A comparison of gene expression and DNA methylation patterns across tissues and species.

Previously published comparative functional genomic data sets from primates using frozen tissue samples, including many data sets from our own group, were often collected and analyzed using nonoptimal study designs and analysis approaches. In addition, when samples from multiple tissues were studied in a comparative framework, individuals and tissues were confounded. We designed a multitissue comparative study of gene expression and DNA methylation in primates that minimizes confounding effects by using a balanced design with respect to species, tissues, and individuals. We also developed a comparative analysis pipeline that minimizes biases attributable to sequence divergence. Thus, we present the most comprehensive catalog of similarities and differences in gene expression and DNA methylation levels between livers, kidneys, hearts, and lungs, in humans, chimpanzees, and rhesus macaques. We estimate that overall, interspecies and inter-tissue differences in gene expression levels can only modestly be accounted for by corresponding differences in promoter DNA methylation. However, the expression pattern of genes with conserved inter-tissue expression differences can be explained by corresponding interspecies methylation changes more often. Finally, we show that genes whose tissue-specific regulatory patterns are consistent with the action of natural selection are highly connected in both gene regulatory and protein-protein interaction networks.

An analysis of 372 patients with anterior uveitis in a large Ibero-American cohort of spondyloarthritis: the RESPONDIA Group.

OBJECTIVES: This study analysed the frequency of anterior uveitis (AU) and its correlations in a large cohort of patients with spondyloarthritis (SpA). METHODS: A common protocol of investigation was prospectively applied to 2012 SpA patients in 85 centres from 10 Ibero-American countries. Clinical and demographic variables and disease indexes were investigated. Categorical variables were compared by χ2 and Fisher's exact test, and continuous variables were compared by ANOVA or Kruskal-Wallis test. A value of p<0.05 was considered significant. RESULTS: AU was referred by 372 SpA patients (18.5%). AU was statistically associated with inflammatory low back pain (p<0.001), radiographic sacroiliitis (p<0.001), enthesopathies (p=0.004), urethritis/acute diarrhoea (p<0.001), balanitis (p=0.002), hip involvement (p=0.002), HLA-B27 (p=0.003), and higher C-reactive protein (p=0.001), whilst it was negatively associated with the number of painful (p=0.03) and swollen (p=0.005) peripheral joints, psoriatic arthritis (p<0.001), psoriasis (p<0.001), nail involvement (p<0.001), and dactilitis (p=0.062; trend). No association with gender, race, and indices (disease activity, functionality and quality of life) was observed. Logistic regression showed that ankylosing spondylitis (p=0.001) and HLA-B27 (p=0.083; trend) was significantly associated with AU, while extra-articular manifestations (predominantly psoriasis) were negatively associated (p=0.016). CONCLUSIONS: Anterior uveitis is a frequent extra-articular manifestation in SpA patients, positively associated with axial involvement and HLA-B27 and negatively associated with peripheral involvement and psoriatic arthritis.

Female gout: age and duration of the disease determine clinical presentation.

OBJECTIVE: This study aimed to compare data and associated diseases between women and men with gout paired for age and duration of the disease. METHODS: Consecutive patients from outpatient gout clinics of 2 rheumatology departments were included in this case-control study. We identified 37 women with gout diagnosis and paired them by age and duration of the disease with 37 men with gout (American College of Rheumatology criteria). Variables were clinical data, associated diseases, and renal function evaluated by 3 methods: creatinine clearance, modification of diet in renal disease, and Cockcroft-Gault. RESULTS: Mean (SD) age was 54.47 (15.13) years in women versus 53.52 (15.23) years in males, and mean (SD) age at onset 46.77 (16.63) years versus 45.62 (16.16) years in women and men, respectively. Hypertension was found in 26 (73%) of 37 women and in 27 (70%) of 37 men, previous diuretics was found in only 1 man, and no significant differences were found between women and men in gout or associated metabolic diseases. Females had lower creatinine clearance than males did (49.8 [29.7] vs. 67.1 [35.5] mL/min, P = 0.039). But, when it was calculated by methods considering sex, there were no significant differences (Cockcroft-Gault 66.4 [37.6] vs. 78.8 [43.8] mL/min [P = 0.2] and modification of diet in renal disease 73.8 [64.6] vs. 73.1 [35.0] mL/min [P = 0.9], females vs. males, respectively). Thirteen women (35%) were premenopausal at onset, 2 had familial history of gout, and 2 had history of lithiasis; other variables were not different from postmenopausal women. CONCLUSIONS: Factors previously associated to female gout seem to be more related to age than to sex or to the disease itself. In our country, patients with gout (males and females) are younger at onset. Gender should be considered to evaluate renal function in females with gout. One third of our female patients with gout were premenopausal and had unexpected higher frequency of lithiasis; no other differences with postmenopausal women were found.

Could Frida Kahlo have had antiphospholipid syndrome?

Frida Kahlo's medical history shows sequelae of polio, a severe traumatic event that caused multiple fractures and a penetrating pelvic injury, as well as a history of countless surgeries. In her biographical accounts and her works, chronic disabling pain always appears for long periods. Besides, a chronic foot ulcer, gangrene that required amputation of the right leg, a history of abortions, and a positive Wasserman reaction suggest that the artist could have suffered from antiphospholipid antibody syndrome (APS).

Two new species of Miersia and their phylogenetic placements alongside the recently described M.putaendensis (Gilliesieae, Allioideae, Amaryllidaceae).

Two new species of the Chilean endemic genus Miersia (Gilliesieae, Allioideae, Amaryllidaceae) are described, M.stellata and M.raucoana, alongside morphological descriptions, a distribution map, illustrations, conservation status assessments, and an updated key to all species of Miersia. Additionally, phylogenetic analyses of DNA sequences were performed to inquire into the evolutionary affinities of both new species and the recently described, M.putaendensis, within the tribe Gilliesieae.

Erratum: Corrigendum: García N, Cuevas C, Sepúlveda JE, Cádiz-Véliz A, Román MJ (2022) Two new species of Miersia and their phylogenetic placements alongside the recently described M.putaendensis (Gilliesieae, Allioideae, Amaryllidaceae). PhytoKeys 211: 107-124. doi: 10.3897/phytokeys.211.87842.

[This corrects the article DOI: 10.3897/phytokeys.211.87842.].

Divergence in alternative polyadenylation contributes to gene regulatory differences between humans and chimpanzees.

While comparative functional genomic studies have shown that inter-species differences in gene expression can be explained by corresponding inter-species differences in genetic and epigenetic regulatory mechanisms, co-transcriptional mechanisms, such as alternative polyadenylation (APA), have received little attention. We characterized APA in lymphoblastoid cell lines from six humans and six chimpanzees by identifying and estimating the usage for 44,432 polyadenylation sites (PAS) in 9518 genes. Although APA is largely conserved, 1705 genes showed significantly different PAS usage (FDR 0.05) between species. Genes with divergent APA also tend to be differentially expressed, are enriched among genes showing differences in protein translation, and can explain a subset of observed inter-species protein expression differences that do not differ at the transcript level. Finally, we found that genes with a dominant PAS, which is used more often than other PAS, are particularly enriched for differentially expressed genes.

Could Frida Kahlo Have Had Antiphospholipid Syndrome?

Frida Kahlo's medical history shows sequelae of polio, a severe traumatic event that caused multiple fractures and a penetrating pelvic injury, as well as a history of countless surgeries. In her biographical accounts and her works, chronic disabling pain always appears for long periods. Besides, a chronic foot ulcer, gangrene that required amputation of the right leg, a history of abortions, and a positive Wasserman reaction suggest that the artist could have suffered from antiphospholipid antibody syndrome (APS).

Gene expression variability in human and chimpanzee populations share common determinants.

Inter-individual variation in gene expression has been shown to be heritable and is often associated with differences in disease susceptibility between individuals. Many studies focused on mapping associations between genetic and gene regulatory variation, yet much less attention has been paid to the evolutionary processes that shape the observed differences in gene regulation between individuals in humans or any other primate. To begin addressing this gap, we performed a comparative analysis of gene expression variability and expression quantitative trait loci (eQTLs) in humans and chimpanzees, using gene expression data from primary heart samples. We found that expression variability in both species is often determined by non-genetic sources, such as cell-type heterogeneity. However, we also provide evidence that inter-individual variation in gene regulation can be genetically controlled, and that the degree of such variability is generally conserved in humans and chimpanzees. In particular, we found a significant overlap of orthologous genes associated with eQTLs in both species. We conclude that gene expression variability in humans and chimpanzees often evolves under similar evolutionary pressures.

First acute gout attacks commonly precede features of the metabolic syndrome.

OBJECTIVE: To determine in gout patients, the temporal relationship between the first gout attack and the diagnosis of metabolic syndrome (MS), its components and complications. SUBJECTS AND METHODS: We included consecutive gout patients attending 2 Rheumatology Departments from Spain (Hospital Universitario Reina Sofía) and México (Hospital General de México). Variables included demographic, clinical, and biochemical data: Hypertension, hypertriglyceridemia, low high density lipoproteins (HDL), obesity, hyperglycemia or diabetes, MS (Adult Treatment Pane III criteria), ischemic heart disease (IHD), and chronic renal failure (CRF). Age and date (year) of the diagnosis of first acute gout attack and associated diseases were obtained. RESULTS: Four hundred seven patients were included (96% men); mean age at onset, mean age at inclusion, and mean duration of the disease were 39.7 +/- 13, 52.5 +/- 13, and 13.7 +/- 9.9 years, respectively. In 90%, the first attack of gout preceded the diagnosis of features of MS, MS itself or its complications (CRF and IHD), 9.8% had previous diagnosis of at least 1 associated disease. At the time of the inclusion (mean, 13.7 years after the first attack), 93% had at least 1 associated disease. The most common were hypertriglyceridemia, 63%; obesity, 54%; hypertension, 45.6%; MS, 40%; hyperglycemia, 37%; low HDL, 17%; diabetes, 15%; CRF, 17%; and IHD, 6.6%. Although patients from the 2 Rheumatology Departments had several demographic and clinical differences, in both groups most of the patients (70% Hospital Universitario Reina Sofía and 95% Hospital General de México) had no diagnosis of any associated disease previous to first bouts and at inclusion most of them had the diagnosis of at least 1 associated disease. CONCLUSIONS: First attacks of gout may precede the diagnosis of metabolic abnormalities and associated diseases, and provids a unique opportunity to diagnose, prevent, and/or retard long-term complications in these patients.

Sustained clinical remission and rate of relapse after tocilizumab withdrawal in patients with rheumatoid arthritis.

OBJECTIVE: Data on when to stop use of biological agents in rheumatoid arthritis (RA) are scant. We assessed the length of remission and the rate of clinical relapse in patients with RA who had to discontinue treatment with tocilizumab (TCZ) because of the ending of longterm (5 yrs) open-label clinical trials. METHODS: All patients at 2 participating centers in Mexico were in remission, defined as Disease Activity Score 28 ≤ 2.6, with no swollen joints at the time of the last TCZ infusion. Patients were followed thereafter every 8 weeks for 12 months or until relapse. Relapse was defined as the presence of ≥ 1 swollen joint. Doses of methotrexate and antiinflammatory drugs were not changed during the followup period. RESULTS: Forty-five patients were analyzed, 87% were women (mean age 52 yrs, mean disease duration 14 yrs). During the 12 months of followup, 44% of patients maintained remission. Relapses occurred in 56% of patients: 14 during the first 3 months after the last TCZ administration. Retreatment using other agents achieved low disease activity or remission. CONCLUSION: Longterm clinical remission is possible in a number of patients with RA after suspension of TCZ. This effect has also been reported with other biologic agents. Additional data are required to support recommendations for discontinuing a biological agent after achieving remission.

The diagnostic value of the proposal for clinical gout diagnosis (CGD).

The purpose of this study is to determine the diagnostic properties of the clinical gout diagnosis (CGD) proposal in patients with gout and other rheumatic diseases. We investigated the presence of current or past history of the previously published CGD criteria: (1) >1 attack of acute arthritis, (2) mono/oligoarthritis attacks, (3) rapid progression of pain and swelling (<24 h), (4) podagra, (5) erythema, (6) unilateral tarsitis, (7) probable tophi, and (8) hyperuricemia. CGD was established in patients with greater than or equal to four out of eight of these criteria. Demographic data and comorbidities were also considered. Statistical analysis included diagnostic test evaluation (sensitivity, specificity, likelihood ratios, positive predictive values and receiving operating characteristic curves). One hundred and sixty-seven patients with the following diagnoses were included: gout (most in intercritical period, n = 75), rheumatoid arthritis (RA, n = 30), osteoarthritis (OA, n = 31) and spondyloarthritis (SpA, n = 31). All gout patients had MSU crystal demonstration and constituted the gold standard for diagnostic test evaluation. There were significant differences across diagnostic groups in most demographic variables and comorbidity. The presence of greater than or equal to four out of eight of the CGD criteria were found in 97% patients with gout, in two patients with SpA, and one each with RA and OA. The sensitivity, specificity, and LR+ of greater than or equal to four out of eight of the CGD criteria were 97.3%, 95.6%, and 22.14, respectively. The presence of more than or equal to four out of eight items from the CGD proposal is highly suggestive of gout.

Diagnosis of chronic gout: evaluating the american college of rheumatology proposal, European league against rheumatism recommendations, and clinical judgment.

OBJECTIVE: Observation of monosodium urate (MSU) crystal is the gold standard for diagnosis of gout, but is rarely performed in daily clinical practice, and diagnosis is based on clinical judgment. Our aim was to identify clinical and paraclinical data included in the European League Against Rheumatism recommendations (EULARr) and American College of Rheumatology proposed criteria (ACRp) for diagnosis of gout in patients with chronic gout according to their attending rheumatologists. METHODS: This cross-sectional and multicenter study included consecutive patients from outpatient clinics with a diagnosis of gout by their attending rheumatologists according to their expertise. The frequency of each item from the ACRp and EULARr was determined. Possible combinations of the items that were frequent, clinically relevant, and simple to evaluate in daily practice were determined. RESULTS: We studied 549 patients (96% men), mean age 50 +/- 14 years. Analysis of MSU crystals was performed in 15%. We selected 7 clinical criteria and 1 laboratory measure because of their frequency, importance, and simplicity to obtain: current or past history of: > 1 attack of acute arthritis (93%); mono or oligoarthritis attacks (74%); rapid progression of pain and swelling (< 24 hours; 74%); podagra (70%); erythema (56%); unilateral tarsitis (33%); tophi (52%); and hyperuricemia (93%). The chronic gout diagnosis (CGD) proposal comprised >or= 4/8 of these; 88% of patients had the criteria of the CGD proposal while 75% had 6/11 ACRp criteria (p = 0.001). When analysis of MSU crystals was added, 90.1% (CGD) and 83.9% (ACRp) met the criteria (p = 0.004). CONCLUSION: Current or past history of >or= 4/8 CGD parameters is highly suggestive of chronic gout.

[Effect of low-intensity pulsed ultrasound on regeneration of joint cartilage in patients with second and third degree osteoarthritis of the knee]. / Efecto del ultrasonido terapéutico pulsátil de baja intensidad sobre la regeneración del cartílago articular en pacientes con gonartrosis de segundo y tercer grado.

OBJECTIVE: To determine if the application of low intensity pulsed ultrasound (LIPUS) therapy has a positive effect over the cartilage repair, functional status and reduction of pain in patients with grade 2 or 3 osteoarthrosis of the knee. DESIGN: This trial was an observational, before and after study without a control group, in which 10 patients (eleven knees) were studied. We applied LIPUS therapy with an intensity of 0.3W/cm(2), duty cycle of 50%, giving a total of 36J/cm(2) per session during 36 sessions (three months). The clinical measures were obtained before the first session and at the end of the 36th session, and were: cartilage thickness by the analysis of magnetic resonance images (MRI) measured by two rheumatologists and a radiology specialist, pain by a visual analog scale (1-10cm) and function/severity by the Lequesne index. We used the non parametric tests of Wilcoxon for comparing medians and the Spearmans rho for the correlation of the inter observer cartilage thickness measurements defining a p value of<0.05 as significant. RESULTS: We observed an effect on pain (VAS mean before 7.09+-2.54 mean after 4.18+-2.22 p 0.005) and on the function/severity index (Lequesne mean before 10.55+-5.42 mean after 5+-4.45 p 0.008). There was poor consistency regarding the cartilage thickness measures by resonance imaging between the three observers (2 rheumatologists and 1 radiologist) so we were not able to define the presence or absence of effect on cartilage thickness augmentation. CONCLUSIONS: LIPUS has a benefic effect over pain and functionality/severity in patients with Kellgren and Lawrence grade 2 and 3 osteoarthritis of the knee. Unfortunately in this study we did not count with a reliable measure method to conclude on its effect over cartilage thickness measured by MRI.

Programa alivio del dolor por cáncer avanzado y cuidados paliativos, Llay-Llay, enero 2001-febrero 2004 / Pain relief and palliative care program for advanced cancer, Llay-Llay, January 2001-February 2004

El cáncer es una realidad presente en la población chilena que obliga al sistema de salud pública a implementar programas abocados a las distintas etapas clínicas del cáncer, entre éstos se encuentra el Programa Nacional de Alivio del Dolor por Cáncer y Cuidados Paliativos. El objetivo de este estudio es evaluar el funcionamiento de este programa en un hospital tipo IV, y establecer si existe cumplimiento de los objetivos propuesto por el Ministerio de Salud. Es un estudio descriptivo de 72 pacientes que se incorporaron al programa analizando variables como tiempo de estadía, disminución del dolor y tratamiento analgésico. El 38,% tiene conocimiento de su patología al ingreso. La mayoría (73,6% permaneció hasta 3 meses en el programa. Al ingreso del programa, el 62% ingresó con un EVA igual o superior a 4. En cambio, al egreso el 95,7% presentaba un EVA menor a 4. El 9,7% ingresó sin tratamiento analgésico, el 23,6% con tratamiento basado en AINES y el 66,7% utilizaba algún opiáceo. El 1,4% al fallecer no recibía ningún tratamiento analgésico. En cuanto a las prestaciones entregadas, existieron 4,7 consultas por mes. En cuanto a las visitas se realizaron 1,47 visitas por mes. Se efectuó un promedio de 1,35 talleres por persona. Este programa puesto en marcha desde 1997, proporciona las prestaciones suficientes para cumplir el principal objetivo propuesto que es disminuir el dolor en los pacientes ingresados y mejorar de esta forma su calidad de vida para lograr así una muerte digna y tranquila.

Cancer is a reality present in the Chilean popularion, a fact which compels the public health system to implement programs dealing with the different clinical stages of cancer, among them,the National Program for Pain Relief in Cancer and its Palliative Care. The aim of this study is that of evaluating the development of this program in a type IV hospital, and establishing whether the objectives propounded by the Ministry of Health are being observed. This is a descriptive study of 72 patients incorporated into the program, analyzing variables such as time of permanence, decrease of pain and analgesic treatment. A 38.9% of the patients were aware of their pathology upon entry. The majority (73.6%) remained in the program for as long as 3 months. Upon entry to the program, 62% had a visual-analogue scale (VAS) equal to 4 or higher. Upon departure, on the other hand, 95.7% had a VAS below 4. A 9.7% entered the program without analgesic treatment, 23.6% with treatment based on non-steroidal antiinflammatory drugs (NSAIDs) and 66.7% using some opiate. The deceased 1.4% received no analgesic treatment. As far as services delivered, there were 4.7 office visits per month. As far as outpatient visits are concerned, 1.47 visits took place per month. An average of 1.35 workshops per person were carried out. This program, which was started in 1997, provides adequate benefits to cover the main objective contemplated, which is that of diminishing pain to the incorporated patients, thus improving their quality of life to reach a worthy and peaceful death.

Estudio del nódulo mamario / Study of mammary nodule

El tumor mamario es un desafio diagnóstico tanto para los médicos generales como para los especialistas. Un diagnóstico exacto, con uso racional de las técnicas diagnosticas es esencial para evitar el uso de métodos invasivos innecesarios. La bibliografía indica que un 9 a un 11 por ciento de las mujeres a quienes se les haya detectado un nódulo mamario tendrán un diagnóstico definitivo de cáncer. Este riesgo aumenta con la edad: de un 1 por ciento de las mujeres hasta los 40 años, a 9 por ciento entre 41 y 50 años, y 37 por ciento de las mayores de 51 años. Considerando que la incidencia del cáncer de mama ha ido en aumento y que el 62 por ciento de los tumores son detectados al examen físico, una correcta evaluación del nódulo mamario se vuelve esencial.