The role of brain biopsy in the clinical management of HIV-related focal brain lesions.

OBJECTIVES: Up to 20% of HIV-related focal brain lesion (FBL) diagnoses cannot be determined without invasive procedures. In such cases, brain biopsy is an important step in the evaluation algorithm. The aims of this study were to describe the clinical outcomes of patients with FBL, the proportion of diagnoses confirmed by brain biopsies and their aetiologies, and to analyse the proportion of patients in whom the biopsy motivated a change in therapeutic management. METHODS: A retrospective cohort study was performed. The data from clinical records of patients with HIV-related FBL admitted between January 2005 and December 2015 were reviewed. RESULTS: A total of 137 patients were included in the study. The median age was 39 years [interquartile range (IQR) 33-44.5 years]. The median CD4 count was 54 cells/µL (IQR 21-124 cells/µL). Cerebral brain biopsy was performed in 21.16% of patients (29 of 137); 68.9% of these individuals (20 of 29) were diagnosed by histology, with results of central nervous system (CNS) lymphoma in 20.6% (six of 29), progressive multifocal leucoencephalopathy in 6.8% (two of 29), toxoplasmosis in 6.8% (two of 29), tuberculoma in 6.8% (two of 29), and other diagnoses in 27.6% (eight of 29). In nine patients, the histology was nonspecific. In 75.8% of patients (22 of 29), the result of the biopsy led to a change in the therapeutic management. We did not observe higher rates of mortality related to the procedure. Overall mortality at 30 and 90 days was similar in patients who were and were not biopsied. CONCLUSIONS: In this retrospective cohort study, cerebral biopsy was associated with significant adjustments in therapeutic management for a high percentage of patients.

Treating lupus patients with antimalarials: analysis of safety profile in a single-center cohort.

This longitudinal retrospective study aims at describing the safety profile and the reasons for discontinuation of antimalarials in patients with systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE), focusing on ocular toxicity. We analyzed the clinical data of 845 SLE and DLE patients; 59% of them were taking antimalarials: 1.4% chloroquine (CQ), 88.5% hydroxychloroquine (HCQ) and 10.1% both. The mean therapy duration was 82.5 ± 77.4 months. At least one side effect was reported by 19.4% of patients, leading to temporary or permanent withdrawal in 9.1% and 10.3% of cases, respectively; 19.3% of patients experienced side effects with HCQ and 8.6% with CQ. In 55.1% of cases, the adverse event was mild or moderate. Ophthalmological alterations were reported by 8.5% but were confirmed by the ophthalmological examination in 5.5% of cases. Retinal alterations were associated with age, disease duration and duration of the antimalarial therapy, but not to drug dose and comorbidities or lupus nephritis. This is the largest monocentric longitudinal study confirming the good safety profile of antimalarials in DLE and SLE patients. The main adverse events during the therapy were mild or moderate, but maculopathy-reported in a low percentage of patients-remains the main cause of treatment withdrawal.

Anti-carbamylated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients: lack of correlation with anti-cyclic citrullinated protein antibodies and rheumatoid factor.

OBJECTIVES: To investigate the prevalence of anti-carbamylated protein antibodies (anti-CarP) in the healthy first-degree relatives (HFDRs) of patients with rheumatoid arthritis (RA). METHODS: We enrolled 141 HFDRs of 63 patients with RA diagnosed accordingly to the 2010 ACR/EULAR criteria. Fifty-six normal healthy subjects (NHS), sex- and age-matched, served as controls. Anti-CarP IgG, anti-cyclic citrullinated peptide antibody (anti-CCP) IgG and rheumatoid factors (RF) isotypes (IgG, IgA, IgM) were assessed by solid-phase ELISA. RESULTS: Anti-CarP were detectable in 13 HFDRs (9.2%), anti-CCP in 9 (6.3%), IgG-RF in 10 (7%), IgA-RF in 17 (12%), and IgM-RF in 13 (9.2%) HFDRs. Twenty-nine (46%) RA patients were positive for anti-CarP, 31 (49.2%) for anti-CCP, and 34 (53.9%) for RF. One NHS (1.7%) resulted positive for anti-CarP, none for anti-CCP and RF. Anti-CarP showed significantly higher serum levels in RA and HFDRs than in NHS (p<0.0001 and p=0.0012, respectively). A significant correlation between anti-CCP and RF were found among RA patients (p=0.0002), whereas no correlations were reported between autoantibodies tested in the HFDRs. CONCLUSIONS: Anti-CarP can be found in the sera of HFDRs of RA patients and their prevalence is significantly higher than in NHS. No correlation of anti-CarP with anti-CCP and RF antibodies in RA HFDRs was found.

Aldosterone does not modify gene expression in human endothelial cells.

The toxic effects of aldosterone on the vasculature, and in particular on the endothelial layer, have been proposed as having an important role in the cardiovascular pathology observed in mineralocorticoid-excess states. In order to characterize the genomic molecular mechanisms driving the aldosterone-induced endothelial dysfunction, we performed an expression microarray on transcripts obtained from both human umbilical vein endothelial cells and human coronary artery endothelial cells stimulated with 10 - 7 M aldosterone for 18 h. The results were then subjected to qRT-PCR confirmation, also including a group of genes known to be involved in the control of the endothelial function or previously described as regulated by aldosterone. The state of activation of the mineralocorticoid receptor was investigated by means of a luciferase-reporter assay using a plasmid encoding a mineralocorticoid and glucocorticoid-sensitive promoter. Aldosterone did not determine any significant change in gene expression in either cell type both in the microarray and in the qRT-PCR analysis. The luciferase-reporter assay showed no activation of the mineralocorticoid receptor following aldosterone stimulation. The status of nonfunctionality of the mineralocorticoid receptor expressed in cultured human umbilical and coronary artery endothelial cells does not allow aldosterone to modify gene expression and provides evidence against either a beneficial or harmful genomic effect of aldosterone on healthy endothelial cells.

[Role of aldosterone in the metabolic syndrome]. / Ruolo dell'aldosterone nella sindrome metabolica.

The purpose of this review is to summarize the current knowledge regarding metabolic syndrome prevalence and features in primary aldosteronism. We will also discuss the link between aldosterone and the different metabolic changes typical of the metabolic syndrome. Hypertensive patients have a high prevalence of obesity, dyslipidemia and hyperglycaemia. These are risk factors for the metabolic syndrome, and are associated with an increased cardiovascular risk profile. In particular, insulin resistance seems to be the major alteration in patients affected by primary aldosteronism. We will then describe the experimental and clinical evidences of the role of aldosterone in the pathogenesis of insulin resistance. Higher rates of cardiovascular events have been recently reported in primary aldosteronism: they could be partly due to the increased prevalence of the metabolic syndrome in this disorder.

Recent advances in diagnosis and treatment of primary aldosteronism.

Primary aldosteronism is the most common form of secondary hypertension. The use of aldosterone/plasma renin activity ratio (ARR) as a screening test has elevated its prevalence up to 10% of hypertensive patients. Idiopathic bilateral adrenal hyperplasia and aldosterone-producing adrenal adenoma are the leading causes of primary aldosteronism. Most patients with this conditions are normokalemic and clinically undistinguishable from essential hypertensives. However, they suffer from anticipated and more severe target organ damage than other hypertensives. Thus, being primary aldosteronism a common, specifically treatable and sometimes surgically cured form of hypertension, a prompt diagnosis is necessary and cannot be overlooked. The measurement of ambulatory ARR represents the screening test and should be performed in the majority of hypertensive patients. ARR higher than a set cutoff suggests the need of a confirmatory test for primary aldosteronism, such as intravenous saline load or fludrocortisone suppression test. If inability to suppress aldosterone is demonstrated, the disease is confirmed. The subtype evaluation is based on adrenal imaging (CT scan) and selective adrenal venous sampling. The latter is the gold standard for the diagnosis of a lateralized aldosterone secretion, as typically observed in aldosterone-producing adenomas. Microadenomas are frequently overlooked by adrenal image. If lateralization is confirmed, unilateral adrenalectomy is the reasonable therapeutic option, leading to a significant reduction of blood pressure, if not normotension. If bilateral aldosterone excess is demonstrated, an aldosterone receptor antagonist should be administered. This article reviews and discusses the new data about prevalence, diagnosis and treatment of primary aldosteronism.

Recent advances in diagnosis and treatment of pheochromocytoma.

Pheochromocytomas are rare tumours of catecholamine-producing chromaffin cells leading to hypertension and symptoms of catecholamine excess. They can be benign or malignant, sporadic or familial tumours. Genetic syndromes associated with pheochromocytoma are MEN II, VHL disease and neurofibromatosis type 1. Usually, pheochromocytomas occur in the adrenal medulla. Clinical manifestations include hypertension (which can be intermittent, stable or in the form of hypertensive peaks) and symptoms related to catecholamine excess such as headache, palpitations and tachycardia, pallor, anxiety and nervousness, nausea, vomiting, weight loss. This clinical syndrome can be mimicked by various hyperkinetic and hyperadrenergic states. When pheochromocytoma is suspected, the first diagnostic step is represented by the measurement of catecholamines and their metabolites (metanephrines) in urine and plasma. Chro-mogranin A measurement can be useful. The clonidine suppression test may be helpful in ruling out other conditions that may elevate catecholamines and metanephrines. Localiza-tion and staging of pheochromocytoma is based on MRI, which is more sensitive than CT scan, and (131)I-MIBG scintiscan. The best therapeutic option for pheochromocytoma is surgery with a laparoscopic approach. An appropriate pre-, intra- and postoperative medical management of the patient is mandatory. In the absence of optimal medical treatment, intraoperative mortality reaches 50%.

Sarcoid: an unusual mimicker of classic pulmonary embolus.

A patient had both the clinical presentations and the ventilation-perfusion scan that simulated pulmonary embolism so closely that anticoagulant therapy was administered. Computed tomography of the chest and Ga-67 citrate scintigraphy identified hilar adenopathy due to sarcoidosis as the cause of a ventilation-perfusion mismatch.

Present and future of PI3K pathway inhibition in cancer: perspectives and limitations.

Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival, motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over-expression of PI3Ks and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I PI3Ks (α, ß, γ, δ isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein, we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on potential side effects, caveats and limitations for PI3K blockade in patients.

Adrenal endothelin-1 levels are not associated with aldosterone secretion in primary aldosteronism.

BACKGROUND: Endothelin-1 (ET-1) may function as an aldosterone secretagogue and, in turn, aldosterone can upregulate ET-1 expression. Hence, the existence of a feedforward loop involving ETs and aldosterone has been speculated in primary aldosteronism (PA). In the present study, we sought to examine ET-1 secretion from the adrenal glands in patients with PA. DESIGN: We determined ET-1 levels in blood samples obtained during adrenal venous sampling of patients affected by PA (n=17). Furthermore, we examined the mRNA expression of the ET system in tissue samples from aldosterone-producing adenomas (APAs, n=9) and control normal adrenals (n=3). METHODS: Blood ET-1 levels were determined by RIA. Tissue mRNA expression of the ET system was assayed with Affymetrix microarrays. RESULTS: ET-1 levels did not differ between inferior vena cava and adrenal vein blood in both bilateral adrenal hyperplasia and APA patients. Moreover, cortisol-normalized ET-1 levels did not show lateralized adrenal ET-1 secretion in APAs. Through gene expression profiling with microarray performed in a distinct set of APA individuals (n=9), we confirmed the adrenal expression of a complete ET system, but we did not detect a significant upregulation of ET components within the APA tissue compared with normal adrenals. CONCLUSIONS: The present data argue against the hypothesis of increased ET-1 secretion from APAs and do not support a general role for adrenal ET-1 in the vascular pathophysiology of PA.

Migraine, cortical blindness, multiple cerebral infarctions and hypocoagulopathy in celiac disease.

We describe the case of a female patient affected by migraine and untreated adult celiac disease who presented with a state of acute migraine accompanied by multiple neurological deficits, including transient cortical blindness with ischemic CT and MRI alterations, and hypocoagulation due to factor VII deficiency. She was receiving estroprogestin therapy. There was a prompt response to cortisone therapy followed by a state of complete well-being, which also led to the disappearance of migraine attacks after five years of dietary treatment alone.

Renal abnormalities in children with hypertrophic pyloric stenosis--fact or fallacy?

Retrospective review of the abdominal ultrasound (US) examination of 274 children studied for hypertrophic pyloric stenosis (HPS) was undertaken to determine if there is an increased incidence of renal disease as previously reported. Five major abnormalities were detected in the 126 children with HPS. Three lesions were newly diagnosed and two had been diagnosed previously. Five children had abnormalities classified as minor or normal variants. Renal abnormalities were found in six of the 148 children who did not HPS. Only three of these were newly diagnosed and medically important. Eight children without HPS had minor abnormalities or normal variants of the kidneys. Newly diagnosed medically important renal lesions were present in 2.4% of children screened for HPS. The incidence of the finding was the similar in children with and without HPS.

Hypertensive brain stem encephalopathy: clinically silent massive edema of the pons.

Hypertensive encephalopathy is a medical emergency whose clinical manifestations are associated with bilateral parieto-occipital lesions. We describe a case of hypertensive brainstem encephalopathy in which high blood pressure was accompanied only by nuchal headaches of violent onset. T2-weighted magnetic resonance images showed hyperintensity and edema of the pons without any parietooccipital lesions, but with hyperintense lesions at the level of the basal nuclei, insula and temporal lobes. The lesions rapidly regressed once the hypertension had been controlled.

Acute cervical radiculopathy due to vertebral A-V fistula.

We report the case of a 28 year old woman with acute, mainly motor, radiculopathy at C5-C6 on the right side secondary to a congenital vertebral arteriovenous fistula. The finding of a bruit at the side of the neck lent weight to the CT and MRI findings. Angiography was diagnostic. The fistula was embolized successfully.

Surgically transplanted ovary simulating a hepatic metastasis.

BACKGROUND: Surgical procedures may alter normal anatomy, confounding the interpretation of cross-sectional imaging studies. This problem is greater if neither a relevant history nor previous comparison studies are available. CASE OUTLINE: In a 29-year-old woman submitted to radical hysterectomy for cervical carcinoma, one ovary was surgically repositioned into the right paracolic gutter out of the radiation field. This ovary simulated a hepatic metastasis on subsequent CT examinations. History was obscure, adding to the interpretive challenge. DISCUSSION: Clues to establishing the correct diagnosis are presented. The availability of an adequate history and previous radiological images are important to prevent diagnostic error.