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- Two Separate Effects Contribute to Regulatory T Cell Defect in Systemic Lupus Erythematosus Patients and Their Unaffected RelativesPublication . Costa, N; Marques, O; Godinho, SI; Carvalho, C; Leal, B; Figueiredo, AM; Vasconcelos, C; Marinho, A; Moraes-Fontes, MF; Gomes da Costa, A; Ponte, C; Campanilho-Marques, R; Cóias, T; Martins, AR; Viana, JF; Lima, M; Martins, B; Fesel, CForkhead box P3 (FoxP3)+ regulatory T cells (Tregs ) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg ) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+ FoxP3+ CD45RO- CD31+ recent thymic emigrant Tregs . This first component effect influenced the proportions of circulating CD4+ FoxP3high CD45RO+ activated Tregs . (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs , SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs , but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg -directed therapies can be monitored more effectively when taking this distinction into account.
- Sacubitril/valsartan: an Important Piece in the Therapeutic Puzzle of Heart FailurePublication . Marques da Silva, P; Aguiar, CSacubitril/valsartan (LCZ696), a supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, was recently approved in the EU and the USA for the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF) (NYHA class II-IV). Inhibition of chronically activated neurohormonal pathways (the renin-angiotensin-aldosterone system [RAAS] and sympathetic nervous system [SNS]) is central to the treatment of chronic HFrEF. Furthermore, enhancement of the natriuretic peptide (NP) system, with favorable cardiovascular (CV) and renal effects in HF, is a desirable therapeutic goal to complement RAAS and SNS blockade. Sacubitril/valsartan represents a novel pharmacological approach that acts by enhancing the NP system via inhibition of neprilysin (an enzyme that degrades NPs) and by suppressing the RAAS via AT1 receptor blockade, thereby producing more effective neurohormonal modulation than can be achieved with RAAS inhibition alone. In the large, randomized, double-blind PARADIGM-HF trial, replacement of an angiotensin-converting enzyme inhibitor (ACEI) (enalapril) with sacubitril/valsartan resulted in a significant improvement in morbidity and mortality in patients with HFrEF. Sacubitril/valsartan was superior to enalapril in reducing the risk of CV death or HF hospitalization (composite primary endpoint) and all-cause death, and in limiting progression of HF. Sacubitril/valsartan was generally well tolerated, with a comparable safety profile to enalapril; symptomatic hypotension was more common with sacubitril/valsartan, whereas renal dysfunction, hyperkalemia and cough were less common compared with enalapril. In summary, sacubitril/valsartan is a superior alternative to ACEIs/ARBs in the treatment of HFrEF, a recommendation that is reflected in many HF guidelines.
- Blood Supply to the Integument of the Abdomen of the Rat: A Surgical PerspectivePublication . Casal, D; Pais, D; Iria, I; Videira, P; Mota-Silva, E; Alves, S; Mascarenhas-Lemos, L; Pen, C; Vassilenko, V; Goyri-O'Neill, JBACKGROUND: Many fundamental questions regarding the blood supply to the integument of the rat remain to be clarified, namely the degree of homology between rat and humans. The aim of this work was to characterize in detail the macro and microvascular blood supply to the integument covering the ventrolateral aspect of the abdominal wall of the rat. METHODS: Two hundred five Wistar male rats weighing 250-350 g were used. They were submitted to gross anatomical dissection after intravascular colored latex injection (n = 30); conversion in modified Spalteholz cleared specimens (n=10); intravascular injection of a Perspex solution, and then corroded, in order to produce vascular corrosion casts of the vessels in the region (n = 5); histological studies (n = 20); scanning electron microscopy of vascular corrosion casts (n = 10); surgical dissection of the superficial caudal epigastric vessels (n = 100); and to thermographic evaluation (n = 30). RESULTS: The ventrolateral abdominal wall presented a dominant superficial vascular system, which was composed mainly of branches from the superficial caudal epigastric artery and vein in the caudal half. The cranial half still received significant arterial contributions from the lateral thoracic artery in all cases and from large perforators coming from the intercostal arteries and from the deep cranial epigastric artery. CONCLUSIONS: These data show that rats and humans present a great deal of homology regarding the blood supply to the ventrolateral aspect of the abdominal integument. However, there are also significant differences that must be taken into consideration when performing and interpreting experimental procedures in rats.
- Management and Outcomes of Patients With Recurrent Neuroendocrine Liver Metastasis After Curative Surgery: An International Multi-Institutional AnalysisPublication . Spolverato, G; Bagante, F; Aldrighetti, L; Poultsides, GA; Bauer, TW; Fields, RC; Maithel, SK; Pinto Marques, H; Weiss, M; Pawlik, TMOBJECTIVE: We sought to characterize the treatment, as well as define the long-term outcomes, of patients with recurrent neuroendocrine liver metastasis (NELM). METHODS: Between 1990 and 2014, 322 patients undergoing curative intent liver surgery for NELM were identified from a multi-institutional database. Recurrences were classified as intrahepatic, extrahepatic, and both intra- and extra-hepatic. RESULTS: Overall, median, 1-, 5-, 10-year DFS were 3.1 years, 75.5%, 40.4%, and 32.1%, respectively. After curative intent liver surgery, 209 patients (64.9%) recurred within a median follow-up of 4.5 years, while 113 (35.1%) patients were alive without disease with a follow-up time ≥3 years. The site of recurrence was intrahepatic only (n = 111, 65.7%), extrahepatic only (n = 19, 11.2%), or intra- and extra-hepatic (n = 39, 23.1%). Compared with intrahepatic only recurrence, extrahepatic only, and combined intra- and extra-hepatic recurrence were associated with a worse long-term outcome (10-year OS: intrahepatic only, 42.5%, 95%CI, 24.9-59.0 vs extrahepatic only, 0% and combined intra- and extra-hepatic, 21.5%, 95%CI, 5.3-44.0) (P < 0.001). Most patients were treated with repeat surgery (n = 49, 36.6%), while 34 (23.5%) patients received a somatostatin analogue, 27 (18.6%) systemic cytotoxic chemotherapy, and 27 (21.4%) patients had intra-arterial therapy. Ten-year OS among patients who underwent repeat surgery or intra-arterial treatments was 60.3% (95%CI, 34.1-78.8) and 52.0% (95%CI, 30.6-69.9), respectively. Patients who received somatostatin analogues (45.9% 95%CI, 22.3-66.9) or systemic chemotherapy (0%) had a shorter long-term survival (P = 0.001). CONCLUSION: Recurrence after surgery for NELM occurred among half of patients. Repeat liver resection for recurrence may offer a reasonable 5-year survival benefit.
- The Status of Intensive Care Medicine Research and a Future Agenda for Very Old Patients in the ICUPublication . Flaatten, H; de Lange, DW; Artigas, A; Bin, D; Moreno, R; Christensen, S; Joynt, GM; Bagshaw, SM; Sprung, CL; Benoit, D; Soares, M; Guidet, BThe "very old intensive care patients" (abbreviated to VOPs; greater than 80 years old) are probably the fastest expanding subgroup of all intensive care unit (ICU) patients. Up until recently most ICU physicians have been reluctant to admit these VOPs. The general consensus was that there was little survival to gain and the incremental life expectancy of ICU admission was considered too small. Several publications have questioned this belief, but others have confirmed the poor long-term mortality rates in VOPs. More appropriate triage (resource limitation enforced decisions), admission decisions based on shared decision-making and improved prediction models are also needed for this particular patient group. Here, an expert panel proposes a research agenda for VOPs for the coming years.
- Left-Sided Reoperations After Arterial Switch Operation: A European Multicenter StudyPublication . Vida, V; Zanotto, L; Zanotto, L; Stellin, G; Padalino, M; Sarris, G; Protopapas, E; Prospero, C; Pizarro, C; Woodford, E; Tlaskal, T; Berggren, H; Kostolny, M; Omeje, I; Asfour, B; Kadner, A; Carrel, T; Schoof, PH; Nosal, M; Fragata, J; Kozłowski, M; Maruszewski, B; Vricella, L; Cameron, D; Sojak, V; Hazekamp, M; Salminen, J; Mattila, I; Cleuziou, J; Myers, P; Hraska, VBACKGROUND: We sought to report the frequency, types, and outcomes of left-sided reoperations (LSRs) after an arterial switch operation (ASO) for patients with D-transposition of the great arteries (D-TGA) and double-outlet right ventricle (DORV) TGA-type. METHODS: Seventeen centers belonging to the European Congenital Heart Surgeons Association (ECHSA) contributed to data collection. We included 111 patients who underwent LSRs after 7,951 ASOs (1.4%) between January 1975 and December 2010. Original diagnoses included D-TGA (n = 99) and DORV TGA-type (n = 12). Main indications for LSR were neoaortic valve insufficiency (n = 52 [47%]) and coronary artery problems (CAPs) (n = 21 [19%]). RESULTS: Median age at reoperation was 8.2 years (interquartile range [IQR], 2.9-14 years). Seven patients died early after LSRs (6.3%); 4 patients with D-TGA (5.9%) and 3 patients with DORV TGA-type (25%) (p = 0.02). Median age at last follow-up was 16.1 years (IQR, 9.9-21.8 years). Seventeen patients (16%) required another reoperation, which was more frequent in patients with DORV- TGA type (4 of 9 [45%]) than in patients with D-TGA (13 of 95 [14%]). Late death occurred in 4 patients (4 of 104 [3.8%]). The majority of survivors were asymptomatic at last clinical examination (84 of 100 [84%]). CONCLUSIONS: Reoperations for residual LSRs are infrequent but may become necessary late after an ASO, predominantly for neoaortic valve insufficiency and CAPs. Risk at reoperation is not negligible, and DORV TGA-type anatomy, as well as procedures on the coronary arteries, were significantly associated with a higher morbidity and a lower overall survival. Recurrent reoperations after LSRs may be required.
- OCT in Alzheimer's Disease: Thinning of the RNFL and Superior HemiretinaPublication . Cunha, JP; Proença, R; Dias-Santos, A; Almeida, R; Águas, H; Alves, M; Papoila, AL; Louro, C; Castanheira-Dinis, ABACKGROUND: Peripapillary retinal nerve fiber layer (pRNFL) and internal macular layer thinning have been demonstrated in Alzheimer's disease (AD) with optical coherence tomography (OCT) studies. The purpose of this study is to compare the pRNFL thickness and overall retinal thickness (RT) in AD patients with non-AD patients, using spectral domain optical coherence tomography (SD-OCT) and determine the sectors most characteristically affected in AD. METHODS: A cross-sectional study was performed to determine the pRNFL and overall macular RT thicknesses in AD and non-AD patients, attending a tertiary hospital center. For pRNFL, the global and six peripapillary quadrants were calculated, and for overall RT values, the nine Early Treatment Diabetic Retinopathy Study (ETDRS) areas were used. A multiple regression analysis was applied to assess the effects of disease, age, gender, spherical equivalent, visual acuity, intraocular pressure, axial length and blood pressure on pRNFL and overall macular RT. RESULTS: A total of 202 subjects, including 50 eyes of 50 patients with mild AD (mean age 73.10; SD = 5.36 years) and 152 eyes of 152 patients without AD (mean age 71.03; SD = 4.62 years). After Bonferroni correction, the pRNFL was significantly thinner for the AD group globally and in the temporal superior quadrant (10.76 μm and 20.09 μm mean decrease, respectively). The RT thickness was also decreased in superior sectors S3 and S6 (mean thinning of 9.92 μm and 11.65 μm, respectively). Spearman's correlation coefficient showed a direct association between pRNFL in the temporal superior quadrant and RT in superior S6 and S3 sectors (rS = 0.41; p < 0.001 and rS = 0.28; p < 0.001, respectively). CONCLUSIONS: Patients with AD showed a significant thickness reduction in global and temporal superior quadrants in pRNFL and in superior pericentral and peripheral sectors of RT. These findings may reflect a peripapillary and retinal changes characteristic of AD, suggesting the importance of SD-OCT as a potential adjuvant in early diagnosis of AD. Further studies are needed to understand which retinal layers and macular sectors are more useful as potential ocular biomarker over time in AD.
- Management of Iatrogenic Urorectal Fistulae in Men with Pelvic CancerPublication . Martins, F; Martins, N; Campos Pinheiro, L; Ferraz, L; Xambre, L; Lopes, TINTRODUCTION: Urorectal fistula (URF) is a devastating complication of pelvic cancer treatments and a surgical challenge for the reconstructive surgeon. We report a series of male patients with URF resulting from pelvic cancer treatments, specifically prostate (PCa), bladder (BCa), and rectal cancer (RCa), and explore the differences and impact on outcomes between purely surgical and non-surgical treatment modalities. METHODS: Between October 2008 and June 2015, 15 male patients, aged 59-78 years (mean 67), with URF induced by pelvic cancer treatments were identified in our institutions. Patients with a history of diverticulitis, inflammatory bowel disease, or other benign conditions were excluded. We reviewed the patients' medical records for symptoms, diagnostic tests performed, type and etiology of the fistula, type of surgical reconstruction, followup, and outcomes. RESULTS: Fourteen patients underwent surgical reconstruction. One patient developed metastatic disease before URF repair and, therefore, was excluded from this study. Mean followup (FU) was 32.7 months (14-79). All patients received diverting colostomy and temporary urinary diversion. An exclusively transperineal approach was used in nine (64.3%) patients and a combined abdominoperineal in five (35.7%). Overall successful URF closure was achieved in 12 (85.7%) patients, nine (64.3%) of whom at the first reconstructive attempt, two (14.3%) after two attempts (in our institution), and one (7.1%) after three attempts (two of which elsewhere). An interposition flap was used in seven (50%) patients. Surgical reconstruction failed ultimately in two (14.3%) patients who still have a colostomy and do not wish any further reconstruction. CONCLUSIONS: Our study has several limitations, including its retrospective nature and the heterogeneity of our small patient cohort. Nonetheless, although surgical reconstruction of URF may be extremely difficult and complex in the non-surgical/energy ablation patients, its successful reconstruction is possible in most through a transperineal, or a more aggressive abdominoperineal, approach with tissue interposition in selected patients.
- Impact of Morphological Status on Long-Term Outcome Among Patients Undergoing Liver Surgery for Intrahepatic CholangiocarcinomaPublication . Bagante, F; Spolverato, G; Weiss, M; Alexandrescu, S; Pinto Marques, H; Aldrighetti, L; Maithel, SK; Pulitano, C; Bauer, TW; Shen, F; Poultsides, GA; Soubrane, O; Martel, G; Groot Koerkamp, B; Guglielmi, A; Itaru, E; Pawlik, TMBACKGROUND: The influence of morphological status on the long-term outcome of patients undergoing liver resection for intrahepatic cholangiocarcinoma (ICC) is poorly defined. We sought to study the impact of morphological status on overall survival (OS) of patients undergoing curative-intent resection for ICC. METHODS: A total of 1083 patients who underwent liver resection for ICC between 1990 and 2015 were identified. Data on clinicopathological characteristics, operative details, and morphological status were recorded and analyzed. A propensity score-matched analysis was performed to reduce confounding biases. RESULTS: Among 1083 patients, 941(86.9%) had a mass-forming (MF) or intraductal-growth (IG) type, while 142 (13.1%) had a periductal-infiltrating (PI) or MF with PI components (MF + PI) ICC. Patients with an MF/IG ICC had a 5-year OS of 41.8% (95% confidence interval [CI] 37.7-45.9) compared with 25.5% (95% CI 17.3-34.4) for patients with a PI/MF + PI (p < 0.001). Morphological type was found to be an independent predictor of OS as patients with a PI/MF + PI ICC had a higher hazard of death (hazard ratio [HR] 1.42, 95% CI 1.11-1.82; p = 0.006) compared with patients who had an MF/IG ICC. Compared with T1a-T1b-T2 MF/IG tumors, T1a-T1b-T2 PI/MF + PI and T3-T4 PI/MF + PI tumors were associated with an increased risk of death (HR 1.47 vs. 3.59). Conversely, patients with T3-T4 MF/IG tumors had a similar risk of death compared with T1a-T1b-T2 MF/IG patients (p = 0.95). CONCLUSION: Among patients undergoing curative-intent resection of ICC, morphological status was a predictor of long-term outcome. Patients with PI or MF + PI ICC had an approximately 45% increased risk of death long-term compared with patients who had an MF or IG ICC.
- Post-Stroke Seizures Are Clinically UnderestimatedPublication . Bentes, C; Martins, H; Peralta, AR; Casimiro, C; Morgado, C; Franco, AC; Fonseca, AC; Geraldes, R; Canhão, P; Pinho e Melo, T; Paiva, T; Ferro, JMCerebrovascular disease is the leading cause of epilepsy in adults, although post-stroke seizures reported frequency is variable and few studies used EEG in their identification. To describe and compare EEG and clinical epileptic manifestations frequency in patients with an anterior circulation ischaemic stroke. Prospective study of acute anterior circulation ischaemic stroke patients, consecutively admitted to a Stroke Unit over 24 months and followed-up for 1 year. All patients underwent standardized clinical and diagnostic assessment. Seizure occurrence was clinically evaluated during hospitalization and by a telephone interview at 6 months and a clinical appointment at 12 months after stroke. Video-EEG was performed in the first 72 h (1st EEG), daily after the 1st EEG for the first 7 days after the stroke, or later if neurological worsening, at discharge, and at 12 months. 151 patients were included (112 men) with a mean age of 67.4 (11.9) years. In the 1st year after stroke, 38 patients (25.2%) had an epileptic seizure. During hospitalization, 27 patients (17.9%) had epileptiform activity (interictal or ictal) in the EEG, 7 (25.9%) of them electrographic seizures. During the first week after stroke, 22 (14.6%) patients had a seizure and 4 (2.6%) non-convulsive status epilepticus criteria. Five (22.7%) acute symptomatic seizures were exclusively electrographic. At least one remote symptomatic seizure occurred in 23 (16%) patients. In the first 7 days after stroke, more than one-fifth of patients with seizures had exclusively electrographic seizures. Without a systematic neurophysiological evaluation the frequency of post-stroke seizures are clinically underestimated.