Search tips
Search criteria

Results 1-25 (27)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
1.  Immunosuppression and Multiple Primary Malignancies in Kidney-Transplanted Patients: A Single-Institute Study 
BioMed Research International  2015;2015:183523.
Immunodeficiency is associated with higher cancer incidence. However, it is unknown whether there is a link between immunodeficiency and development of multiple primary malignancies. In the present study we analyse this link focusing on kidney-transplanted patients, as they are at higher risk of developing cancer due to the chronic assumption of immunosuppressants. We followed up 1200 patients who underwent kidney transplantation between 1980 and 2012. A total of 77/1200 kidney-transplanted patients developed cancer and 24 of them developed multiple cancers. Most multiple cancers were synchronous with a nonsignificant association between cancer and rejection episodes. In the general cancer population, one-ninth of patients are at higher risk of developing a second tumor over a lifetime; hence it would be reasonable to conclude that, from a merely theoretical and statistical viewpoint, long-term transplanted patients potentially have a higher risk of developing MPMs. However, data did not confirm this assumption, probably because these patients die before a second primary malignancy appears. Despite many observations on the increased incidence of different tumor types in immunodeficient patients and despite immunosuppression certainly being a predisposing factor for the multicancer syndrome, data so far are not robust enough to justify a correlation between immunodeficiency and multiple primary malignancies in transplanted patients.
PMCID: PMC4491567  PMID: 26185750
2.  A Clinical and Biochemical Analysis in the Differential Diagnosis of Idiopathic Normal Pressure Hydrocephalus 
Idiopathic normal pressure hydrocephalus (iNPH) can be misdiagnosed with other neurodegenerative diseases, especially in the early disease stages. Considering the opportunity of the shunt surgery, iNPH should be diagnosed with accuracy. Here, we evaluate the utility of CSF biomarkers and their relationship with clinical features in the diagnosis of iNPH.
We performed a multivariate analysis of the CSF levels of Aβ42, t-tau, and p-tau collected from four groups of patients: 14 iNPH, 14 progressive supranuclear palsy (PSP), 14 Alzheimer’s disease (AD), 14 controls (CTL). Diagnostic accuracy of biomarkers was determined by the receiver operating characteristic curve analysis. Statistical correlation was calculated between each CSF biomarker and single clinical items of iNPH.
Aβ42 levels in iNPH were lower than controls, although not as low as in AD. Likewise, CSF t-tau and p-tau were lower in iNPH than in controls. Of interest, t-tau and p-tau were higher in AD than in controls and hence both t-tau and p-tau were significantly lower in iNPH than in AD. No differences were found between iNPH and PSP. CSF biomarkers levels did not correlate to clinical features of iNPH, whereas two significant correlations emerged within clinical parameters: cognitive impairment was related to gait difficulties, while ventricular enlargement correlated with continence disturbances.
Measurement of CSF biomarker levels may be helpful in the differential diagnosis between iNPH and AD but not between iNPH and PSP. Both Aβ42 and tau levels appear unrelated to main clinical features of iNPH.
PMCID: PMC4407581  PMID: 25954245
idiopathic normal pressure hydrocephalus; CSF biomarkers; progressive supranuclear palsy
3.  Effect of Paricalcitol vs Calcitriol on Hemoglobin Levels in Chronic Kidney Disease Patients: A Randomized Trial 
PLoS ONE  2015;10(3):e0118174.
Recent studies suggest that vitamin D deficiency represents an additional cofactor of renal anemia, with several mechanisms accounting for this relationship. In line with it, the administration of vitamin D or its analogues has been associated with an improvement of anemia. There are no data, however, about a direct effect of paricalcitol on hemoglobin (Hb) levels. Therefore, we conducted a study to determine whether paricalcitol, compared to calcitriol, improves anemia in patients with chronic kidney disease (CKD).
In this randomized trial 60 CKD patients stage 3b-5 and anemia (Hb levels: 10-12.5 g/dL) were assigned (1:1) to receive low doses of calcitriol (Group Calcitriol) or paricalcitol (Group Paricalcitol) for 6 months. All the patients had normal values of plasma calcium, phosphorus and PTH, a stable iron balance, and normal values of C-Reactive Protein. The primary endpoint was to evaluate the effects of the two treatments on Hb levels; the modifications in 24hr-proteinuria (UProt) were also evaluated.
A significant Group x Time interaction effect was observed in the longitudinal analysis of Hb levels (F(1,172)=31.4, p<0.001). Subjects in Paricalcitol experienced a significant monthly increase of Hb levels equal to +0.16 g/dL [95% C.I. 0.10 to +0.22, p<0.001) while in Group Calcitriol, Hb decrease throughout the follow-up with an average monthly rate of -0.10 g/dL (95% C.I.: -0.17 to -0.04, p<0.001). In Group Paricalcitol, UProt was significantly reduced after 6 months [0.35 (0.1-1.2) vs 0.59 (0.2-1.6), p<0.01], whereas no significant difference emerged in Group Calcitriol. Plasma levels of calcium, phosphate, PTH and of inflammation markers remained in the normal range in both groups throughout the study.
Short-term exposure to paricalcitol results in an independent increase in Hb levels, which occurred with no modification of iron balance, inflammatory markers, and PTH plasma concentrations, and was associated with a decrease in UProt.
Trial Registration NCT01768351
PMCID: PMC4363688  PMID: 25781618
4.  Prevention of Contrast-Induced Nephropathy through a Knowledge of Its Pathogenesis and Risk Factors 
The Scientific World Journal  2014;2014:823169.
Contrast-induced nephropathy (CIN) is an iatrogenic acute renal failure (ARF) occurring after the intravascular injection of iodinated radiographic contrast media. During the past several years, in many patients undergoing computed tomography, iodinated contrast media have not been used for the fear of ARF, thereby compromising the diagnostic procedure. But recent studies have demonstrated that CIN is rarely occurring in patients with normal renal function and that preexisting chronic renal failure and/or diabetes mellitus represent(s) predisposing condition(s) for its occurrence. After the description of CIN and its epidemiology and pathophysiology, underlying the important role played by dehydration and salt depletion, precautions for prevention of CIN are listed, suggested, and discussed. Maximum priority has to be given to adequate hydration and volume expansion prior to radiographic procedures. Other important precautions include the need for monitoring renal function before, during, and after contrast media injection, discontinuation of potentially nephrotoxic drugs, use of either iodixanol or iopamidol at the lowest dosage possible, and administration of antioxidants. A long list of references is provided that will enable readers a deep evaluation of the topic.
PMCID: PMC4266998  PMID: 25525625
5.  Fanconi syndrome with lysinuric protein intolerance 
Clinical Kidney Journal  2014;7(6):599-601.
We present the case of a 9-year-old child with lysinuric protein intolerance and Fanconi syndrome. She was referred to our hospital with a persistent metabolic acidosis and polyuria. Renal investigations revealed all laboratory signs of Fanconi syndrome, with glucosuria, generalized aminoaciduria, phosphaturia and severe hypercalciuria. The diagnosis of Fanconi syndrome was confirmed by a renal biopsy that showed extensive lesions of proximal tubular epithelial cells with vacuolation of these cells and a sloughing of the brush border.
PMCID: PMC4389143  PMID: 25859380
Fanconi syndrome; hyperammonaemia; lysinuric protein intolerance
6.  A strange epigastric pain 
Clinical Kidney Journal  2014;7(5):493-494.
PMCID: PMC4379346  PMID: 25878786
Autosomal dominant polycystic kidney disease; Laparoscopic cyst's fenestration; Giant hepatic cyst
7.  Acute Kidney Injury by Radiographic Contrast Media: Pathogenesis and Prevention 
BioMed Research International  2014;2014:362725.
It is well known that iodinated radiographic contrast media may cause kidney dysfunction, particularly in patients with preexisting renal impairment associated with diabetes. This dysfunction, when severe, will cause acute renal failure (ARF). We may define contrast-induced Acute Kidney Injury (AKI) as ARF occurring within 24–72 hrs after the intravascular injection of iodinated radiographic contrast media that cannot be attributed to other causes. The mechanisms underlying contrast media nephrotoxicity have not been fully elucidated and may be due to several factors, including renal ischaemia, particularly in the renal medulla, the formation of reactive oxygen species (ROS), reduction of nitric oxide (NO) production, and tubular epithelial and vascular endothelial injury. However, contrast-induced AKI can be prevented, but in order to do so, we need to know the risk factors. We have reviewed the risk factors for contrast-induced AKI and measures for its prevention, providing a long list of references enabling readers to deeply evaluate them both.
PMCID: PMC4150431  PMID: 25197639
8.  Engineering animal models of dystonia 
Dystonia is a neurological disorder characterized by abnormal involuntary movements that are prolonged and often cause twisting and turning. Several genetically modified worms, fruit flies, and rodents have been generated as models of genetic dystonias, and in particular DYT1, DYT11, and DYT12 dystonias. Although these models do not show overt dystonic symptoms, the rodent models exhibit pronounced motor deficits in specialized behavioral tasks, such as the rotarod and beam-walking tests. For example, in a rodent model of DYT12 dystonia, which is generally stress triggered, motor deficits are observed only after the animal is stressed. Moreover, in a rodent model of DYT1 dystonia, the motor and electrophysiological deficits can be rescued by trihexyphenidyl, a common anticholinergic medication used to treat dystonic symptoms in human patients. Biochemically, the DYT1 and DYT11 animal models also share some similarities to patients, such as a reduction in striatal D2 dopamine receptor and binding activities. Additionally, conditional knockout mouse models for DYT1 and DYT11 dystonia show that the loss of the causal dystonia related proteins in the striatum lead to motor deficits. Interestingly, loss of the DYT1 dystonia causal protein in Purkinje cells shows an improvement in motor performance, suggesting that gene therapy targeting of the cerebellum or intervention in its downstream pathways may be useful. Finally, recent studies using DYT1 dystonia worm and mouse models led to a potential novel therapeutic agent, which is currently undergoing clinical trials. These results indicate that genetic animal models are an extremely powerful tool to elucidate the pathophysiology and to further develop new therapeutics for dystonia.
PMCID: PMC3800691  PMID: 23893455
9.  Molecular Mechanisms of Renal Cellular Nephrotoxicity due to Radiocontrast Media 
BioMed Research International  2014;2014:249810.
Modern iodinated radiocontrast media are all based on the triiodinated benzene ring with various chemical modifications having been made over the last few decades in order to reduce their toxicity. However, CIN remains a problem especially in patients with pre-existing renal failure. In vitro studies have demonstrated that all RCM are cytotoxic. RCM administration in vivo may lead to a decrease in renal medullary oxygenation leading to the generation of reactive oxygen species that may cause harmful effects to renal tissue. In addition, endothelin and adenosine release and decreased nitric oxide levels may worsen the hypoxic milieu. In vitro cell culture studies together with sparse in vivo rat model data have shown that important cell signalling pathways are affected by RCM. In particular, the prosurvival and proproliferative kinases Akt and ERK1/2 have been shown to be dephosphorylated (deactivated), whilst proinflammatory/cell death molecules such as the p38 and JNK kinases and the transcription factor NF-κB may be activated by RCM, accompanied by activation of apoptotic mediators such as caspases. Increasing our knowledge of the mechanisms of RCM action may help to develop future therapies for CIN.
PMCID: PMC3976916  PMID: 24745009
10.  Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia 
Neurobiology of disease  2010;38(3):434-445.
DYT1 dystonia is an inherited disease linked to mutation in the TOR1A gene encoding for the protein torsinA. Although the mechanism by which this genetic alteration leads to dystonia is unclear, multiple lines of clinical evidence suggest a link between dystonia and a reduced dopamine D2 receptor (D2R) availability. Based on this evidence, herein we carried out a comprehensive analysis of electrophysiological, behavioral and signaling correlates of D2R transmission in transgenic mice with the DYT1 dystonia mutation. Electrophysiological recordings from nigral dopaminergic neurons showed a normal responsiveness to D2-autoreceptor function. Conversely, postsynaptic D2R function in hMT mice was impaired, as suggested by the inability of a D2R agonist to re-establish normal corticostriatal synaptic plasticity and supported by the reduced sensitivity to haloperidol-induced catalepsy. Although an in situ hybridization analysis showed normal D1R and D2R mRNA expression levels in the striata of hMT mice, we found a significant decrease of D2R protein, coupled to a reduced ability of D2Rs to activate their cognate Go/i proteins.
Of relevance, we found that pharmacological blockade of adenosine A2A receptors (A2ARs) fully restored the impairment of synaptic plasticity observed in hMT mice.
Together, our findings demonstrate an important link between torsinA mutation and D2R dysfunction and suggest that A2AR antagonism is able to counteract the deficit in D2R-mediated transmission observed in mutant mice, opening new perspectives for the treatment of this movement disorder.
PMCID: PMC3906674  PMID: 20227500
Dystonia; D2 dopamine receptor; Adenosine
11.  Efficacy of a reduced pill burden on therapeutic adherence to calcineurin inhibitors in renal transplant recipients: an observational study 
The aim of this study was to determine the prevalence of nonadherence in a cohort of renal transplant recipients (RTRs) and to evaluate prospectively whether more intense clinical surveillance and reduced pill number enhanced adherence.
Patients and methods
The study was carried out in 310 stable RTRs in whom adherence, life satisfaction, and transplant care were evaluated by specific questionnaires (time 0). The patients under tacrolimus (TAC; bis in die [BID]) were then shifted to once-daily TAC (D-TAC) to reduce their pill burden (Shift group) and were followed up for 6 months to reevaluate the same parameters. Patients on cyclosporin or still on BID-TAC constituted a time-control group.
The prevalence of nonadherence was 23.5% and was associated with previous rejection episodes (P<0.002), and was inversely related to Life Satisfaction Index, anxiety, and low glomerular filtration rate (minimum P<0.03). Nonadherent patients were significantly less satisfied with their medical care and their relationships with the medical staff. A shift from BID-TAC to D-TAC was performed in 121 patients, and the questionnaires were repeated after 3 and 6 months. In the Shift group, a reduction in pill number was observed (P<0.01), associated with improved adherence after 3 and 6 months (+36%, P<0.05 versus basal), with no change in controls. Decreased TAC trough levels after 3 and 6 months (−9%), despite a slight increase in drug dosage (+6.5%), were observed in the Shift group, with no clinical side effects.
The reduced pill burden improves patients’ compliance to calcineurin-inhibitors, but major efforts in preventing nonadherence are needed.
PMCID: PMC3891638  PMID: 24470756
adherence; calcineurin inhibitors; once-daily tacrolimus; renal transplant
12.  Role of Reactive Oxygen Species in Pathogenesis of Radiocontrast-Induced Nephropathy 
BioMed Research International  2013;2013:868321.
In vitro and in vivo studies have demonstrated enhanced hypoxia and formation of reactive oxygen species (ROS) in the kidney following the administration of iodinated contrast media, which play a relevant role in the development of contrast media-induced nephropathy. Many studies indeed support this possibility, suggesting a protective effect of ROS scavenging or reduced ROS formation with the administration of N-acetylcysteine and bicarbonate infusion, respectively. Furthermore, most risk factors, predisposing to contrast-induced nephropathy, are prone to enhanced renal parenchymal hypoxia and ROS formation. In this review, the association of renal hypoxia and ROS-mediated injury is outlined. Generated during contrast-induced renal parenchymal hypoxia, ROS may exert direct tubular and vascular endothelial injury and might further intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and dysregulation of tubular transport. Preventive strategies conceivably should include inhibition of ROS generation or ROS scavenging.
PMCID: PMC3891610  PMID: 24459673
13.  Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia 
Neurobiology of disease  2009;34(1):133-145.
DYT1 dystonia is caused by a deletion in a glutamic acid residue in the C-terminus of the protein torsinA, whose function is still largely unknown. Alterations in GABAergic signaling have been involved in the pathogenesis of dystonia. We recorded GABA- and glutamate-mediated synaptic currents from a striatal slice preparation obtained from a mouse model of DYT1 dystonia. In medium spiny neurons (MSNs) from mice expressing human mutant torsinA (hMT), we observed a significantly higher frequency, but not amplitude, of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature currents (mIPSCs), whereas glutamate-dependent spontaneous excitatory synaptic currents (sEPSCs) were normal. No alterations were found in mice overexpressing normal human torsinA (hWT). To identify the possible sources of the increased GABAergic tone, we recorded GABAergic Fast-Spiking (FS) interneurons that exert a feed-forward inhibition on MSNs. However, both sEPSC and sIPSC recorded from hMT FS interneurons were comparable to hWT and non-transgenic (NT) mice. In physiological conditions, dopamine (DA) D2 receptor act presynaptically to reduce striatal GABA release. Of note, application of the D2-like receptor agonist quinpirole failed to reduce the frequency of sIPSCs in MSNs from hMT as compared to hWT and NT mice. Likewise, the inhibitory effect of quinpirole was lost on evoked IPSCs both in MSNs and FS interneurons from hMT mice. Our findings demonstrate a disinhibition of striatal GABAergic synaptic activity, that can be at least partially attributed to a D2 DA receptor dysfunction.
PMCID: PMC3786200  PMID: 19187797
Electrophysiology; Dystonia; D2 dopamine receptor; Medium Spiny neurons; Fast-spiking interneuron
14.  Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein TorsinA 
Neurobiology of Disease  2012;47(3):416-427.
DYT1 dystonia, a common and severe primary dystonia, is caused by a 3-bp deletion in TOR1A which encodes torsinA, a protein found in the endoplasmic reticulum. Several cellular functions are altered by the mutant protein, but at a systems level the link between these and the symptoms of the disease is unclear. The most effective known therapy for DYT1 dystonia is use of anticholinergic drugs. Previous studies have revealed that in mice, transgenic expression of human mutant torsinA under a non-selective promoter leads to abnormal function of striatal cholinergic neurons. To investigate what pathological role torsinA plays in cholinergic neurons, we created a mouse model in which the Dyt1 gene, the mouse homolog of TOR1A, is selectively deleted in cholinergic neurons (ChKO animals). These animals do not have overt dystonia, but do have subtle motor abnormalities. There is no change in the number or size of striatal cholinergic cells or striatal acetylcholine content, uptake, synthesis, or release in ChKO mice. There are, however, striking functional abnormalities of striatal cholinergic cells, with paradoxical excitation in response to D2 receptor activation and loss of muscarinic M2/M4 receptor inhibitory function. These effects are specific for cholinergic interneurons, as recordings from nigral dopaminergic neurons revealed normal responses. Amphetamine stimulated dopamine release was also unaltered. These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder.
PMCID: PMC3392411  PMID: 22579992
15.  Phytoestrogens/insoluble fibers and colonic estrogen receptor β: Randomized, double-blind, placebo-controlled study 
AIM: To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas.
METHODS: A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples.
RESULTS: No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69 vs 37.708 ± 5.31, P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13, P = 0.04), mRNA (2.278 ± 1.19 vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67, P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06 vs 0.532 ± 0.11, P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07).
CONCLUSION: The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.
PMCID: PMC3718900  PMID: 23885143
Estrogen receptor-β; Estrogen receptor-α; Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; Sporadic adenomatous polyposis; Phytoestrogens; Insoluble fibers
16.  Torsin A Localization in the Mouse Cerebellar Synaptic Circuitry 
PLoS ONE  2013;8(6):e68063.
Torsin A (TA) is a ubiquitous protein belonging to the superfamily of proteins called “ATPases associated with a variety of cellular activities” (AAA+ ATPase). To date, a great deal of attention has been focused on neuronal TA since its mutant form causes early-onset (DYT1) torsion dystonia, an inherited movement disorder characterized by sustained muscle contractions and abnormal postures. Interestingly, it has been proposed that TA, by interacting with the cytoskeletal network, may contribute to the control of neurite outgrowth and/or by acting as a chaperone at synapses could affect synaptic vesicle turnover and neurotransmitter release. Accordingly, both its peculiar developmental expression in striatum and cerebellum and evidence from DYT1 knock-in mice suggest that TA may influence dendritic arborization and synaptogenesis in the brain. Therefore, to better understand TA function a detailed description of its localization at synaptic level is required. Here, we characterized by means of rigorous quantitative confocal analysis TA distribution in the mouse cerebellum at postnatal day 14 (P14), when both cerebellar synaptogenesis and TA expression peak. We observed that the protein is broadly distributed both in cerebellar cortex and in the deep cerebellar nuclei (DCN). Of note, Purkinje cells (PC) express high levels of TA also in the spines and axonal terminals. In addition, abundant expression of the protein was found in the main GABA-ergic and glutamatergic inputs of the cerebellar cortex. Finally, TA was observed also in glial cells, a cellular population little explored so far. These results extend our knowledge on TA synaptic localization providing a clue to its potential role in synaptic development.
PMCID: PMC3686744  PMID: 23840813
17.  Nephrotic syndrome and autosomal dominant polycystic kidney disease 
Clinical Kidney Journal  2012;5(6):508-511.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the development and growth of cysts in the kidneys and other organs. In ADPKD patients, nephrotic range proteinuria is unusual and needs to be investigated further to exclude coexisting glomerular disease. Among the anecdotal case reports of ADPKD associated with nephrotic syndrome, focal segmental glomerulosclerosis occurs most frequently.
We report the case of a 26-year-old male with ADPKD and concomitant nephrotic syndrome, in which an ultrasound (US)-guided renal biopsy showed a mesangioproliferative glomerulonephritis. We treated the patient with prednisone 1 mg/kg/day, because of the failure of treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker association.
After 6 months of steroid treatment, we observed a stability of his GFR and a reduction of proteinuria.
This case report and other cases of the literature underline the importance of a renal biopsy in patients with ADPKD and nephrotic syndrome in order to make an accurate diagnosis and an appropriate treatment/prevention of renal function deterioration.
PMCID: PMC4400568  PMID: 26069794
autosomal dominant polycystic kidney disease; glomerulonephritis; nephrotic syndrome; renal biopsy
18.  Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease 
Alterations in blood–brain barrier permeability have been proposed to represent a relevant factor contributing to Parkinson’s disease progression. However, few studies have addressed this issue in patients at different stages of disease.
Albumin was measured in cerebrospinal fluid and serum samples obtained from 73 non-demented subjects with idiopathic Parkinson’s disease and 47 age-matched control subjects. The albumin ratio (AR) was calculated to assess blood-cerebrospinal fluid and blood–brain barrier function. The group of patients with Parkinson’s disease included 46 subjects with Hoehn-Yahr staging between 1 and 2 and 27, with a score ranging from 2.5 to 4.
Statistically significant differences in albumin ratio were found between patients with advanced disease, and both early-stage and unaffected groups. Conversely, early-phase patients did not differ from healthy subjects. Additionally, dopaminergic treatment seems to exert a possible effect on AR values.
Our study demonstrates that possible dysfunction of the blood-cerebrospinal fluid barrier, blood–brain barrier, or both, characterize Parkinson’s disease progression. The associations between clinical scores, treatments and biochemical findings suggest a progressive impairment of barrier integrity during the course of the disease.
PMCID: PMC3441323  PMID: 22870899
Albumin ratio; Blood–brain barrier; Blood-cerebrospinal fluid barrier; Cerebrospinal fluid; Parkinson’s disease
19.  A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report 
Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of a lysosomal hydrolase, the enzyme α-galactosidase A (GLA). This inactivation is responsible for the storage of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. The incidence of disease is estimated at 1:40,000 in the general population, although neonatal screening initiatives have found an unexpectedly high prevalence of genetic alterations, up to 1:3,100, in newborns in Italy, and have identified a surprisingly high frequency of newborn males with genetic alterations (about 1:1,500) in Taiwan.
Case presentation
We describe the case of a 40-year-old female patient who presented with transient ischemic attack (TIA), discomfort in her hands, intolerance to cold and heat, severe angina and palpitations, chronic kidney disease. Clinical, biochemical and molecular studies were performed.
Reported symptoms, peculiar findings in a renal biopsy – the evidence of occasional lamellar inclusions in podocytes and mesangial cells – and left ventricular (LV) hypertrophy, which are considered to be specific features of FD, as well as molecular evaluations, suggested the diagnosis of a classical form of FD.
We detected four mutations in the GLA gene of the patient: -10C>T (g.1170C>T), c.370-77_-81del (g.7188-7192del5), c.640-16A>G (g.10115A>G), c.1000-22C>T (g.10956C>T). These mutations, located in promoter and intronic regulatory regions, have been observed in several patients with manifestations of FD. In our patient clinical picture showed a multisystemic involvement with early onset of symptoms, thus suggesting that these intronic mutations can be found even in patients with classical form of FD.
PMCID: PMC3425126  PMID: 22682330
Fabry disease; α-galactosidase A; GLA; Globotriaosylceramide; High resolution melting
20.  Measuring and Estimating GFR and Treatment Effect in ADPKD Patients: Results and Implications of a Longitudinal Cohort Study 
PLoS ONE  2012;7(2):e32533.
Trials failed to demonstrate protective effects of investigational treatments on glomerular filtration rate (GFR) reduction in Autosomal Dominant Polycystic Kidney Disease (ADPKD). To assess whether above findings were explained by unreliable GFR estimates, in this academic study we compared GFR values centrally measured by iohexol plasma clearance with corresponding values estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas in ADPKD patients retrieved from four clinical trials run by a Clinical Research Center and five Nephrology Units in Italy. Measured baseline GFRs and one-year GFR changes averaged 78.6±26.7 and 8.4±10.3 mL/min/1.73 m2 in 111 and 71 ADPKD patients, respectively. CKD-Epi significantly overestimated and aMDRD underestimated baseline GFRs. Less than half estimates deviated by <10% from measured values. One-year estimated GFR changes did not detect measured changes. Both formulas underestimated GFR changes by 50%. Less than 9% of estimates deviated <10% from measured changes. Extent of deviations even exceeded that of measured one-year GFR changes. In ADPKD, prediction formulas unreliably estimate actual GFR values and fail to detect their changes over time. Direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research.
PMCID: PMC3291245  PMID: 22393413
21.  Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia 
PLoS ONE  2011;6(9):e24261.
DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear.
Methods and Results
We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development.
These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.
PMCID: PMC3166312  PMID: 21912682
22.  Centrality of Striatal Cholinergic Transmission in Basal Ganglia Function 
Work over the past two decades revealed a previously unexpected role for striatal cholinergic interneurons in the context of basal ganglia function. The recognition that these interneurons are essential in synaptic plasticity and motor learning represents a significant step ahead in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction. Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum appears to be the trigger for pathophysiological changes occurring in basal ganglia disorders. Accordingly, there is now compelling evidence showing profound changes in cholinergic markers in these disorders, in particular Parkinson's disease and dystonia. Based on converging experimental and clinical evidence, we provide an overview of the role of striatal cholinergic transmission in physiological and pathological conditions, in the context of the pathogenesis of movement disorders.
PMCID: PMC3036975  PMID: 21344017
acetylcholine; striatum; interneuron; Parkinson's disease; dystonia; movement disorders
23.  Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine 
Brain  2009;132(9):2336-2349.
DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been documented. The loss of LTD and SD on one hand, and the increase in LTP on the other, demonstrate that a ‘loss of inhibition’ characterizes the impairment of synaptic plasticity in this model of DYT1 dystonia. More importantly, our results indicate that an unbalanced cholinergic transmission plays a pivotal role in these alterations, providing a clue to understand the ability of anticholinergic agents to restore motor deficits in dystonia.
PMCID: PMC2766181  PMID: 19641103
dystonia; synaptic plasticity; striatum; acetylcholine; electrophysiology
24.  Loss of Muscarinic Autoreceptor Function Impairs Long-Term Depression But Not Long-Term Potentiation in the Striatum 
The Journal of Neuroscience  2008;28(24):6258-6263.
Muscarinic autoreceptors regulate cholinergic tone in the striatum. We investigated the functional consequences of genetic deletion of striatal muscarinic autoreceptors by means of electrophysiological recordings from either medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) in slices from single M4 or double M2/M4 muscarinic acetylcholine receptor (mAChR) knock-out (−/−) mice. In control ChIs, the muscarinic agonist oxotremorine (300 nm) produced a self-inhibitory outward current that was mostly reduced in M4−/− and abolished in M2/M4−/− mice, suggesting an involvement of both M2 and M4 autoreceptors. In MSNs from both M4−/− and M2/M4−/− mice, muscarine caused a membrane depolarization that was prevented by the M1 receptor-preferring antagonist pirenzepine (100 nm), suggesting that M1 receptor function was unaltered. Acetylcholine has been involved in striatal long-term potentiation (LTP) or long-term depression (LTD) induction. Loss of muscarinic autoreceptor function is predicted to affect synaptic plasticity by modifying striatal cholinergic tone. Indeed, high-frequency stimulation of glutamatergic afferents failed to induce LTD in MSNs from both M4−/− and M2/M4−/− mice, as well as in wild-type mice pretreated with the M2/M4 antagonist AF-DX384 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,1 1-dihydro-6H-pyrido[2,3b][1,4] benzodiazepin-6-one). Interestingly, LTD could be restored by either pirenzepine (100 nm) or hemicholinium-3 (10 μm), a depletor of endogenous ACh. Conversely, LTP induction did not show any difference among the three mouse strains and was prevented by pirenzepine. These results demonstrate that M2/M4 muscarinic autoreceptors regulate ACh release from striatal ChIs. As a consequence, endogenous ACh drives the polarity of bidirectional synaptic plasticity.
PMCID: PMC3849426  PMID: 18550768
cholinergic interneuron; long-term depression; long-term potentiation; striatal slices; electrophysiology; muscarine
25.  Neuroacanthocytosis associated with a defect of the 4.1R membrane protein 
BMC Neurology  2007;7:4.
Neuroacanthocytosis (NA) denotes a heterogeneous group of diseases that are characterized by nervous system abnormalities in association with acanthocytosis in the patients' blood. The 4.1R protein of the erythrocyte membrane is critical for the membrane-associated cytoskeleton structure and in central neurons it regulates the stabilization of AMPA receptors on the neuronal surface at the postsynaptic density. We report clinical, biochemical, and genetic features in four patients from four unrelated families with NA in order to explain the cause of morphological abnormalities and the relationship with neurodegenerative processes.
Case presentation
All patients were characterised by atypical NA with a novel alteration of the erythrocyte membrane: a 4.1R protein deficiency. The 4.1R protein content was significantly lower in patients (3.40 ± 0.42) than in controls (4.41 ± 0.40, P < 0.0001), reflecting weakened interactions of the cytoskeleton with the membrane. In patients IV:1 (RM23), IV:3 (RM15), and IV:6 (RM16) the 4.1 deficiency seemed to affect the horizontal interactions of spectrin and an impairment of the dimer self-association into tetramers was detected. In patient IV:1 (RM16) the 4.1 deficiency seemed to affect the skeletal attachment to membrane and the protein band 3 was partially reduced.
A decreased expression pattern of the 4.1R protein was observed in the erythrocytes from patients with atypical NA, which might reflect the expression pattern in the central nervous system, especially basal ganglia, and might lead to dysfunction of AMPA-mediated glutamate transmission.
PMCID: PMC1805452  PMID: 17298666

Results 1-25 (27)