Sandra Domingues Santos

Introduction: Diabetes is the leading cause of chronic kidney disease and end-stage kidney disease worldwide. A kidney biopsy in a diabetic patient must be considered when non-diabetic renal disease is suspected, such as in the presence of a rapid decline in renal function or severe unexplained proteinuria. However, the timing and criteria of a biopsy remain controversial in these patients. We aimed to identify clinical and histological markers that could help differentiate diabetic and non-diabetic renal disease and decide if this invasive approach is needed or not. Subjects and Methods: We reviewed 30 years of biopsies from diabetic patients performed at a tertiary hospital. We collected patient demographic data, biopsy indications, histological findings, and clinical and analytical data both at the moment of the biopsy and extensive followup. Based on kidney biopsy findings, patients were categorized as isolated diabetic nephropathy, non-diabetic kidney disease, or non-diabetic kidney disease superimposed on diabetic nephropathy (diabetic kidney disease). Results and Discussion: We enrolled 92 patients, mostly with type 2 diabetes, with a mean age of 62.9 ± 13.2 years. Nearly half of them had isolated diabetic nephropathy (53.3%), and 15.2% had diabetic nephropathy superimposed on non-diabetic kidney disease, comprising a total of 63 patients (68.5%) with diabetic kidney disease. Twenty-nine patients (31.5%) were considered to have non-diabetic kidney disease. These last patients were significantly less likely to need insulin therapy (p=0.002), had more frequently an acute deterioration of renal function (p=0.01), lower albumin levels (p=0.03), and a higher prevalence of microhematuria (p=0.001). We found the latter to be an independent predictor of non-diabetic kidney disease. Further, patients with the primary diagnosis of diabetic nephropathy had higher survival than those who had nondiabetic kidney disease, contradicting published data. Conclusions: The criteria for performing a biopsy in diabetic patients still lack consensus, although the priority to identify non-diabetic kidney disease prevails. We believe the non-diabetic kidney disease predictors we describe may prove helpful for determining the need for a histological assessment in diabetic patients.

The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser⁸⁴⁵. Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor–dependent synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic plasticity that underlies learning.

Introduction: Whipple’s disease is a rare, chronic, systemic disease caused by the actinomycete Tropheryma whipplei. Clinical manifestations vary widely depending on the affected system, the most common being the digestive tract. Case Presentation: The authors report the case of a 52-year-old man with malabsorption syndrome, diarrhea, marked weight loss, melanoderma, and visual and proprioception disorders. Periodic acid-Schiff staining of a proximal small bowel biopsy and peripheral-blood PCR identification of T. whipplei confirmed the disease. The patient was initially treated with intravenous ceftriaxone, followed by oral trimethoprim/sulfamethoxazole with significant clinical improvement. Conclusions: This case is reported due to its rarity and the diagnostic challenge it presents. Although uncommon, Whipple’s disease should be considered as a differential diagnosis of malabsorption syndrome due to its systemic impact and possible treatment with targeted antibiotic therapy.

Synaptic plasticity of the neuronal circuits associated with feeding behavior is regulated by peripheral signals as a response to changes in the energy status of the body. These signals include glucose, free fatty acids, leptin and ghrelin and are released into circulation, being able to reach the brain. Ghrelin, a small peptide released from the stomach, is an orexigenic hormone produced in peripheral organs, and its action regulates food intake, body weight and glucose homeostasis. Behavioral studies show that ghrelin is implicated in the regulation of both hedonic and homeostatic feeding and of cognition. Ghrelin-induced synaptic plasticity has been described in neuronal circuits associated with these behaviors. In this review, we discuss the neuromodulatory mechanisms induced by ghrelin in regulating synaptic plasticity in three main neuronal circuits previously associated with feeding behaviors, namely hypothalamic (homeostatic feeding), ventral tegmental (hedonic and motivational feeding) and hippocampal (cognitive) circuits. Given the central role of ghrelin in regulating feeding behaviors, and the altered ghrelin levels associated with metabolic disorders such as obesity and anorexia, it is of paramount relevance to understand the effects of ghrelin on synaptic plasticity of neuronal circuits associated with feeding behaviors.

Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan’s syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control of mRNAs implicated in different stages of synaptic scaling, but their role in these mechanisms is still undervalued. Here, we report that chronic blockade of glutamate receptors of the AMPA and NMDA types in hippocampal neurons in culture induces changes in the neuronal mRNA and miRNA transcriptomes, leading to synaptic upscaling. Specifically, we show that synaptic activity blockade persistently down-regulates miR-186-5p. Moreover, we describe a conserved miR-186-5p-binding site within the 3′UTR of the mRNA encoding the AMPA receptor GluA2 subunit, and demonstrate that GluA2 is a direct target of miR-186-5p. Overexpression of miR-186 decreased GluA2 surface levels, increased synaptic expression of GluA2-lacking AMPA receptors, and blocked synaptic scaling, whereas inhibition of miR-186-5p increased GluA2 surface levels and the amplitude and frequency of AMPA receptor-mediated currents, and mimicked excitatory synaptic scaling induced by synaptic inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation of AMPA receptor expression.

Organising pneumonia (OP) is a clinical, radiological and histopathological entity with unknown etiology, previously named bronchiolitis obliterans with organising pneumonia. A 74-year-old female, presented with asthenia and dyspnea. In the three days before she was on levofloxacin without benefit. She had a previous history of breast cancer and arterial fibrillation under daily amiodarone. During the year before she was three times hospitalized with pneumonia with a weak response to treatments and relapse after apparent resolution. She was re-hospitalized with community acquired pneumonia (CAP) diagnosis having, again, poor response to antibiotics. As there were no clinical or radiological improvements, a chest computed tomography (CT) scan was performed showing diffused pulmonary condensations with air bronchogram. Cryptogenic organizing pneumonia (COP) diagnosis was confirmed through a transbronchial lung biopsy (TLB). This diagnosis difficulty was increased by the interference of concomitant amiodarone intake or even by paraneoplastic hypothesis due to previous breast cancer history, which had to be promptly excluded. Corticotherapy allowed sequential radiological pattern normalization, clinical and analytical improvement. In recurrent pneumonia cases, COP must be considered and further diagnostic tools should be used.

Significance: Ghrelin is a peptide released from the empty stomach into circulation, and which acts on the brain to promote appetite. Recent studies showed that ghrelin also affects cognition, but the mechanism for this effect is unknown. We show that activation of ghrelin receptors in the hippocampus enhances synaptic signaling by glutamate, the major excitatory neurotransmitter in the brain. Ghrelin promotes the synaptic accumulation of glutamate receptors of the AMPA subtype, and increases long-term potentiation, one form of synaptic plasticity that is thought to underlie learning and memory. These molecular effects of ghrelin in the hippocampus may contribute to the cognition-enhancing role of ghrelin.