Burden of herpes zoster and post-herpetic neuralgia in Sweden.

BACKGROUND: The societal economic burden of herpes zoster in Sweden is not well described today. This study is a top-down analysis of Swedish registers with the objective to describe the burden of herpes zoster and post-herpetic neuralgia in Sweden during 2011. METHODS: Data for inpatient care; outpatient primary and specialized cares; the prescriptions of drugs, sick leave and the number or diagnostic tests were collected from Swedish national databases. The incidence of the disease was estimated based on the number of prescriptions of antiviral drugs. RESULTS: The incidence of herpes zoster was estimated to 315 and 577 cases per 100,000 people for patients at all ages and > = 50 years, respectively. Almost 30,000 patients at all ages were diagnosed with herpes zoster and the societal cost to treat these patients, including the cost to treat those patients who later developed post-herpetic neuralgia, added up to nearly 227 MSEK (31.6 M€) which corresponds to 7,600 SEK (€870) per patient. The main contributors to the total cost for the treatment of HZ patients were primary care (43 %); sick leave (28 %); hospitalization (10 %) and specialist care (7 %). Medication was a relatively small contributor with 8.5 MSEK (4 %; 1.0 M€) to the overall costs for patients at all ages. The corresponding total cost including only patients 50 years and older was 168 MSEK (19.2 M€) or 8,200 SEK (€939) per patient. CONCLUSIONS: The current study demonstrates that the burden of herpes zoster is significant in Sweden. The society, the health care payers and the patients potentially have a lot to gain by introducing a vaccination program to patients 50 years and older and as a consequence reduce the economic and clinical burden of herpes zoster and post-herpetic neuralgia.

Burden of severe rotavirus disease leading to hospitalization assessed in a prospective cohort study in Sweden.

BACKGROUND: The aim of this prospective cohort study was to estimate the burden of severe disease caused by rotavirus-induced gastroenteritis in Swedish children aged < 5 y. METHODS: Rotavirus-positive children admitted to hospitals serving 3 geographical regions with 155,838 children aged < 5 y, were offered inclusion in this 1-year study. Rotavirus strains identified were genotyped using multiplex PCR. Disease progression was documented through interviews and chart reviews. RESULTS: In total, 604 children with rotavirus-induced gastroenteritis were included in the study. Forty-nine of 604 (8.1%) fulfilled the criteria for nosocomial infection. The minimum incidence was 388 per 100,000, with significant variability between study regions, ranging from 280 to 542 per 100,000. In all regions, the peak season occurred in February-April, but the season start varied, with first cases observed in October in the eastern region and December in the northern region. Genotypes identified differed between the regions: G1[P8] was most prevalent in all regions (77%), while the most varied pattern was observed in the western region, with G1[P8] observed in 61%, G4[P8] in 13%, G9[P8] in 10%, G2[P4] in 8%, and G3[P8] in 8% of the children. The median age of hospitalized children was 14 months and the median total duration of diarrhoea was 6.9 days. Sixty-eight percent reported a temperature > 38.5°C upon admission. Complications occurred in > 10% of the children, with hypertonic dehydration (32/604) and seizures (10/604) occurring most frequently. CONCLUSIONS: Rotaviruses may cause severe febrile acute gastroenteritis leading to dehydration requiring acute rehydration in hospital. In addition, further complications occurred in > 10% of hospitalized children.

Disease burden of herpes zoster in Sweden--predominance in the elderly and in women - a register based study.

BACKGROUND: The herpes zoster burden of disease in Sweden is not well investigated. There is no Swedish immunization program to prevent varicella zoster virus infections. A vaccine against herpes zoster and its complications is now available. The aim of this study was to estimate the herpes zoster burden of disease and to establish a pre-vaccination baseline of the minimum incidence of herpes zoster. METHODS: Data were collected from the Swedish National Health Data Registers including the Patient Register, the Pharmacy Register, and the Cause of Death Register. The herpes zoster burden of disease in Sweden was estimated by analyzing the overall, and age and gender differences in the antiviral prescriptions, hospitalizations and complications during 2006-2010 and mortality during 2006-2009. RESULTS: Annually, 270 per 100,000 persons received antiviral treatment for herpes zoster, and the prescription rate increased with age. It was approximately 50% higher in females than in males in the age 50+ population (rate ratio 1.39; 95% CI, 1.22 to 1.58). The overall hospitalization rate for herpes zoster was 6.9/100,000 with an approximately three-fold increase for patients over 80 years of age compared to the age 70-79 group. A gender difference in hospitalization rates was observed: 8.1/100,000 in females and 5.6/100,000 in males. Herpes zoster, with a registered complication, was found in about one third of the hospitalized patients and the most common complications involved the peripheral and central nervous systems. Death due to herpes zoster was a rare event. CONCLUSIONS: The results of this study demonstrate the significant burden of herpes zoster disease in the pre-zoster vaccination era. A strong correlation with age in the herpes zoster- related incidence, hospitalization, complications, and mortality rates was found. In addition, the study provides further evidence of the female predominance in herpes zoster disease.

Pre-vaccination incidence of genital warts in 15-23-year-old women and men attending youth clinics in Stockholm, Sweden.

BACKGROUND: Human papillomavirus (HPV) vaccines were introduced to the market in 2006 and 2007. The present pilot study was designed to examine the incidence of genital warts in the population up to 23 y of age in the county of Stockholm before the start of mass HPV vaccination. METHODS: Data from the electronic health records of 9 youth clinics in the county of Stockholm were collected retrospectively for the y 2006-2008. RESULTS: In total, 49,985 patients visited the study youth clinics during 2006-2008. Of these, 1817 were denoted genital warts patients. An extrapolation of the study data was done in an attempt to estimate the annual number of genital warts cases in the full Stockholm County population aged 15-23 y. Results showed that there were approximately 1792 genital warts patients in the age group 15-23 y each year in Stockholm County. Female cases represented approximately 62% of all cases in the age group 15-23 y. The peak incidence was at around 20 y of age for females, while males had a more flattened peak incidence around 19-23 y of age. CONCLUSION: This pilot study demonstrates that, compared to other reported data, genital warts are at least as common in Sweden as in other countries among 15-23 y old females and males.

The XPD subunit of TFIIH is required for transcription-associated but not DNA double-strand break-induced recombination in mammalian cells.

Mutations in the XPD gene can give rise to three phenotypically distinct disorders: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) or combined XP and Cockayne syndrome (CS) (XP/CS). The role of Xeroderma Pigmentosum group D protein (XPD) in nucleotide excision repair explains the increased risk of skin cancer in XP patients but not all the clinical phenotypes found in XP/CS or TTD patients. Here, we describe that the XPD-defective UV5 cell line is impaired in transcription-associated recombination (TAR), which can be reverted by the introduction of the wild-type XPD gene expressed from a vector. UV5 cells are defective in TAR, despite having intact transcription and homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Interestingly, we find reduced spontaneous HR in XPD-defective cells, suggesting that transcription underlies a portion of spontaneous HR events. We also report that transcription-coupled repair (TCR)-defective cells, mutated in the Cockayne syndrome B (CSB) protein, have a defect in TAR, but not in DSB-induced HR. However, the TAR defect may be associated with a general transcription defect in CSB-deficient cells. In conclusion, we show a novel role for the XPD protein in TAR, linking TAR with TCR.

Transcription-associated recombination is dependent on replication in Mammalian cells.

Transcription can enhance recombination; this is a ubiquitous phenomenon from prokaryotes to higher eukaryotes. However, the mechanism of transcription-associated recombination in mammalian cells is poorly understood. Here we have developed a construct with a recombination substrate in which levels of recombination can be studied in the presence or absence of transcription. We observed a direct enhancement in recombination when transcription levels through the substrate were increased. This increase in homologous recombination following transcription is locus specific, since homologous recombination at the unrelated hprt gene is unaffected. In addition, we have shown that transcription-associated recombination involves both short-tract and long-tract gene conversions in mammalian cells, which are different from double-strand-break-induced recombination events caused by endonucleases. Transcription fails to enhance recombination in cells that are not in the S phase of the cell cycle. Furthermore, inhibition of transcription suppresses induction of recombination at stalled replication forks, suggesting that recombination may be involved in bypassing transcription during replication.

Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks.

Homologous recombination is vital to repair fatal DNA damage during DNA replication. However, very little is known about the substrates or repair pathways for homologous recombination in mammalian cells. Here, we have compared the recombination products produced spontaneously with those produced following induction of DNA double-strand breaks (DSBs) with the I-SceI restriction endonuclease or after stalling or collapsing replication forks following treatment with thymidine or camptothecin, respectively. We show that each lesion produces different spectra of recombinants, suggesting differential use of homologous recombination pathways in repair of these lesions. The spontaneous spectrum most resembled the spectra produced at collapsed replication forks formed when a replication fork runs into camptothecin-stabilized DNA single-strand breaks (SSBs) within the topoisomerase I cleavage complex. We found that camptothecin-induced DSBs and the resulting recombination repair require replication, showing that a collapsed fork is the substrate for camptothecin-induced recombination. An SSB repair-defective cell line, EM9 with an XRCC1 mutation, has an increased number of spontaneous gammaH2Ax and RAD51 foci, suggesting that endogenous SSBs collapse replication forks, triggering recombination repair. Furthermore, we show that gammaH2Ax, DSBs, and RAD51 foci are synergistically induced in EM9 cells with camptothecin, suggesting that lack of SSB repair in EM9 causes more collapsed forks and more recombination repair. Furthermore, our results suggest that two-ended DSBs are rare substrates for spontaneous homologous recombination in a mammalian fibroblast cell line. Interestingly, all spectra showed evidence of multiple homologous recombination events in 8 to 16% of clones. However, there was no increase in homologous recombination genomewide in these clones nor were the events dependent on each other; rather, we suggest that a first homologous recombination event frequently triggers a second event at the same locus in mammalian cells.

Regulation of postnatal lung development and homeostasis by estrogen receptor beta.

Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor alpha (ERalpha) is undetectable in the lung, and this has left many unanswered questions about the mechanism of estrogen action in this organ. Here we show, both in vivo and in vitro, that ERbeta is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ERbeta gene (ERbeta(-/-)) revealed decreased numbers of alveoli in adult female ERbeta(-/-) mice and findings suggesting deficient alveolar formation as well as evidence of surfactant accumulation. Platelet-derived growth factor A (PDGF-A) and granulocyte-macrophage colony-stimulating factor (GM-CSF), key regulators of alveolar formation and surfactant homeostasis, respectively, were decreased in lungs of adult female ERbeta(-/-) mice, and direct transcriptional regulation of these genes by ERbeta was demonstrated. This suggests that estrogens act via ERbeta in the lung to modify PDGF-A and GM-CSF expression. These results provide a potential molecular mechanism for the gender differences in alveolar structure observed in the adult lung and establish ERbeta as a previously unknown regulator of postnatal lung development and homeostasis.

C/EBP transcription factors in the lung epithelium.

During recent years, the biological roles of CCAAT/enhancer binding proteins (C/EBPs) in the lung have started to be uncovered. C/EBPs form a family within the basic region-leucine zipper class of transcription factors. In the lung epithelium C/EBPalpha, -beta, and -delta are expressed. Lung-specific target genes for these transcription factors include the surfactant proteins A and D, the Clara cell secretory protein, and the P450 enzyme CYP2B1. As more information is gathered, a picture is emerging in which C/EBPalpha has a role in regulating proliferation as well as differentiation-dependent gene expression, whereas C/EBPbeta and -delta, in addition to a partly overlapping role in regulating expression of differentiation markers, also seem to be involved in responses to injury and hormones.

Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men.

OBJECTIVE: The objective of this work was to explore the role of peroxisome proliferator-activated receptor delta (PPARD) in lipid metabolism in humans. METHODS AND RESULTS: PPARD is a nuclear receptor involved in lipid metabolism in primates and mice. We screened the 5'-region of the human gene for polymorphisms to be used as tools in association studies. Four polymorphisms were detected: -409C/T in the promoter region, +73C/T in exon 1, +255A/G in exon 3, and +294T/C in exon 4. The frequencies of the rare alleles were 4.2%, 4.2%, 1.2% and 15.6%, respectively, in a population-based group of 543 healthy men. Only the +294T/C polymorphism showed significant association with a metabolic trait. Homozygotes for the rare C allele had a higher plasma LDL-cholesterol concentration than homozygotes for the common T allele, which was verified in an independent cohort consisting of 282 healthy men. Transfection studies showed that the rare C allele had higher transcriptional activity than the common T allele. Electrophoretic mobility shift assays demonstrated that the +294T/C polymorphism influenced binding of Sp-1. An interaction with the PPAR alpha L162V polymorphism was also detected for several lipid parameters. CONCLUSIONS: These findings suggest that PPARD plays a role in cholesterol metabolism in humans.

Synergistic transactivation of the differentiation-dependent lung gene Clara cell secretory protein (secretoglobin 1a1) by the basic region leucine zipper factor CCAAT/enhancer-binding protein alpha and the homeodomain factor Nkx2.1/thyroid transcription factor-1.

The basic region-leucine zipper transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) and the homeodomain transcription factor Nkx2.1/thyroid transcription factor-1 are essential for normal lung morphogenesis. Nkx2.1 is expressed from the onset of lung development, whereas C/EBPalpha expression is turned on at later stages. The expression of C/EBPalpha correlates to the appearance of lung-specific proteins with differentiation-dependent expression patterns, such as the Clara cell secretory protein (secretoglobin 1a1 (Scgb1a1), CCSP). In this study, we demonstrate synergistic transactivation by C/EBPalpha and Nkx2.1 in the regulation of the CCSP gene. We show that the synergistic activity of C/EBPalpha and Nkx2.1 originates from cis-acting elements in the proximal promoter of CCSP and that the synergism is dependent on NH(2)-terminal transactivation domains of C/EBPalpha and Nkx2.1. Our results suggest that the cooperation of C/EBPalpha and Nkx2.1 is a major determinant for the high level, lung epithelial-specific expression of CCSP during the later stages of lung development and in the adult lung.

Glucocorticoids regulate the CCSP and CYP2B1 promoters via C/EBPbeta and delta in lung cells.

Glucocorticoids have several important roles in the lung and play a key role in lung development and maturation. However, the specific molecular mechanisms of glucocorticoid action in lung are unclear. In this study, we have investigated two glucocorticoid-regulated genes expressed in the lung epithelium, the secretory protein CCSP, and the P450-enzyme CYP2B1. In transient transfections of lung epithelial cells, glucocorticoids increased expression from the CCSP and CYP2B1 promoters and we demonstrated that induction was dependent on the integrity of C/EBP-binding sites in both promoters. Electrophoretic mobility shift assays revealed increased DNA-binding of C/EBPbeta and C/EBPdelta after glucocorticoid treatment, which was not correlated to altered protein levels. The results of this study indicate a previously unknown role for C/EBP transcription factors in glucocorticoid signaling in the lung epithelium.

Different regulation of the LXRalpha promoter activity by isoforms of CCAAT/enhancer-binding proteins.

LXRs have recently been shown to regulate key enzymes in cholesterol degradation, reverse transport of cholesterol from peripheral cells, cholesterol uptake and lipogenesis. The LXRalpha promoter was thus studied to investigate if LXRalpha gene expression is under the regulation of transcription factors involved in adipogenesis. We report that the C/EBP transcription factor interacts with the promoter of the LXRalpha gene. In in vitro footprinting experiments, protein extracts from several tissues gave footprints covering a putative C/EBP recognition site. Transfection experiments and EMSA showed a direct effect of these transcription factors on the LXRalpha promoter. C/EBPalpha upregulated expression of the reporter gene in an NIH 3T3-L1 preadipocyte cell line, while C/EBPbeta and C/EBPdelta had no effect. In liver hepatoma Fao II and Cos-7 kidney cells, both C/EBPalpha and C/EBPbeta downregulated expression of the reporter gene while C/EBPdelta induced activity, indicating that the functional consequences of C/EBP isoform interactions with the LXRalpha promoter are dependent on the cellular context. Monitoring of the LXR mRNA levels during adipose tissue differentiation showed that LXRbeta is constitutively expressed during the entire differentiation process while LXRalpha is induced upon addition of differentiation mix.

Decreased serum and bronchoalveolar lavage levels of Clara cell secretory protein (CC16) is associated with bronchiolitis obliterans syndrome and airway neutrophilia in lung transplant recipients.

BACKGROUND: The major hinderance for long-term survival after lung transplantation is chronic rejection in the form of bronchiolitis obliterans syndrome (BOS). BOS is a fibrosing process in the small airways causing irreversible airway obstruction. BOS is associated with increased oxidative burden and activation of inflammatory and growth-stimulating mediators. The Clara cell secretory protein (CCSP or CC16) is a secreted differentiation marker for the bronchiolar epithelium with both antioxidative and antiinflammatory/immmunomodulatory properties. We asked whether this molecule could have a role in the development of BOS. METHODS: Serum and bronchoalveolar lavage (BAL) fluid samples were collected from 22 consecutive lung transplant recipients, the majority (19) was followed for 2 years. Six patients developed BOS. CCSP in serum was measured in 162 samples from 19 patients with an ELISA method, and CCSP in 191 BAL samples from 22 patients with quantitative Western blot. RESULTS: CCSP in both serum and BAL was significantly lower in BOS compared with acute rejection or no rejection. After the first postoperative month, serum and BAL CCSP levels were consistently lower in the patients who developed BOS than in those who did not. The percentage of neutrophils in BAL correlated negatively with CCSP in BAL. CONCLUSIONS: Levels of CCSP in serum and BAL is lowered in BOS. Serum CCSP could have a potential as an early marker for BOS. The correlation between decreased CCSP and increased neutrophils in BAL suggests a loss of local airway defense capacity in BOS.