residual clustering of breast cancer. At last, IBIS model assumes a third dominantly inherited gene to explain this residual clustering. Moreover, this model incorporates environmental factors. We applied the Claus, BRCAPRO, BOADICEA and IBIS models to four clinical situations, corresponding to more or less heavy family histories, in order to study the consistency of the risk estimates. The three more recent models (BRCAPRO, BOADICEA and IBIS) gave the closer estimations. These estimates could be useful in clinical practice in front of complex analysis of breast and/or ovarian cancers family history.

[Cancer genetics: estimation of the needs of the population in France for the next ten years]. / Oncogénétique : estimation des besoins de la population en France pour les dix ans à venir.

Organised since 1990 in France, cancer genetics has been strengthened since 2003 by the programme "Plan Cancer" which resulted in an improvement of the organisation of activities. The aim of this review is to present an update of the estimation of the needs of the population in this field for the next ten years, provided by a group of experts mandated by the French National Cancer Institute. Identification and management of major hereditary predispositions to cancer have a major impact on decrease in mortality and incidence. Sensitivity of criteria for the detection of BRCA1/2 mutations could be substantially improved by enlarging the indication for genetic testing to isolated cases of ovarian cancer occurring before 70 years and to familial cases occurring after this age limit. In the Lynch syndrome, the present criteria would have an excellent sensitivity for the detection of mutations in the mismatch repair (MMR) genes if the pre-screening of tumours on microsatellite instability (MSI) phenotype was effective, but these criteria are actually poorly applied. However, genetic testing should not be proposed to all the patients affected by tumours belonging to the spectrum of major predispositions and a fortiori to unaffected persons unless an affected relative has been identified as a carrier. The prescription of tests should continue to be strictly controlled and organised, in patients as well as in at-risk relatives. The enlargement of criteria and the improvement in the spreading of recommendations should result in an increase of genetic counselling activity and of the prescriptions of tests by a factor 2 to 4, and to a lesser extent in the clinical management of at risk persons. In a near future, it appears important to mandate experts on specific issues such as the determinants of the lack of effective application of tumour screening for MSI phenotype, the recommendations for the identification and the management of MYH-associated polyposis, or the predictive value of tumour characteristics for the identification of BRCA1/2 mutations. The expected increase in cancer genetics activity will need an optimal organisation to increase the throughput. Such measures will help in facing up to new predispositions that will probably be identified in common cancers.

Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families.

Epidemiological studies have indicated that ataxia-telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case-control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ-line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence-assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype-phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, beta-adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.

Interactions between genetic and reproductive factors in breast cancer risk in a French family sample.

Considerable progress has been made in the characterization of the genetic component of breast cancer (BC). However, BC still remains a complex disease involving a genetic component and many other risk factors essentially linked to reproductive-life factors. To search for interactions between genetic and reproductive-life factors in the etiology of BC, a systematic family study was performed in two French hospitals from December 1987 to January 1990 and led to recruitment of 288 families, the IGRC data ("IGRC" refers to the Institut Gustave Roussy and Institut Curie, where the data were obtained). Detailed information on reproductive factors was recorded for probands and female first-degree relatives. Segregation analysis of BC was conducted by taking into account a variable age at onset of disease, by use of the class D regressive logistic model, as implemented in the REGRESS computer program. Segregation analyses of BC in IGRC data showed evidence for the segregation of a dominant gene and additional sister-sister dependence, both when reproductive factors were ignored and when they were included. A significant interaction was detected between the dominant gene and age when reproductive factors were taken into account. Among the reproductive factors included in segregation analysis, parity was found to interact with the dominant-gene effect, and there was an indication of an interaction, albeit not significant, between the dominant gene and age at menarche. Whereas the usual protective effect conferred on breast-cancer risk by high parity remained in nonsusceptible women, it disappeared in susceptible women. The increased BC risk associated with a late age at menarche was higher in susceptible women than in nonsusceptible women. Interactions between inherited predisposition to BC and reproductive factors were detected here for the first time by segregation analysis. It would be of major interest to confirm these results by family studies in other populations.

Evidence against involvement of the acid lysosomal sphingomyelinase in the tumor-necrosis-factor- and interleukin-1-induced sphingomyelin cycle and cell proliferation in human fibroblasts.

The hydrolysis of sphingomyelin (SPM) has been reported to mediate a number of responses to extracellular agents, including cytokines. The so-called SPM cycle may result from the activation of different types of sphingomyelinases (SPMases). We investigated the hypothetical contribution of acid lysosomal SPMase in the SPM signal-transduction pathway. We examined the ability of human skin fibroblasts with a genetic deficiency of acid lysosomal SPMase activity to respond to tumour necrosis factor alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta). We report that both cytokines promoted SPM hydrolysis in fibroblasts derived from patients with Niemann-Pick disease or I-cell disease, similar to that observed in normal cells. Treatment of normal fibroblasts with cationic amphiphilic drugs resulted in inhibition of acid SPMase activity, but had no effect on cytokine-induced SPM turnover. In addition, TNF-alpha and IL-1 beta stimulated [3H]thymidine incorporation in Niemann-Pick fibroblasts, as in normal cells. Thus our results argue against a role for acid endolysosomal SPMase in mediating the cytokine-induced SPM signalling cascade.

Genetic analysis of human breast cancer: implications for family study designs.

Genetic analysis of human breast cancer, as with many common diseases, raises several problems including sampling strategies, genetic heterogeneity, and gene-environment interactions. A reanalysis of 200 Danish breast cancer pedigrees, under the unified mixed model, was conducted to investigate more specifically these three points. We found that use of different sampling schemes leads to similar conclusions: familial transmission of breast cancer in this whole Danish sample cannot be accounted for by the Mendelian segregation of a dominant gene. Homogeneity tests, based on an a priori subdivision of the sample, were all nonsignificant under a given genetic model. However, it was possible to isolate a particular subgroup of pedigrees displaying only breast cancer, which was compatible with the segregation of a dominant gene. We have also shown that correct specification of a liability indicator according to epidemiological factors is of major importance to detect a major effect under the mixed model. Our results emphasize the need to design family studies including various types of information in the probands and family members to permit some progress in the understanding of complex diseases.