Reversal of memory and autism-related phenotypes in Tsc2+/- mice via inhibition of Nlgn1.

Tuberous sclerosis complex (TSC) is a rare monogenic disorder co-diagnosed with high rates of autism and is caused by loss of function mutations in the TSC1 or TSC2 genes. A key pathway hyperactivated in TSC is the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which regulates cap-dependent mRNA translation. We previously demonstrated that exaggerated cap-dependent translation leads to autism-related phenotypes and increased mRNA translation and protein expression of Neuroligin 1 (Nlgn1) in mice. Inhibition of Nlgn1 expression reversed social behavior deficits in mice with increased cap-dependent translation. Herein, we report elevated translation of Nlgn1 mRNA and an increase in its protein expression. Genetic or pharmacological inhibition of Nlgn1 expression in Tsc2 +/- mice rescued impaired hippocampal mGluR-LTD, contextual discrimination and social behavior deficits in Tsc2 +/- mice, without correcting mTORC1 hyperactivation. Thus, we demonstrate that reduction of Nlgn1 expression in Tsc2 +/- mice is a new therapeutic strategy for TSC and potentially other neurodevelopmental disorders.

Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1.

MAPK interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterized substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that, whereas deletion of Mnk1/2 (Mnk double knockout) impairs synaptic plasticity and memory in mice, ablation of phospho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between the Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 because Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk double knockout mice. Knockdown of Syngap1 reversed memory deficits in Mnk double knockout mice and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.

Clinical Characteristics of Patients with co-Existent Diabetic Peripheral Neuropathy and Depression: A Systematic Review.

OBJECTIVES: Both diabetic peripheral neuropathy and depression have significant implications on patients' quality of life, management and outcomes. We aimed to evaluate all available evidence concerning patients with co-existent diabetic peripheral neuropathy and depression, and describe their clinical characteristics, in order to promote early recognition and management. METHODS: Systematic search of PubMed for studies providing data on patients with diabetic peripheral neuropathy and depression. The primary outcome was to evaluate all available evidence related to characteristics of diabetes, diabetic peripheral neuropathy and depression. Secondary study outcomes included comorbid conditions and complications in these patients. RESULTS: Final analysis included 24 studies with data on 205 patients. Most patients were adults between 18-65 years of age. Mean HbA1c value was above 8% and most patients were treated with insulin. Neuropathy was predominantly painful and most patients with available data were considered to have major depressive disorder. In addition to diabetic peripheral neuropathy and depression, diabetes-related complications were recorded in 43 patients, the most common being autonomic neuropathy, retinopathy and nephropathy. The most frequently reported comorbidities were weight loss (72 patients), impotence (60 patients), hypertension (23 patients) and coronary artery disease (22 patients). CONCLUSIONS: The present study describes the characteristics of patients with co-existent diabetic peripheral neuropathy and depression, aiming for prompt detection, prevention of further deterioration and improvement of patient outcomes. Available evidence shows that the majority of these patients are adults, with painful peripheral neuropathy and with insulin-treated and inadequately controlled diabetes.

Epicardial adipose tissue deposition in patients with diabetes and renal impairment: Analysis of the literature.

Diabetes mellitus (DM) is defined as a chronic disease of disordered metabolism with an ongoing increase in prevalence and incidence rates. Renal disease in patients with diabetes is associated with increased morbidity and premature mortality, particularly attributed to their very high cardiovascular risk. Since this group of patients frequently lacks specific symptomatology prior to the adverse events, a screening tool for the identification of high-risk patients is necessary. The epicardial adipose tissue (EAT) is a biologically active organ having properties similar to visceral adipose tissue and has been associated with metabolic diseases and coronary artery disease. Superior to conventional cardiovascular risk factors and anthropometric measures, including body mass index and waist circumference, the EAT can early predict the development of coronary artery disease. Assessment of EAT can be performed by two-dimensional echocardiography, magnetic resonance imaging or computer tomography. However, its role and significance in patients with DM and nephropathy has not been thoroughly evaluated. The aim of the current editorial is to evaluate all available evidence regarding EAT in patients with DM and renal impairment. Systematic search of the literature revealed that patients with DM and nephropathy have increased EAT measurements, uncontrolled underlying disease, high body mass index and raised cardiovascular risk markers. Acknowledging the practical implications of this test, EAT assessment could serve as a novel and non-invasive biomarker to identify high-risk patients for cardiovascular adverse events.

Fever of unknown origin caused by infectious diseases in the era of migrant and refugee crisis.

Concern exists in Europe about the possibility of importation of infectious diseases due to the recent influx of migrants and refugees after 2011. In this retrospective 6-year study, we examined the epidemiology of fever of unknown origin (FUO) in Greece over the past years. Forty-eight patients with classical FUO were included. The proportion of infectious causes of FUO (29.2%) was similar to previous studies in Greece and all infections were endemic to the area. Disease-related mortality was 12.5% and no deaths due to infection were recorded. In conclusion, none of the diagnosed infectious causes of FUO raised concerns about the possibility of imported diseases or pathogens. These results re-inforce the perception that migrants and refugees are not carriers of communicable diseases that can cause public health problems to European countries.

Adrenal Aging and Its Implications on Stress Responsiveness in Humans.

Normal aging results in subtle changes both in ACTH and cortisol secretion. Most notable is the general increase in mean daily serum cortisol levels in the elderly, without a noteworthy alteration in the normal circadian rhythm pattern. Glucocorticoid excess seen in the elderly population can have serious consequences in both the structural and functional integrity of various key areas in the brain, including the hippocampus, amygdala, prefrontal cortex, with consequent impairment in normal memory, cognitive function, and sleep cycles. The chronically elevated glucocorticoid levels also impinge on the normal stress response in the elderly, leading to an impaired ability to recover from stressful stimuli. In addition to the effects on the brain, glucocorticoid excess is associated with other age-related changes, including loss of muscle mass, hypertension, osteopenia, visceral obesity, and diabetes, among others. In contrast to the increase in glucocorticoid levels, other adrenocortical hormones, particularly serum aldosterone and DHEA (the precursor to androgens and estrogens) show significant decreases in the elderly. The underlying mechanisms for their decrease remain unclear. While the adrenomedullary hormone, norephinephrine, shows an increase in plasma levels, associated with a decrease in clearance, no notable changes observed in plasma epinephrine levels in the elderly. The multiplicity and complexity of the adrenal hormone changes observed throughout the normal aging process, suggests that age-related alterations in cellular growth, differentiation, and senescence specific to the adrenal gland must also be considered.

Severe Murine Typhus Presenting with Acalculous Cholecystitis: A Case Report and Literature Review.

A 54-year-old otherwise healthy male, who was being evaluated for prolonged fever, developed clinical and ultrasonographic signs compatible with acute acalculous cholecystitis. Diagnosis of murine typhus was confirmed by serology and the patient was treated with doxycycline. He improved rapidly and all clinical and laboratory abnormalities returned to normal. The present case dictates that knowledge of the local epidemiology and keeping a high index of clinical suspicion can help recognize uncommon manifestations of murine typhus, in order to treat appropriately and avoid unnecessary investigations and interventions.

Clinical and laboratory characteristics, epidemiology, and outcomes of murine typhus: A systematic review.

Murine or endemic typhus, a febrile disease caused by Rickettsia typhi, is often misdiagnosed due to its non-specific presentation. We sought to evaluate all available evidence in the literature regarding the clinical and laboratory manifestations, epidemiological characteristics, and outcomes of murine typhus. Pubmed was searched for all articles providing available data. In an effort to incorporate contemporary data, only studies from 1980 were included. Thirty-three case series including 2074 patients were included in final analysis. Available evidence suggests that the classic triad of fever, headache and rash is encountered in only one-third of patients. Other frequent symptoms were chills, malaise, myalgia, and anorexia. A tetrad of reported laboratory abnormalities consisting of elevated liver enzymes, lactate dehydrogenase, erythrocyte sedimentation rate and hypoalbuminemia was detected. Complications were observed in one-fourth of patients, reported mortality was extremely low, but untreated patients had notably longer duration of fever. Among epidemiological characteristics, a seasonal distribution with most cases reported during warmer months, was the most prominent finding. Murine typhus in children exhibits several different characteristics, with abdominal pain, diarrhea, and sore throat reported more commonly, higher frequency of anemia, lower frequency of hypoalbuminemia, hematuria and proteinuria and a much lower rate of complications. This systematic review of published evidence provides a thorough description of the clinical and laboratory features of murine typhus and highlights important differences in children.

Hsf-1 affects podocyte markers NPHS1, NPHS2 and WT1 in a transgenic mouse model of TTRVal30Met-related amyloidosis.

INTRODUCTION: Familial amyloid polyneuropathy is characterized by transthyretin (TTR) deposition in various tissues, including the kidneys. While deposition induces organ dysfunction, renal involvement in TTR-related amyloidosis could manifest from proteinuria to end-stage kidney failure. As proteinuria is considered result of glomerular filtration barrier injury we investigated whether TTR deposition affects either glomerular basement membrane (GBM) or podocytes. MATERIALS AND METHODS: Immunohistochemistry, immunoblot and gene expression studies for nephrin, podocin and WT1 were run on renal tissue from human-TTRV30M transgenic mice hemizygous or homozygous for heat shock factor one (Hsf-1). Transmission electron microscopy was used for evaluation of podocyte foot process width (PFW) and GBM thickness in Hsf-1 hemizygous mice with or without TTRV30M or amyloid deposition. RESULTS: Glomeruli of hsf-1 hemizygous transgenic mice showed lower nephrin and podocin protein levels but an increased podocyte number when compared to Hsf-1 homozygous transgenic mice. Nephrin, podocin and WT1 gene expression levels were unaffected by the Hsf-1 carrier status. TTRV30M deposition was associated with increased PFW and GBM thickness. CONCLUSIONS: Under the effect of Hsf-1 hemizygosity, TTRV30M deposition has deleterious effects on GBM thickness, PFW and slit diaphragm composition, without affecting nephrin and podocin gene expression.