Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans.

Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.

Portable gamma camera guidance in sentinel lymph node biopsy: prospective observational study of consecutive cases.

INTRODUCTION: Sentinel lymph node biopsy is the most important tool available for node staging in patients with melanoma. OBJECTIVES: To analyze sentinel lymph node detection and dissection with radio guidance from a portable gamma camera. To assess the number of complications attributable to this biopsy technique. METHODS: Prospective observational study of a consecutive series of patients undergoing radioguided sentinel lymph node biopsy. We analyzed agreement between nodes detected by presurgical lymphography, those detected by the gamma camera, and those finally dissected. RESULTS: A total of 29 patients (17 women [62.5%] and 12 men [37.5%]) were enrolled. The mean age was 52.6 years (range, 26-82 years). The sentinel node was dissected from all patients; secondary nodes were dissected from some. In 16 cases (55.2%), there was agreement between the number of nodes detected by lymphography, those detected by the gamma camera, and those finally dissected. The only complications observed were seromas (3.64%). No cases of wound dehiscence, infection, hematoma, or hemorrhage were observed. CONCLUSIONS: Portable gamma-camera radio guidance may be of use in improving the detection and dissection of sentinel lymph nodes and may also reduce complications. These goals are essential in a procedure whose purpose is melanoma staging.

Management of cerebral venous thrombosis in Spain: MOTIVATE descriptive study.

INTRODUCTION: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults. Early, accurate diagnosis can reduce the rate and severity of complications. OBJECTIVE: The aim of this study was to analyse the clinical characteristics, management, and treatment of CVT in different centres in Spain. METHODS: We conducted a multicentre, retrospective, descriptive study of patients hospitalised due to CVT between 2008 and 2017 at 10 Spanish centres. RESULTS: We included 256 patients, with a mean age (SD) of 49.8 (18.7) years; 51% of patients were women. The most frequent symptoms were headache (73%), focal deficits (50%), epileptic seizures (33%), and encephalopathy (21%). The most frequent localisations were the superior sagittal sinus (12.5%), the transverse sinus (10.9%), and 2 or more sinuses or veins (66.4%). Thrombophilia was the most frequent known aetiology (24%), and was most commonly associated with the prothrombin G20210A mutation (19%). Forty-six percent of patients were treated with antithrombotics for 3 to 6 months, 21% for one year, and 22.6% required indefinite anticoagulation. Endovascular therapy was performed in 5% of cases, and 33% required neurosurgery. Regarding outcomes, 75% of patients were independent at 3 months (modified Rankin Scale [mRS] score ≤ 2), with papilloedema (P =  .03), focal deficits (P = .001), and encephalopathy (P < .001) showing a statistically significant association with poor prognosis (mRS > 3). The in-hospital mortality rate was 4.3%, with a 3-month mortality rate of 6.3%. CONCLUSION: The diverse risk factors and variable presentation of CVT represent a challenge in the diagnosis and treatment of this condition. To improve prognosis and reduce mortality, it is essential to establish management protocols for this entity.

Expression of PD-L1 in renal cancer, prognostic features and clinical utility of its routine staining.

INTRODUCTION: The expression of PD-L1 in renal cell carcinoma (RCC) is associated with worse survival and prognostic clinical-pathological features. However, they seem to respond better to new therapeutic agents. Knowing the behavior of RCC according to the presence of PD-L1 has implications for medical counseling and therapeutic approaches. OBJECTIVE: To identify the presence of PD-L1 in renal tumor cells and analyze its association with patients' prognostic factors, overall survival (OS) and cancer-specific survival (CSS). METHODOLOGY: Retrospective analysis of RCC tissue samples, obtained between 2018 and 2021. Immunohistochemistry analysis with mouse monoclonal Anti PD-L1, clone 22C3. Definition of PD-L1 "positive" as a Tumor Proportion Score ≥1%. Comparison of prognostic factors according to the presence or absence of PD-L1, and univariate analysis for OS and CSS. RESULTS: 14% (n = 11) of the sample were PD-L1(+). Average age was 59 years. There were no statistically significant differences between PD-L1 status and TNM stages, nuclear grade and histology. PD-L1(+) had worse OS with a HR of 5.27 (CI: 1.1-23.7; P = .03) and CSS showed a unfavorable tendency for PD-L1(+) with a HR of 4.79 (CI: 0.79-28.95; P = .08). CONCLUSION: The prevalence of PD-L1 in RCC is considerable. In this study PD-L1(+) was associated with unfavorable OS and CSS. It seems reasonable to incorporate its routine use in RCC.

Reperfusion therapy in acute ischaemic stroke due to cervical and cerebral artery dissection: Results from a Spanish multicentre study.

INTRODUCTION: Ischaemic stroke (IS) due to cervical and cerebral artery dissection (CAD) is a rare entity, and few data are available on the use of such reperfusion therapies as intravenous fibrinolysis and mechanical thrombectomy in these patients. We analysed the use of these treatments in patients with IS due to CAD and compared them against patients receiving reperfusion treatment for IS of other aetiologies. METHODS: We conducted an observational, retrospective, multicentre study of patients with IS due to CAD recorded in the National Stroke Registry of the Spanish Society of Neurology during the period 2011-2019. Comparative analyses were performed between: a) patients with CAD treated and not treated with reperfusion therapies and b) patients treated with reperfusion for IS due to CAD and patients treated with reperfusion for IS due to other causes. Epidemiological data, stroke variables, and outcomes at discharge and at 3 months were included in the analysis. RESULTS: The study included 21,037 patients with IS: 223 (1%) had IS due to CAD, of whom 68 (30%) received reperfusion treatment. Reperfusion treatments were used less frequently in cases of vertebral artery dissection and more frequently in patients with carotid artery occlusion. Compared to patients with IS due to other causes, patients with CAD were younger, more frequently underwent mechanical thrombectomy, and less frequently received intravenous fibrinolysis. Rates of haemorrhagic complications, mortality, and independence at 3 months were similar in both groups. CONCLUSIONS: Reperfusion therapy is frequently used in patients with IS due to CAD. The outcomes of these patients demonstrate the efficacy and safety of reperfusion treatments, and are comparable to the outcomes of patients with IS due to other aetiologies.

Systematic review on active treatment for urinary fistula after partial nephrectomy.

INTRODUCTION: Urinary fistula is expected to become more frequent in urological practice as a result of expanding indication of partial nephrectomy given it's oncological results equivalent to those of radical nephrectomy but at a lower risk of progression to chronic kidney disease, lower cardiovascular morbidity, and overall mortality. OBJECTIVES: Review and compare different techniques of contemporary active management for urinary fistula after partial nephrectomy. METHODS: A systematic literature search on the MEDLINE database was conducted in March 2020, combining the terms: "urine leak", "urine leakage", "urinary leak" and "urinary fistula", with: "partial nephrectomy", "nephron sparing surgery" and "renal sparing surgery". This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Only articles related to active treatment were eligible. Abstracts in English and Spanish from the last two decades were screened. No restriction based on study design nor the length of follow-up. PRIMARY OUTCOMES: 1) Leak resolution rate 2) Time course of leak resolution and 3) Number of interventions needed for resolution. RESULTS: Multiple studies were found. There were no randomized controlled trials. Urinary fistula can be solved in many ways with active treatment, with a high success rate (97.5%), an average of 1.4 intervention-per-patients and a mean time for leak resolution of 11 days (median of 3 days). CONCLUSION: There is a high risk of bias due to the study's methodology. There is a broad range of effective alternatives and various approaches to solve urinary fistula in an appropriate timing.

Attention to acute cerebrovascular disease in Guipúzcoa: description of the results of a reference hospital in a centralized care model.

INTRODUCTION: In the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario Donostia (HUD), improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model. MATERIAL AND METHODS: We performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients' baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year. RESULTS AND DISCUSSION: We identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in < 6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2. CONCLUSIONS: After the strategic changes implemented in acute stroke care in Guipuzkoa, including the centralisation of the acute stroke care model, mortality rates at discharge and at one year are lower in 2015 than the previously reported rates, with similar rates of independence. These results are consistent with those published by other Spanish and European centres.

Management of cerebral venous thrombosis in Spain: MOTIVATE descriptive study. / Manejo de la trombosis venosa cerebral en España: estudio descriptivo MOTIVATE.

INTRODUCTION: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults. Early, accurate diagnosis can reduce the rate and severity of complications. OBJECTIVE: The aim of this study was to analyse the clinical characteristics, management, and treatment of CVT in different centres in Spain. METHODS: We conducted a multicentre, retrospective, descriptive study of patients hospitalised due to CVT between 2008 and 2017 at 11 Spanish centres. RESULTS: We included 256 patients, with a mean age (SD) of 49.8 (18.7) years; 51% of patients were women. The most frequent symptoms were headache (73%), focal deficits (50%), epileptic seizures (33%), and encephalopathy (21%). The most frequent localisations were the superior sagittal sinus (12.5%), the transverse sinus (10.9%), and 2 or more sinuses or veins (66.4%). Thrombophilia was the most frequent known aetiology (24%), and was most commonly associated with the prothrombin G20210A mutation (19%). Forty-six percent of patients were treated with antithrombotics for 3-6 months, 21% for one year, and 22.6% required indefinite anticoagulation. Endovascular therapy was performed in 5% of cases, and 33% required neurosurgery. Regarding outcomes, 75% of patients were independent at 3 months (modified Rankin Scale [mRS] score ≤ 2), with papilloedema (P=.03), focal deficits (P=.001), and encephalopathy (P <.001) showing a statistically significant association with poor prognosis (mRS> 3). The in-hospital mortality rate was 4.3%, with a 3-month mortality rate of 6.3%. CONCLUSION: The diverse risk factors and variable presentation of CVT represent a challenge in the diagnosis and treatment of this condition. To improve prognosis and reduce mortality, it is essential to establish management protocols for this entity.

Expression of Siglec-1, -3, -5 and -10 in porcine cDC1 and cDC2 subsets from blood, spleen and lymph nodes and functional capabilities of these cells.

Dendritic cells are professional antigen-presenting cells that play a critical role in the development of immune responses. DCs express a variety of Siglecs on their surface, which play a regulatory role modulating their activation through interaction with sialylated structures expressed by cells or pathogens. Here, we characterized the phenotype of porcine conventional dendritic cells subsets from blood, spleen and lymph nodes, emphasizing the analysis of the expression of Siglecs. Siglec-1 was detected in type 1 cDC and, at lower levels, in type 2 cDC in the spleen, being low to negative in blood and lymph node cDC. Siglec-3 and Siglec-5 were expressed in cDC1 at lower levels than in cDC2. Porcine cDCs did not express Siglec-10. cDC2 showed a higher capacity to phagocytose microspheres and to process DQ™-OVA than cDC1, but none of these functions was affected by engagement of Siglec-3 and -5 with antibodies on blood cDC.

Reperfusion treatment in acute ischaemic stroke due to cervical and cerebral artery dissection: results of a Spanish national multicentre study. / Tratamiento de reperfusión en el ictus isquémico agudo por disección arterial cervicocerebral: descripción de los resultados de un estudio nacional multicéntrico.

INTRODUCTION: Ischaemic stroke (IS) due to cervical and cerebral artery dissection (CAD) is a rare entity, and few data are available on the use of such reperfusion therapies as intravenous fibrinolysis and mechanical thrombectomy in these patients. We analysed the use of these treatments in patients with IS due to CAD and compared them against patients receiving reperfusion treatment for IS of other aetiologies. METHOD: We conducted an observational, retrospective, multicentre study of patients with IS due to CAD recorded in the National Stroke Registry of the Spanish Society of Neurology during the period 2011-2019. Comparative analyses were performed between: a) patients with CAD treated and not treated with reperfusion therapies and b) patients treated with reperfusion for IS due to CAD and patients treated with reperfusion for IS due to other causes. Epidemiological data, stroke variables, and outcomes at discharge and at 3 months were included in the analysis. RESULTS: The study included 21,037 patients with IS: 223 (1%) had IS due to CAD, of whom 68 (30%) received reperfusion treatment. Reperfusion treatments were used less frequently in cases of vertebral artery dissection and more frequently in patients with carotid artery occlusion. Compared to patients with IS due to other causes, patients with CAD were younger, more frequently underwent mechanical thrombectomy, and less frequently received intravenous fibrinolysis. Rates of haemorrhagic complications, mortality, and independence at 3 months were similar in both groups. CONCLUSIONS: Reperfusion therapy is frequently used in patients with IS due to CAD. The outcomes of these patients demonstrate the efficacy and safety of reperfusion treatments, and are comparable to the outcomes of patients with IS due to other aetiologies.

Duplications in addition to terminal deletions are present in a proportion of ring chromosomes: clues to the mechanisms of formation.

BACKGROUND AND METHODS: Ring chromosomes are often associated with abnormal phenotypes because of loss of genomic material at one or both ends. In some cases no deletion has been detected and the abnormal phenotype has been attributed to mitotic ring instability. We investigated 33 different ring chromosomes in patients with phenotypic abnormalities by array based comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH). RESULTS: In seven cases we found not only the expected terminal deletion but also a contiguous duplication. FISH analysis in some of these cases demonstrated that the duplication was inverted. Thus these ring chromosomes derived through a classical inv dup del rearrangement consisting of a deletion and an inverted duplication. DISCUSSION: Inv dup del rearrangements have been reported for several chromosomes, but hardly ever in ring chromosomes. Our findings highlight a new mechanism for the formation of some ring chromosomes and show that inv dup del rearrangements may be stabilised not only through telomere healing and telomere capture but also through circularisation. This type of mechanism must be kept in mind when evaluating possible genotype-phenotype correlations in ring chromosomes since in these cases: (1) the deletion may be larger or smaller than first estimated based on the size of the ring, with a different impact on the phenotype; and (2) the associated duplication will in general cause further phenotypic anomalies and might confuse the genotype-phenotype correlation. Moreover, these findings explain some phenotypic peculiarities which previously were attributed to a wide phenotypic variation or hidden mosaicism related to the instability of the ring.

Analysis of the expression of porcine CD200R1 and CD200R1L by using newly developed monoclonal antibodies.

CD200R1 and CD200R1-like are paired receptors which modulate activation of immune cells. Here, we describe the characterisation of their porcine homologues. Analysis of database porcine sequences shows an exceptionally high homology between the extracellular Ig-like domains of these receptors, being the rest more dissimilar. We have obtained two mAbs, PCT1 and PCT3, against a CD200R1-Fc recombinant protein, that bind on CHO cells expressing GFP-tagged CD200R1. The specificity of these mAbs was analysed on CD200R1 L, and also on a CD200R1 splicing variant that lacks the V-type Ig domain. PCT1 bound to both CD200R1 and CD200R1L, but not to the splicing variant, what suggests that recognises an epitope in the V-type Ig domain. PCT3 reacted with both CD200R1 variants, but not CD200R1L, probably binding to an epitope in the N-terminal sequence of CD200R1. Analysis of porcine cells with these mAbs showed expression of CD200R1/CD200R1L on B cells, monocytes and alveolar macrophages.

Attention to acute cerebrovascular disease in Guipúzcoa: Description of the results of a reference hospital in a centralized care model. / Atención a la enfermedad cerebrovascular aguda en Guipúzcoa: descripción de los resultados de un hospital de referencia en un modelo de atención centralizado.

INTRODUCTION: In the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario Donostia (HUD), improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model. MATERIAL AND METHODS: We performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients' baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year. RESULTS AND DISCUSSION: We identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in <6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2. CONCLUSIONS: After the strategic changes implemented in acute stroke care in Guipuzkoa, including the centralisation of the acute stroke care model, mortality rates at discharge and at one year are lower in 2015 than the previously reported rates, with similar rates of independence. These results are consistent with those published by other Spanish and European centres.

Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with 131I: comparison of the results obtained in recurrent and newly diagnosed tumors.

Two murine monoclonal antibodies, BC-2 and BC-4, raised against tenascin and labeled with 131I were infused locally in the site of neoplastic disease by means of a removable (16 patients) or indwelling (34 patients) catheter. Fifty patients bearing a malignant glioma were treated. Twenty-six of these were suffering from recurrent disease; their tumors relapsed within 9 months (median) after treatment. The remaining 24 cases had a newly diagnosed tumor, and local radioimmunotherapy (RIT) was given immediately after surgery and radiochemotherapy. All efforts were made to reduce the tumor before the infusion of the radiopharmaceutical. Therefore, 22 cases with relapsing glioma underwent additional debulking surgery, which led to total or subtotal removal of tumor in 9 of the patients. Altogether, 28 patients had intralesional RIT when the disease was minimal or microscopic. Conversely, 22 cases underwent local RIT with a tumor the diameter of which was > 2 cm. In many cases, the infusions were repeated up to six times to achieve complete destruction of the neoplastic tissue. The local treatment did not give rise to systemic or to cerebral adverse effects. The labeled monoclonal antibodies, given directly in the site of the lesion, concentrated in very high amount in the neoplastic tissue and remained fixed in the target for a long period of time. For these reasons, the radiation dose to the tumor was remarkable (on average > 30,000 cGy/cycle) and consequently led to promising results. The median survival was, in total, 20 months (18 in recurrent tumors and 23 in newly diagnosed lesions). Moreover, median survival was 17 months in patients with bulky tumors (both recurrent and newly diagnosed tumors) and 26 months in patients with minimal or microscopic disease. The median time to progression was 3 months in recurrent and 7 months in newly diagnosed gliomas. Finally, RIT produced 3 CRs (all in recurrent tumors), 6 PRs (4 in recurrent and 2 in newly diagnosed), and 11 stabilizations of disease (4 in recurrent and 7 in newly diagnosed). In 19 cases (13 recurrent and 6 newly diagnosed) the progression of tumor was recorded. Eleven patients (2 recurrent and 9 newly diagnosed) who were treated by RIT when their disease was minimal and nondetectable by radiological methods remained disease-free and were classified as NED. The overall response rate (NED plus CR plus PR) was 40% (34.6% recurrent and 45.8% newly diagnosed).(ABSTRACT TRUNCATED AT 400 WORDS)

Immunoscintigraphy of adenocarcinomas by means of radiolabeled F(ab')2 fragments of an anti-carcinoembryonic antigen monoclonal antibody: a multicenter study.

F(ab')2 fragments of anti-carcinoembryonic antigen (CEA) monoclonal antibody F023C5, determined to be more suitable than intact IgG and Fab fragments for immunoscintigraphy, were labeled with 131I or conjugated to DTPA for instant 111In-labeling, and administered i.v. (2-3 mCi/0.5 mg) to 509 patients in 11 nuclear medicine departments: 284 patients had gastrointestinal adenocarcinomas, 204 had nongastrointestinal adenocarcinomas and 21 were control; serum CEA was elevated in 169 patients, normal in 115, and not determined in 225. The following results were obtained: (a) no adverse reactions; (b) tumor imaging in 324 patients (in particular, in 81.5% CEA-seropositive and in 69.0% CEA-seronegative patients); (c) no significant difference in sensitivity among the results of the 11 departments; (d) no significant difference in overall sensitivity between 131I-and 111In-labeled immunoradiopharmaceuticals; (e) the fraction of documented lesions imaged was 73.3% in CEA-seropositive and 53.7% in CEA-seronegative patients; (f) the detection of liver metastases was hampered, particularly when using the 111In-labeled reagent, by nonspecific radioactivity uptake; (g) the major cause of negative immunoscintigraphy results was a lack of CEA in tumor lesions, as documented by immunohistochemistry; (h) lesion size is also important since the sensitivity was 64% for lesions up to 2 cm in diameter and 84% for larger lesions; (i) many "unexpected" radiolocalizations were recorded. Most were identified as occult tumor lesions. In 35 patients, this finding contributed to the early detection of tumor recurrences.