Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

The proteomics of roadside hawk (Rupornis magnirostris), broad-snouted caiman (Caiman latirostris) and loggerhead sea turtle (Caretta caretta) tears.

BACKGROUND: Tears play an important role in ocular surface protection, and help wild animals maintain visual acuity in the face of air and water friction. The proteomics of tears has only been described for mammals. The knowledge of the proteomics of wild animal tears can aid not only in the setting of normal standards for ocular disease studies in these animals, but also to base the search for new molecules to be used in ophthalmology therapeutics. We therefore set out to describe the proteomic profile of roadside hawk (Rupornis magnirostris), broad-snouted caiman (Caiman latirostris) and loggerhead sea turtle (Caretta caretta) tears. Tears were collected from healthy animals, their spectral profiles were obtained with an LTQ Orbitrap XL mass spectrometer, and the dataset was analyzed against reference taxa. RESULTS: For roadside hawk, 446 proteins were identified, the most abundant being albumin, transferrin, globulin and actin. For broad-snouted caiman and loggerhead sea turtle, 1358 and 163 proteins were identified, respectively. Uncharacterized proteins and transferrin were highly abundant in both species. The roadside hawk tear components and their properties were similar to those described for humans, but with a higher albumin concentration. Broad-snouted caiman tears presented a wide diversity of ontological functions, with an abundant presence of enzymatic compounds. In loggerhead sea turtle tears, the predominance of proteins with ion-transport functions was consistent with possible osmolality-maintenance mechanisms. CONCLUSION: These data enhance our understanding of birds and reptiles' tears microcomposition and may be used to base the discovery of new molecules with high biotechnological potential.

Clinical features and long-term outcomes of systemic lupus erythematosus: comparative data of childhood, adult and late-onset disease in a national register.

Systemic lupus erythematosus (SLE) affects predominantly women at reproductive age but may present at any age. Age at disease onset has a modulating effect on presentation and course of disease, but controversies persist regarding its impact on long-term outcome. Our aims were to characterize clinical features, co-morbidities and cumulative damage in childhood-onset, adult-onset and late-onset SLE. Patients with childhood-onset SLE fulfilling ACR 1997 criteria were identified in a nationwide register-Reuma.pt/SLE (N = 89) and compared with adult-onset and late-onset counterparts matched 1:1:1 for disease duration. 267 SLE patients with mean disease duration of 11.9 ± 9.3 years were analyzed. Skin (62 %), kidney (58 %), neurological (11 %) and hematologic involvement (76 %) were significantly more common in childhood-onset SLE and disease activity was higher in this subset than in adult- and late-onset disease (SLEDAI-2K 3.4 ± 3.8 vs. 2.2 ± 2.7 vs. 1.6 ± 2.8, respectively; p = 0.004). Also, more childhood-onset patients received cyclophosphamide (10 %) and mycophenolate mofetil (34 %). A greater proportion of women (96 %), prevalence of arthritis (89 %) and anti-SSA antibodies (34 %) were noted in the adult-onset group. There was a significant delay in the diagnosis of SLE in older ages. Co-morbidities such as hypertension, diabetes and thyroid disease were significantly more frequent in late-onset SLE, as well as the presence of irreversible damage evaluated by the SLICC/ACR damage index (20 vs. 26 vs. 40 %; p < 0.001). Greater organ involvement as well as the frequent need for immunosuppressants supports the concept of childhood-onset being a more severe disease. In contrast, disease onset is more indolent but co-morbidity burden and irreversible damage are greater in late-onset SLE, which may have implications for patients' management.

Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry.

BACKGROUND: Although the survival rate has considerably improved, many patients with systemic lupus erythematosus (SLE) develop irreversible organ damage. OBJECTIVES: The objectives of this paper are to characterize cumulative damage in SLE patients and identify variables associated with its presence and severity. METHODS: A cross-sectional analysis of SLE patients from the Portuguese Lupus register Reuma.pt/SLE in whom damage assessment using the SLICC/ACR-Disability Index (SDI) was available was performed. Predictor factors for damage, defined as SDI ≥ 1, were determined by logistic regression analyses. A sub-analysis of patients with severe damage (SDI ≥ 3) was also performed. RESULTS: In total, 976 patients were included. SDI was ≥1 in 365 patients, of whom 89 had severe damage. Musculoskeletal (24.4%), neuropsychiatric (24.1%) and ocular (17.2%) domains were the most commonly affected. Older age, longer disease duration, renal involvement, presence of antiphospholipid antibodies and current therapy with steroids were independently associated with SDI ≥ 1. The subpopulation with severe damage had, in addition, a greater interval between the first manifestation attributable to SLE and the clinical diagnosis as well as and more frequently early retirement due to SLE. CONCLUSIONS: This large lupus cohort confirmed that demographic and clinical characteristics as well as medication are independently associated with damage. Additionally, premature retirement occurs more often in patients with SDI ≥ 3. Diagnosis delay might contribute to damage accrual.

Evaluation of ophthalmic and hemodynamic parameters in capuchin monkeys (Sapajus sp.) submitted to dissociative anesthetic protocols.

BACKGROUND: Dissociative drugs are used for chemical restraint in monkeys. The aim was to evaluate muscle relaxation, recovery, and ophthalmic and hemodynamic parameters in 24 capuchin monkeys subjected to four dissociative anesthesia protocols. METHODS: Animals were anesthetized with tiletamine-zolazepam (TZ), ketamine-xylazine (KX), ketamine-midazolam (KM), or ketamine-dexmedetomidine (KD). Muscle relaxation, digital reflex, lacrimal production, intraocular pressure (IOP), heart and respiratory rates, oxygen saturation (SpO2 ), rectal temperature, non-invasive arterial blood pressure, palpebral and pupillary reflexes, and eyeball positioning were evaluated every 5 minutes for 20 minutes. RESULTS: Muscle relaxation was highest in KM and KD. At 5-minute post-injection, IOP was higher in TZ than in all other groups. There was a significant difference between groups and times in heart and respiratory rates and temperature. There were no significant differences in SpO2, arterial blood pressure, and lacrimal production between groups. CONCLUSIONS: The established parameters may help in clinical and ophthalmic examinations of primates.

Untreated sewage contamination of beach sand from a leaking underground sewage system.

Thirty people (mostly children) experienced an episode of skin rash days after a sand sifting beach operation at Porto Pim Beach in Faial, Azores during June 2019. An environmental and epidemiologic investigation was conducted to identify the cause of the outbreak of skin rash. The epidemiologic investigation found that some of the patients experiencing symptoms had never entered the beach water. During the pollution period and throughout the epidemiologic investigation, faecal indicator bacteria levels (94 CFU/100 ml for intestinal enterococci and 61 CFU/100 ml for Escherichia coli) in water remained under the limits used for the ninety-five percentile calculation of an Excellent coastal and transitional bathing water defined in the Portuguese Legislation (100 CFU/100 ml for intestinal enterococci and 250 CFU/100 ml for Escherichia coli). Thus sand contact was considered as a likely primary exposure route. Sand microbiological analysis for faecal indicator organisms and electron microscopy strongly suggested faecal contamination. Chemical analysis of the sand also revealed a concomitant substance compatible with sodium-hypochlorite as analysed using gas chromatography and subsequently confirmed by free chlorine analysis. Inspection of the toilet facilities and sewage disposal system revealed a leaking sewage distribution box. Collectively, results suggest that the cause of the outbreak was the leaking underground sewage distribution box that serviced the beach toilet facilities (40 m from beach), where sodium-hypochlorite was used for cleaning and disinfection. This sewage then contaminated the surficial sands to which beach goers were exposed. Chlorine being an irritant substance, was believed to have been the cause of the symptoms given the sudden presentation and dissipation of skin rashes. No gastro-intestinal illness was reported during this episode and during the following 30 days. Like water, beach sand should also be monitored for safety, especially for areas serviced by aged infrastructure.

Primary small cell carcinoma of the larynx. Survival time of 47 months. Case report.

Small cell carcinoma (SCC) of the larynx is a rare type of neuroendocrine carcinoma (NEC), few cases of which have been described in the literature. The prognosis for this type of carcinoma is poor, with a survival time typically not exceeding two years. We describe the case of a 54-year-old male patient with a primary tumor in the right ventricular band and a biopsy compatible with SCC. The patient underwent radiotherapy (RT) and concomitant chemotherapy (QT) and, after a relapse at 17 months, underwent total laryngectomy with bilateral neck dissection. The survival time was 47 months. Further studies are required to elucidate the possible causes of the better prognosis in some cases.

Repetition suppression and semantic enhancement: an investigation of the neural correlates of priming.

The priming of a stimulus by another has become an important tool for exploring the neural underpinnings of conceptual representations. However, priming effects can derive from many different types of relationships and it is important to distinguish between them in order to be able to develop theoretical accounts of the representation of conceptual knowledge. While it is well known that repetition priming (the repeated presentation of the same stimulus) is associated with a reduced neural response, called repetition suppression (RS), the neural correlates of semantic priming (when two stimuli are related in meaning but not identical) are not so well established. We compared the neural correlates of repetition and semantic priming using written words, independently manipulating form and meaning. In an fMRI study, subjects saw single words and made a concrete-abstract decision. Two consecutive words were identical (town-town) or varied along a continuum of semantic relatedness, from highly related (cord-string) to unrelated (face-sail). We found distinct patterns of activation for repetition and semantic priming. Repetition priming was associated with RS in LIFG, bilateral parahippocampal gyrus and R fusiform gyrus. We also observed increased activation for word repetition in the RMFG and RMTG/STG, which may reflect recognition of item's earlier presentation. There was no evidence of suppression for semantic relatedness. Semantic priming was associated with enhanced activation in multiple bilateral fronto-temporal areas, i.e. semantic enhancement. The results suggest that repetition and semantic priming in visual word recognition depend on distinct cognitive processes and neural substrates.

Human papillomavirus infection and cervical lesions in rheumatic diseases: a systematic review.

An association between immune-mediated diseases and cervical pre-malignant and malignant lesions is described, having the human papillomavirus (HPV) infection a causal role. Related studies have been generally focused on systemic lupus erythematosus (SLE) patients, but relatively to other diseases, such as rheumatoid arthritis (RA), Sjögren's syndrome (SS) and systemic sclerosis (SSc), data has not been systematically evaluated. We conducted a systematic review analysis of the literature in PubMed, including articles published until March of 2015, in patients with RA, SS, SLE and SSc, to evaluate the frequency of HPV infection, cervical dysplasia and cervical cancer, and associated factors, with particular interest on the role of glucocorticoids and immunosuppressive treatment. Moreover, safety and efficacy of HPV vaccines in these patients was investigated. Of 476 articles identified, 27 were finally included. The studies showed an increased prevalence of cervical dysplasia and cancer, with the HPV infection being an important associated factor, in particular in SLE patients. The data relatively to other rheumatic diseases was very scarse, but an increased prevalence of smear abnormalities was also found in RA. Patients exposed to glucocorticoids and to long-term immunosuppression, particularly cyclophosphamide, have increased risk of presenting more pre-malignant lesions than the general population. The available vaccines seem to be generally safe and immunogenic in the short- period evaluation, but long-term follow-up is required to evaluate the impact of the vaccine in the protection against HPV infection and occurrence of high-grade cervical lesions.

High condylectomy versus proportional condylectomy: is secondary orthognathic surgery necessary?

The objective of this study was to assess the need for secondary orthognathic surgery in patients undergoing two different condylectomy protocols for active unilateral condylar hyperplasia (UCH). A retrospective cohort study evaluated UCH patients treated by condylectomy. Two groups were established: group 1 comprised those who had undergone a high condylectomy (5 mm removed) and group 2 comprised those who had undergone a proportional condylectomy (removing the difference observed between the measurements of the hyperplastic and the healthy side). Data analysis was done with the Levene test and t-test; a P-value of <0.05 indicated a statistically significant relationship. Forty-nine patients, with an average age of 19.83 years, were analyzed; 11 were included in group 1 and 38 in group 2. There was no statistical difference between the two groups with regard to age or sex (P=0.781). An average of 5.81 mm was removed in the high condylectomy group, while an average of 9.28 mm was removed in the proportional condylectomy group; this difference was statistically significant (P=0.042). Comparing the two groups, proportional condylectomy reduced the need for secondary orthognathic surgery (P<0.001). The proportional condylectomy can be used as the sole surgical treatment in cases of UCH, thus avoiding the need for secondary orthognathic surgery.

Leaf malate and succinate accumulation are out of phase throughout the development of the CAM plant Ananas comosus.

In plants with Crassulacean Acid Metabolism (CAM), organic acids, mainly malate are crucial intermediates for carbon fixation. In this research we studied the circadian oscillations of three organic anions (malate, citrate, and succinate) in Ananas comosus, assessing the effect of season and plant development stage. Seasonal and plant development dependencies were observed. The circadian oscillations of malate and citrate were typical of CAM pathways reported in the literature. Citrate content was quite stable (25-30 µmol g(-1) FW) along the day, with a seasonal effect. Succinate was shown to have both diurnal and seasonal oscillations and also a correlation with malate, since it accumulated during the afternoon when malate content was normally at a minimum, suggesting a possible mechanistic effect between both anions in CAM and/or respiratory metabolisms.

Rheumatoid arthritis and associated large granular lymphocytic leukemia--successful treatment with rituximab.

Large granular lymphocytic (LGL) leukemia is an uncommon, usually indolent, lymphoproliferative disorder strongly associated with various autoimmune diseases. The authors report a case of a 67-year-old woman with a long-standing rheumatoid arthritis, who developed neutropenia and associated recurrent infections, diagnosed with LGL leukemia. We describe the treatment approach and the response to an anti-TNF and the rituximab.

Endoscopic biopsy and cytology in the diagnosis of malignant gastric ulcers.

Endoscopy significantly improves the diagnosis of tumors of the stomach; however, its value may be limited in differentiating benign from malignant gastric ulcers (MGUs). The accuracy of endoscopy was compared in 20 patients with MGU studied by endoscopy, biopsy, and cytology. Endoscopy correctly diagnosed 13 cases (65%), with endoscopic signs being benign or indeterminate in the remaining seven. However, all 20 MGUs were accurately diagnosed since biopsy and cytology increased the diagnostic accuracy of endoscopy in the remaining seven patients. The combination of biopsy and cytology yielded a positive diagnosis in 19 patients (95%); the remaining patient was operated on with only the endoscopic diagnosis of MGU. The complementarity of these three techniques was highlighted in five cases where only one of the procedures unequivocally diagnosed malignancy. It is concluded that biopsy and cytology are useful complementary techniques and should always be performed together in categorizing the nature of all gastric ulcers despite a benign macroscopic appearance at endoscopy.

Exfoliative cytodiagnosis of gastric adenocarcinoma. Comparison with biopsy and endoscopy.

Endoscopy complemented by directed biopsies and exfoliative cytology was performed on 593 patients with different gastric lesions. Of the 194 cases of proven adenocarcinoma of the stomach, cytology was positive for malignancy in 176 (90.7%) and yielded the highest diagnostic rate. Endoscopy correctly diagnosed 171 cases (88.1%), and biopsy had the lowest accuracy, 153 cases (78.9%). The combined use of the three techniques increased the positive diagnosis to 185 adenocarcinomas (95.4%). Only three early gastric cancers were diagnosed by the combined methods, with only cytology positive in all three cases. There were five (1.3%) false-positive cytologic reports, principally due to benign gastric ulcers. It is concluded that these techniques have a complementary function in distinguishing benign from malignant gastric lesions. Since the value of endoscopic signs is limited, biopsy and cytology should always be performed. Exfoliative cytology plays an effective diagnostic role in cancer of the gastrointestinal tract and should be used more frequently by gastroenterologists, who, however, should be aware of the risk of false-positive results.

Correlations between ldh isoenzyme patterns and brushing cytology in ulcerative colitis.

Forty-one rectal samples from 22 patients with ulcerative colitis and eight rectal samples from normal controls were studied cytologically, histologically and histochemically (LDH isoenzyme pattern). The cytological specimens from patients were classified into three groups (A, B and C) and the degree of cellular atypia was compared with the modifications of LDH isoenzymogram. The differences between the polypeptide M levels of the group A, B and C were statistically significant, as well as those between groups B and C versus the normal controls. The highest percentages of M were observed in group C and correlate with the presence of large single or double nucleoli. These results most likely represent active cellular regeneration, and further investigations are needed to elucidate whether the histochemical alterations could be useful to detect precocious malignant changes in patients with long-standing ulcerative colitis.

[A follow-up by telephone of patients wearing a pacemaker--the experience of the Cardiac Pacing Center of the Hospitais de Universidade de Coimbra]. / Follow-up trans-telefónico de doentes portadores de pacemaker--a experiência do Centro de Pacing Cardíaco dos Hospitais da Universidade de Coimbra.

OBJECTIVE: To demonstrate the viability of the transtelephonic follow-up of paced patients, and its economical, human and practical consequences. SETTING: Pacing center of a central university hospital and departments of cardiology in district hospitals. INTERVENTIONS: 400 patients under transtelephonic follow-up, between April 1983 and December 1992, with a total of 1200 transtelephonic consultations. Analysis of the parameters of the stimulation and of the ECG tracings transmitted by a Transmitter Receptor Medtronic Teletrace 9403. RESULTS: No technical problems were found in the transtelephonic transmission and clear ECG tracings were recorded. A very substantial decrease in follow-up costs was so obtained. CONCLUSION: The transtelephonic monitoring of paced patients is a possible, useful and accurate method of follow-up.

Manejo de Herida Quirúrgica en Infección del Territorio Maxilofacial / Management of Surgical Wound Infection of Maxillofacial Area

El manejo de infecciones maxilofaciales leves o graves tiene como objetivos generales la protección de la vía aérea, eliminación quirúrgica de la fuente de infección, drenajes quirúrgicos de la lesión, antibioterapia adecuada, control de evolución de la lesión y herida facial hasta la resolución completa del proceso infeccioso. El objetivo de este artículo es presentar un caso clínico de una infección del territorio maxilofacial, de difícil manejo local y su respuesta al tratamiento junto a la evolución y manejo de la herida facial resultante. Paciente sexo masculino de 48 años de edad, sin antecedentes mórbidos relevantes se presenta en el servicio de Urgencias del Hospital Base de Valdivia con el diagnóstico de flegmón facial izquierdo. Evoluciona con resistencia al tratamiento convencional y lenta cicatrización de herida quirúrgica posterior al vaciamiento del flegmón abscedado. Se utiliza un hidrogel como coadyudante a la terapia, resultando finalmente en la resolución del cuadro clínico. Se discute evolución del cuadro infeccioso junto a las diferentes terapias coadyuvantes para un proceso infeccioso severo.

The general objective in the management of mild or severe maxillofacial infections, is to protect the airway, realize surgical removal of the source of infection, surgical drainageof the lesion and adequate antibiotic therapy, control during onset of the lesion and facial injury until resolution the infectious process is complete. The aim of this paper is to present a case of an infection of maxillofacial area, difficult to manage locally and its response to treatment with development and management of theresulting facial wound. Patient is a 48 year-old male, without significant morbid history and is treated at the emergency department of the Base Hospital of Valdivia with a subsequent diagnosis of left facial phlegmon. During onset patient presented resistance to conventional treatment and wound healing was slow after emptying abscessed phlegmon. A hydrogel is used as an adjunct to therapy, leading finally to the resolution of clinical case. We discuss evolution of infectious event with various intervention therapies for severe infectious process.

The normal values of spatial velocity in the second part of QRS (a cooperative study of 229 healthy individuals).

The Spatial Velocity (SV) represents the inscription velocity from spatial vectors of the QRS loop. According to Sano, this parameter has revealed a diagnostic capacity for some well defined pathologies. Using Hellerstein and Hamlin's formula, the SV has been determined from the orthogonal Frank leads in a 250 mm/sec recording. Using Simonson's criteria, 229 normal individuals, arranged in seven groups according to age and sex, were used in an attempt to get normal values for the second half of the QRS loop. SV was determined in six time intervals of 2.5 msec from the 25 msec vector before the end of QRS. We found significant difference between the values obtained from each time interval, except in the 35--37.5 msec and 37.5--40 msec vectors. On the other hand, no significant differences were found among the normal individual groups. The 96th percentile distribution was used to get the normal extreme values in the entire group of individuals.