Síndrome de Kartagener y artritis reumatoide. Reporte de caso / Kartagener Syndrome and Rheumatoid Arthritis. Case Report

Presentación del caso. Se trata de una mujer de 26 años de edad, en seguimiento por la especialidad de reumatología desde los 17 años, cuando consultó con historia de un año de evolución de síndrome poliarticular de grandes y pequeñas articulaciones, aditivo, simétrico acompañado de fatiga, rigidez matutina mayor de una hora. Se reportó además factor reumatoide positivo. La radiografía de ambas manos presentó erosiones, que confirmó el diagnóstico de artritis reumatoide. Adicionalmente, la paciente tenía el antecedente de procesos sinobronquiales a repetición desde su infancia. En la evaluación médica se identificó dolor en los senos paranasales, dextrocardia y bronquiectasias, confirmados por los estudios de imágenes, que permitió concluir en el diagnóstico de síndrome de Kartagener. Intervención terapéutica. La paciente presentaba actividad clínica severa de la artritis reumatoide, se inició el tratamiento con metotrexato 10 mg vía oral un día a la semana, prednisona 5 mg al día y ácido fólico 5 mg a la semana y citas periódicas, controlando los datos de actividad y efectos adversos de los medicamentos, con pruebas hepáticas, hemograma y transaminasas. La especialidad de neumología recomendó la inclusión de la paciente en un programa de rehabilitación respiratoria, así como el uso de azitromicina 500 mg cada día por tres días en los períodos de agudización. Evolución clínica. El tratamiento logró mantener una actividad leve de la artritis reumatoide y sin exacerbación de los síntomas respiratorios

Case presentation. A 26-year-old woman, under follow-up by the rheumatology specialty since she was 17 years old, when she consulted with a history of one year of evolution of polyarticular disease of large and small joints, additive, symmetrical, accompanied by fatigue and morning stiffness for more than one hour. Positive rheumatoid factor was also reported. Additionally, the patient had a history of repeated sinobronchial processes since childhood. Medical examination revealed sinus pain in the paranasal sinuses, dextrocardia, and bronchiectasis, confirmed by imaging studies, which led to the diagnosis of Kartagener's syndrome. Treatment. The patient presented the severe clinical activity of rheumatoid arthritis. The treatment was started with methotrexate 10 mg orally one day a week, prednisone 5 mg a day, and folic acid 5 mg a week and periodic appointments, controlling the activity data and adverse effects of the drugs, with liver tests, hemogram, and transaminases. The pneumology department recommended the inclusion of the patient in a respiratory rehabilitation program as well as the use of azithromycin 500 mg every day for three days during periods of exacerbation. Outcome. The treatment was successful in maintaining a mild activity of the rheumatoid arthritis and without exacerbation of respiratory symptoms

Multidisciplinary approach as a treatment option for abdominal wall reconstruction in patients with heart failure: A case report.

INTRODUCTION AND IMPORTANCE: Incisional hernias are among the most frequent complications of abdominal surgery, with an incidence of 4-10 % of patients [1]. The multidisciplinary approach according to the patient's needs and their comorbidities has been shown to improve postoperative outcomes. This case report highlights the importance of a multidisciplinary approach including cardiology, general surgery, plastic surgery anesthesiology and intensive care unit for abdominal wall reconstruction in a patient with heart failure and reduced ejection fraction. CLINICAL PRESENTATION: We present a case of a 61-year-old patient with long-standing incisional hernia, without surgical correction due to the patient's condition and multiple comorbidities, advanced heart failure with reduced left ejection fraction (10-15 %) who underwent a multidisciplinary approach by cardiology, plastic surgery, anesthesiology, intensive care unit, and general surgery. DISCUSSION: The patient underwent abdominal wall reconstruction without complications. Due to multiple comorbidities, the patient was admitted in the ICU in the immediate postoperative period. He was discharged 9 days after surgery. The patient did not report long-term complications. CONCLUSION: Heart failure is associated with an increased risk of cardiovascular complications during surgical hospitalization. In patients with multiple comorbidities, the multidisciplinary approach represents an essential strategy in order to improve the surgical outcome, reduce costs to the health care system, and improve the patient's quality of life.

Naked (N) mutant mice carry a nonsense mutation in the homeobox of Hoxc13.

Loss of function mutations in HOXC13 have been associated with Ectodermal Dysplasia-9, Hair/Nail Type (ECTD9) in consanguineous families, characterized by sparse to complete absence of hair and nail dystrophy. Here we characterize the spontaneous mouse mutation Naked (N) as a terminal truncation in the Hoxc13 (homeobox C13) gene. Similar to previous reports for homozygous Hoxc13 knock-out (KO) mice, homozygous N/N mice exhibit generalized alopecia with abnormal nails and a short lifespan. However, in contrast to Hoxc13 heterozygous KO mice, N/+ mice show generalized or partial alopecia, associated with loss of hair fibres, along with normal lifespan and fertility. Our data point to a lack of nonsense-mediated Hoxc13 transcript decay and the presence of the truncated mutant protein in N/N and N/+ hair follicles, thus suggesting a dominant-negative mutation. To our knowledge, this is the first report of a semi-dominant and potentially dominant-negative mutation affecting Hoxc13/HOXC13. Furthermore, recreating the N mutant allele in mice using CRISPR/Cas9-mediated genome editing resulted in the same spectrum of deficiencies as those associated with the spontaneous Naked mutation, thus confirming that N is indeed a Hoxc13 mutant allele. Considering the low viability of the Hoxc13 KO mice, the Naked mutation provides an attractive new model for studying ECTD9 disease mechanisms.

Circulating angiogenic factors are associated with progression to preeclampsia and the occurrence of adverse outcomes in women with gestational hypertension.

OBJECTIVE: Gestational hypertension is characterized by an imbalance in angiogenic factors. The goal of the current study was to evaluate whether circulating concentrations of proangiogenic and antiangiogenic factors are associated with the risk of progression to preeclampsia and development of adverse outcomes in women with gestational hypertension. METHODS: We studied 496 women with gestational hypertension. Patients were divided into three groups based on their degree of angiogenic imbalance, evaluated by the soluble fms-like tyrosine kinase-1/placental growth factor ratio: no angiogenic imbalance (≤38), mild angiogenic imbalance (>38-<85), and severe angiogenic imbalance (≥85) or stratified into tertiles according to soluble endoglin (sEng) levels. RESULTS: The concentrations of all angiogenic factors were significantly different in patients with gestational hypertension than in healthy pregnancy. A significant trend towards higher serum sEng levels was observed as the degree of angiogenic imbalance increased. Patients with severe angiogenic imbalance had higher rates of adverse maternal and perinatal outcomes and progression to preeclampsia (P < 0.001) when compared with patients with no or mild angiogenic imbalance. The risk of combined adverse maternal outcomes and specific adverse outcomes (hemolysis, elevated liver enzymes, low platelet count syndrome, preterm delivery, small-for-gestational-age infant, perinatal death, and progression to preeclampsia within 7, 14, 28, and 56 days) was higher in patients with severe angiogenic imbalance or sEng values in the highest tertile (odds ratio ≥5.6 and ≥2.0, respectively), compared with no angiogenic imbalance or the lowest tertile. CONCLUSION: In women with gestational hypertension at the time of initial evaluation, circulating concentrations of the soluble fms-like tyrosine kinase-1/placental growth factor ratio and sEng appear to be suitable markers to assess the risk of adverse maternal and perinatal outcomes and progression to preeclampsia.

Variability and Performance Study of the Sound Absorption of Used Cigarette Butts.

There has been increasing interest in new sustainable materials that can be used as construction materials. Among them, sound-absorbing materials have an important role in both acoustical room conditioning and in room insulation. As a proposal for recycling, one of the most common residues in the world, cigarette butts, is studied. Samples were prepared with used cigarette butts as acoustical absorbent materials. Several samples were prepared and grouped by similarity. Variability analyses of the samples prepared in each group were performed. Moreover, the analysis of some possible influences on absorption properties, such as the length of butts, presence of burnt regions, presence of wrapping paper, etc., were analyzed. The results show the potentiality of this residue to be used as an acoustical absorbent since the absorption coefficients found are greater than 0.8 for frequencies over 2000 Hz. The observed variability in the study group and samples can be considered low, as it was below 2% for the major part of frequencies. Influences on the absorption coefficient, for both the length and status of the butts, were statistically confirmed.

Mismatch repair gene mutations lead to lynch syndrome colorectal cancer in rhesus macaques.

Colorectal cancer accounts for a substantial number of deaths each year worldwide. Lynch Syndrome is a genetic form of colorectal cancer (CRC) caused by inherited mutations in DNA mismatch repair (MMR) genes. Although researchers have developed mouse models of Lynch Syndrome through targeted mutagenesis of MMR genes, the tumors that result differ in important ways from those in Lynch Syndrome patients. We identified 60 cases of CRC in rhesus macaques (Macaca mulatta) at our facility since 2001. The tumors occur at the ileocecal junction, cecum and proximal colon and display clinicopathologic features similar to human Lynch Syndrome. We conducted immunohistochemical analysis of CRC tumors from several rhesus macaques, finding they frequently lack expression of MLH1 and PMS2 proteins, both critical MMR proteins involved in Lynch Syndrome. We also found that most macaque cases we tested exhibit microsatellite instability, a defining feature of Lynch Syndrome. Whole genome sequencing of rhesus macaque CRC cases identified mutations in MLH1 and/or MSH6 that are predicted to disrupt protein function. We conclude that this population of rhesus macaques constitutes a spontaneous model of Lynch Syndrome, matching the human disease in several significant characteristics, including genetic risk factors that parallel human Lynch Syndrome.

COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer.

The pro-oncogenic kinase PKCε is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE2 production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCε, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation, as well as angiogenesis in a mouse model of prostate-specific PKCε expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-κB pathway and its target gene COX2 as PKCε effectors, and highlight the potential of PKCε as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer.

Boar sperm hyperactivated motility is induced by temperature via an intracellular calcium-dependent pathway.

Herein we describe a new protocol to induce boar sperm hypermotility: temperature-induced hypermotility (TIH). Briefly, spermatozoa stored at 17°C in a calcium-free Tyrode's basal medium (containing EGTA) were exposed to increased temperature by incubation at 38.5°C. Hypermotility induced by the calcium ionophore A23187 was used as a control (calcium ionophore-induced hyperactivity (CIIH)). The increase in temperature led to an increase in the percentage of hypermotile spermatozoa. When the slope of the temperature increase is near zero, sperm hyperactivity becomes a more progressive movement. Motility parameters of sperm hyperactivation induced by TIH were different from those following CIIH. Cluster analysis revealed that these two populations of hyperactivated spermatozoa are different. TIH is independent of extracellular Ca2+ but dependent on intracellular Ca2+ release. Moreover, TIH is unaffected by protein kinase A (PKA) inhibition, whereas CIIH is reduced by half in the presence of a PKA inhibitor. In conclusion, we have demonstrated that: (1) a temperature increase in boar spermatozoa is a stimulus that can induce a hyperactive population, which is differs from the hyperactive sperm population induced by calcium ionophore; (2) the temperature increase in spermatozoa triggers the release of Ca2+ from intracellular stores; (3) extracellular calcium is not required for TIH; and (4) TIH in boar spermatozoa is independent of PKA activity.

MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques.

Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans.

The p53 R72P polymorphism does not affect the physiological response to ionizing radiation in a mouse model.

Tissue culture and mouse model studies show that the presence of the arginine (R) or proline (P) coding single nucleotide polymorphism (SNP) of the tumor suppressor gene p53 at codon 72 (p53 R72P) differentially affects the responses to genotoxic insult. Compared to the P variant, the R variant shows increased apoptosis in most cell cultures and mouse model tissues in response to genotoxins, and epidemiological studies suggest that the R variant may enhance cancer survival and reduce the risks of adverse reactions to genotoxic cancer treatment. As ionizing radiation (IR) treatment is often used in cancer therapy, we sought to test the physiological effects of IR in mouse models of the p53 R72P polymorphism. By performing blood counts, immunohistochemical (IHC) staining and survival studies in mouse populations rigorously controlled for strain background, sex and age, we discovered that p53 R72P polymorphism did not differentially affect the physiological response to IR. Our findings suggest that genotyping for this polymorphism to personalize IR therapy may have little clinical utility.

Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway.

PKCε, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCε with other genetic alterations, as well as the effectors contributing to its tumorigenic and metastatic phenotype. Here, we demonstrate that PKCε cooperates with the loss of the tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCε overexpression and Pten loss individually and synergistically upregulate the production of the chemokine CXCL13, which involves the transcriptional activation of the CXCL13 gene via the non-canonical nuclear factor κB (NF-κB) pathway. Notably, targeted disruption of CXCL13 or its receptor, CXCR5, in prostate cancer cells impaired their migratory and tumorigenic properties. In addition to providing evidence for an autonomous vicious cycle driven by PKCε, our studies identified a compelling rationale for targeting the CXCL13-CXCR5 axis for prostate cancer treatment.

Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene.

Here we describe a spontaneous mutation in the Zdhhc13 (zinc finger, DHHC domain containing 13) gene (also called Hip14l), one of 24 genes encoding palmitoyl acyltransferase (PAT) enzymes in the mouse. This mutation (Zdhhc13luc) was identified as a nonsense base substitution, which results in a premature stop codon that generates a truncated form of the ZDHHC13 protein, representing a potential loss-of-function allele. Homozygous Zdhhc13luc/Zdhhc13luc mice developed generalized hypotrichosis, associated with abnormal hair cycle, epidermal and sebaceous gland hyperplasia, hyperkeratosis, and increased epidermal thickness. Increased keratinocyte proliferation and accelerated transit from basal to more differentiated layers were observed in mutant compared with wild-type (WT) epidermis in untreated skin and after short-term 12-O-tetradecanoyl-phorbol-13-acetate treatment and acute UVB exposure. Interestingly, this epidermal phenotype was associated with constitutive activation of NF-κB (RelA) and increased neutrophil recruitment and elastase activity. Furthermore, tumor multiplicity and malignant progression of papillomas after chemical skin carcinogenesis were significantly higher in mutant mice than WT littermates. To our knowledge, this is the first report of a protective role for PAT in skin carcinogenesis.

Activation of nuclear factor κB (NF-κB) in prostate cancer is mediated by protein kinase C epsilon (PKCepsilon).

Protein kinase C ε (PKCε) has emerged as an oncogenic kinase and plays important roles in cell survival, mitogenesis and invasion. PKCε is up-regulated in most epithelial cancers, including prostate, breast, and lung cancer. Here we report that PKCε is an essential mediator of NF-κB activation in prostate cancer cells. A strong correlation exists between PKCε overexpression and NF-κB activation status in prostate cancer cells. Moreover, transgenic overexpression of PKCε in the mouse prostate causes preneoplastic lesions that display significant NF-κB hyperactivation. PKCε RNAi depletion or inhibition in prostate cancer cells diminishes NF-κB translocation to the nucleus with subsequent impairment of both activation of NF-κB transcription and induction of NF-κB responsive genes in response to the proinflammatory cytokine tumor necrosis factor α (TNFα). On the other hand, PKCε overexpression in normal prostate cells enhances activation of the NF-κB pathway. A mechanistic analysis revealed that TNFα activates PKCε via a C1 domain/diacylglycerol-dependent mechanism that involves phosphatidylcholine-phospholipase C. Moreover, PKCε facilitates the assembly of the TNF receptor-I signaling complex to trigger NF-κB activation. Our studies identified a molecular link between PKCε and NF-κB that controls key responses implicated in prostate cancer progression.

Transgenic overexpression of PKCε in the mouse prostate induces preneoplastic lesions.

It is well established that protein kinase C (PKC) isozymes play distinctive roles in mitogenic and survival signaling as well as in cancer progression. PKCε, the product of the PRKCE gene, is up-regulated in various types of cancers including prostate, lung and breast cancer. To address a potential role for PKCs in prostate cancer progression we generated three mouse transgenic lines expressing PKCα, PKCδ, or PKCε in the prostate epithelium under the control of the rat probasin (PB) promoter. Whereas PB-PKCε and PB-PKCδ mice did not show any evident phenotype, PB-PKCε mice developed prostate hyperplasia as well as prostate intraepithelial neoplasia (PIN) that displayed enhanced phospho-Akt, phospho-S6, and phospho-Stat3 levels, as well as enhanced resistance to apoptotic stimuli. PKCε overexpression was insufficient to drive neoplastic changes in the mouse prostate. Notably, overexpression of PKCε by adenoviral means in normal immortalized RWPE-1 prostate cells confers a growth advantage and hyperactivation of Erk and Akt. Our results argue for a causal link between PKCε overexpression and prostate cancer development.

Morbilidad por IMA en pacientes mayores de 60 años. Unidad de cuidados intensivos coronarios. Año 2004 / Morbidity in Acute Myocardial Infarction in patients older than 60 years. Coronary Intensive Care Units- 2004

El Infarto Miocardio Agudo (IMA), se ha mantenido año tras año en la cumbre de las causas de muerte de los países desarrollados y en vías de desarrollo, por lo anterior expuesto nos motivamos a realizar este trabajo para valorar la morbilidad por IMA en pacientes mayores de 60 años en la Unidad de Cuidados Coronarios del Hospital Abel Santamaría en el año 2004. Para ello de un universo de 347 pacientes se tomó una muestra de 219 y se revisaron las historias clínicas donde las principales variables a medir fueron edad, sexo, cara del corazón afectada y las complicaciones más frecuentes, utilizando el método porcentual aritmético, concluyendo que la edad más frecuente osciló entre 60 y 65 años de edad, la cara del corazón afectada fue la anterior, el sexo el masculino y las complicaciones eléctricas fueron las más frecuentes.

Acute myocardial infarction (AMI) has maintained the pinnacle of the causes of death in developed and developing countries year after year, this was the motivation to conduct this research paper that was aimed at assessing the morbidity due to AMI in patients older than 60 years old in the Coronary Intensive Care Unit at “Abel Santamaria Cuadrado” University Hospital in 2004. The target group was comprised of 347 patients and the sample 219, clinical histories were examined and the main variables analyzed were age, sex, most affected face of the heart and frequent complications using arithmetic percentage methods. Conclusion: Ages most affected oscillated between 60 and 65, the affected face of the heart was the anterior, male sex prevailed and electric complications were the most frequent.