Recurrent IgA Nephropathy or Subclinical Chronic Humoral Rejection With Predominance of Plasma Cells: A Case Report.

Both antibody-mediated rejection and recurrence of kidney disease are major causes of allograft loss. A possible strategy to address the former is donor-specific antibody (DSA) monitoring. In this patient with IgA nephropathy, DSA detection triggered biopsy 10 years after transplant despite preserved graft function and normal urinary examination. Biopsy showed mild glomerulitis, mild capillaritis, and transplant glomerulopathy with no C4d peritubular capillary staining, along with IgA-dominant mesangial immunofluorescence staining. Interstitial inflammation had a notable predominance of plasma cells, a finding that has been variably attributed to rejection and worse prognosis. Immunosuppression was optimized with the working diagnosis of recurrent IgA nephropathy and/or chronic active humoral rejection with predominance of plasma cells, with favorable response at follow-up. This case illustrates the conflicting role of DSA monitoring and allograft biopsy to optimize immunosuppression management. Despite imperfect correlation with each other and clinical outcomes, they are key to tailor therapy. In the future, characterization of the role of plasma cell infiltrates in rejection might further enable prognosis and treatment individualization.

Adenosine A2A Receptors Shut Down Adenosine A1 Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation.

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A1 and A2A receptors (A1R, A2AR), respectively. Supramaximal activation of A1R can block hippocampal synaptic transmission, and the tonic engagement of A1R-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that A2AR activation decreases A1R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A1R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A2AR antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A2AR with CGS21680 (30 nM) decreased the potency of the A1R agonist CPA (6-60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A2AR play a key role in dampening A1R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A1R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP.

Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress.

Increased ATP release and its extracellular catabolism through CD73 (ecto-5'-nucleotidase) lead to the overactivation of adenosine A2A receptors (A2AR), which occurs in different brain disorders. A2AR blockade blunts mood and memory dysfunction caused by repeated stress, but it is unknown if increased ATP release coupled to CD73-mediated formation of extracellular adenosine is responsible for A2AR overactivation upon repeated stress. This was now investigated in adult rats subject to repeated stress for 14 consecutive days. Frontocortical and hippocampal synaptosomes from stressed rats displayed an increased release of ATP upon depolarization, coupled to an increased density of vesicular nucleotide transporters and of CD73. The continuous intracerebroventricular delivery of the CD73 inhibitor α,ß-methylene ADP (AOPCP, 100 µM) during restraint stress attenuated mood and memory dysfunction. Slice electrophysiological recordings showed that restraint stress decreased long-term potentiation both in prefrontocortical layer II/III-layer V synapses and in hippocampal Schaffer fibers-CA1 pyramid synapses, which was prevented by AOPCP, an effect occluded by adenosine deaminase and by the A2AR antagonist SCH58261. These results indicate that increased synaptic ATP release coupled to CD73-mediated formation of extracellular adenosine contributes to mood and memory dysfunction triggered by repeated restraint stress. This prompts considering interventions decreasing ATP release and CD73 activity as novel strategies to mitigate the burden of repeated stress.

Feedback facilitation by adenosine A2A receptors of ATP release from mouse hippocampal nerve terminals.

The adenosine modulation system is mostly composed by inhibitory A1 receptors (A1R) and the less abundant facilitatory A2A receptors (A2AR), the latter selectively engaged at high frequency stimulation associated with synaptic plasticity processes in the hippocampus. A2AR are activated by adenosine originated from extracellular ATP through ecto-5'-nucleotidase or CD73-mediated catabolism. Using hippocampal synaptosomes, we now investigated how adenosine receptors modulate the synaptic release of ATP. The A2AR agonist CGS21680 (10-100 nM) enhanced the K+-evoked release of ATP, whereas both SCH58261 and the CD73 inhibitor α,ß-methylene ADP (100 µM) decreased ATP release; all these effects were abolished in forebrain A2AR knockout mice. The A1R agonist CPA (10-100 nM) inhibited ATP release, whereas the A1R antagonist DPCPX (100 nM) was devoid of effects. The presence of SCH58261 potentiated CPA-mediated ATP release and uncovered a facilitatory effect of DPCPX. Overall, these findings indicate that ATP release is predominantly controlled by A2AR, which are involved in an apparent feedback loop of A2AR-mediated increased ATP release together with dampening of A1R-mediated inhibition. This study is a tribute to María Teresa Miras-Portugal.

[Evaluation of the Manchester Triage System in Patients with Acute Primary Angle Closure Attack: A Retrospective Study]. / Avaliação do Sistema de Triagem de Manchester em Doentes com Crise de Encerramento Agudo Primário do Ângulo Iridocorneano: Um Estudo Retrospetivo.

INTRODUCTION: Acute primary angle closure attack is an ophthalmological emergency. The aim of this study was to describe the cases diagnosed in the Emergency Department, by correlating the initial complaint with the Manchester triage level and ultimately the time needed until ophthalmological evaluation and iridotomy. MATERIAL AND METHODS: Retrospective analysis of the electronic medical records of patients with acute primary angle closure attack that attended the Ophthalmology Emergency Department of our tertiary center between January 2010 and December 2020. Overall, 2228 Emergency Department episodes coded with the diagnoses glaucoma or ocular hypertension were retrieved, followed by screening of each episode for correct identification of true acute primary angle closure attacks. Clinical data was gathered, including Manchester triage level, presenting complaint, intraocular pressure at presentation, first medical specialty that observed the patient, time until observation by Ophthalmology and time until laser iridotomy. RESULTS: Among the 120 patients identified, 84 (70%) were female and the mean age was 68 ± 12 years. Mean intraocular pressure at admission was 53.4 ± 12.4 mmHg, and 9.2% of patients presented only non-ocular complaints, while 9.2% presented mixed complaints (ocular and non-ocular). Most patients (68.1%) with only non-ocular or mixed complaints were triaged to a non-ophthalmologist (p < 0.001). Concerning the triage system, at admission, most patients (66.7%) were labelled yellow (urgent), while 9.2% and none were labelled as orange (very urgent) or red (emergent), respectively. Most patients (83.3%) were directly sent to Ophthalmology (properly triaged), while the remaining were incorrectly assigned to a non-ophthalmologist. Median time until observation by Ophthalmology was 49 minutes in the properly triaged group (min. 15, max. 404), while it was 288 minutes (min. 45, max. 871) in those who were incorrectly triaged (p < 0.001). Likewise, median time until treatment with laser iridotomy was 203 minutes in the properly triaged group (min. 22, max. 1440) and 353 minutes in the incorrectly triaged group (min.112, max. 947) (p < 0.001). CONCLUSION: Most patients with acute primary angle closure attack were not properly triaged according to the level of the Manchester triage system. There was a significant delay in the diagnosis and treatment of those patients who were first assigned to non-ophthalmologists. There is a need to raise awareness regarding the presenting signs and symptoms of an acute primary angle closure attack in order to avoid preventable vision loss.

Introdução: A crise de encerramento agudo primário do ângulo iridocorneano é uma emergência oftalmológica. O objetivo deste estudo foi descrever os casos admitidos no Serviço de Urgência do Centro Hospitalar Universitário São João, correlacionando a queixa inicial com o nível de triagem de Manchester atribuído e o tempo até observação por Oftalmologia e realização de iridotomia. Material e Métodos: Análise retrospetiva dos registos clínicos dos doentes com encerramento agudo primário do ângulo, admitidos no Serviço de Urgência entre janeiro de 2010 e dezembro de 2020. Foram revistos 2228 episódios com diagnóstico de glaucoma ou hipertensão ocular para identificação correta dos casos de crise de encerramento do ângulo. Foram extraídas variáveis, nomeadamente o nível de triagem de Manchester atribuído, queixa principal, pressão intraocular à admissão, especialidade responsável pelo primeiro contacto médico e tempos até observação por Oftalmologia e até iridotomia. Resultados: Foram identificados 120 doentes, 84 (70%) do sexo feminino, com idade média de 68 ± 12 (desvio padrão) anos. A pressão intraocular média à admissão foi de 53,4 ± 12,4 mmHg. Em 9,2% dos doentes a queixa principal foi não-ocular, enquanto 9,2% apresentavam queixas não-oculares e oculares associadas. A maioria (68,1%) dos doentes com queixas não-oculares ou mistas foi triada para um não-oftalmologista. Segundo o sistema de triagem, a maioria (66,7%) dos doentes foi triada com nível amarelo (urgente), 9,2% foram triados com laranja (muito urgente) e nenhum vermelho (emergente). O primeiro especialista a observar os doentes após a triagem foi um oftalmologista em 83,3% dos casos (corretamente triados), enquanto os restantes foram inicialmente observados por outra especialidade. O tempo mediano até observação por Oftalmologia foi de 288 minutos (min. 45, máx. 871) num doente incorretamente triado e 49 minutos (min. 15, máx. 404) (p < 0,001) em doentes corretamente triados. O tempo mediano até realização de iridotomia laser foi de 353 minutos (min. 112, máx. 947) nos doentes incorretamente triados e 203 minutos (min. 22, máx. 1440) nos corretamente triados (p < 0,001). Conclusão: A maioria dos doentes com crise de encerramento agudo primário do ângulo iridocorneano não foi triada de acordo com o grau de prioridade apropriado segundo o sistema de triagem de Manchester. Nos doentes que não foram imediatamente seguidos por Oftalmologia verificou-se um atraso significativo no diagnóstico e início do tratamento. Torna-se premente a consciencialização dos profissionais de saúde sobre esta condição clínica e a otimização do processo de triagem para minimizar a perda de visão.

Pertuzumab in Combination with Trastuzumab and Docetaxel in the Neoadjuvant Treatment for HER2-Positive Breast Cancer.

Introduction: This study aims to assess safety and effectiveness of pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant treatment (NeoT) of HER2-positive breast cancer. Methods: Two consecutive retrospective cohorts (n = 94, 2012-2015 and 2015-2017) of adult women with HER2-positive breast cancer, receiving NeoT at the breast clinic in Portugal (IPO-Porto), were followed. All patients had surgery and received trastuzumab as adjuvant therapy. The 2012-2015 cohort received doxorubicin, cyclophosphamide, docetaxel plus trastuzumab, whereas the 2015-2017 cohort was treated with the same protocol plus pertuzumab. Results: The 2012-2015 cohort was older (median 53 years), with locally advanced tumors (48.1%), mostly hormone receptor positive (59.3%). The 2015-2017 cohort was younger (median 43 years) with 60% operable tumors. Pathologic complete response (pCR) improved in the second cohort, while maintaining a good safety profile and tolerability. Clinical staging (p = 0.001) and hormone receptor (p = 0.003) were significant predictors of pCR, but not treatment regimen (p = 0.304). Conclusion: Further research with larger samples and longer follow-up is needed to understand the clinical differences. Clinical effectiveness of treatment should also be measured through overall and progression-free survival.

Increased ATP Release and Higher Impact of Adenosine A2A Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

Extracellular ATP can be a danger signal, but its role in striatal circuits afflicted in Parkinson's disease (PD) is unclear and was now investigated. ATP was particularly released at high stimulation intensities from purified striatal nerve terminals of mice, which were endowed with different ATP-P2 receptors (P2R), although P2R antagonists did not alter corticostriatal transmission or plasticity. Instead, ATP was extracellularly catabolized into adenosine through CD73 to activate adenosine A2A receptors (A2AR) modulating corticostriatal long-term potentiation (LTP) in mice. In the presymptomatic phase of a 6-hydroxydopamine rat model of PD, ATP release from striatal nerve terminals was increased and was responsible for a greater impact of CD73 and A2AR on corticostriatal LTP. These observations identify increased ATP release and ATP-derived formation of extracellular adenosine bolstering A2AR activation as a key pathway responsible for abnormal synaptic plasticity in circuits involved in the onset of PD motor symptoms. The translation of these findings to humans prompts extending the use of A2AR antagonists from only co-adjuvants of motor control in Parkinsonian patients to neuroprotective drugs delaying the onset of motor symptoms.

C3 Glomerulonephritis Presenting With Nephritic and Nephrotic Syndromes: Spontaneous Remission After Six Months on Dialysis.

C3 glomerulopathy is a rare and complex renal disease driven by complement dysregulation, with variable presentation and pathophysiology. We report the case of a middle-aged male patient presenting with nephritic and nephrotic syndromes and low serum C3, whose biopsy established the diagnosis of C3 glomerulonephritis. He was found to be homozygous for the complement factor H-related protein (CFHR)3-CFHR1 deletion, which has been associated with the development of anti-factor H autoantibodies. However, the lack of consistent and accessible nephritic factor assays prevented full clarification of the mechanisms involved in the disease. Interestingly, despite not receiving treatment due to suspicion of malignancy and perceived poor renal prognosis, there was spontaneous recovery after six months on hemodialysis. This case reflects the enduring challenges in establishing the diagnosis and prognosis of C3 glomerulonephritis.

Relação da Ascensão Matinal da Pressão Arterial com a Hipertrofia Ventricular Esquerda em Hipertensos Obesos / Association between Morning Surge and Left Ventricular Hypertrophy in Obese Hypertensive Patients

Resumo Fundamento O aumento do peso frequentemente desencadeia mecanismos que elevam a pressão arterial. A obesidade causa mudanças estruturais no miocárdio, incluindo aumento da massa ventricular, dilatação atrial, bem como disfunções diastólicas e sistólicas. Além disso, variações pressóricas nos hipertensos obesos, como a ascensão matinal (AM), podem ter relevância clínica na prevenção dos eventos cardiovasculares. A AM da pressão arterial é um fenômeno fisiológico, que quando elevada pode ser considerada um fator de risco independente para eventos cardiovasculares. Objetivo Avaliar valores da elevação da AM e sua associação com a hipertrofia ventricular esquerda (HVE) e com o Descenso do Sono (DS) em obesos e não obesos hipertensos. Métodos Estudo transversal que avaliou medidas pressóricas à monitorização ambulatorial da pressão arterial (MAPA) e a presença de HVE, avaliada pela ecocardiografia, em 203 pacientes hipertensos em tratamento ambulatorial, separados em dois grupos: 109 não obesos e 94 hipertensos obesos. O nível de significância adotado foi de 0,05 em testes bicaudais. Resultados A AM acima de 20 mmHg à MAPA foi detectada em 59,2% dos pacientes do grupo "não obesos" e em 40,6% no grupo "obesos". A HVE foi encontrada em 18,1% no grupo dos não-obesos e em 39,3% no grupo de obesos, p<0,001. No grupo "obesos" foi observado que AM >16 mmHg esteve associada à HVE, com [razão de prevalência: 2,80; IC95% (1,12-6,98), p=0,03]. Para o grupo dos "não obesos", o ponto de corte da AM para essa associação foi >22 mmHg. Conclusão A AM elevada associou-se positivamente com HVE, com comportamento peculiar na população de hipertensos e obesos.

Abstract Background Weight gain can trigger mechanisms that increase blood pressure. Nevertheless, obesity causes structural changes in the myocardium, including increased ventricular mass, atrial dilatation, and diastolic and systolic dysfunction. Additionally, blood pressure variations, like morning surge (MS) in obese hypertensive patients may have clinical relevance in cardiovascular events. Although morning blood pressure surge is a physiological phenomenon, excess MS can be considered an independent risk factor for cardiovascular events. Objective To evaluate MS values and their association with left ventricular hypertrophy (LVH) and nocturnal dipping (ND) in obese and non-obese hypertensive patients. Methods A cross-sectional study that evaluated BP measurements by ambulatory blood pressure monitoring (ABPM) and the presence of LVH by echocardiography in 203 hypertensive outpatients, divided into two groups: 109 non-obese and 94 obese hypertensives patients. The significance level was set at 0.05 in two-tailed tests. Results A MS above 20 mmHg by ABPM was detected in 59.2% of patients in the non-obese group and 40.6% in the obese group. LVH was found in 18.1% and 39.3% of patients in the non-obese and obese groups, respectively, p<0.001. In the "obese group", it was observed that a MS>16 mmHg was associated with LVH, [prevalence ratio: 2.80; 95%CI (1.12-6.98), p=0.03]. For the non-obese group, the cut-off point of MS for this association was >22 mmHg. Conclusion High MS was positively associated with LVH, with a particular behavior in the hypertensive obese group.

Laserterapia e tratamento medicamentoso tópico na onicomicose em pessoas com diabetes: série de casos* / Terapia láser y tratamiento con medicamento tópico para onicomicosis en personas con diabetes: serie de casos / Laser therapy and topical drug treatment for onychomycosis in people with diabetes: A case-series study

Objetivo: descrever os efeitos da laserterapia de baixa intensidade e do tratamento medicamentoso tópico da onicomicose em pessoas com diabetes. Método: estudo quantitativo, do tipo série de casos. Os participantes foram 21 pessoas com diabetes divididas em dois grupos, sendo o primeiro tratado com laser e o segundo com medicamento tópico no período de outubro de 2020 a agosto de 2021. Os dados foram coletados em histórico e exame clínico das lâminas ungueais e organizados em banco de dados, cuja análise ocorreu por meio de estatística descritiva. Resultados: identificou-se que no grupo I 30% das lâminas ungueais obtiveram cura clínica e no II 26%. Ao avaliar a resposta satisfatória o grupo I apresentou 63% e o II 53%. Conclusão: o tratamento da onicomicose com laserterapia apresentou maior prevalência de resposta satisfatória e cura clínica do que o tratamento medicamento tópico.

Objective: to describe the effects of low-level laser therapy and of topical drug treatment for onychomycosis in people with diabetes. Method: a qualitative study of the case-series type. The participants were 21 individuals with diabetes divided into two groups, the first treated with laser and the second with topical medication from October 2020 to August 2021. The data were collected in a clinical history and examination of the nail plates and organized in a database, whose analysis took place through descriptive statistics. Results: it was identified that 30% and 26% of the nail plates attained clinical cure in groups I and II, respectively. When assessing the satisfactory response, groups I and II presented 63% and 53%, respectively. Conclusion: the onychomycosis treatment with laser therapy presented higher prevalence of satisfactory response and clinical cure than the topical drug treatment.

Objetivo: describir los efectos de la Terapia Láser de Baja Intensidad y del tratamiento con medicamento tópico para la onicomicosis en personas con diabetes. Método: estudio cuantitativo del tipo serie de casos. Los participantes fueron 21 personas con diabetes divididas en dos grupos: el primero tratado con láser y el segundo con un medicamento tópico entre octubre de 2020 y agosto de 2021. Los datos se recolectaron de las historias y los exámenes clínicos de las placas ungueales y se los organizó en una base de datos, cuyo análisis se realizó por medio de estadística descriptiva. Resultados: se identificó que el 30% y el 26% de las placas ungueales alcanzaron cura clínica en los grupos I y II, respectivamente. Al evaluar la respuesta satisfactoria, los grupos I y II presentaron 63% y 53%. Conclusión: el tratamiento de la onicomicosis con terapia láser presentó mayor prevalencia de respuestas satisfactoria y cura clínica que el tratamiento con predicamento tópico.

Acute Myeloid Leukaemia Presenting as B12 Vitamin Deficiency When Multiple Horses Become a Zebra.

Vitamin B12 deficiency is a common finding in medical practice. It is easily treated with supplementation and typically has a favourable prognosis. In rare circumstances, it can hide a severe disease that should be promptly addressed. We report the case of an acute myeloid leukaemia presenting as an initially predictable B12 deficiency in a vegetarian patient with chronic gastritis. The supplementation rapidly corrected the deficit and the accompanying cytopenias. However, in the following month the cell counts fell once again, leading to the suspicion that other aetiology could be lying beneath the surface. Maintaining a normal peripheral blood smear, the bone marrow biopsy showed myeloblasts and extensive fibrosis compatible with the diagnosis of acute myeloid leukaemia. The neoplasm justified the vitamin deficit by excessive cellular turnover, a vicious cycle only uncovered after supplementation and that ultimately led to the patient's death. LEARNING POINTS: Vitamin B12 is a common aetiology of pancytopenia and is usually caused by gastric malabsorption.When supplementation does not correct the haematological deficit, central causes must be considered. Acute myeloid leukaemia is one possibility, but causes peripheral blood smear abnormalities in almost all patients. Diagnosis should include lumbar puncture and a thorough search for the aetiology; treatment is directed towards the aetiology.Neoplastic diseases should be always excluded when correction of the deficit does not resolve cytopenias.

Laserterapia de baixa intensidade com terapia fotodinâmica no tratamento de onicomicose / Low intensity laser therapy with photodynamic therapy in the treatment of onychomycosis / Terapia láser de baja intensidad con terapia fotodinámica en el tratamiento de la onicomicosis

Objetivo: avaliar os resultados da aplicação da laserterapia de baixa intensidade com terapia fotodinâmica no tratamento da onicomicose em pacientes com Diabetes Mellitus tipo 2. Método: estudo observacional do tipo série de casos, realizado em um serviço de Podiatria Clínica no Estado do Rio de Janeiro. A população foram 11 pacientes diabéticos com onicomicose que receberam 5 sessões de intervenção e avaliados antes e depois. O estudo ocorreu de fevereiro a março de 2021, após aprovação do comitê de ética. Os dados foram analisados através de estatística descritiva. Resultados: verificou-se, após aplicação da intervenção, a evolução satisfatória do aspecto clínico das lâminas ungueais em 70% da amostra. Apenas 30% da amostra não apresentou modificação no aspecto da lâmina. Conclusão: a laserterapia com terapia fotodinâmica no tratamento da onicomicose em pacientes com Diabetes Mellitus tipo 2 apresenta resultados promissores com melhora clínica da maioria dos casos.

Objective: to evaluate the results of the application of low-level laser therapy with photodynamic therapy in the treatment of onychomycosis in patients with type 2 Diabetes Mellitus. Method: case series observational study, performed in a Clinical Podiatrics service in the state of Rio de Janeiro. The population was 11 diabetic patients with onychomycosis who received 5 intervention sessions and evaluated before and after. The study took place from February to March 2021, after approval by the ethics committee. Data were analyzed using descriptive statistics. Results: after the intervention, the satisfactory evolution of the clinical aspect of the nail plates was verified in 70% of the sample. Only 30% of the sample showed no change in the appearance of the the blade. Conclusion: laser therapy with photodynamic therapy in the treatment of onychomycosis in patients with type 2 Diabetes Mellitus shows promising results with clinical improvement in most cases.

Objetivo: evaluar los resultados de la aplicación de la terapia láser de baja intensidad con terapia fotodinámica en el tratamiento de la onicomicosis en pacientes con Diabetes Mellitus tipo 2. Método: estudio observacional de serie de casos, realizado en una Clínica Servicio de podología en el estado de Río de Janeiro. La población fue de 11 pacientes diabéticos con onicomicosis que recibieron 5 sesiones de intervención y evaluados antes y después. El estudio se llevó a cabo de febrero a marzo de 2021, previa aprobación del comité de ética. Los datos fueron analizados utilizando estadística descriptiva. Resultados: Posterior a la intervención se verificó la evolución satisfactoria del aspecto clínico de las láminas ungueales en el 70% de la muestra. Solo el 30% de la muestra no mostró cambios en la apariencia de las láminas. Conclusión: La terapia láser con terapia fotodinámica en el tratamiento de la onicomicosis en pacientes con Diabetes Mellitus tipo 2 muestra resultados prometedores con mejoría clínica en la mayoría de los casos.

CD73-Mediated Formation of Extracellular Adenosine Is Responsible for Adenosine A2A Receptor-Mediated Control of Fear Memory and Amygdala Plasticity.

Adenosine A2A receptors (A2AR) control fear memory and the underlying processes of synaptic plasticity in the amygdala. In other brain regions, A2AR activation is ensured by ATP-derived extracellular adenosine formed by ecto-5'-nucleotidase or CD73. We now tested whether CD73 is also responsible to provide for the activation of A2AR in controlling fear memory and amygdala long-term potentiation (LTP). The bilateral intracerebroventricular injection of the CD73 inhibitor αß-methylene ADP (AOPCP, 1 nmol/ventricle/day) phenocopied the effect of the A2AR blockade by decreasing the expression of fear memory, an effect disappearing in CD73-knockout (KO) mice and in forebrain neuronal A2AR-KO mice. In the presence of PPADS (20 µM) to eliminate any modification of ATP/ADP-mediated P2 receptor effects, both AOPCP (100 µM) and the A2AR antagonist, SCH58261 (50 nM), decreased LTP magnitude in synapses of projection from the external capsula into the lateral amygdala, an effect eliminated in slices from both forebrain neuronal A2AR-KO mice and CD73-KO mice. These data indicate a key role of CD73 in the process of A2AR-mediated control of fear memory and underlying synaptic plasticity processes in the amygdala, paving the way to envisage CD73 as a new therapeutic target to interfere with abnormal fear-like emotional processing.

Adenosine A2A receptors control synaptic remodeling in the adult brain.

The molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling system(s) controlling axon specification/growth during neurodevelopment reactivated during epileptogenesis. Since adenosine A2A receptors (A2AR) control axon formation/outgrowth and synapse stabilization during development, we now examined the contribution of A2AR to MF sprouting. A2AR blockade significantly attenuated status epilepticus(SE)-induced MF sprouting in a rat pilocarpine model. This involves A2AR located in dentate granule cells since their knockdown selectively in dentate granule cells reduced MF sprouting, most likely through the ability of A2AR to induce the formation/outgrowth of abnormal secondary axons found in rat hippocampal neurons. These A2AR should be activated by extracellular ATP-derived adenosine since a similar prevention/attenuation of SE-induced hippocampal MF sprouting was observed in CD73 knockout mice. These findings demonstrate that A2AR contribute to epilepsy-related MF sprouting, most likely through the reactivation of the ability of A2AR to control axon formation/outgrowth observed during neurodevelopment. These results frame the CD73-A2AR axis as a regulator of circuit remodeling in the mature brain.

Association between serum phosphorus and mortality in NHANES 2003-2006: the effect of gender and renal function.

BACKGROUND: The impact of high serum phosphorus in the general population is still debated. Studies are heterogeneous, most lack an adjustment for parathyroid hormone, vitamin D and phosphorus intake and the effect might differ by gender and renal function. We investigated the association between serum phosphorus and mortality in American adults. METHODS: We prospectively analyzed 5698 non-pregnant and non-CKD adults from the National Health and Nutrition Examination Survey (NHANES) 2003-2006. Serum phosphorus and potential confounders including parathyroid hormone, 25(OH)vitamin D and phosphorus intake were evaluated. All-cause, cardiovascular- and cancer-related deaths were recorded through December 31st, 2015. Sex-specific terciles of serum phosphorus were used to fit adjusted Cox proportional hazard models for mortality. Analysis was stratified by gender and renal function. RESULTS: A total of 590 deaths were recorded over a median follow-up of 81 months. Women showed higher serum phosphorus than men. The adjusted hazard ratio (HR) for all-cause mortality was 1.35 (95% CI 1.08-1.58) (p = 0.033) for the third tercile (versus second tercile). This increased risk was present in participants with estimated glomerular filtration rate (eGFR) below 90 ml/min/1.73 m2 but not above, although interaction was not significant (p = 0.12). Interaction by gender, phosphorus intake, PTH and fasting time was also not detected. For cardiovascular and cancer mortality, the adjusted HR was 0.81 (95% CI 0.33-2.00) (p = NS) and 1.45 (95% CI 0.77-2.72) (p = NS), respectively. CONCLUSIONS: We demonstrated that the highest tercile of serum phosphorus is associated with increased all-cause mortality, irrespective of PTH, 25(OH)vitamin D or phosphorus intake. This association may differ by gender and renal function, but larger studies testing for effect modification are needed.

A pacemaker pocket mass has many faces.

The development of malignant neoplasms over the site of pacemaker implantation is a rare event, with a limited number of published case reports. We report the case of a 78-year-old male who presented with discomfort and pocket mass expansion, reportedly following trauma. Due to initial presumption of a simple hematoma, dissection and drainage were performed without tissue collection for histology. Later presentation with an exophytic ulcerated mass led to biopsy and identification of a lymphoplasmacytic lymphoma. To the best of our knowledge this is the first reported case of a cutaneous lymphoplasmacytic lymphoma presenting as a pacemaker pocket mass, and underlines the importance of systematic pacemaker inspection, of adequate histological characterization and of a high degree of clinical suspicion for the identification malignancy in this context. .

Convergence of adenosine and GABA signaling for synapse stabilization during development.

During development, neural circuit formation requires the stabilization of active γ-aminobutyric acid­mediated (GABAergic) synapses and the elimination of inactive ones. Here, we demonstrate that, although the activation of postsynaptic GABA type A receptors (GABAARs) and adenosine A2A receptors (A2ARs) stabilizes GABAergic synapses, only A2AR activation is sufficient. Both GABAAR- and A2AR-dependent signaling pathways act synergistically to produce adenosine 3',5'-monophosphate through the recruitment of the calcium­calmodulin­adenylyl cyclase pathway. Protein kinase A, thus activated, phosphorylates gephyrin on serine residue 303, which is required for GABAAR stabilization. Finally, the stabilization of pre- and postsynaptic GABAergic elements involves the interaction between gephyrin and the synaptogenic membrane protein Slitrk3. We propose that A2ARs act as detectors of active GABAergic synapses releasing GABA, adenosine triphosphate, and adenosine to regulate their fate toward stabilization or elimination.

The addition of neoadjuvant pertuzumab for the treatment of HER2+ breast cancer: a cost estimate with real-world data.

BACKGROUND: Breast cancer (BC) is largely prevalent worldwide. HER2-positive BC account for roughly 20-25% of all BC cases and has an overall survival lower than other BC. Innovation on BC therapeutics is a constant, but novel therapies have higher costs. Therefore, cost-effectiveness research is essential to provide healthcare decision-makers with solid foundations for a resource allocation. This study aims to estimate the average direct medical costs/patient and cost-effectiveness of adding pertuzumab in neoadjuvant treatment (NeoT) for HER2-positive breast cancer (BC). METHODS: Two retrospective real-world consecutive cohorts of ≥18yo female patients diagnosed with HER2-positive BC treated with NeoT at the Breast Clinic of IPO-Porto were studied. The AC-DH regimen (2012-2015) comprised 8 cycles of neoadjuvant therapy (4 cycles of doxorubicin + cyclosphosphamide followed by 4 cycles ofdocetaxel + trastuzumab), while the AC-DHP regimen (2015-2017) included also pertuzumab as NeoT. NeoT was followed by surgery and adjuvant trastuzumab. Micro-costing technique and a bottom-up approach was used comprising all medical direct costs from the hospital perspective. Unit costs were obtained from government official prices or from IPO-Porto costing system. Costs were adjusted to 2017 and are expressed in euros. Multivariable logistic regression models were used for effectiveness assessment, while generalized linear models with gamma distribution were used for costs. ICER was calculated using the pathological complete response (pCR) as the preferential measure of effectiveness. Sensitivity analysis was also performed. RESULTS: AC-DHP (n = 40) and AC-DH (n = 54) cohorts had heterogenous patient profiles (median age 43y/53y; 67.5%/59.3% positive HR; 60.0%/27.8% operable; 25.0%/24.1% inflammatory, respectively). The AC-DHP average total cost/patient was 56,375€, with pertuzumab accounting for 13,978€ (24.79%) and increasing in 15,982€ the average cost/patient (p < 0.001). Clinical staging and hormone receptors (HR) were significantly associated with pCR. ICER was 1.370€ per percentage point of pCR. CONCLUSIONS: ICER was more favourable in stage III HR negative BC patients compared to other patient profiles. Innovative treatments access is critical to deliver high-quality healthcare, but sustainability must be considered. These results suggest the importance of establishing a cost-effectiveness profile of Pertuzumab in NeoT for HER2-positive BC.

Small cell lung cancer treatment and survival in Portugal: A retrospective analysis from the I-O Optimise initiative.

OBJECTIVE: We aim to describe treatment patterns and overall survival (OS) among a Portuguese cohort of patients with small cell lung cancer (SCLC). METHODS: This study utilised a database held by IPO-Porto, Portugal's largest oncology hospital. Adult patients diagnosed with SCLC at IPO-Porto between January 2012 and June 2017, with follow-up to December 2017, were included. Patients were stratified into subgroups with limited disease (LD) or extensive disease (ED). Treatment analyses were performed from 2015 onwards. RESULTS: Overall, 227 patients diagnosed with SCLC (37 LD; 190 ED) were analysed. Median OS (interquartile range [IQR]) was 15.0 months (3.8-39.3) for LD-SCLC and 5.0 months (1.7-10.3) for ED-SCLC. Among 19 patients diagnosed with LD-SCLC from 2015 onwards, 12 (63.2%) received initial treatment with systemic anticancer therapy (SACT) ± radiotherapy; 6 (31.6%) received best supportive care (BSC). Among 89 patients with ED-SCLC, 57 (68.5%) received SACT ± palliative radiotherapy; 28 (31.5%) received BSC. For patients receiving platinum doublet chemotherapy (±radiotherapy), median OS (IQR) was not reached for LD-SCLC and 5.4 months (2.3-10.9) for ED-SCLC. CONCLUSION: This real-world data analysis from a large Portuguese oncology hospital demonstrates a high disease burden for patients diagnosed with SCLC, particularly those with ED, and highlights a need for more effective therapies.