Decreased risk of prostate cancer after skin cancer diagnosis: a protective role of ultraviolet radiation?

Ultraviolet radiation causes skin cancer but may protect against prostate cancer. The authors hypothesized that skin cancer patients had a lower prostate cancer incidence than the general population. In the southeastern part of the Netherlands, a population-based cohort of male skin cancer patients diagnosed since 1970 (2,620 squamous cell carcinomas, 9,501 basal cell carcinomas, and 1,420 cutaneous malignant melanomas) was followed up for incidence of invasive prostate cancer until January 1, 2005, within the framework of the Eindhoven Cancer Registry. The incidence rates of prostate cancer among skin cancer patients were compared with those in the reference population, resulting in standardized incidence ratios. Skin cancer patients were at decreased risk of developing prostate cancer compared with the general population (standardized incidence ratio (SIR) = 0.89, 95% confidence interval (CI): 0.78, 0.99), especially shortly after diagnosis. The risk of advanced prostate cancer was significantly decreased (SIR = 0.73, 95% CI: 0.56, 0.94), indicating a possible antiprogression effect of ultraviolet radiation. Patients with a skin cancer in the chronically ultraviolet radiation-exposed head and neck area (SIR = 0.84, 95% CI: 0.73, 0.97) and those diagnosed after the age of 60 years (SIR = 0.86, 95% CI: 0.75, 0.97) had decreased prostate cancer incidence rates. These results support the hypothesis that ultraviolet radiation protects against prostate cancer.     

Sun exposure, vitamin D receptor gene polymorphisms, and breast cancer risk in a multiethnic population

Considerable evidence indicates that vitamin D may reduce the risk of several cancers, including breast cancer. This study examined associations of breast cancer with sun exposure, the principal source of vitamin D, and vitamin D receptor gene (VDR) polymorphisms (FokI, TaqI, BglI) in a population-based case-control study of Hispanic, African-American, and non-Hispanic White women aged 35-79 years from the San Francisco Bay Area of California (1995-2003). In-person interviews were obtained for 1,788 newly diagnosed cases and 2,129 controls. Skin pigmentation measurements were taken on the upper underarm (a sun-protected site that measures constitutive pigmentation) and on the forehead (a sun-exposed site) using reflectometry. Biospecimens were collected for a subset of the study population (814 cases, 910 controls). A high sun exposure index based on reflectometry was associated with reduced risk of advanced breast cancer among women with light constitutive skin pigmentation (odds ratio = 0.53, 95% confidence interval: 0.31, 0.91). The association did not vary with VDR genotype. No associations were found for women with medium or dark pigmentation. Localized breast cancer was not associated with sun exposure or VDR genotype. This study supports the hypothesis that sunlight exposure reduces risk of advanced breast cancer among women with light skin pigmentation.     

Iron deficiency and NRAMP1 polymorphisms (INT4, D543N and 3'UTR) do not contribute to severity of anaemia in tuberculosis in the Indonesian population

Fe-deficiency anaemia is the most common cause of anaemia in developing countries. In these settings, many chronic infections, including tuberculosis (TB), are highly prevalent. Fe is an essential nutrient for both host and mycobacteria that play a pivotal role in host immunity and mycobacterial growth. A case-control study was performed in a TB-endemic region in Jakarta, Indonesia, among 378 pulmonary TB patients and 436 healthy controls from the same neighbourhood with the same socio-economic status. In a number of these subjects the Fe status could be explored. The distribution of three polymorphisms in the natural resistance-associated macrophage protein gene (NRAMP1) including INT4, D543N and 3'UTR was examined for a possible association with susceptibility to TB. Anaemia (corrected for sex) was present in 63.2 % of active TB compared with 6.8 % of controls, with female patients more often affected. Anaemia was more pronounced in advanced TB as diagnosed by chest radiography. Lower Hb concentrations in TB patients were accompanied by lower plasma Fe concentrations, lower Fe-binding capacity and higher plasma ferritin. After successful TB therapy, Fe parameters improved towards control values and Hb levels normalised, even without Fe supplementation. NRAMP1 gene polymorphisms were not associated with TB susceptibility, TB severity or anaemia. In conclusion, most active TB patients had anaemia, which was probably due to inflammation and not to Fe deficiency since TB treatment without Fe supplementation was sufficient to restore Hb concentration.     

Seroprevalences and local variation of human and livestock brucellosis in two villages in Gharbia Governorate, Egypt

This study aimed at assessing the epidemiology of brucellosis among both human and livestock populations in an endemic area in Egypt. A cross-sectional survey was conducted in two villages, where 616 inhabitants (aged 3-75 years) and 350 livestock of 97 households were enrolled. Sera were tested for Brucella spp. antibodies by tube agglutination test for both populations. Proportions of seropositive sera were 0.0 and 1.7% among the inhabitants, and 0.0 and 16% among livestock of villages I and II, respectively. Calculated seroprevalences considering the clustering of brucellosis within households were 0.03 for people and 5.2 for livestock in village II. The village variable (P=0.07) and keeping sheep in the household (P=0.01) were significant risk factors for human brucellosis, whereas only the village was significant for livestock (P<0.001). Sheep showed the highest seropositive proportions of brucellosis among livestock. No association could be detected between human and livestock brucellosis. In conclusion, we found local variation of seroprevalences of brucellosis among human and livestock in the two surveyed villages. Further epidemiological studies have to be conducted in randomly selected governorates, not only to confirm the low seroprevelance of human brucellosis, but also to assess the risk factors of livestock infection for terms of prophylaxis.     

Do not eat the red food!: prohibition of snacks leads to their relatively higher consumption in children

Overweight is becoming more prevalent in children. Parents' behaviours play an important role in children's eating behaviour and weight status. In addition to modelling and providing meals, parents also have an influence by using control techniques. One frequently used technique is restriction of intake. In this study, it was tested whether a prohibition of food in the first phase would lead to an increase in desire for the target food and overeating in the second phase. Sure enough, desire increased significantly in the prohibition group, whereas it remained constant in the no-prohibition group. Though no significant differences between groups were found in the absolute consumption of the target food, the proportion of consumed target food (target food intake/total food intake) was significantly higher in the prohibition group. Finally, children whose parents imposed either very little or a lot of restriction at home consumed more kilocalories during the whole experiment, as opposed to children who were exposed to a moderate level of restriction at home. These data indicate that restriction can have adverse effects on children's food preference and caloric intake.     

Characterization of a PSE-4 Mutant with Different Properties in Relation to Penicillanic Acid Sulfones: Importance of Residues 216 to 218 in Class A β-Lactamases

Class A β-lactamases are inactivated by the suicide inactivators sulbactam, clavulanic acid, and tazobactam. An examination of multiple alignments indicated that amino acids 216 to 218 differed among class A enzymes. By random replacement mutagenesis of codons 216 to 218 in PSE-4, a complete library consisting of 40,864 mutants was created. The library of mutants with mutations at positions 216 to 218 in PSE-4 was screened on carbenicillin and ampicillin with the inactivator sulbactam; a collection of 14 mutants was selected, and their bla genes were completely sequenced. Purified wild-type and mutant PSE-4 β-lactamases were used to measure kinetic parameters. One enzyme, V216S:T217A:G218R, was examined for its peculiar pattern of inhibition. There was an increase in the K_m from 68 μM for the wild type to 271 μM for the mutant for carbenicillin and 33 to 216 μM for ampicillin. Relative to the wild-type PSE-4 enzyme, 37- and 30-fold increases in K_i values were observed for the mutant enzyme for sulbactam and tazobactam, respectively. The results that were obtained suggested that positions 216 to 218 are important for interactions with penicillanic acid sulfone inhibitors. In contrast, V216 and A217 in the TEM-1 class A β-lactamase do not tolerate amino acid residue substitutions. However, for the PSE-4 β-lactamase, 11 of 14 mutants from the library of mutants with mutations at positions 216 to 218 whose sequences were determined had substitutions at position 216 (G, R, A, S) and position 217 (A, S). The data showed the importance of residues 216 to 218 in their atomic interactions with inactivators in the PSE-4 β-lactamase structure.The production of β-lactamases is one of several means by which bacteria can become resistant to β-lactam antibiotics. These enzymes hydrolyze the amide bond in the β-lactam ring of antibiotics, leading to a product that has lost its antibacterial properties (22). A way to counter this resistance is to use compounds that incapacitate the β-lactamase and that act in synergy with an antibiotic (19). These agents are known as suicide inactivators and include clavulanic acid and the penicillanic acid sulfones tazobactam and sulbactam (7).Clavulanic acid inactivates group 2a, 2b, and 2be β-lactamases, rendering the combination of clavulanic acid and ticarcillin effective in vitro and in animal models of infections (2, 6, 11). Tazobactam has been shown to be an inactivator of many group 2 β-lactamases (6). This suicide inactivator acts irreversibly against both serine-based β-lactamases and metallo-β-lactamases (7). Studies have demonstrated that the combination of tazobactam and piperacillin has a wide spectrum of activity that includes gram-positive organisms such as staphylococci, as well as many gram-negative aerobic and anaerobic bacteria (9).Wise et al. (32) have shown that the sulfone sulbactam enhances the activities of penicillin G, ampicillin, and carbenicillin against certain β-lactamase-producing bacteria like Bacteroides fragilis, Staphylococcus aureus, and Escherichia coli in vitro.All three inactivators are used clinically in combination with antibiotics to treat intra-abdominal infections, skin and soft tissue infections, and upper and lower respiratory tract infections (9, 12, 20). Different combinations of antibiotics and inactivators are used: ticarcillin with clavulanate, amoxicillin with clavulanate, piperacillin with tazobactam, and ampicillin with sulbactam. These combinations are used to treat infections caused by bacteria producing enzymes in group 2, including Pseudomonas aeruginosa, Serratia marcescens, E. coli, and others (5, 6, 10, 12, 20, 30).The model enzyme used in the study described here is PSE-4, a plasmid-derived β-lactamase from gram-negative bacteria. It was first found in P. aeruginosa (25). It is a class A β-lactamase of 271 amino acids, with the mature protein having a molecular mass of 29,810 Da. The PSE-4 β-lactamase has a very high rate of hydrolysis of carbenicillin and is genetically related to the PSE-1, CARB-3, and CARB-4 carbenicillinases (3). Analysis of the PSE-4 flanking DNA region revealed an integration site common to antibiotic resistance genes inserted into transposons of the Tn21 family (3).In this report we describe the structural and functional features of a mutant PSE-4 β-lactamase, V216S:T217A:G218R, with different properties related to inhibition by penicillanic acid sulfones such as sulbactam and tazobactam as they relate to amino acids 216 to 218 (by the standard numbering system for class A enzymes of Ambler et al. [1]) in the PSE-4 enzyme. We suggest that residues 216 to 218 could be crucial amino acids that have atomic interactions with suicide inactivators. This was established by computer-assisted modeling and structural comparisons from a three-dimensional structure model of PSE-4 constructed for TEM-1 (18), S. aureus PC1 (13, 14), and Bacillus licheniformis 749/C (23) enzymes.