Pharmacogenetic biomarkers of response in Crohn's disease.

Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment. Several studies have considered the possibility that these differences in response are caused by the genetic variability of patients. Many genes have been investigated as potential predictors of response to biological drugs, such as ADAM17, ATG16L1, EMSY, CASP9, CCNY, CNTN5, FASLG, FCGR, NOD2, PTGER4, IL13, IL1B, IL27, IL11, IL17F, TNF and TNFR genes. In this review, we will gather the information on influence of gene polymorphisms investigated to date on response to biological drugs in CD patients.

mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review.

Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.

Randomised crossover trial showed that using breast milk or sucrose provided the same analgesic effect in preterm infants of at least 28 weeks.

AIM: Repeated, ongoing exposure to pain influences the growth, cognitive and motor functions, behaviour, personality and neurodevelopment of preterm infants. We compared the analgesic effects of expressed breast milk (EBM) and 24% oral sucrose on preterm neonates during venipuncture. METHODS: This multicentre randomised, noninferiority, crossover trial focused on five neonatal university units in Madrid, Spain, from October 2013 to October 2014. It comprised 66 preterm infants born at less than 37 weeks and randomly split into two groups. They received either EBM or sucrose two minutes before venepuncture, together with nonnutritive sucking and swaddling, then the opposite procedure at a later point. Pain was measured with the premature infant pain profile (PIPP) and crying was also measured. RESULTS: There were no statistically significant differences between the groups. The PIPP scores were seven (4-9) with breast milk and six (4-8.25) with sucrose (p = 0.28). The 11 infants born at under 28 weeks of age showed higher median scores of nine (9-14) for breast milk and four (4-7) for sucrose (p = 0.009). CONCLUSION: EBM and 24% sucrose had the same analgesic effect during venipuncture in most of the preterm neonates, but sucrose worked better in extremely preterm infants.

Clinicobiological features and prognostic impact of diffuse large B-cell lymphoma component in the outcome of patients with previously untreated follicular lymphoma.

BACKGROUND: The co-existence at diagnosis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) components (FL/DLBCL) has been considered a transformed lymphoma and accordingly treated although clinicobiological information on these patients is scarce. The aim of this study was to analyze the initial features and outcome of FL/DLBCL patients in the rituximab era. PATIENTS AND METHODS: All patients consecutively diagnosed at a single institution with FL/DLBCL (n = 40), as well as those with pure FL (n = 328) or de novo DLBCL (n = 510) as controls. RESULTS: The proportion of the DLBCL component was highly variable (median 50%). In 29 FL/DLBCL cases analyzed, the cell of origin was GCB in 86%, ABC in 10% and unclassifiable in 4%. NOTCH1-2 was mutated in 10% of these cases. The proportion of DLBCL component did not impact on overall survival (OS). Regarding initial characteristics, patients with FL/DLBCL were closer to FL in terms of primary nodal origin, good performance status and advanced stage, whereas the other features were intermediate between FL and DLBCL. FL/DLBCL patients were treated as DLBCL with no further intensification. Complete response and primary refractory rates were 65% and 20%, respectively, with these figures being similar to DLBCL and worse than FL. Progression-free survival and OS were intermediate between FL and DLBCL (5-year OS: 85%, 73% and 63% for FL, FL/DLBCL and DLBCL, respectively). FL/DLBCL histology did not reach independent prognostic value for OS in the multivariate analyses. CONCLUSIONS: The outcome of FL/DLBCL patients is not worse than that of de novo DLBCL. These cases should be treated with immunochemotherapy as DLBCL, but intensification with ASCT may not be necessary. The biological insights of FL/DLBCL warrants further genetic and molecular studies.

Broadening the phenotypic spectrum of POP1-skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia.

Processing of Precursor 1 (POP1) is a large protein common to the ribonuclease-mitochondrial RNA processing (RNase-MRP) and RNase-P (RMRP) endoribonucleoprotein complexes. Although its precise function is unknown, it appears to participate in the assembly or stability of both complexes. Numerous RMRP mutations have been reported in individuals with cartilage-hair hypoplasia (CHH) but, to date, only three POP1 mutations have been described in two families with features similar to anauxetic dysplasia (AD). We present two further individuals, one with severe short stature and a relatively mild skeletal dysplasia and another in whom AD was suspected. Biallelic POP1 mutations were identified in both. A missense mutation and a novel single base deletion were detected in proband 1, p.[Pro582Ser]:[Glu870fs*5]. Markedly reduced abundance of RMRP and elevated levels of pre5.8s rRNA was observed. In proband 2, a homozygous novel POP1 mutation was identified, p.[(Asp511Tyr)];[(Asp511Tyr)]. These two individuals show the phenotypic extremes in the clinical presentation of POP1-dysplasias. Although CHH and other skeletal dysplasias caused by mutations in RMRP or POP1 are commonly cited as ribosomal biogenesis disorders, recent studies question this assumption. We discuss the past and present knowledge about the function of the RMRP complex in skeletal development.

Ascorbic acid PEG-2L is superior for early morning colonoscopies in colorectal cancer screening programs: a prospective non-randomized controlled trial.

BACKGROUND: The quality of colon cleansing and the tolerability of anterograde preparation are essential to the success of colorectal cancer screening. AIM: To compare the tolerability and efficacy of low-volume preparations vs the standard regimen in individuals scheduled for an early morning colonoscopy. STUDY: Participants in a population-based colorectal cancer screening program using the fecal immunochemical test who were scheduled for a colonoscopy from 09:00 a.m. to 10:20 a.m. were prospectively included and assigned to: (1) control group (PEG-ELS 4L): PEG 4L and electrolytes; (2) group AscPEG-2L: a combination of PEG and ascorbic acid 2L; and (3) group PiMg: sodium picosulfate and magnesium citrate 500 mL plus 2L of clear fluids. Tolerability was evaluated with a questionnaire and the quality of bowel preparation with the Boston Bowel Preparation Scale. RESULTS: A total of 292 participants were included: 98 in the PEG-ELS 4L control group, 96 in the AscPEG-2L study group and 98 in the PiMg study group. Low-volume treatments were better tolerated than the standard solution (AscPEG-2L 94.8% and PiMg 93.9% vs PEG-ELS 4L 75.5%; p < 0.0001). The effectiveness of AscPEG-2L was superior to that of PEG-ELS 4L and PiMg (p = 0.011 and p = 0.032, respectively). Patient acceptance was higher for single-dose than for split-dose administration but efficacy was higher with the split dose than with other doses. CONCLUSIONS: In early morning colonoscopies, ascPEG-2L appears to be the best option, especially when administered in a split-dose.

Evaluation and selection of indicators for land degradation and desertification monitoring: methodological approach.

An approach to derive relationships for defining land degradation and desertification risk and developing appropriate tools for assessing the effectiveness of the various land management practices using indicators is presented in the present paper. In order to investigate which indicators are most effective in assessing the level of desertification risk, a total of 70 candidate indicators was selected providing information for the biophysical environment, socio-economic conditions, and land management characteristics. The indicators were defined in 1,672 field sites located in 17 study areas in the Mediterranean region, Eastern Europe, Latin America, Africa, and Asia. Based on an existing geo-referenced database, classes were designated for each indicator and a sensitivity score to desertification was assigned to each class based on existing research. The obtained data were analyzed for the various processes of land degradation at farm level. The derived methodology was assessed using independent indicators, such as the measured soil erosion rate, and the organic matter content of the soil. Based on regression analyses, the collected indicator set can be reduced to a number of effective indicators ranging from 8 to 17 in the various processes of land degradation. Among the most important indicators identified as affecting land degradation and desertification risk were rain seasonality, slope gradient, plant cover, rate of land abandonment, land-use intensity, and the level of policy implementation.

Evaluation and selection of indicators for land degradation and desertification monitoring: types of degradation, causes, and implications for management.

Indicator-based approaches are often used to monitor land degradation and desertification from the global to the very local scale. However, there is still little agreement on which indicators may best reflect both status and trends of these phenomena. In this study, various processes of land degradation and desertification have been analyzed in 17 study sites around the world using a wide set of biophysical and socioeconomic indicators. The database described earlier in this issue by Kosmas and others (Environ Manage, 2013) for defining desertification risk was further analyzed to define the most important indicators related to the following degradation processes: water erosion in various land uses, tillage erosion, soil salinization, water stress, forest fires, and overgrazing. A correlation analysis was applied to the selected indicators in order to identify the most important variables contributing to each land degradation process. The analysis indicates that the most important indicators are: (i) rain seasonality affecting water erosion, water stress, and forest fires, (ii) slope gradient affecting water erosion, tillage erosion and water stress, and (iii) water scarcity soil salinization, water stress, and forest fires. Implementation of existing regulations or policies concerned with resources development and environmental sustainability was identified as the most important indicator of land protection.

Prevalence and characteristics of anemia in patients with diabetes mellitus aged 50 or older in health unit area of Cadiz (Spain).

BACKGROUND: Anemia is a common comorbidity in patients with diabetes mellitus (DM), particularly in older adults. However, there is a lack of data on the prevalence and the characteristics of anemia in this population in Spain. OBJECTIVE: To describe the prevalence and the characteristics of anemia in patients with DM aged 50 or older (PDM50) in a healthcare district in the province of Cádiz. METHODS: A retrospective cross-sectional study was conducted that included outpatient's laboratory tests (OLT) performed over 30 months at PDM50. RESULTS: The prevalence of anemia was 29.9% (95% CI: 28.7%-31.1%), predominating in women (33.3% vs 26.7%; P < .01), in older people stratified by decades (61.7% in 9th decade vs 12% in 5th decade; P < .01), and in those with kidney disease (44.7% vs 28%; P < .01). Most cases were mild (68.3%), normocytic (78.7%), and hypochromic (52%). Similarly, moderate-to-severe anemia was more frequent in women (39% vs 23%), their prevalence increased with age (45% in the 9th decade vs 24% in the 5th decade), and with the progression of kidney damage, either measured by a decreased glomerular filtration rate (GFR) (49% in G4 vs 25% in G1), or the presence of albuminuria (P < .01). No association was found between DM control, based on glycated hemoglobin (HbA1c), and anemia in either sex (P = .887). CONCLUSION: This study describes a high prevalence of anemia in PDM50, particularly in women, in the most advantageous people and in the presence of kidney disease, even in early stages, highlighting the clinical importance of this coexistence.

The present and future of gene profiling in breast cancer.

Gene signatures can provide prognostic and predictive information to help in the treatment of early-stage breast cancer. Although many of these signatures have been described, only a few have been properly validated. MammaPrint and OncoType offer prognostic information and identify low-risk patients who do not benefit from adjuvant chemotherapy. With regard to prediction of response, molecular subtypes of breast cancer differ in their sensitivity to chemotherapy, although further studies are needed in this field. Cost, small sample size, and the need to use central laboratories are common limitations to the widespread use of these tools.

Daily rhythms of blood glucose differ in diurnal and nocturnal European sea bass (Dicentrarchus labrax L.) undergoing seasonal phase inversions.

Sea bass change their feeding rhythms from diurnal to nocturnal in winter, returning to diurnal feeding in spring. Despite behavioral data, the physiological changes that take place during such changes remain unexplored. In this paper, blood glucose rhythms of European sea bass with diurnal/nocturnal self-feeding rhythms were investigated during phase inversions of their feeding behavior (in winter and spring) when both diurnal and nocturnal fish coexist. Blood glucose showed daily variations in both seasons (ANOVA, p < 0.03), fitting a cosine function (COSINOR, p < 0.05) in all cases, except in diurnal fish in spring. The average blood glucose levels of nocturnal fish in winter (2.67 ± 0.09 mmol/l, mean ± SEM) were significantly (t test, p < 0.01) higher than in spring (2.20 ± 0.08 mmol/l), while they were similar (~2.25 mmol/l) in diurnal fish in both seasons. These findings revealed for the first time insights into the seasonal physiological changes that accompany changes in behavioral rhythms in diurnal and nocturnal sea bass.

Women's leadership in clinical research: A retrospective observational study over two decades in Spain.

BACKGROUND AND OBJECTIVE: Available data support differences by gender in the leadership of clinical investigations (CI). This study analyzes to what extent women lead these investigations. MATERIALS AND METHODS: Observational-retrospective study in a tertiary university hospital associated with one of the most important health research institutes in Spain. We analyzed the principal investigators (PI) by gender from 2001 to 2020. MAIN OUTCOME: proportion of CI led by female doctors (FD) during the study period. SECONDARY OUTCOMES: differences in PI by gender according to the type of study: clinical trials (CT) or non-interventional-researches (NIR) and according to type of funding. DATA SOURCES: Research Ethics Committee (REC) and Human Resources Department registries. RESULTS: During the study, the REC approved 8466 protocols, 52% (4408/8466) were EC, the rest were NIR. Women led 39.7% (3360/8466) of the total. The gender gap was observed mainly in EC: FD were IP of 31.5% of them (1391/4408) and 48.5% (1969/4058) of NIR. This despite the increasing trend in the number of FD staff. By type of funding, when the studies were supported by private sector there was a wider gap markedly unfavorable for women. CONCLUSIONS: Our results show that there is underrepresentation of women in research leadership, mainly those with private financing. This study reinforces the idea that there is still a long way to go in this field. More studies are necessary to identify the existing differences that allow the implementation of actions at the institutional and cultural level that promote gender equality in the field of clinical research.

Is the use of the new Chronic Kidney Disease Epidemiology Consortium (CKD-EPI 2021) formula appropriate for the Spanish population?

INTRODUCTION: United States nephrology societies recommend changing from the CKD-EPI 2009 equation to the new CKD-EPI 2021 equation, which does not include the race coefficient, for calculating estimated glomerular filtration rate (eGFR). It is unknown how this change might affect the distribution of kidney disease in the predominantly Caucasian Spanish population. METHODS: Two databases of adults from the province of Cádiz, DB-SIDICA (N=264,217) and DB-PANDEMIA (N=64,217), that had plasma creatinine measurements recorded between 2017 and 2021 were studied. Changes in eGFR and the consequent reclassification into different categories of the KDIGO 2012 classification resulting from substituting the CKD-EPI 2009 equation for the 2021 equation were calculated. RESULTS: Compared to the 2009 equation, CKD-EPI 2021 yielded a higher eGFR, with a median of 3.8mL/min/1.73m2 (IQR 2.98-4.48) in DB-SIDICA and 3.89mL/min/1.73m2 (IQR 3.05-4.55) in DB-PANDEMIA. The first consequence was that 15.3% of the total population in DB-SIDICA and 15.1% of the total population in DB-PANDEMIA were reclassified into a higher category of eGFR, as were 28.1% and 27.3%, respectively, of the population with CKD (G3-G5); no subjects were classified into the more severe category. The second consequence was that the prevalence of kidney disease decreased from 9% to 7.5% in both cohorts. CONCLUSIONS: Implementing the CKD-EPI 2021 equation in the Spanish population, which is predominantly Caucasian, would increase eGFR by a modest amount (greater in men and those who are older or have a higher GFR). A significant proportion of the population would be classified into a higher eGFR category, with a consequent decrease in the prevalence of kidney disease.

[Chronic postoperative pain after general anesthesia with or without a single-dose preincisional paravertebral nerve block in radical breast cancer surgery]. / Comparación entre anestesia general con o sin bloqueo paravertebral preincisional con dosis única y dolor crónico postquirúrgico, en cirugía radical de cáncer de mama.

BACKGROUND AND OBJECTIVE: Over 50% of patients still experience pain a year after mastectomy with or without lymphadenectomy. We aimed to determine the association between anesthetic technique, acute postoperative pain intensity, and the development of chronic postoperative pain. PATIENTS AND METHODS: Forty patients were randomly assigned to receive general anesthesia with or without a paravertebral nerve block for modified radical mastectomy. Postoperative pain was assessed on a visual analog scale at 60 minutes and 24 hours; the patients were also asked to respond to a telephone questionnaire on chronic pain 4 to 5 months later. RESULTS: No significant differences in acute pain were observed. Twenty-nine responded to the telephone questionnaire. Only 1 patient in the paravertebral block group reported chronic neuropathic pain and none had phantom breast pain. Only 1 patient (6.7%) in the paravertebral block group reported chronic neuropathic pain and none had phantom breast pain. In the group that received general anesthesia alone, 1 patient reported phantom breast pain and 6 patients had neuropathic pain, associated with phantom breast pain in 2 cases (incidence of chronic pain 50%; P = .01, Fischer exact test; relative risk, 7.5, 95% confidence interval, 1.0-53.5). The incidences of myofascial pain (neck muscle tightness) were similar in the 2 groups. CONCLUSIONS: Four to 5 months after mastectomy, fewer cases of chronic pain developed in the group operated under general anesthesia with a preincisional paravertebral block than in the group that received only general anesthesia, with postoperative morphine chloride for analgesia.

A deletion variant of the Aspergillus fumigatus ribotoxin Asp f 1 induces an attenuated airway inflammatory response in a mouse model of sensitization.

BACKGROUND: Aspergillus fumigatus is the most prevalent airborne fungal pathogen, and the ribotoxin Asp f 1 is one of its major allergens. Alpha-Sarcin is a natural variant of Asp f 1 produced by the nonpathogenic fungus Aspergillus giganteus. Both proteins show a sequence identity of 87% and almost identical 3-dimensional structures. Alpha-Sarcin delta(7-22) is a deletion mutant that displays reduced immunoglobulin (Ig) E reactivity and is much less cytotoxic than wild-type proteins against human transformed cells. OBJECTIVE: A murine model of sensitization to Asp f 1 was established to test the response elicited by this alpha-sarcin delta(7-22) deletion mutant. METHODS: BALB/c mice were treated intraperitoneally with different mixtures of recombinant wild-type Asp f 1 and/or a suspension of a commercially available A. fumigatus standard extract. Mice were then intranasally challenged with Asp f 1 or alpha-sarcin delta(7-22). Sera were collected for subsequent measurement of Ig levels and histological analysis of the nostrils and lungs. RESULTS: Sensitization to Asp f 1 was successful only when the purified protein was first administered together with the A fumigatus suspension. The model was characterized by elevated levels of total IgE in serum and histological lesions in the lungs and nostrils. These symptoms were less severe when the deletion variant was the protein administered, thus confirming in vivo its lower toxic character. CONCLUSIONS: An easily reproducible mouse model of A fumigatus Asp f 1 sensitization was established. This model revealed alpha-sarcin delta(7-22) to be a potential candidate for immunotherapy.

[Protocolisation of parenteral artificial nutrition: Methodological and organisational bases for process design and review]. / Protocolización de la Nutrición Artificial por vía Parenteral: Bases metodológicas y organizativas para el diseño y revisión del proceso.

In the field of parenteral artificial nutrition (PN) there is debate over the application of such concepts as standardisation, individualisation, protocolisation and normalisation. Artificial Nutrition Units (ANU) that are designing or reviewing their PN provision system must take into account the existing methodological and regulatory references as well as the resources available for implementing the process. The aim of this article is to review and evaluate the possibilities that exist for designing an efficient, safe process, applying the methodology of continuous quality improvement. Current requirements are reviewed in terms of quality of formulation, safety, and cost containment, as well as the resources available to avoid jeopardising the possibilities of adapting the treatment to suit patient needs or compromising its efficacy. The solution to the problem of whether the chosen approach in the system of PN provision is appropriate must come from review of the quality of service through the evaluation of indicators both of process and results. In this task, the hospital pharmacist plays a significant role as an agent in guaranteeing compliance with good practice guidelines.

[Axillary recurrences after sentinel lymph node biopsy in initial breast cancer]. / Análisis de recurrencias axilares tras biopsia selectiva del ganglio centinela en cáncer de mama inicial.

OBJECTIVE: The aim of our study was to analyze the application of the Selective Sentinel Lymph Node Biopsy (SLNB) in early Breast Cancer of our population, through the analysis of axillary recurrences in patients with false negative sentinel node procedures without complete axillary lymphadenectomy, after a subsequent clinical follow-up. MATERIAL AND METHODS: A total of 218 early Breast Cancer patients who underwent SLNB after being diagnosed of early breast cancer (T1-2N0) with complete axillary dissection only when the SLNB was positive in the histopathological analysis. In every case, a 2-day protocol was used to localize the sentinel node after injection of (99m)Tc-Nanocolloid. RESULTS: The mean subsequent clinical follow-up was 27 months. A total of 413 sentinel nodes were removed with a median of 1.89/p (range 1-5). Infiltration was detected in 33.9% of patients (59.45% macrometastasis, 22.97% micrometastasis and 17.5% Isolated Tumor Cells (ITC)) and negative for the other nodes excised after conventional lymphadenectomy in 60% of cases. In our population, there was only one case of false negative (FN) SLN due to massive lymphatic blockage, and an abnormal lymph node without uptake adjacent to the SLN was identified intraoperatively. No case of axillary recurrence was detected during an average follow-up of 27 months. CONCLUSION: The absence of axillary recurrences in our population with negative SLNB without complete axillary dissection demonstrates the appropriate local control offered by this procedure in early Breast Cancer.

[Pulmonary torsion complicating lobectomy: report of 2 cases]. / Torsión pulmonar como complicación de una lobectomía pulmonar, descripción de dos casos.

We report 2 cases of pulmonary torsion discovered during the early postoperative recovery of patients who had undergone lobectomy. Early diagnosis, based on chest radiography and confirmed by computed tomography, meant we were able to avoid major surgical resection and the development of further complications. Pulmonary torsion is a rare but potentially serious abnormality. Prompt diagnosis is the key to preventing tissue injury and complications such as necrotizing pneumonitis, thromboembolic disease, or septic shock. Among the diagnostic tests that can be carried out if there is good reason to suspect torsion, we emphasize simple chest radiography and fiberoptic bronchoscopy, supported by computed tomography or arteriography, even though a firm diagnosis requires surgical exploration of the affected lung. Definitive treatments range from reversing the torsion and securing the lung to resecting the lung if the parenchymal tissue has been fully compromised.