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ABSTRACT Methionine (Met) and cysteine (Cys) are nutrients in broiler diets, responsible for strengthening protein synthesis, immunity, and metabolic regulation. To estimate the ideal digestible Met + Cys:digestible Lysine (Lys) ratio for broilers under a lipopolysaccharide (LPS) inflammatory challenge, 384 male broilers were distributed in a completely randomized 4×2 factorial design, with four ratios of dig. Met + Cys:dig. Lys (0.69, 0.73, 0.77, and 0.81) and two conditions (with or without challenge). Each treatment had eight replicates, with six birds per experimental unit (EU). The evaluated parameters included broilers’ weight gain (WG), feed intake (FI), and feed conversion ratio (FCR); jejunum mRNA transcript levels of nuclear factor kappa-B (NF-Κb), glutathione peroxidase (GPX), superoxide dismutase (SOD), glutathione synthetase (GSS), and methionine adenosyltransferase 2 (MAT2); relative weights of liver and spleen, and fat mass (%) and lean mass (%). A linear regression model would estimate the ideal ratio if an effect had occurred. No interaction (p>0.05) was observed between the factors for all the data, nor did the different ratios had any effect (p>0.05) either. LPS-administered exhibited reduced performance, heavier liver and spleen, and lower GSS expression. Hence, the lowest dig Met + Cys:dig Lys ratio (0.69) was sufficient to maintain the performance parameters, the relative weight of lymphoid organs, fat and lean mass, and NF-Kb, GPX, SOD, GSS, MAT2, and CBS mRNA transcript levels in the jejunum.

Purpose: To assess Meibomian gland dysfunction using meibography in patients with xeroderma pigmentosum and correlate with ocular surface changes., Methods: This cross-sectional study evaluated patients with xeroderma pigmentosum. All patients underwent a comprehensive and standardized interview. The best-corrected visual acuity of each eye was determined. Detailed ophthalmic examination was conducted, including biomicroscopy examination of the ocular surface, Schirmer test type I, and meibography, and fundus examination was also performed when possible. Meibomian gland dysfunction was assessed by non-contact meibography using Oculus Keratograph® 5M (OCULUS Inc., Arlington, WA, USA). Saliva samples were collected using the Oragene DNA Self-collection kit (DNA Genotek Inc., Ottawa, Canada), and DNA was extracted as recommended by the manufacturer. Factors associated with abnormal meiboscores were assessed using generalized estimating equation models., Results: A total of 42 participants were enrolled, and 27 patients underwent meibography. The meiboscore was abnormal in the upper eyelid in 8 (29.6%) patients and in the lower eyelid in 17 (62.9%). The likelihood of having abnormal meiboscores in the lower eyelid was 16.3 times greater than that in the upper eyelid. In the final multivariate model, age (p=0.001), mutation profile (p=0.006), and presence of ocular surface malignant tumor (OSMT) (p=0.014) remained significant for abnormal meiboscores. For a 1-year increase in age, the likelihood of abnormal meiboscores increased by 12%. Eyes with OSMT were 58.8 times more likely to have abnormal meiboscores than eyes without ocular surface malignant tumor., Conclusion: In the final model, age, xeroderma pigmentosum profile, previous cancer, and clinical alterations on the eyelid correlated with a meiboscore of ≥2. Meibomian gland dysfunction was common in patients with xeroderma pigmentosum, mainly in the lower eyelid. The severity of Meibomian gland dysfunction increases with age and is associated with severe eyelid changes.

Xeroderma pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk of developing cutaneous neoplasms in sunlight-exposed regions. These cells are deficient in the translesion synthesis (TLS) DNA polymerase eta, responsible for bypassing different types of DNA lesions. From the exome sequencing of 11 skin tumors of a genetic XP-V patients' cluster, classical mutational signatures related to sunlight exposure, such as C>T transitions targeted to pyrimidine dimers, were identified. However, basal cell carcinomas also showed distinct C>A mutation spectra reflecting a mutational signature possibly related to sunlight-induced oxidative stress. Moreover, four samples carry different mutational signatures, with C>A mutations associated with tobacco chewing or smoking usage. Thus, XP-V patients should be warned of the risk of these habits. Surprisingly, higher levels of retrotransposon somatic insertions were also detected when the tumors were compared with non-XP skin tumors, revealing other possible causes for XP-V tumors and novel functions for the TLS polymerase eta in suppressing retrotransposition. Finally, the expected high mutation burden found in most of these tumors renders these XP patients good candidates for checkpoint blockade immunotherapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cellular homeostasis requires the use of multiple environmental sensors that can respond to a variety of endogenous and exogenous compounds. The aryl hydrocarbon receptor (AHR) is classically known as a transcription factor that induces genes that encode drug metabolizing enzymes when bound to toxicants such as 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD). The receptor has a growing number of putative endogenous ligands, such as tryptophan, cholesterol, and heme metabolites. Many of these compounds are also linked to the translocator protein (TSPO), an outer mitochondrial membrane protein. Given a portion of the cellular pool of the AHR has also been localized to mitochondria and the overlap in putative ligands, we tested the hypothesis that crosstalk exists between the two proteins. CRISPR/Cas9 was used to create knockouts for AHR and TSPO in a mouse lung epithelial cell line (MLE-12). WT, AHR-/-, and TSPO-/- cells were then exposed to AHR ligand (TCDD), TSPO ligand (PK11195), or both and RNA-seq was performed. More mitochondrial-related genes were altered by loss of both AHR and TSPO than would have been expected just by chance. Some of the genes altered included those that encode for components of the electron transport system and the mitochondrial calcium uniporter. Both proteins altered the activity of the other as AHR loss caused the increase of TSPO at both the mRNA and protein level and loss of TSPO significantly increased the expression of classic AHR battery genes after TCDD treatment. This research provides evidence that AHR and TSPO participate in similar pathways that contribute to mitochondrial homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Fast volumetric imaging of large fluorescent samples with high-resolution is required for many biological applications. Oblique plane microscopy (OPM) provides high spatiotemporal resolution, but the field of view is typically limited by its optical train and the pixel number of the camera. Mechanically scanning the sample or decreasing the overall magnification of the imaging system can partially address this challenge, albeit by reducing the volumetric imaging speed or spatial resolution, respectively. Here, we introduce a novel dual-axis scan unit for OPM that facilitates rapid and high-resolution volumetric imaging throughout a volume of 800 × 500 × 200 microns. This enables us to perform volumetric imaging of cell monolayers, spheroids and zebrafish embryos with subcellular resolution. Furthermore, we combined this microscope with a multi-perspective projection imaging technique that increases the volumetric interrogation rate to more than 10 Hz. This allows us to rapidly probe a large field of view in a dimensionality reduced format, identify features of interest, and volumetrically image these regions with high spatiotemporal resolution., Competing Interests: The authors declare no conflicts of interest., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

In this paper, we investigate a class of boundary value problems involving Caputo fractional derivative $ {{}^C\mathcal{D}^{\alpha}_{a}} $ of order $ \alpha \in (2, 3) $, and the usual derivative, of the form $ \begin{equation*} ({{}^C\mathcal{D}^{\alpha}_{a}}x)(t)+p(t)x'(t)+q(t)x(t) = g(t), \quad a\leq t\leq b, \end{equation*} $ for an unknown $ x $ with $ x(a) = x'(a) = x(b) = 0 $, and $ p, \; q, \; g\in C^2([a, b]) $. The proposed method uses certain integral inequalities, Banach's Contraction Principle and Krasnoselskii's Fixed Point Theorem to identify conditions that guarantee the existence and uniqueness of the solution (for the problem under study) and that allow the deduction of Ulam-Hyers and Ulam-Hyers-Rassias stabilities.

Competing Interests: Conflicts of interest None disclosed.

Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes. Six patients carry a novel homozygote mutation in the POLH/XPV gene, c.672_673insT (p.Leu225Serfs*33), while one patient carries a homozygote mutation in the XPC gene, c.2251-1G>C. This latter mutation was previously described in Southeastern Africa (Comoro Island and Mozambique), Pakistan, and in a high incidence in Brazil. The XP-C patient had the first symptoms before the first year of life with aggressive ophthalmologic tumor progression and a melanoma onset at 7 years of age. The XP-V patients presented a milder phenotype with later onset of the disorder (mean age of 16 years old), and one of the six XP-V patients developed melanoma at 72 years. The photoprotection is minimal among them, mainly for the XP-V patients. The differences in the disease severity between XP-C (more aggressive) and XP-V (milder) patients are obvious and point to the major role of photoprotection in the XPs. We estimate that the incidence of XP patients at Montanhas can be higher, but with no diagnosis, due to poor health assistance. Patients still suffer from the stigmatization of the condition, impairing diagnosis, education for sun protection, and medical care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Castro, Batista-Vieira, de Souza, Timoteo, Coutinho, Pinheiro de Almeida, Henriques, Azevedo, Rosa, Kannouche, Sarasin, Menck and Petta.)

Xeroderma pigmentosum (XP) is a rare inherited disease caused by deficiencies in DNA damage repair, which mainly results from the failure of nucleotide excision repair or defects in translesion DNA synthesis. The development of multiple malignancies is one of the most prominent features of this condition, which is clinically characterized by the occurrence of hyperpigmentation and lesions associated with sunlight exposure. Lip squamous cell carcinoma in patients with XP has rarely been reported, and information regarding the genetic analysis of these patients is limited. In this report, a case of a 20-year-old patient who developed squamous cell carcinoma in the lower lip is described. Although the tumor was surgically excised, the patient presented with recurrence a few months later. Targeted sequencing using a customized panel of DNA repair genes revealed a mutation in POLH, the gene encoding DNA polymerase eta. Therefore, molecular characterization is important to further improve the understanding of possible phenotype-genotype correlations and mechanisms involved in the pathogenesis of XP., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system., Objectives: To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP., Methods: Twenty-seven families were screened for germline variants in eight XP-related genes., Results: All patients (N = 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma., Conclusions: We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described., (© 2020 European Academy of Dermatology and Venereology.)

In central Brazil, in the municipality of Faina (state of Goiás), the small and isolated village of Araras comprises a genetic cluster of xeroderma pigmentosum (XP) patients. The high level of consanguinity and the geographical isolation gave rise to a high frequency of XP patients. Recently, two founder events were identified affecting that community, with two independent mutations at the POLH gene, c.764 + 1 G > A (intron 6) and c.907 C > T; p.Arg303* (exon 8). These deleterious mutations lead to the xeroderma pigmentosum variant syndrome (XP-V). Previous reports identified both mutations in other countries: the intron 6 mutation in six patients (four families) from Northern Spain (Basque Country and Cantabria) and the exon 8 mutation in two patients from different families in Europe, one of them from Kosovo. In order to investigate the ancestry of the XP patients and the age for these mutations at Araras, we generated genotyping information for 22 XP-V patients from Brazil (16), Spain (6) and Kosovo (1). The local genomic ancestry and the shared haplotype segments among the patients showed that the intron 6 mutation at Araras is associated with an Iberian genetic legacy. All patients from Goiás, homozygotes for intron 6 mutation, share with the Spanish patients identical-by-descent (IBD) genomic segments comprising the mutation. The entrance date for the Iberian haplotype at the village was calculated to be approximately 200 years old. This result is in agreement with the historical arrival of Iberian individuals at the Goiás state (BR). Patients from Goiás and the three families from Spain share 1.8 cM (family 14), 1.7 cM (family 15), and a more significant segment of 4.7 cM within family 13. On the other hand, the patients carrying the exon 8 mutation do not share any specific genetic segment, indicating an old genetic distance between them or even no common ancestry., Competing Interests: Declarations of Competing Interest The authors declare no competing or conflict interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

UVA-induced mutagenesis was investigated in human pol eta-deficient (XP-V) cells through whole-exome sequencing. In UVA-irradiated cells, the increase in the mutation frequency in deficient cells included a remarkable contribution of C>T transitions, mainly at potential pyrimidine dimer sites. A strong contribution of C>A transversions, potentially due to oxidized bases, was also observed in non-irradiated XP-V cells, indicating that basal mutagenesis caused by oxidative stress may be related to internal tumours in XP-V patients. The low levels of mutations involving T induced by UVA indicate that pol eta is not responsible for correctly replicating T-containing pyrimidine dimers, a phenomenon known as the 'A-rule'. Moreover, the mutation signature profile of UVA-irradiated XP-V cells is highly similar to the human skin cancer profile, revealing how studies involving cells deficient in DNA damage processing may be useful to understand the mechanisms of environmentally induced carcinogenesis., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Somatic hypermutation of immunoglobulin genes is a highly mutagenic process that is B cell-specific and occurs during antigen-driven responses leading to antigen specificity and antibody affinity maturation. Mutations at the Ig locus are initiated by Activation-Induced cytidine Deaminase and are equally distributed at G/C and A/T bases. This requires the establishment of error-prone repair pathways involving the activity of several low fidelity DNA polymerases. In the physiological context, the G/C base pair mutations involve multiple error-prone DNA polymerases, while the generation of mutations at A/T base pairs depends exclusively on the activity of DNA polymerase η. Using two large cohorts of individuals with xeroderma pigmentosum variant (XP-V), we report that the pattern of mutations at Ig genes becomes highly enriched with large deletions. This observation is more striking for patients older than 50 years. We propose that the absence of Pol η allows the recruitment of other DNA polymerases that profoundly affect the Ig genomic landscape.

Rehydrated and ensiled mature ground corn has high ruminal starch digestibility, but particle size (PS) and dietary starch proportion (ST) can affect starch digestion and lactating cow performance. We evaluated the effect of rehydrated and ensiled corn (REC), PS, and ST on intake, lactation performance, nutrient digestibility, ruminal fermentation profile, and chewing behavior of dairy cows. Kernels from an 84% vitreousness hybrid were finely (FN) or coarsely (CS) ground, yielding geometric mean particle sizes of 1,591 and 2,185 µm, respectively. Ground kernels were rehydrated [60% dry matter (DM)] and ensiled in 200-L buckets for ≥205 d. The grinding rate (t/h) was 3.9 for FN and 11.7 for CS. The PS did not affect DM loss (11.3% of ensiled) or silage pH (3.8). Samples of each bucket (n = 15/PS) before and after silage fermentation were incubated in situ for 0, 3, 6, 18, and 48 h in 4 rumen-cannulated lactating cows. Ensiling increased the effective ruminal in situ DM degradation (63.7 vs. 34.1%), regardless of PS. Sixteen Holstein cows (152 ± 96 d in milk) in 4 × 4 Latin squares (21-d periods) were individually fed a 2 × 2 factorial combination of low (LO) or high (HI) starch diets with FN or CS. Cows were fed the same REC incubated in situ. Varied concentration of starch in the diet (29.2 vs. 23.5% of DM) was achieved by partial replacement of REC (22.0 vs. 14.2% of DM) with citrus pulp (0 vs. 8.2% of DM). Milk, protein, fat, and lactose yields did not differ. Milk fat percentage was reduced and protein percentage was increased by HI. Treatment FN increased feed efficiency (energy-corrected milk/digestible organic matter intake) when fed with HI. Total-tract starch digestibility tended to be reduced by CS (96.4 vs. 97.2% of starch intake). Serum β-hydroxybutyrate was increased by LO. High-starch diet reduced the molar proportions of acetate and butyrate in ruminal fluid and increased propionate and isoacids. Particle size did not affect ruminal fermentation profile. Coarse grinding reduced plasma d-lactate concentration with HI. Diet HI reduced the proportion of daily intake from 1900 to 0700 h and induced preferential intake of feed particles <8 mm and greater refusal of particles >19 mm in the morning. Fine REC reduced rumination time per day and increased eating time per DM intake. Milk and plasma urea-N did not differ. Ensiling of mature flint corn for >200 d largely eliminated the effect of the PS of REC on the studied outcomes. The proportion of REC in the diet affected ruminal fermentation profile and milk solids concentration, but did not affect short-term performance and digestibility. Coarse grinding of REC may allow increasing the grinding rate and thus save labor and energy during ensiling., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Objectives: This study explored the assessment of resilience at work among 1st-line nurse managers (NMs)., Background: Resilience is the ability to cope with stress. NMs have stressful roles and may ultimately withdraw from management if they lack resilient behaviors. Having a measurement of resilience at work in NMs and other healthcare workers may facilitate resilience development approaches., Methods: In a descriptive, cross-sectional design, an electronic survey of 25-item, 7-subscale Resilience at Work (RAW) self-report assessment was distributed to 77 NMs., Results: The highest reported subscale was living authentically; lowest was maintaining perspective. Total years as NM was related to overall RAW mean, maintaining perspective, staying healthy., Conclusion: The application of an instrument to determine resilience may focus support for NMs on maintaining perspective, for example. Further study exploring the application of the RAW assessment to healthcare workers is indicated.

Background: Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants)., Objectives: To identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes., Methods: Functional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community., Results: Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease., Conclusions: This work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe., (© 2016 British Association of Dermatologists.)

Genome lesions trigger biological responses that help cells manage damaged DNA, improving cell survival. Pol eta is a translesion synthesis (TLS) polymerase that bypasses lesions that block replicative polymerases, avoiding continued stalling of replication forks, which could lead to cell death. p53 also plays an important role in preventing cell death after ultraviolet (UV) light exposure. Intriguingly, we show that p53 does so by favoring translesion DNA synthesis by pol eta. In fact, the p53-dependent induction of pol eta in normal and DNA repair-deficient XP-C human cells after UV exposure has a protective effect on cell survival after challenging UV exposures, which was absent in p53- and Pol H-silenced cells. Viability increase was associated with improved elongation of nascent DNA, indicating the protective effect was due to more efficient lesion bypass by pol eta. This protection was observed in cells proficient or deficient in nucleotide excision repair, suggesting that, from a cell survival perspective, proper bypass of DNA damage can be as relevant as removal. These results indicate p53 controls the induction of pol eta in DNA damaged human cells, resulting in improved TLS and enhancing cell tolerance to DNA damage, which parallels SOS responses in bacteria., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objective: To evaluate the effect of a low-fluoride (F) toothpaste supplemented with sodium trimetaphosphate (TMP) on enamel remineralization in situ., Design: Bovine enamel blocks were selected on the basis of their surface hardness (SH) after caries-like lesions had been induced, and randomly divided into 4 treatment groups, according to the toothpastes used: without F or TMP (placebo); 500 ppm F; 500 ppm F plus 1% TMP; and 1,100 ppm F. The study design was blinded and crossover and performed in 4 phases of 3 days each. Eleven subjects used palatal appliances containing 4 bovine enamel blocks which were treated 3 times per day during 1 min each time, with natural slurries of saliva and toothpaste formed in the oral cavity during toothbrushing. After each phase, the percentages of surface (%SHR) and subsurface hardness recovery (%ΔKHNR) were calculated. F, calcium (Ca), and phosphorus (Pi) contents in enamel were also determined. Data were analyzed by 1-way, repeated-measures ANOVA, followed by the Student-Newman-Keuls test (p < 0.05)., Results: Toothpaste with 500 ppm F + TMP and 1,100 ppm F showed similar %SHR and %ΔKHNR as well as enamel F, Ca, and Pi concentrations., Conclusion: The addition of TMP to a low-fluoride toothpaste promoted a similar remineralizing capacity to that of a standard (1,100 ppm F) toothpaste in situ., (© 2016 S. Karger AG, Basel.)

Introduction: lymphoblastic lymphoma (LBL) is the second most common subtype of non-Hodgkin lymphoma in children. The aim of this study was to characterize the clinical course of children and adolescents with LBL treated at a tertiary center., Methods: this is a retrospective cohort study of 27 patients aged 16 years or less with LBL admitted between January 1981 and December 2013. Patients received intensive chemotherapy regimen derived from acute lymphoblastic leukemia (ALL) therapy. Diagnosis was based on biopsy of tumor and/or cytological examination of pleural effusions. The overall survival was analyzed using the Kaplan-Meier method., Results: the median age at diagnosis was 11.6 years (interquartile range, 4.6-13.8). LBL had T cell origin in 16 patients (59%). The most common primary manifestation in T-cell LBL was mediastinum involvement in 9 patients (56%). Intra-abdominal tumor was the major site of involvement in patients with pB-LBL. Most patients had advanced disease (18 patients - 67%) at diagnosis. Twenty-four patients (89%) achieved complete clinical remission. After a median follow-up of 43 months (interquartile range, 6.4-95), 22 patients (81%) were alive in first complete remission. Five children (18.5%) died, three of them soon after admission and two after relapsing. The probability of survival at five years for 20 patients with de novo LBL was 78% (SD 9.4)., Conclusion: our findings confirm the favorable prognosis of children with LBL with an intensive chemotherapy regimen derived from ALL therapy.

Introduction: lymphoblastic lymphoma (LBL) is the second most common subtype of non-Hodgkin lymphoma in children. The aim of this study was to characterize the clinical course of children and adolescents with LBL treated at a tertiary center., Methods: this is a retrospective cohort study of 27 patients aged 16 years or younger with LBL admitted between January 1981 and December 2013. Patients were treated according to the therapy protocol used for acute lymphoblastic leucemia. Diagnosis was based on biopsy of tumor and/or cytological examination of pleural effusions. The overall survival was analyzed using the Kaplan-Meier method., Results: the median age at diagnosis was 11.6 years (interquartile range, 4.6- 13.8). LBL had T-cell origin in 16 patients (59%). The most common primary manifestation in T-cell LBL was mediastinal involvement, in 9 patients (56%). Intra-abdominal tumor was the major site of involvement in patients with precursor B-LBL. Most patients had advanced disease (18 patients - 67%) at diagnosis. Twenty-four patients (89%) achieved complete clinical remission. After a median follow-up of 43 months (interquartile range, 6.4-95), 22 patients (81%) were alive in first complete remission. Five children (18.5%) died, three of them soon after admission and two after relapsing. The probability of survival at five years for 20 patients with de novo LBL was 78% (SD 9.4)., Conclusion: our findings confirm the favorable prognosis of children with LBL with an intensive chemotherapy regimen derived from ALL therapy.

Purpose: To evaluate the renal and hepatic function, through biochemical analysis after 14 days of creatine supplementation in physically inactive rats., Methods: Twenty four male, adult, Wistar rats were used which were kept in individual metabolic cages and were distributed into four groups, and received the following treatments by gavage:1) CONTROL: distilled water; 2)Creatine 0.5g/Kg/day; 3) Creatine 1g/Kg/day; 4) Creatine 2g/Kg/day. Their urinary outputs as well as food and water intake were daily measured. At the end of the experiment, the animals were euthanized and serum samples were stored for biochemical analysis., Results: Creatine supplementation at the doses given produced no significant changes in plasma levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin, total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, glucose, creatinine, urea, and creatinine clearance, compared to control group (p> 0.05) Similarly, water and food intake, as well as urinary output, did not show significant changes among the four groups studied., Conclusion: At the doses used, oral creatine supplementation did not result in renal and/or hepatic toxicity.

Objective: The aim of the present study was to evaluate in situ whether a toothpaste with low fluoride associated with sodium trimetaphosphate (TMP) would provide similar effect to that of a 1,100 ppm F toothpaste., Design: This crossover double-blind study consisted of 4 phases (14 days each), during which 10 volunteers wore oral appliances containing 4 enamel bovine blocks. The cariogenic challenge was performed by the application of a 20% sucrose solution (6×/day). The toothpaste treatments (2×/day) were: placebo, 500 ppm F, 500 ppm F plus 1% TMP, and 1,100 ppm F. At the end, enamel mineral loss and biofilm composition were analyzed., Results: The toothpaste with 500 ppm F plus 1% TMP showed the lowest mineral loss (p < 0.05). Regarding the fluoride and calcium concentrations in the enamel and in the biofilm, there were no significant differences between 500 ppm F plus 1% TMP, and 1,100 ppm F toothpastes (p > 0.569), but they were significantly different when compared to toothpaste with 500 ppm F (p < 0.050)., Conclusion: The addition of 1% TMP to a low-fluoride toothpaste reduces enamel demineralization in situ similar to a 1,100 ppm F toothpaste., (© 2015 S. Karger AG, Basel.)

Objective: To describe the development and implementation of a human papillomavirus (HPV) vaccine patient assistance program (PAP) for university students, and to acquire information on the number who accessed the program and completed the series., Setting: University of Texas at El Paso University Student Health Clinic Pharmacy, Fall 2011-Spring 2014., Practice Description: A community pharmacy located within the university student health clinic providing services to an underinsured student population., Practice Innovation: Existing evidence shows the benefit of using PAP in community pharmacies but is nonspecific regarding the use of PAP for vaccines in an uninsured and underinsured Hispanic student population. The implementation of this unique HPV vaccine program in a community setting aims to increase awareness, access, and rates., Main Outcome Measures: Primary measures included results from a needs-assessment questionnaire that were used to implement the HPV vaccine program. After implementation, utilization data were collected on the number of students who qualified and enrolled in the HPV PAP and the number of students who completed the HPV series., Results: The preliminary data from a needs assessment indicated that a majority (72.1%, n = 80) of students did not understand how HPV is transmitted. A total of 89 students qualified for PAP. The majority were women (81%). A total of 71 students (79.8%) received their second dose and 43 (48.3%) completed the series., Conclusions: Although pharmacists continue to provide vaccine services, minorities such as the Hispanic population continue to be underimmunized. Students may not be taking the proper precautions to prevent the acquisition of HPV. For these reasons services such as this HPV vaccine program are warranted. Pharmacists need to continue to educate and advocate on the importance of vaccines and how they prevent disease.

Association between H. pylori infection, iron deficiency and iron deficiency anaemia has been described, but the mechanisms involved have not been established. We hypothesized that in H. pylori infected children increased gastric concentrations of IL-1β and/or TNF-α, both potent inhibitors of gastric acid secretion that is essential for iron absorption, are predictors for low blood concentrations of ferritin and haemoglobin, markers of early depletion of iron stores and anaemia, respectively. We evaluated 125 children undergoing endoscopy to clarify the origin of gastrointestinal symptoms. Gastric specimens were obtained for H. pylori status and cytokine evaluation and blood samples for determination of iron deficiency/iron deficiency anaemia parameters and IL1 cluster and TNFA polymorphisms that are associated with increased cytokine secretions. Higher IL-1β and TNF-α gastric concentrations were observed in H. pylori-positive (n = 47) than in -negative (n = 78) children. Multiple linear regression models revealed gastric IL-1β, but not TNF-α, as a significant predictor of low ferritin and haemoglobin concentrations; results were reproduced in young children in whom IL1RN polymorphic genotypes associated with higher gastric IL-1β expression and lower blood ferritin and haemoglobin concentrations. In conclusion, high gastric levels of IL-1β can be the link between H. pylori infection and iron deficiency/iron deficiency anaemia in childhood.

Objective: To present 5-year results of sleeve gastrectomy (SG) with transit bipartition (TB) as a metabolic intervention for obesity., Background: Recent data suggest that high glycemic index foods may lead to a hormonally hyperactive proximal gut and a hypoactivate distal gut, which are linked to metabolic syndrome. TB was designed to counterbalance these effects., Methods: A total of 1020 obese patients with body mass index (BMI) ranging from 33 to 72 Kg/m underwent SG and TB (SG + TB). TB creates a gastroileal anastomosis in the antrum after the SG; nutrient transit is maintained in the duodenum, avoiding blind loops and minimizing malabsorption. The stomach retains 2 outflow pathways. A lateral enteroanastomosis connects both segments at 80 cm proximal to the cecum., Results: Adequate follow-up data were collected in 59.1% of patients from 4 months to 5 years. The average percent of excess BMI loss was 91%, 94%, 85%, 78%, and 74% in the first, second, third, fourth, and fifth year, respectively. Patients experienced early satiety and major improvement in presurgical comorbidities, including diabetes (86% in remission), following surgery. Two deaths occurred (0.2%). Other surgical complications occurred in 6% of patients. Signs of malabsorption were rare., Conclusions: SG + TB is a simple procedure that results in rapid weight loss and remission or major improvement of comorbidities. Strictly aiming at physiological correction, TB avoids prostheses, narrow anastomoses, excluded segments, and malabsorption. Weight and comorbidities are much improved. Diabetes is improved without duodenal exclusion. TB is an excellent complement to an SG.

Background: Polymorphisms in genes linked to the innate and adaptive immune response may be involved in inflammatory bowel disease pathogenesis. Our aim was to investigate associations among IL1B-511, IL1B-31, IL1RN, TNFA-307, TLR-2, TLR-4, IL2-330, NOD2 G908R, NOD2 L1007fsinsC polymorphisms and both Crohn's disease (CD) and ulcerative colitis (UC) in a Brazilian population., Methods: We studied 43 patients with CD, 42 with UC, and 541 blood donors. Polymorphisms were evaluated by PCR, PCR-CTPP, or PCR-RFLP. Data were analyzed in multivariate models adjusting for confounding factors., Results: IL1RN VNTR (P = 0.00, odds ratio [OR] = 2.43, 95% confidence interval [CI] = 1.50-3.90), as well as TNFA-307 polymorphic allele (P = 0.05, OR = 1.70, 95% CI = 1.00-2.94) were associated with UC. Both NOD2 mutations (G908R, P = 0.02, OR = 6.83, 95% CI = 1.62-25.45, and L1007fsinsC, P = 0.00, OR = 20.00, 95% CI = 3.21-124.69) were associated with CD., Conclusions: Our analyses showed positive associations between proinflammatory polymorphisms at IL1RN and TNFA-307 loci and UC, as well as polymorphisms in the NOD2 gene and CD. These results highlight the importance of different genetic profiles associated with CD and UC.

One way to reduce dental fluorosis is by reducing the fluoride (F) concentration in dentifrice, but low-F dentifrice should be as effective as a standard dentifrice. This study evaluated in vitro whether the supplementation with sodium trimetaphosphate (TMP) of a dentifrice with low F content (500 microg/g) would provide a similar effect to that of a standard dentifrice. Bovine enamel blocks were submitted to a pH cycling regime incorporating daily exposures to a slurry of dentifrice: a low-F dentifrice with or without 0.1-3.0% TMP; an F-free, phosphate-free dentifrice (negative control), or a dentifrice with 1,100 microg/g F (positive control). The addition of TMP to dentifrice with or without F was associated with higher surface hardness and decreased loss of integrated subsurface hardness after pH cycling. The combination of 1% TMP and 500 microg F/g had a greater effect than the positive control dentifrice. It is concluded that the addition of TMP to the 500-microg F/g dentifrice allowed a similar or larger effect as compared with a standard dentifrice in this in vitro model., (Copyright 2009 S. Karger AG, Basel.)

Objectives: To define the sensitivity, specificity and accuracy of the ultrasound triangular cord sign and hepatic histopathology, in isolation or in combination, for diagnostic differentiation between biliary atresia and intrahepatic cholestasis., Methods: This was a retrospective study carried out between January 1990 and December 2004. Fifty-one cases of biliary atresia and 45 of intrahepatic cholestasis were analyzed. Histopathology was performed blind by a pathologist. The triangular cord sign was identified in ultrasound reports as the only diagnostic sign of biliary atresia. Sensitivity, specificity and accuracy were calculated for the triangular cord sign and histology both in isolation and in combination. The gold standard for diagnosis of biliary atresia was the appearance of the extrahepatic biliary tree via laparotomy., Results: The triangular cord sign alone had sensitivity of 49%, specificity of 100% and accuracy of 72.5%. Histopathology compatible with extrahepatic biliary obstruction alone had 90.2% sensitivity, 84.6% specificity and 87.8% accuracy. The triangular cord sign and histopathology in isolation or combination resulted in sensitivity of 93.2%, specificity of 85.7% and accuracy of 90.3%., Conclusions: Finding the triangular cord sign on ultrasound is an indication for laparotomy. If the triangular cord sign is negative, liver biopsy is indicated; if histopathology reveals signs of biliary atresia, explorative laparotomy is indicated. In cases where the triangular cord sign is absent and histopathology indicates neonatal hepatitis or other intrahepatic cholestasis, clinical treatment or observation are recommended in accordance with the diagnosis.

This paper presents the comparison of nine nanofiltration membranes to treat water coming from an aquifer recharged with wastewater and used as municipal supply in the Tula Valley, Mexico. The comparison was made based on (a) the amount of water produced; (c) the capability to produce a <1 mg TOC/L effluent without entirely eliminating salts, (b) the removal of specific organic and microbiological pollutants, and (c) the reduction of toxicity and mutagenicity from water. From the tested membranes, only four produce an effluent with <1 TOC mg/L, and three totally retained dibutyl phthalate, diethyl phthalate and hydroxytoluene butylate. Influent mutagenicity (Ames test) was negative but these was a certain degree of toxicity when Tetrahymena pyriformis was used as indicator. Toxicity was partially reduced by some of the NF membranes. The best membrane had a flux of 95 L m(-2)h(-1) and removal efficiencies of 98% for TOC, 92% for AUV(254), and 92% for TDS. The permeate had a final hardness of 76 mg/L and an alkalinity of 124 mg/L. Additionally, this membrane removed totally specific organic compounds, total and fecal coliforms and almost all the somatic coliphages., (Copyright IWA Publishing 2008.)

The histiocytoses are rare diseases caused by alterations in the monocyte-histiocytic series with several clinical findings. Among the cutaneous syndromes of non-Langerhans cells, xanthoma disseminatum is the only disease of this group that has been classically associated to the central diabetes insipidus (CDI). The case reported describes a 30-year-old man that two years after presenting with CDI developed non confluent disseminated cutaneous brown papular lesions throughout the body. The histopathology, immunohistochemistry, and electronic microscopy were compatible with the diagnosis of non-Langerhans histiocytoses, suggesting the diagnosis of juvenile xanthogranuloma. The endocrine-metabolic evaluation did not show other alterations besides CDI in a 10-year follow up. The magnetic resonance of hypophysis showed absence of the pituitary hyperintense sign (bright spot). The radiologic and scinthigraphic evaluation of the bones did not show the presence of osteolytic lesions. This case prints out the importance of skin examination in cases of CDI and its association with cutaneous non-Langerhans histiocytoses in a broader spectrum, rather then restricted to the cases of xanthoma disseminatum.

Background: Osteoporosis affects approximately 30% of postmenopausal women. Gastrectomy, pernicious anemia, and more recently Helicobacter pylori infection, have all been implicated in the pathogenesis of osteoporosis. A reduced parietal cell mass is a common feature in these conditions., Aim: To study a possible relationship between chronic gastritis, parietal cell density of the oxyntic mucosa and bone mineral density in postmenopausal women, as chronic gastritis, Helicobacter pylori infection and osteoporosis are frequently observed in the elderly., Methods: Fifty postmenopausal women (61.7 +/- 7 years) were submitted to gastroduodenal endoscopy and bone densitometry by dual energy X-ray absorptiometry. Glandular atrophy was evaluated objectively by the determination of parietal cell density. Helicobacter pylori infection was evaluated by histology, urease test and breath test with 13C., Results: Thirty-two patients (64%) presented chronic multifocal gastritis, and 20 of them (40%) showed signs of gastric mucosa atrophy. Lumbar spine osteoporosis was found in 18 patients (36%). The parietal cell density in patients with and without osteoporosis was 948 +/- 188 and 804 +/- 203 cells/mm(2), respectively. Ten osteoporotic patients (55%) and 24 non-osteoporotic patients (75%) were infected by Helicobacter pylori., Conclusion: Postmenopausal women with osteoporosis presented a well-preserved parietal cell density in comparison with their counterparts without osteoporosis. Helicobacter pylori infection was not different between the two groups. We concluded that neither atrophic chronic gastritis nor Helicobacter pylori seem to be a reliable risk factor to osteoporosis in postmenopausal women.

Background: Helicobacter pylori infection increases gastric epithelial cell apoptosis; however, the influence of cagA status is still controversial. We aimed to investigate if cagA status is related to apoptosis in H. pylori gastritis at different anatomic sites of the gastric mucosa., Materials and Methods: We studied by immunohistochemistry (streptavidin-biotin method) pro-apoptotic (Bax and Bak) and antiapoptotic (Bcl-2 and Bcl-x) proteins expression, scored from 0 to 4, in gastric biopsies, at the antrum (lesser and greater curvatures), incisura, and corpus (greater curvature) from 50 patients with H. pylori gastritis (22 males, 28 females, median age 40 years) and eight non-infected patients (6 males, median age 39.6 years). H. pylori and cagA status were determined by polymerase chain reaction., Results: Apoptotic proteins were expressed in a granular pattern, in the cytoplasm of foveolar cells; Bax and Bak expression was higher than Bcl-2 and Bcl-x in most cases and was significantly higher in patients infected by cagA-positive strains than in those infected by cagA-negative strains (p = .001). Bak expression was higher at the lesser curvature (antrum and incisura) than in the other regions (p = .002) and was correlated with atrophy. Anti-apoptotic proteins were significantly more expressed at the antral lesser curvature than in the other regions of the stomach (Bcl-2: p = .02; Bcl-x: p < .001)., Conclusions: Infection with cagA-positive strains is significantly associated with overexpression of pro-apoptotic proteins in the gastric mucosa, mainly at the antral lesser curvature, which may have a role on atrophy development. Anti-apoptotic proteins were also overexpressed at the lesser curvature, which may occur to keep epithelial cell turnover or might be related to malignant transformation.

Generalized lymphadenopathy is a rare manifestation of metastatic prostate cancer. Here, we report the case of a 65-year-old patient with supraclavicular, mediastinal, hilar, and retroperitoneal lymphadenopathy and pulmonary infiltration, which suggested the diagnosis of lymphoma. There were no urinary symptoms, and the serum prostate-specific antigen (PSA) was only mildly increased with a normal free PSA. A biopsy of the supraclavicular lymph node was compatible with adenocarcinoma, whose prostatic origin was shown by immunohistochemical staining with PSA. The origin of the primary tumor was confirmed by directed prostate biopsy. We emphasize that a suspicion of prostate cancer in men with adenocarcinoma of undetermined origin is important for an adequate diagnostic and therapeutic approach.

Background: Helicobacter species are associated with inflammatory bowel disease in rodents and in nonhuman primates. Therefore, we prospectively investigated the presence of Helicobacter species in the intestinal mucosa of patients with and without Crohn's disease by culture and polymerase chain reaction (PCR) assays., Materials and Methods: Mucosal fragments were obtained from the ileum, different colon regions, and rectum of 43 patients with Crohn's disease and of 74 patients without inflammatory bowel disease., Results: Helicobacter pylori strains, identified by 16S rRNA gene sequencing, were more frequently isolated and PCR-detected in the intestinal mucosa of patients with ulcerative colitis-like Crohn's disease than in intestinal mucosa of the control group. Otherwise, anti-H. pylori immunoglobulin G levels were significantly lower in fibrostenosing and fistulating Crohn's disease subgroups. No other Helicobacter species were found in the intestinal mucosa of the patients., Conclusions: Although our results suggest an association between the presence of H. pylori in the intestine and ulcerative colitis-like phenotype of Crohn's disease, H. pylori infection in the actual causality of Crohn's disease is still to be determined.

Cell growth and pediocin production by Pediococcus acidilactici NRRL B-5627 on whey were compared by using batch fermentation and re-alkalized fed-batch fermentation. The batch fermentations were performed on DWG [DW (diluted whey) supplemented with 1% (w/v) glucose], DWYE [DW supplemented with 2% (w/v) yeast extract] and DWGYE (DW supplemented with 1% glucose plus 2% yeast extract) media. The fed-batch culture on DWYE medium was fed with a mixture of concentrated whey (48 g of total sugars/l) supplemented with 2% yeast extract and 400 g/l concentrated glucose. The re-alkalized fed-batch culture was characterized by higher biomass (6.57 g/l) and pediocin [517.6 BU (bacteriocin activity units)/ml] concentrations compared with the batch processes on MRS (de Man, Rogosa and Sharpe) broth (1.76 g/l and 493.2 BU/ml), DW (0.17 g/l and 57.7 BU/ml), DWG (0.14 g/l and 53.6 BU/ml), DWYE (1.43 g/l and 187.6 BU/ml) and DWGYE (1.28 g/l and 167.3 BU/ml) media. A mixed acid fermentation was observed during the growth of P. acidilactici NRRL B-5627 in the fed-batch culture on DWYE medium, and other products (acetic acid and ethanol) in addition to lactic acid accumulated in the medium. Mathematical models were set up to describe fed-batch production of biomass and pediocin by P. acidilactici. The models developed offer a better fit and a more realistic description of the experimental biomass and pediocin production data when compared with the logistic and Luedeking and Piret model.

Objective: To assess treatment withdrawal in children and adolescents with autoimmune hepatitis, with clinical and laboratory remission for a minimum period of 24 months, determining the relapse rate after treatment withdrawal., Methods: This is a descriptive, retrospective and partially prospective study of 21 children and adolescents with type 1 autoimmune hepatitis treated at the Outpatient Division of Pediatric Hepatology, Teaching Hospital of Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil, between January 1986 and December 2001., Results: We assessed 54 patients and selected 21, of whom 19 were female subjects (90.5%), aged between 5.7 and 17.6 years (median = 13.8 years), with a mean follow-up of 5.1+/-2.4 years (median = 4.4 years) and an average clinical and laboratory remission of 4.1+/-1.5 years (median = 4.1 years). Out of the 21 patients studied, 10 (47.6%) manifested some inflammatory activity that prevented the discontinuation of treatment, which was withdrawn in 11 patients (52.4%). Out of these, six patients (54.5%) presented reactivation of the disease and five maintained clinical and laboratory remission with a mean follow-up of 4+/-1 years (median = 3.9 years). The time interval between discontinuation of treatment and reactivation of the disease ranged from 29 days to 40.3 months (median = 2.2 months)., Conclusions: We observed a high relapse rate (54.5%) in this group of patients with autoimmune hepatitis, which was more frequent within the first 12 months after treatment withdrawal, in addition to a high number of patients that presented some degree of inflammatory activity despite the long period of clinical and laboratory remission.

Background: Helicobacter pylori treatment failure is a growing problem in daily practice., Aim: To determine the efficacy of the combination of rabeprazole, levofloxacin and furazolidone as a rescue therapy., Methods: Duodenal ulcer patients previously submitted, without success, to at least two H. pylori treatment regimens were included. Gastroscopy (urease test, histological examination and culture) and (13)C-urea breath test were performed. All patients received a combination of rabeprazole 20 mg, levofloxacin 500 mg and furazolidone 200 mg (two tablets) administered in a single dose in the morning for 10 days. Clinical examination and a new (13)C-urea breath test were performed 90 days after therapy., Results: Twelve patients (eight females and four males), mean age 43 (30-58) years were included. Two patients failed to complete the treatment because of nausea and vomiting. Ten patients completed the study and took all the medications as advised. Culture was obtained in six patients: 100 and 83% of the samples were sensitive to furazolidone and levofloxacin, respectively. Per-protocol and intention-to-treat eradication rates were 100 and 83% (P = 0.019)., Conclusions: the combination of rabeprazole, levofloxacin and furazolidone in a single daily dose for 10 days constitutes a highly-effective and low-cost alternative as a third-line therapy in patients infected with H. pylori.

Aims: Production of a nisin-containing cellophane-based coating to be used in the packaging of chopped meat., Methods and Results: The adsorption of nisin to cellophane 'P' type surface was studied at 8, 25, 40 and 60 degrees C using different concentrations of nisin. Then, the antimicrobial activity of adsorbed nisin to cellophane surface was determined in fresh veal meat for effectiveness in reducing the total aerobic bacteria. The adsorption of nisin to cellophane was higher at 8 degrees C. The developed bioactive cellophane reduced significantly the growth of the total aerobic bacteria (by ca 1.5 log units) through 12 days of storage at 4 degrees C., Conclusions: Bioactive cellophane packaging could be used for controlling the microbial growth in chopped meat., Significance and Impact of the Study: Nisin-adsorbed bioactive cellophane would result in an extension of the shelf life of chopped meat under refrigeration temperatures.

Reports of neuroectodermal primary scrotal tumors are scarce. Primary paratesticular neuroblastomas seem even rarer, and only five infants with this condition have been previously described. To the authors' knowledge, this would be the first report of a neonatal congenital paratesticular neuroblastoma. However, the authors postulate that ischemic compressive features in testis could lead to misdiagnosis as testicular torsion and the condition could usually go undetected. A newborn male baby with a left scrotal tumefaction was referred to the authors in May 2003. Doppler ultrasonography findings were inconclusive, and a diagnosis of intrauterine torsion of the testis was suspected. Surgery showed a paratesticular mass with a small attachment to an intra-abdominal epiploon. Pathologic examination clearly established the diagnosis of neuroblastoma. Cytogenetic findings (no amplification of N-myc oncogene, aneuploidy, and no deletion of chromosome 1p) were favorable. As the tumor was classified as International Neuroblastoma Staging System stage I, no additional chemotherapy was administered. All markers showed a progressive decrease, and herniorrhaphy and orchidopexy of the contralateral side were performed at 4 months of age. The patient was tumor-free at 11 months follow-up.

In a search for Helicobacter species in the intestinal mucosae of 42 patients with ulcerative colitis (UC) and 74 without UC, only H. pylori was found. Although the bacterium was detected in UC patients by culture (7.1%) and nested PCR (19.0%), its presence was not associated with the disease (P = 0.13).