Mediterranean springs: Keystone ecosystems and biodiversity refugia threatened by global change.

Mediterranean spring ecosystems are unique habitats at the interface between surface water and groundwater. These ecosystems support a remarkable array of biodiversity and provide important ecological functions and ecosystem services. Spring ecosystems are influenced by abiotic, biotic, and anthropogenic factors such as the lithology of their draining aquifers, their climate, and the land use of their recharge area, all of which affect the water chemistry of the aquifer and the spring discharges. One of the most relevant characteristics of spring ecosystems is the temporal stability of environmental conditions, including physicochemical features of the spring water, across seasons and years. This stability allows a wide range of species to benefit from these ecosystems (particularly during dry periods), fostering an unusually high number of endemic species. However, global change poses important threats to these freshwater ecosystems. Changes in temperature, evapotranspiration, and precipitation patterns can alter the water balance and chemistry of spring water. Eutrophication due to agricultural practices and emergent pollutants, such as pharmaceuticals, personal care products, and pesticides, is also a growing concern for the preservation of spring biodiversity. Here, we provide a synthesis of the main characteristics and functioning of Mediterranean spring ecosystems. We then describe their ecological value and biodiversity patterns and highlight the main risks these ecosystems face. Moreover, we identify existing knowledge gaps to guide future research in order to fully uncover the hidden biodiversity within these habitats and understand the main drivers that govern them. Finally, we provide a brief summary of recommended actions that should be taken to effectively manage and preserve Mediterranean spring ecosystems for future generations. Even though studies on Mediterranean spring ecosystems are still scarce, our review shows there are sufficient data to conclude that their future viability as functional ecosystems is under severe threat.

Cadmium exposure and risk of breast cancer: A meta-analysis.

BACKGROUND: Cadmium is a heavy metal with carcinogenic properties, highly prevalent in industrialized areas worldwide. Prior reviews evaluating whether cadmium influences breast cancer have been inconclusive and not reflected several recent studies. OBJECTIVE: To evaluate the association between cadmium exposure and female breast cancer incidence, with an emphasis on separately estimating dietary vs. airborne vs. biomarker measures of cadmium and studies published until October 2022. METHODS: We evaluated risk of bias using set criteria and excluded one study judged to have high risk based on self-report of breast cancer and insufficient adjustment. We conducted a random effects meta-analysis of epidemiological studies, including subgroups by exposure route and by menopausal status. RESULTS: A total of 17 studies were eligible for our meta-analysis. Only 2 studies addressed airborne cadmium directly. Breast cancer risk was elevated in women exposed to higher levels of cadmium across all studies - pooled odds ratio: 1.13 (95% confidence interval: 1.00, 1.28), with notable heterogeneity between studies (I2 = 77%). When examining separately by exposure route, dietary cadmium was not linked with an elevated risk - (OR: 1.05; 95%CI: 0.91, 1.21; I2 = 69%), consistent with prior reviews, but biomarker-based studies showed an elevated but non-significant pooled measure (OR: 1.37; 95%CI: 0.96, 1.94; I2 = 84%). We did not observe any clear patterns of different risk by menopausal status. CONCLUSION: Findings from our meta-analysis suggest that exposure to higher cadmium increases the risk of breast cancer in women, but with remaining questions about whether non-dietary exposure may be more risky or whether residual confounding by constituents of tobacco smoke may be at play.

Carbon sequestration and water yield tradeoffs following restoration of abandoned agricultural lands in Mediterranean mountains.

Abandoned cropland areas have the potential to contribute to climate change mitigation through natural revegetation and afforestation programs. These programs increase above and belowground carbon sequestration by expanding forest cover. However, this potential to mitigate climate change often involves tradeoffs between carbon sequestration and water availability. Particularly in a water limited environments such as the Mediterranean region, any loss of recharge to groundwater or streamflow can have critical societal consequences. In this study, we used an ecohydrologic model, Regional Hydro-Ecological Simulation System (RHESSys), to quantify these tradeoffs for land management plans in abandoned cropland areas in Mediterranean mountains. Changes to Net Ecosystem Production (NEP), water yield and Water-Use Efficiency (WUE) under different land management and climate scenarios were estimated for Arnás, a catchment with similar geology, vegetation and climate to many of the locations targeted for land abandonment restoration in the Spanish Pyrenees. Results showed significant changes to both carbon and water fluxes related to land management, while changes related to a warming scenario were not significant. Afforestation scenarios showed the highest average annual carbon sequestration rates (112 g C·m-2·yr-1) but were also associated with the lowest water yield (runoff coefficient of 26%) and water use efficiency (1.4 g C·mm-1) compared to natural revegetation (-27 g C·m-2·yr-1, 50%, 1.7 g C·mm-1 respectively). Under both restoration scenarios, results showed that the catchment ecosystem is a carbon sink during mid-February to July, coinciding with peak monthly transpiration and WUE, while during the rest of the year the catchment ecosystem is a carbon source. These results contribute to understanding carbon and water tradeoffs in Mediterranean mountains and can help adapt restoration plans to address both carbon sequestration and water management objectives.

74 Ge( n , γ ) cross section below 70 keV measured at n_TOF CERN.

Neutron capture reaction cross sections on 74 Ge are of importance to determine 74 Ge production during the astrophysical slow neutron capture process. We present new resonance data on 74 Ge( n , γ ) reactions below 70 keV neutron energy. We calculate Maxwellian averaged cross sections, combining our data below 70 keV with evaluated cross sections at higher neutron energies. Our stellar cross sections are in agreement with a previous activation measurement performed at Forschungszentrum Karlsruhe by Marganiec et al., once their data has been re-normalised to account for an update in the reference cross section used in that experiment.

Rifabutin for treating tuberculosis in solid organ transplant recipients: A retrospective observational study and literature review.

BACKGROUND: The treatment of tuberculosis (TB) in solid organ transplant (SOT) recipients is challenging owing to interactions between rifampin and immunosuppressive drugs. Rifabutin, a rifamycin with excellent activity against Mycobacterium tuberculosis and that induces cytochrome p450 less, may facilitate treatment. We report our experience with rifabutin for treating TB in SOT recipients and review the available literature. METHODS: A retrospective observational study of all SOT recipients with TB between January 2000 and December 2019. The clinical characteristics and outcomes of patients treated with and without rifabutin-containing regimens were compared and a literature review was conducted. RESULTS: We included 31 SOT recipients with TB, among whom 22 (71%) were men and the median age was 62 years (interquartile range 50-20). There were no significant differences between patients treated with rifabutin (n = 12), rifampin (n = 14), and non-rifamycins (n = 5) in clinical cure rates (83.3%, 64.3%, and 100%, respectively; P = .21), side effects (25%, 37.5%, and 20%, respectively; P = .74), or mortality (16.7%, 35.7%, and 0%, respectively; P = .21). Only one patient, treated with rifampin, suffered graft rejection. The literature review identified 59 SOT recipients with TB treated with rifabutin-containing regimens from 8 publications. Overall, the clinical cure, graft rejection, and mortality rates were 93.2%, 5.1%, and 6.8%, respectively. CONCLUSIONS: Rifabutin-containing regimens offer a reliable alternative to rifampin when treating TB in SOT recipients.

Academia in cardiovascular radiology: are we doing enough for the future of the subspecialty?

AIM: To explore barriers to academic activities that cardiovascular radiology-oriented radiology trainees face worldwide. MATERIALS AND METHODS: An international call for participation in an online survey was distributed via social media and radiological societies to radiology trainees. Questions covered barriers and involvement in academic activities during radiology training. Participants interested in cardiovascular radiology were selected for analysis with appropriate statistical methods. RESULTS: Of the 892 respondents, 120 (13.5%) reported an interest in cardiovascular imaging. The majority (63.3%, 76/120) were from Europe and 57.5% (69/120) were men. There were gender discrepancies in academic involvement and in perceived gender-related barriers (perceived gender barrier in academic work between women and men: 15/48 versus 5/69, respectively, p=0.001). The main barriers were lack of time, mentorship, and support. Most did not have protected academic time for research nor for teaching (61.7%, 74/120 and 57.5%, 69/120, respectively). Nonetheless, 40% (48/120) published as first authors, 77.5% (91/120) were involved academically in conferences, 71.7% (85/120) were positive about academic activities, 70.8% plan working in an academic setting, and 78.3% (94/120) would consider research training abroad. CONCLUSION: Although the majority of respondents are positive about academic activities and plan to continue in the future, most do not have protected time. Lack of time, mentorship, and support were the main barriers. Fewer women declare involvement in academic work and output. There are significant perceived gender barriers to academic activities.

Long-term time-scale bonds between discharge regime and catchment specific landscape traits in the Spanish Pyrenees.

An analysis of long-term databases with information on precipitation and discharge records was undertaken to characterize the temporal structure response of four experimental catchments, located in the Central Spanish Pyrenees, with a gradient of land-cover (from a relatively pristine forested catchment, through an abandoned cultivated catchment with progressive plant recolonization, to an afforested catchment and ending with a degraded badlands catchment). Precipitation and discharge records are non-stationary and the wavelet transform methodology was thus applied to perform a temporal scale-by-scale analysis of each catchment response to the hydroclimatic characteristics of the area. This temporal decomposition analysis illustrates how land-use and land-cover legacy control the temporal distribution of flow events occurring at different and non-similar time-scales, thus reflecting the timing, variability and physical mechanisms of water storage/transport in each catchment. Intra-annual and annual time-scales are led by climatological characteristics of the catchment sites (seasonal patterns of mountainous Pyrenees catchments). Multi-year scale is mainly shaped by land-cover and land-use legacy. Badlands catchment, with its large proportion of bare land, shows a discharge response closely synchronized with precipitation patterns for all time-scales. On the contrary, for the forested catchment the global hydrological response is mainly governed by the multi-year time-scale. Afforested catchment and abandoned cultivated catchment, which move towards a pristine forest response, are impacted by the former grazing and agriculture activities and intra-annual temporal variability still play a major role on the global discharge response of the catchment. This suggests that vegetated catchments located in the same region can show hydrological responses at different time-scales to the same climatic input. We argue that differences in land-cover and historical land-use changes are not only valuable to understand the current discharge temporal behaviour, but they will also play a significant role in characterizing the future catchment dynamics due to changing climate conditions.

Dogs as a source of Salmonella spp. in apparently healthy dogs in the Valencia Region. Could it be related with intestinal lactic acid bacteria?

BACKGROUND: Although salmonellosis is considered one of the most important food-borne zoonotic diseases in Europe, close contact between dogs and their owners can also be a potential source of Salmonella spp. for humans. This study assessed the prevalence and antimicrobial resistance of Salmonella spp. in apparently healthy dogs in the Valencian Region, eastern Spain. Moreover, a macroscopic comparison of lactic acid bacteria in both Salmonella-positive and Salmonella-negative dogs was carried out. RESULTS: Of a total of 325 dogs sampled, 6 (1.85%) were positive for Salmonella spp. with 3 different serotypes, Havana (3), Mikawasima (2) and monophasic Typhimurium (1). All isolates were susceptible to all antimicrobials tested except monophasic S. Typhimurium, which was resistant to ampicillin. Finally, macroscopic results revealed that lactic acid bacteria had higher heterogeneity in the Salmonella-negative dogs than in the Salmonella-positive dogs. Although the results in our study showed a low prevalence of Salmonella spp., raw food has been suggested as a risk factor for bacteria in dog faeces. CONCLUSIONS: Public awareness campaigns on good hygiene practices, especially after handling canine faeces or raw food, are necessary. Furthermore, to reduce the potential transmission of bacteria, dogs should be fed food that has been properly cooked, as raw or undercooked food can be a source of zoonotic pathogens. Moreover, further studies must be performed to determine the relationship between lactic acid bacteria and Salmonella spp. in dog faeces.

Impact and risk factors of non-adherence to 5-aminosalicylates in quiescent ulcerative colitis evaluated by an electronic management system.

BACKGROUND AND OBJECTIVE: To determine the impact of non-adherence to 5-Aminosalicylates (5-ASA) on the risk of flares and to identify risk factors of non-adherence. METHODS: Observational, cohort study of ulcerative colitis (UC) patients in clinical remission at least 6 months on 5-ASA monotherapy maintenance prescribed by an electronic management program. Adherence was considered when 80% of the prescribed 5-ASA had been dispensed at the pharmacy. The study analyzed the existence and degree of 5-ASA adherence, disease course, UC phenotypic expression, and 5-ASA dose and regimen, and consumption of non-UC chronic drugs during 2-year follow-up. RESULTS: The study included 274 patients, 49% males with a median age of 38 (27-49) years old. Overall, 41% of patients were non-adherent to 5-ASA. Risk of flares was reduced in the adherent group (36% vs 54%; OR = 0,484; p = 0,004), mainly the mild ones (26% vs 38%; OR = 0,559; p = 0,031). Non-adherence was associated with younger age at diagnosis (32 (26-45) vs 41.5 (21-50), p = 0.000) and no-consumption of other chronic treatments (1.1 vs 2.1; OR = 1709; p = 0,048). CONCLUSION: Non-adherence to 5-ASA evaluated by the pharmaceutical management system was at 41% with a higher risk of relapse. Younger patients and patients who do not receive non-UC chronic treatments showed lower adherence rate.

Dynamic gut microbiome changes following regional intestinal lymphatic obstruction in primates.

The pathogenesis of inflammatory bowel disease (IBD) has been linked with lymphostasis, but whether and how lymphatic obstruction might disturb the intestinal microbiome in the setting of Crohn's Disease (CD) is currently unknown. We employed a new model of CD in African Green monkeys, termed 'ATLAS' (African green monkey truncation of lymphatics with obstruction and sclerosis), to evaluate how gut lymphatic obstruction alters the intestinal microbiome at 7, 21 and 61 days. Remarkable changes in several microbial sub- groupings within the gut microbiome were observed at 7 days post-ATLAS compared to controls including increased abundance of Prevotellaceae and Bacteroidetes-Prevotella-Porphyromonas (BPP), which may contribute to disease activity in this model of gut injury. To the best of our knowledge, these findings represent the first report linking lymphatic structural/gut functional changes with alterations in the gut microbiome as they may relate to the pathophysiology of CD.

Diarrhoeagenic Escherichia coli and Escherichia albertii in Brazil: pathotypes and serotypes over a 6-year period of surveillance.

Diarrhoeagenic Escherichia coli (DEC) is a leading cause of infectious diarrhoea worldwide. In recent years, Escherichia albertii has also been implicated as a cause of human enteric diseases. This study describes the occurrence of E. coli pathotypes and serotypes associated with enteric illness and haemolytic uremic syndrome (HUS) isolated in Brazil from 2011 to 2016. Pathotypes isolated included enteropathogenic E. coli (EPEC), enteroaggregative E. coli (EAEC), enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC) and Shiga toxin-producing E. coli (STEC). PCR of stool enrichments for DEC pathotypes was employed, and E. albertii was also sought. O:H serotyping was performed on all DEC isolates. A total of 683 DEC and 10 E. albertii strains were isolated from 5047 clinical samples. The frequencies of DEC pathotypes were 52.6% (359/683) for EPEC, 32.5% for EAEC, 6.3% for ETEC, 4.4% for EIEC and 4.2% for STEC. DEC strains occurred in patients from 3 months to 96 years old, but EPEC, EAEC and STEC were most prevalent among children. Both typical and atypical isolates of EPEC and EAEC were recovered and presented great serotype heterogeneity. HUS cases were only associated with STEC serotype O157:H7. Two E. albertii isolates belonged to serogroup O113 and one had the stx2f gene. The higher prevalence of atypical EPEC in relation to EAEC in community-acquired diarrhoea in Brazil suggests a shift in the trend of DEC pathotypes circulation as previously EAEC predominated. This is the first report of E. albertii isolation from active surveillance. These results highlight the need of continuing DEC and E. albertii surveillance, as a mean to detect changes in the pattern of pathotypes and serotypes circulation and provide useful information for intervention and control strategies.

Evaluation of inhibitors for development of a selective medium for isolation of Leptospira spp. from clinical samples.

This study was conducted to develop a selective medium for the detection of Leptospira spp. in clinical samples. Serovars of Leptospira spp., environmental bacteria and the fungus from contaminated cultures of patients with suspected leptospirosis were inoculated into EMJH medium containing amphotericin B, 5-fluorouracil (5-FU), furazolidone and neomycin used singly or combined. Medium with 5-FU at the concentration of 200 µg ml-1 did not show any inhibitory effect against the fungus, Gram-negative bacilli and any of the leptospira strains except serovar Pyrogenes. The highest concentration of neomycin and furazolidone that did not inhibit the growth of leptospires was 4 µg ml-1 . All strains of Leptospira spp. grew on 5-FU (100 µg ml-1 ) in combination with neomycin (4 µg ml-1 ) and on 5-FU (100 µg ml-1 ) in combination with furazolidone (4 µg ml-1 ). The highest concentration of amphotericin B (500 µg ml-1 ) that inhibited the growth of the fungus also inhibited the bacteria and most of serovars of Leptospira spp. The most effective antibiotic combinations that inhibited the majority of environmental bacteria growth without affecting leptospiral growth were EMJH with 5-FU (100 µg ml-1 ) in combination with neomycin (4 µg ml-1 ). In conclusion, these findings will help the development of new selective media to isolate leptospires. SIGNIFICANCE AND IMPACT OF THE STUDY: Leptospirosis is one of the most widespread zoonotic diseases in the world. Since certain serovars are often associated with the symptoms and severity of the disease, the isolation and identification of the leptospires usually permits the prediction of sources of infection. Attempts to isolate Leptospira spp. from clinical specimens are often frustrated by overgrowth of the slow-growing bacteria by more rapidly growing contaminants. In this study, we evaluated selective agents to develop a new selective medium to isolate leptospires. The results demonstrated that the association of drugs in concentrations that allowed the growth of leptospires is to be more effective in inhibiting bacterial contaminants.

Clearing shrubland and extensive livestock farming: Active prevention to control wildfires in the Mediterranean mountains.

Forest fires are one of the main environmental problems in Mediterranean environments and different fire prevention policies have been applied: livestock grazing, prescribed fires and a combination of both. However, none present satisfactory results. In that context, in 1986 the Regional Government of La Rioja started the Plan for Shrub Clearing (PSC), combining shrub clearings and livestock grazing to control fires and improve the land management of abandoned mountain areas. Our study aims to analyse the effects of shrub clearings on forest fires in La Rioja and to compare the main results with those observed in Spain in the last 30 years. We apply an interdisciplinary methodology based on the analysis of the evolution of cleared areas, the evolution of wildfires in La Rioja and Spain, mapping land use and land cover changes, and quantifying the combustibility. Results obtained in La Rioja are very positive compared with the evolution of Spain, both in the reduction of the number of fires and the burned areas. Decreases in the combustible material, fuel load and biomass and in the occurrence of fires (>1 ha) were observed. In addition, clearing shrubland and extensive livestock provided other environmental benefits (i.e. mosaic landscapes, ecosystem services). Finally, this study suggested that they are good and sustainable techniques to prevent and control wildfires and they could be used as a land management strategy in other Mediterranean areas.

Effect of kaolin silver complex on the control of populations of Brettanomyces and acetic acid bacteria in wine.

In this work, the effects of kaolin silver complex (KAgC) have been evaluated to replace the use of SO2 for the control of spoilage microorganisms in the winemaking process. The results showed that KAgC at a dose of 1 g/L provided effective control against the development of B. bruxellensis and acetic acid bacteria. In wines artificially contaminated with an initial population of B. bruxellensis at 104 CFU/mL, a concentration proven to produce off flavors in wine, only residual populations of the contaminating yeast remained after 24 days of contact with the additive. Populations of acetic bacteria inoculated into wine at concentrations of 102 and 104 CFU/mL were reduced to negligible levels after 72 h of treatment with KAgC. The antimicrobial effect of KAgC against B. bruxellensis and acetic bacteria was also demonstrated in a wine naturally contaminated by these microorganisms, decreasing their population in a similar way to a chitosan treatment. Related to this effect, wines with KAgC showed lower concentrations of acetic acid and 4-ethyl phenol than wines without KAgC. The silver concentration from KAgC that remained in the finished wines was below the legal limits. These results demonstrated the effectiveness of KAgC to reduce spoilage microorganisms in winemaking.

Aberrant expression of interleukin-10 in rheumatoid arthritis: Relationship with IL10 haplotypes and autoantibodies.

Interleukin 10 (IL-10) is an immunomodulatory cytokinethat plays a central rolein the pathogenesis of autoimmune diseases. Different studies consistently show increased IL-10 serum levels in rheumatoid arthritis (RA) and it appears to be caused by genetic variants. Three polymorphisms situated at positions -1082, -819 and -592 of IL10 gene and its major haplotypes have been associated with regulating IL10 promoter activity. In this study, we evaluated whether IL10 haplotypes are associated with mRNA expression and IL-10 serum levels as well as susceptibility to RA in a Western Mexican population. A total of 240 RA patients and 240 control subjects (CS) were included. Genotyping of IL10 polymorphisms was performed by PCR and PCR-RFLP, respectively. IL10 mRNA expression was determined by real-time PCR and IL-10 serum levels were measured using an ELISA kit. IL10 mRNA expression was 50-fold higher in RA patients than CS (p<0.001), while IL-10 serum levels did not show differences between groups. However, high IL-10 serum levels were positively related to a higherseropositivityfor rheumatoid factor (FR) and anti-CCP antibodies (p<0.05). No significant differences between the distribution of haplotype frequencies were observed between both study groups, but GCC haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients (p<0.05). In addition, patients carrying ATA and GCC haplotypes showed higher mRNA expression than ACC (5.4-fold and 8.8-fold, respectively) and surprisingly, this trend was reversed in the controls, although it was not significant. In conclusion, our findings suggest that IL10 (GCC, ACC, and ATA) haplotypes may not be a susceptibility marker for RA in a population from Western Mexico. Nevertheless, independently of the presence of these variants, there is an aberrant overexpression of IL10 gene in RA, and it may play an important role in the pathogenesis of RA.

Biodegradation of high doses of commercial pesticide products in pilot-scale biobeds using olive-oil agroindustry wastes.

Biobeds systems containing soil, peat and straw (SPS) are used worldwide to eliminate pesticide point-source contamination, but implantation is difficult when peat and/or straw are not available. Novel biobeds composed of soil, olive pruning and wet olive mill cake (SCPr) or its vermicompost (SVPr) were assayed at pilot scale for its use in olive grove areas. Their removal efficiency for five pesticides applied at high concentration was compared with the biobed with SPS. The effect of a grass layer on the efficiency of these biobeds was also evaluated. Pesticides were retained mainly in the upper layer. In non-planted biobeds with SCPr and SVPr, pesticides dissipation was higher than in SPS, except for diuron. In the biobed with SVPr, with the highest pesticide dissipation capacity, the removed amount of dimethoate, imidacloprid, tebuconazole, diuron and oxyfluorfen was 100, 80, 73, 75 and 50%, respectively. The grass layer enhanced dehydrogenase and diphenol-oxidase activities, modified the pesticides dissipation kinetics and favored the pesticide downward movement. One metabolite of imidacloprid, 3 of oxyfluorfen and 4 of diuron were identified by GC-MS. These novel biobeds represent an alternative to the traditional one and a contribution to promote a circular economy for the olive-oil production.

[Effect of mixed edaphic bacterial inoculants in the early development of improved cocoa cultivars (Theobroma cacao L.) in a traditional agroforestry system of Oaxaca, Mexico]. / Efecto de inoculantes bacterianos edáficos mixtos en el desarrollo temprano de cultivares mejorados de cacao (Theobroma cacao L.) en un sistema agroforestal tradicional del norte de Oaxaca, México.

Cocoa plant (Theobroma cacao L.) is native from South America and it represents one of the most significant "bio-cultural" resources of Mesoamerica, since it is a region where it was domesticated and had a relevance as ritual drink and as currency in many pre-hispanic cultures until the arrival of the Spaniards who spread its use worldwide, and became it one of the most consumed commodity goods. Through this research, an alternative is proposed to address the problem of cultivars through the introduction of a wide variety of cocoa plants in traditional agroforestry systems, in synergy with the inoculation of nitrogen-fixing and insoluble phosphor solubilizing edaphic bacterial consortia. Four cultivars of improved grafted cocoa plants were introduced in a traditional agroforestry plot and three fertilization treatments were applied: application of biofertilizer, application of chemical fertilizer and control. Measurements of height, stem diameter, number of leaves and branches were recorded at 2 and 12 months after planting and rhizosphere microbial populations were characterized. Growth results showed good potential for all studied cultivars and it was observed that biofertilization foresees significant effects in some of the growth indicators of cocoa plant. Thereby, plant associations in an agroforestry system could be favorable to promote fruit development and resistance to pests and diseases.

Parathyroid Hormone Polymorphism RS6254 is Associated with the Development and Severity of Osteoporosis in Asymptomatic but not Normocalcemic Hyperthyroidism.

Although normocalcemic and asymptomatic hyperparathyroidism (HPT) are becoming more common, they remain only partially understood. Parathyroid hormone (PTH) polymorphisms have been associated with disease severity in classical HPT. The aim of the present study was to evaluate the clinical effect of PTH polymorphism (rs6254) in normocalcemic and asymptomatic HPT. A prospective study of 61 consecutive patients with normocalcemic or asymptomatic HPT was carried out. Secondary causes of HPT were ruled out. All patients were followed for≥1 year. Calcium and phosphorus metabolism parameters were assessed at least twice during the follow-up period to classify as normocalcemic or asymptomatic HPT. Bone mineral density (BMD) and the rs6254 polymorphism genotype were also assessed. Genotype rs6254GG was observed in 23 patients (37.7%) whereas GA and AA genotypes were presented in 29 (47.5%) and 9 (14.8%) patients, respectively. Age, sex and genotype distributions were comparable in both groups. In asymptomatic but not normocalcemic HPT patients, the GG genotype was associated with a significantly higher level of intact PTH [200.2 (SD 76.5) vs. 113.3 (SD 25.9) pg/ml; p<0.01], and significantly lower Z-score densitometry at the femoral neck, proximal femur, and lumbar spine. Both remained significant after adjusting for major confounding factors by multiple linear regression. The present study supports the independent pathogenic effect of rs6254GA polymorphism on the development and severity of BMD complications in patients with asymptomatic but not normocalcemic HPT. Further studies are needed to confirm this finding and to assess the effect of other polymorphisms in normocalcemic and asymptomatic HPT.

Clinical Expression of Calcium Sensing Receptor Polymorphism (A986S) in Normocalcemic and Asymptomatic Hyperparathyroidism.

Normocalcemic and asymptomatic hyperparathyroidism diagnosis are becoming more common. However, their pathophysiology is incompletely known. The aim of the present study was to evaluate the clinical effect of calcium-sensing receptor polymorphism (A986S) in normocalcemic and asymtomatic HPT. Prospective study conducted with 61 consecutive normocalcemic and asymptomatic HPT patients was followed up during a minimum period of 1 year. Secondary causes of hyperparathyroidism were ruled out. Calcium and phosphorus metabolism parameters were evaluated in at least 2 determinations during follow-up to classify as normocalcemic or asymptomatic hyperparathyroidism. Bone mineral density and A986S polymorphism genotype were also analyzed. Thiry-eight patients (62.3%) had the genotype A986A, and 23 (36.7%) patients had A986S (20 patients, 32.8%) or S986S (3 patients, 4.9%). Age, sex, and genotype distributions were comparable in both normocalcemic and asymptomatic hyperparathyroidism. In normocalcemic patients, S allele genotype was associated to statistically significant higher level of intact PTH: 92.0 (SD 18.5) vs. 110.6 (SD 24.4) pg/ml, p<0.05; and remained significant after adjustment by multiple linear regression. In asymptomatic hyperparathyroidism, A986A genotype resulted in a statistically significant higher level of intact PTH, alkaline phosphatase and procollagen amino-terminal propeptide; but only serum calcium remained as an independent predictor of serum intact PTH levels after a multiple linear regression. Bone mineral densitometry between genotypes did not show statistically significant differences. A986S polymorphism of CaSR is an independent predictor of PTH level in normocalcemic hyperparathyroidism patients, but not in asymptomatic hyperparathyroidism. More studies are needed to evaluate the effect of other polymorphisms in normocalcemic and asymptomatic hyperparathyroidism.

Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus.

OBJECTIVE: B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE). METHODS: BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF-R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38-/ + naïve; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs). RESULTS: Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006). CONCLUSIONS: Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients.