An eQTL-based approach reveals candidate regulators of LINE-1 RNA levels in lymphoblastoid cells.

Long interspersed element 1 (LINE-1; L1) are a family of transposons that occupy ~17% of the human genome. Though a small number of L1 copies remain capable of autonomous transposition, the overwhelming majority of copies are degenerate and immobile. Nevertheless, both mobile and immobile L1s can exert pleiotropic effects (promoting genome instability, inflammation, or cellular senescence) on their hosts, and L1's contributions to aging and aging diseases is an area of active research. However, because of the cell type-specific nature of transposon control, the catalogue of L1 regulators remains incomplete. Here, we employ an eQTL approach leveraging transcriptomic and genomic data from the GEUVADIS and 1000Genomes projects to computationally identify new candidate regulators of L1 RNA levels in lymphoblastoid cell lines. To cement the role of candidate genes in L1 regulation, we experimentally modulate the levels of top candidates in vitro, including IL16, STARD5, HSD17B12, and RNF5, and assess changes in TE family expression by Gene Set Enrichment Analysis (GSEA). Remarkably, we observe subtle but widespread upregulation of TE family expression following IL16 and STARD5 overexpression. Moreover, a short-term 24-hour exposure to recombinant human IL16 was sufficient to transiently induce subtle, but widespread, upregulation of L1 subfamilies. Finally, we find that many L1 expression-associated genetic variants are co-associated with aging traits across genome-wide association study databases. Our results expand the catalogue of genes implicated in L1 RNA control and further suggest that L1-derived RNA contributes to aging processes. Given the ever-increasing availability of paired genomic and transcriptomic data, we anticipate this new approach to be a starting point for more comprehensive computational scans for regulators of transposon RNA levels.

Survival of patients with mucosal melanoma in Cali, Colombia: a retrospective cohort study.

BACKGROUND: Mucosa melanoma is a rare condition with aggressive behavior and a less favorable prognosis compared to cutaneous melanoma. The objective of this study was to estimate the overall survival and clinical outcomes of patients diagnosed with mucosal melanoma in a Colombian hospital. METHODS: A retrospective cohort study was conducted at Fundación Valle del Lili, a single center located in Cali, Colombia. Patients aged ≥ 18 years, both sexes, diagnosed with mucosal melanoma by histopathology study were included between 2010-2019. Patients who received extra-institutional treatment or whose vital status was unknown during follow-up were excluded. Demographic, clinical and laboratory data were obtained from medical records and laboratory and pathology databases. A descriptive analysis was performed. Survival analysis was conducted using the Kaplan-Meier method. RESULTS: A total of 23 patients were included. Median age was 63 years old (IQR: 57-68) and 52.2% were woman. Clinical stage was 34.8% early, 26.1% locally advanced and 39.1% metastatic. The main primary locations were nasopharynx (30.4%), genitals (26.1%), rectum (21.7%), oral cavity (13%) and paranasal sinuses (8.7%). The majority received surgery (30.4%) and immunotherapy (26.1%) as first line treatment. Overall survival at one year was 80.8%, at three years 44.3%, and at five years 36.9%. CONCLUSION: Mucosal melanoma is a rare, aggressive disease with adverse oncological outcomes due to late diagnosis and limited treatment options. This study provides real-world data in a single-center of Colombia.

Transposable elements, circular RNAs and mitochondrial transcription in age-related genomic regulation.

Our understanding of the molecular regulation of aging and age-related diseases is still in its infancy, requiring in-depth characterization of the molecular landscape shaping these complex phenotypes. Emerging classes of molecules with promise as aging modulators include transposable elements, circRNAs and the mitochondrial transcriptome. Analytical complexity means that these molecules are often overlooked, even though they exhibit strong associations with aging and, in some cases, may directly contribute to its progress. Here, we review the links between these novel factors and age-related phenotypes, and we suggest tools that can be easily incorporated into existing pipelines to better understand the aging process.

Floor-plate-derived netrin-1 is dispensable for commissural axon guidance.

Netrin-1 is an evolutionarily conserved, secreted extracellular matrix protein involved in axon guidance at the central nervous system midline. Netrin-1 is expressed by cells localized at the central nervous system midline, such as those of the floor plate in vertebrate embryos. Growth cone turning assays and three-dimensional gel diffusion assays have shown that netrin-1 can attract commissural axons. Loss-of-function experiments further demonstrated that commissural axon extension to the midline is severely impaired in the absence of netrin-1 (refs 3, 7, 8, 9). Together, these data have long supported a model in which commissural axons are attracted by a netrin-1 gradient diffusing from the midline. Here we selectively ablate netrin-1 expression in floor-plate cells using a Ntn1 conditional knockout mouse line. We find that hindbrain and spinal cord commissural axons develop normally in the absence of floor-plate-derived netrin-1. Furthermore, we show that netrin-1 is highly expressed by cells in the ventricular zone, which can release netrin-1 at the pial surface where it binds to commissural axons. Notably, Ntn1 deletion from the ventricular zone phenocopies commissural axon guidance defects previously described in Ntn1-knockout mice. These results show that the classical view that attraction of commissural axons is mediated by a gradient of floor-plate-derived netrin-1 is inaccurate and that netrin-1 primarily acts locally by promoting growth cone adhesion.

Can We Predict Prostate Cancer Metastasis Based on Biomarkers? Where Are We Now?

The incidence of prostate cancer (PC) has risen annually. PC mortality is explained by the metastatic disease (mPC). There is an intermediate scenario in which patients have non-mPC but have initiated a metastatic cascade through epithelial-mesenchymal transition. There is indeed a need for more and better tools to predict which patients will progress in the future to non-localized clinical disease or already have micrometastatic disease and, therefore, will clinically progress after primary treatment. Biomarkers for the prediction of mPC are still under development; there are few studies and not much evidence of their usefulness. This review is focused on tissue-based genomic biomarkers (TBGB) for the prediction of metastatic disease. We develop four main research questions that we attempt to answer according to the current evidence. Why is it important to predict metastatic disease? Which tests are available to predict metastatic disease? What impact should there be on clinical guidelines and clinical practice in predicting metastatic disease? What are the current prostate cancer treatments? The importance of predicting metastasis is fundamental given that, once metastasis is diagnosed, quality of life (QoL) and survival drop dramatically. There is still a need and space for more cost-effective TBGB tests that predict mPC disease.

The Colombian Chemoprevention Trial: 20-Year Follow-Up of a Cohort of Patients With Gastric Precancerous Lesions.

BACKGROUND & AIMS: Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population. METHODS: A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo. Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location. RESULTS: Overall, 356 individuals completed 20 years of follow-up. Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93). H pylori-negative status had a beneficial effect on the score over time (P = .036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC. CONCLUSIONS: In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression. Incomplete IM is a strong predictor of GC risk.

Does microwave and hydrogen peroxide disinfection reduce Candida albicans biofilm on polymethyl methacrylate denture surfaces?

STATEMENT OF PROBLEM: Whether the disinfection of polymethyl methacrylate (PMMA) dentures eliminates Candida albicans biofilm is unclear. PURPOSE: The purpose of this in vitro study was to determine the antimicrobial effect of immersion in hydrogen peroxide (H2O2) and subsequent application of microwaves on the formation of C albicans biofilm on the surface of polished and unpolished PMMA disks. MATERIAL AND METHODS: Polished and unpolished PMMA disks (n=40) were mounted in a Center for Disease Control (CDC) biofilm reactor by adding yeast-dextrose-peptone (YPD) broth inoculated with C albicans in a cell suspension for 24 hours. After this period, the PMMA disks (n=8) were disinfected with 5 different solutions: saline solution, 1% sodium hypochlorite (NaOCl), H2O2, H2O2 microwaved at 650 W for 3 minutes (H2O2/µw), and distilled water microwaved at 650 W for 3 minutes (H2O/µw). On the polished and unpolished surface of each disk, arbitrary fluorescence units (AFU) were quantified with the live/dead bacterial viability kit (Invitrogen) by using confocal laser scanning microscopy (CLSM) to evaluate 10 different areas of each surface; these were counted as the colony-forming units (CFUs). The mean values were compared by using the Mann-Whitney U test (α=.05). RESULTS: Polished surfaces disinfected with H2O2/µw obtained the lowest viable cells (9.76 AFU) and nonviable cells (12.46 AFU) compared with H2O/µw and H2O2. In the unpolished surface the lowest mean values of viable cells (14.64 AFU) and nonviable cells (12.46 AFU) were obtained for the PMMA disks disinfected with H2O/µw compared with H2O2/µw and H2O2. Both polished and unpolished disks showed significant difference (P<.05) compared with the group of PMMA disks immersed in saline solution. No CFUs were detected in the polished or unpolished PMMA disks immersed in H2O2/µw or in NaOCl. CONCLUSIONS: H2O2 alone did not eliminate the formation of the biofilm of C albicans; however, in combination with the use of the microwave at 650 W for 3 minutes, the biofilm formation of C albicans on polished surfaces was reduced. The number of AFUs of viable-nonviable cells and CFUs depended on whether the surfaces are polished or unpolished.

[Prognostic factors in patients with upper urinary tract urothelial carcinoma undergoing nephro-ureterectomy]. / Tabaquismo y tumores mayores de 2 centímetros son predictores de mortalidad en pacientes sometidos a nefro-ureterectomías por carcinoma de urotelio alto.

BACKGROUND: Upper urinary tract urothelial carcinoma (UTUC) represents 5-10% of urothelial carcinomas. It is managed with nephroureterectomy (NUR); however, kidney-sparing techniques are growingly used. AIM: To report the results of a 20-year series of NUR conducted in an academic center. PATIENTS AND METHODS: Review of clinical and pathological characteristics of patients undergoing NUR between 1999 and 2020. Patients were followed for 63 months. Global survival curves (OS) and mortality predictors were established through Cox regression. RESULTS: We included 90 patients with a median age of 68 years undergoing NUR, of whom 68 (75%) had a pelvic tumor and 22 (25%) had a proximal ureteral tumor. A laparoscopic NUR was performed in 60 patients (66%). Thirty-three patients (37%) had tumors confined to the urothelium (pTa), penetrating the lamina propria (pT1) or carcinoma in situ (CIS), 10 patients (11%) had a tumor spreading to the muscle layer (pT2) and 47 (52%) had a tumor spreading to nearby organs (pT3 / T4). Average tumor size was 3.69 cm, nodal disease (pN) was present 12 patients (13%). Twelve patients (13%) received adjuvant chemotherapy. A higher mortality was observed among smokers (Hazard ratio (HR) 8.79, 95% confidence intervals (CI) 1.5-49.0, p = 0.01), patients with tumors classfied as pT≥ 2 (HR 1.09, 95% CI 0.01-1.0, p = 0.04) and those with tumors larger than 2 cm (HR 14.79, CI 95% 1.5-272, p = 0.01). CONCLUSIONS: Smoking patients, those with invasive tumors (T2-T4) and greater than 2 cm have higher mortality. Therefore, they should not be candidates for conservative management.

[Vena cava thrombectomy in kidney cancer. Report of 32 nephrectomies]. / Nefrectomía radical con trombectomía de vena cava: 20 años de cirugías por tumor renal.

BACKGROUND: Vena cava (VC) involvement in kidney tumors occurs in 4 to 10% of cases, and is associated with a higher mortality. Nephrectomy with thrombectomy of the VC, performed by a multidisciplinary team, improves survival. AIM: To report a series of consecutive nephrectomies with caval thrombectomy performed in an academic center. PATIENTS AND METHODS: We report 32 patients with cT3b and 3c renal tumors, who underwent radical nephrectomy with VC thrombectomy between 2001 and 2021. A descriptive analysis of clinical, surgical and pathological variables was performed. Overall survival (OS) and cancer-specific survival (CSS) was calculated using Kaplan-Meier curves. RESULTS: The mean tumor size was 9.7 cm. According to Mayo classification 3/32 (9%) patients had a type I thrombus, 10/32 (31%) had a type II thrombus, 8/32 (25%) had a type III thrombus, and 5/32 (16%) had a type IV thrombus. The mean bleeding was 2000 cc. There was one intraoperative death. Nineteen percent of patients had complications >= 3 according to Clavien-Dindo classification. Reoperations occurred in 9%. Pre and postoperative creatinine levels were 1.17 and 1.91 mg/dl respectively (p < 0.01). Pre and postoperative Hematocrit levels were 47.9 and 31% respectively (p = 0.02). Sixty six percent of tumors were clear cell renal cancer, 9% were papillary and 3% were chromophobic. Mean OS was 10 months. Two-year SCE was 40%. CONCLUSIONS: Our results are similar to those reported elsewhere. Despite being an unusual pathology, the surgical technique has been improving, thanks to the multidisciplinary work of urologists and surgeons.

Commissural neurons transgress the CNS/PNS boundary in absence of ventricular zone-derived netrin 1.

During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in Ntn1 hypomorphic embryos and Dcc knockouts. However, whether netrin 1 also plays a similar role in the brain is unknown. In the hindbrain, precerebellar neurons migrate tangentially under the pial surface, and their ventral migration is guided by netrin 1. Here, we show that pontine neurons and inferior olivary neurons, two types of precerebellar neurons, are not confined to the CNS in Ntn1 and Dcc mutant mice, but that they invade the trigeminal, auditory and vagus nerves. Using a Ntn1 conditional knockout, we show that netrin 1, which is released at the pial surface by ventricular zone progenitors is responsible for the CNS confinement of precerebellar neurons. We propose, that netrin 1 distribution sculpts the CNS boundary by keeping CNS neurons in netrin 1-rich domains.

Instantaneous Disturbance Index for Power Distribution Networks.

The stability of power systems is very sensitive to voltage or current variations caused by the discontinuous supply of renewable power feeders. Moreover, the impact of these anomalies varies depending on the sensitivity/resilience of customer and transmission system equipment to those deviations. From any of these points of view, an instantaneous characterization of power quality (PQ) aspects becomes an important task. For this purpose, a wavelet-based power quality indices (PQIs) are introduced in this paper. An instantaneous disturbance index (ITD(t)) and a Global Disturbance Ratio index (GDR) are defined to integrally reflect the PQ level in Power Distribution Networks (PDN) under steady-state and/or transient conditions. With only these two indices it is possible to quantify the effects of non-stationary disturbances with high resolution and precision. These PQIs offer an advantage over other similar because of the suitable choice of mother wavelet function that permits to minimize leakage errors between wavelet levels. The wavelet-based algorithms which give rise to these PQIs can be implemented in smart sensors and used for monitoring purposes in PDN. The applicability of the proposed indices is validated by using a real-time experimental platform. In this emulated power system, signals are generated and real-time data are analyzed by a specifically designed software. The effectiveness of this method of detection and identification of disturbances has been proven by comparing the proposed PQIs with classical indices. The results confirm that the proposed method efficiently extracts the characteristics of each component from the multi-event test signals and thus clearly indicates the combined effect of these events through an accurate estimation of the PQIs.

Widespread sex dimorphism in aging and age-related diseases.

Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex dimorphism in various aspects of aging and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.

Molecular regionalization of the developing amphioxus neural tube challenges major partitions of the vertebrate brain.

All vertebrate brains develop following a common Bauplan defined by anteroposterior (AP) and dorsoventral (DV) subdivisions, characterized by largely conserved differential expression of gene markers. However, it is still unclear how this Bauplan originated during evolution. We studied the relative expression of 48 genes with key roles in vertebrate neural patterning in a representative amphioxus embryonic stage. Unlike nonchordates, amphioxus develops its central nervous system (CNS) from a neural plate that is homologous to that of vertebrates, allowing direct topological comparisons. The resulting genoarchitectonic model revealed that the amphioxus incipient neural tube is unexpectedly complex, consisting of several AP and DV molecular partitions. Strikingly, comparison with vertebrates indicates that the vertebrate thalamus, pretectum, and midbrain domains jointly correspond to a single amphioxus region, which we termed Di-Mesencephalic primordium (DiMes). This suggests that these domains have a common developmental and evolutionary origin, as supported by functional experiments manipulating secondary organizers in zebrafish and mice.

Effect of dental restorative materials surface roughness on the in vitro biofilm formation of Streptococcus mutans biofilm.

PURPOSE: To evaluate Streptococcus mutans biofilm formation over different restorative dental materials. METHODS: Using a bioreactor over 72 hours, four commercially available ceramics were evaluated: IPS E-max Press, IPS E-max CAD, Lava Ultimate CAD-CAM, Vita Enamic and two resin composites (SR Nexco Paste and Brilliant NG). The results were evaluated using atomic force microscopy and confocal microscopy, the biofilm was stained and the arbitrary fluorescence units (AFU) quantified. RESULTS: The results showed that IPS E-max CAD had the lowest roughness values (4.29±1.79 nm), while the highest values were observed for Vita Enamic discs ( (77.13±17.35 nm). Analysis of S. mutans biofilm formation by AFU revealed lower values for IPS E-max CAD (6.77±1.67 nm); the highest values were found for Lava Ultimate (79.99±22.23 nm). Regarding the composite groups, SR Nexco Paste showed roughness values of 15.07±2.77 nm and lower arbitrary fluorescence units of 30.92±12.01 nm than Brilliant NT. There was a correlation between the surface roughness of ceramics and composite with S. mutans biofilm formation. CLINICAL SIGNIFICANCE: The adhesion of oral bacteria to restorative dental materials plays a key role in the success of dental treatment; the surface roughness influences the S. mutans biofilm formation.

Bacterial Analogs of Plant Tetrahydropyridine Alkaloids Mediate Microbial Interactions in a Rhizosphere Model System.

Plants expend significant resources to select and maintain rhizosphere communities that benefit their growth and protect them from pathogens. A better understanding of assembly and function of rhizosphere microbial communities will provide new avenues for improving crop production. Secretion of antibiotics is one means by which bacteria interact with neighboring microbes and sometimes change community composition. In our analysis of a taxonomically diverse consortium from the soybean rhizosphere, we found that Pseudomonas koreensis selectively inhibits growth of Flavobacterium johnsoniae and other members of the Bacteroidetes grown in soybean root exudate. A genetic screen in P. koreensis identified a previously uncharacterized biosynthetic gene cluster responsible for the inhibitory activity. Metabolites were isolated based on biological activity and were characterized using tandem mass spectrometry, multidimensional nuclear magnetic resonance, and Mosher ester analysis, leading to the discovery of a new family of bacterial tetrahydropyridine alkaloids, koreenceine A to D (metabolites 1 to 4). Three of these metabolites are analogs of the plant alkaloid γ-coniceine. Comparative analysis of the koreenceine cluster with the γ-coniceine pathway revealed distinct polyketide synthase routes to the defining tetrahydropyridine scaffold, suggesting convergent evolution. Koreenceine-type pathways are widely distributed among Pseudomonas species, and koreenceine C was detected in another Pseudomonas species from a distantly related cluster. This work suggests that Pseudomonas and plants convergently evolved the ability to produce similar alkaloid metabolites that can mediate interbacterial competition in the rhizosphere.IMPORTANCE The microbiomes of plants are critical to host physiology and development. Microbes are attracted to the rhizosphere due to massive secretion of plant photosynthates from roots. Microorganisms that successfully join the rhizosphere community from bulk soil have access to more abundant and diverse molecules, producing a highly competitive and selective environment. In the rhizosphere, as in other microbiomes, little is known about the genetic basis for individual species' behaviors within the community. In this study, we characterized competition between Pseudomonas koreensis and Flavobacterium johnsoniae, two common rhizosphere inhabitants. We identified a widespread gene cluster in several Pseudomonas spp. that is necessary for the production of a novel family of tetrahydropyridine alkaloids that are structural analogs of plant alkaloids. We expand the known repertoire of antibiotics produced by Pseudomonas in the rhizosphere and demonstrate the role of the metabolites in interactions with other rhizosphere bacteria.

Impact of a Primary Care intervention on the colorectal cancer early detection programme. / Impacto de una intervención de Atención Primaria en el programa de detección precoz de cáncer colorrectal.

AIM: To assess the effectiveness of a telephonic interview performed by primary care professionals among non-participants in the first round of the colorectal cancer early detection programme in the basic urban health area Guineueta in Barcelona, Spain. PATIENTS AND METHODS: The Primary Healthcare Team of La Guineueta contacted people who did not respond to the invitation to the first round of the colorectal cancer early detection programme using a standardised telephone call protocol. We analysed the impact of the intervention based on participation and diagnosed disease. RESULTS: We made 3,327 phone calls to 2,343 people. After the intervention the participation rate was 54.9%, which meant an increase of 5.7% with respect to the participation in the usual protocol for the programme (49.2%). The intervention allowed 5cancers, 2high-risk neoplasms and 8low- and intermediate-risk lesions to be diagnosed. An average of 9phone calls was necessary to achieve the participation of one additional person. DISCUSSION: The telephonic intervention performed by primary care professionals has significantly increased the population participation rate and the detection of neoplasms with respect to the usual colorectal cancer early detection programme protocol.

Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial.

OBJECTIVE: To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. DESIGN: 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1-6). The score difference between baseline and 16 years was modelled by generalised linear models. RESULTS: Individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001). CONCLUSIONS: Long-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.

Cysteamine (Cystagon®) adherence in patients with cystinosis in Spain: successful in children and a challenge in adolescents and adults.

BACKGROUND: Cysteamine has improved survival and prognosis in cystinosis. Increasing numbers of patients reach adulthood and face new challenges such as compliance that wanes over time. The aim of this study was to evaluate adherence to cysteamine treatment in a group of cystinotic patients in Spain in an attempt to identify potential therapy pitfalls and improve the overall care of affected individuals. Despite the impact of cysteamine on prognosis, there is a paucity of data regarding adherence. METHOD: Thirty-four cystinotic patients (21 male) 38% ≥18 years were enrolled in a voluntary, anonymous survey. Replies were obtained from patients (15/34), mothers (11/34), fathers (4/34) and both parents (4/34). RESULTS: Patient age (median and interquartile range) at diagnosis was 1 year (0.57-1), and patient age at Cystagon® initiation was also 1 year (0.8-1.8). Sixteen (47%) were kidney transplant (KTx) recipients; six were retransplanted. Age at first KTx 10 years (8.7-13.7). Patient understanding of multiorgan involvement in cystinosis: 4.1 organs reported; eye 97% and kidney 91%. Cysteamine was given by mother (100%) and father (83%) in <11 year olds, or self-administered (94%) in ≥11 year olds. Four daily doses in 89% versus 56% in <11 year olds or ≥11 year olds, with fixed schedule in 94% versus 50% in <11 or ≥11 year olds and progressive loss of reminders over time. Furthermore, 44% complained of unpleasant smell. Motivation for treatment compliance was 100% versus 40% in <11 versus ≥11 year olds, respectively. Disease impact in patients <18 years is as follows: school (29%), social (14%), 'feeling different' (10%); in patients ≥18 years: 'feeling different' (62%), professional (39%) and job absenteeism (31%). Referring physician: paediatric nephrologist (94%) and nephrologist (63%) in <11 versus ≥11 year olds. Ophthalmological follow-up: 83% versus 38% in <11 versus ≥11 year olds. Patient opinion of physician expertise: paediatric nephrologist (94%) and nephrologist (44%). New treatment options (65%) and better information (42%) were demanded to improve adherence. CONCLUSION: Treatment with Cystagon is effective in young patients. However, adherence diminishes over time in adolescents and adults despite disease impact. Strategies such as better information on the disease, patient self-care promotion and facilitated transition to adult healthcare services are required to improve compliance and the clinical management of cystinosis.

Growth and differentiation factor 10 (Gdf10) is involved in Bergmann glial cell development under Shh regulation.

Growth differentiation factor 10 (Gdf10), also known as Bmp3b, is a member of the transforming growth factor (TGF)-ß superfamily. Gdf10 is expressed in Bergmann glial cells, which was investigated by single-cell transcriptional profiling (Koirala and Corfas, (2010) PLoS ONE 5: e9198). Here we provide a detailed characterization of Gdf10 expression from E14, the stage at which Gdf10 is expressed for the first time in the cerebellum, until P28. We detected Gdf10 expression in both germinal zones: in the ventricular zone (VZ) of the 4th ventricle as well as in the rhombic lip (RL). The VZ has been postulated to give rise to GABAergic neurons and glial cells, whereas the RL gives rise to glutamatergic neurons. Thus, it was very surprising to discover a gene that is expressed exclusively in glial cells and is not restricted to an expression in the VZ, but is also present in the RL. At postnatal stages Gdf10 was distributed equally in Bergmann glial cells of the cerebellum. Furthermore, we found Gdf10 to be regulated by Sonic hedgehog (Shh), which is secreted by Purkinje cells of the cerebellum. In the conditional Shh mutants, glial cells showed a reduced expression of Gdf10, whereas the expression of Nestin and Vimentin was unchanged. Thus, we show for the first time, that Gdf10, expressed in Bergmann glial cells, is affected by the loss of Shh as early as E18.5, suggesting a regulation of glial development by Shh.

Cinacalcet for hypercalcaemic secondary hyperparathyroidism after renal transplantation: a multicentre, retrospective, 3-year study.

AIMS: Our aim was to evaluate the long-term effect of cinacalcet in patients with hypercalcaemic secondary hyperparathyroidism (SHPT) after renal transplantation (RT) in order to expand real-world data in this population. METHODS: We performed a multicentre, observational, retrospective study in 17 renal transplant units from Spain. We collected data from renal recipients with hypercalcaemic (calcium >10.2 mg/dL) SHPT (intact parathyroid hormone (iPTH) > 120 pg/mL) who initiated cinacalcet in the clinical practice. RESULTS: We included 193 patients with a mean (standard deviation (SD)) age of 52 (12) years, 58% men. Cinacalcet treatment was initiated at a median of 20 months after RT (median dose 30 mg/day). Mean calcium levels decreased from a mean (SD) of 11.1 (0.6) at baseline to 10.1 (0.8) at 6 months (9.0% reduction, P < 0.0001). Median iPTH was reduced by 23.0% at 6 months (P = 0.0005) and mean phosphorus levels increased by 11.1% (P < 0.0001). The effects were maintained up to 3-years. No changes were observed in renal function or anticalcineurin drug levels. Only 4.1% of patients discontinued cinacalcet due to intolerance and 1.0% due to lack of efficacy. CONCLUSIONS: In renal transplant patients with hypercalcaemic SHPT, cinacalcet controlled serum calcium, iPTH and phosphorus levels up to 3 years. Tolerability was good.