Different peripheral expression patterns of the nicotinic acetylcholine receptor in dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: The diffuse distribution of nicotinic cholinergic receptors (nAChRs) in both brain and peripheral immune cells points out their involvement in several pathological conditions. Indeed, the deregulated function of the nAChR was previously correlated with cognitive decline and neuropsychiatric symptoms in Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB). The evaluation in peripheral immune cells of nAChR subtypes, which could reflect their expression in brain regions, is a prominent investigation area. OBJECTIVES: This study aims to evaluate the expression levels of both the nAChR subunits and the main known inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) of patients with DLB and AD to better characterize their involvement in these two diseases. RESULTS: Higher gene expression levels of TNFα, IL6 and IL1ß were observed in DLB and AD patients in comparison with healthy controls (HC). In our cohort, a reduction of nAChRα4, nAChRß2 and nAChRß4 was detected in both DLB and AD with respect to HC. Considering nAChR gene expressions in DLB and AD, significant differences were observed for nAChRα3, nAChRα4, nAChRß2 and nAChRß4 between the two groups. Moreover, the acetylcholine esterase (AChE) gene expression was significantly higher in DLB than in AD. Correlation analysis points out the relation between different nAChR subtype expressions in DLB (nAChRß2 vs nAChRα3; nAChRα4 vs nAChRα3) and AD (nAChRα4 vs nAChRα3; nAChRα4 vs nAChRß4; nAChRα7 vs nAChRα3; nAChRα7 vs nAChRα4). CONCLUSIONS: Different gene expressions of both pro-inflammatory cytokines and nAChR subtypes may represent a peripheral link between inflammation and neurodegeneration. Inflammatory cytokines and different nAChRs should be valid and accurate peripheral markers for the clinical diagnosis of DLB and AD. However, although nAChRs show a great biological role in the regulation of inflammation, no significant correlation was detected between nAChR subtypes and the examined cytokines in our cohort of patients.

Cerebral cortical thickness and gyrification changes in first-episode psychoses and multi-episode schizophrenia.

Cortical thickness (CT) and local gyrification index (LGI) in psychotic disorders may show modifications that relate to clinical course. This observational study aimed to analyse such variables in patients with schizophrenia, compared to healthy controls (HCs). We compared CT and LGI of 18 patients with first-episode psychosis with that of 21 with multi-episode schizophrenia and 16 HCs. CT corrected for false-positive cases (Family-Wise Error Rate) showed a reduction in the multi-episode group compared to HCs in left temporal and parietal, and right temporal, parietal, occipital, and hippocampal cortices. Family-wise corrected LGI was increased in the left inferior and middle frontal cortices, and in the right fusiform gyrus, cingulate, lingual, and parahippocampal gyri in first onset patients compared to HCs. Increased LGI was absent from later stages of psychosis, suggesting that specific CT and LGI alterations may underlie different stages of illness.

The Italian dementia with Lewy bodies study group (DLB-SINdem): toward a standardization of clinical procedures and multicenter cohort studies design.

Dementia with Lewy bodies (DLB) causes elevated outlays for the National Health Systems due to high institutionalization rate and patients' reduced quality of life and high mortality. Furthermore, DLB is often misdiagnosed as Alzheimer's disease. These data motivate harmonized multicenter longitudinal cohort studies to improve clinical management and therapy monitoring. The Italian DLB study group of the Italian Neurological Society for dementia (SINdem) developed and emailed a semi-structured questionnaire to 572 national dementia centers (from primary to tertiary) to prepare an Italian large longitudinal cohort. The questionnaire surveyed: (1) prevalence and incidence of DLB; (2) clinical assessment; (3) relevance and availability of diagnostic tools; (4) pharmacological management of cognitive, motor, and behavioural disturbances; (5) causes of hospitalization, with specific focus on delirium and its treatment. Overall, 135 centers (23.6 %) contributed to the survey. Overall, 5624 patients with DLB are currently followed by the 135 centers in a year (2042 of them are new patients). The percentage of DLB patients was lower (27 ± 8 %) than that of Alzheimer's disease and frontotemporal dementia (56 ± 27 %) patients. The majority of the centers (91 %) considered the clinical and neuropsychological assessments as the most relevant procedure for a DLB diagnosis. Nonetheless, most of the centers has availability of magnetic resonance imaging (MRI; 95 %), electroencephalography (EEG; 93 %), and FP-CIT single photon emission-computerized tomography (SPECT; 75 %) scan for clinical applications. It will be, therefore, possible to recruit a large harmonized Italian cohort of DLB patients for future cross-sectional and longitudinal multicenter studies.

Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice.

Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-)) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1(+/-) mice, compared to their wild-type PINK1(+/+) littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations. Mice were exposed to a range of concentrations of rotenone (0.01-1mg/kg). Chronic treatment with concentrations of rotenone up to 0.8mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1(+/-) and PINK1(+/+) mice. Moreover, rotenone (up to 0.8mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1(+/-) striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1(+/-), a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1(+/-) mice treated with a low rotenone (0.1mg/kg) concentration. Even lower concentrations (0.01mg/kg) blocked LTP induction in heterozygous PINK1(+/-) MSNs compared to PINK1(+/+) mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations. In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but profoundly impaired the expression of long-term plasticity at corticostriatal synapses in PINK1 heterozygous knockout mice, suggesting that disruption of synaptic plasticity may represent an early feature of a pre-manifesting state of the disease, and a potential tool to test novel neuroprotective agents.

Akinetic crisis in dementia with Lewy bodies.

BACKGROUND AND PURPOSE: Dementia with Lewy bodies (DLB) is characterised by neuroleptic hypersensitivity. It is unclear, however, whether the neuroleptic hypersensitivity implies an increased incidence of neuroleptic malignant syndrome (NMS) or of akinetic crisis (AC), which are expressions of the same possibly lethal clinical event, and whether AC in DLB can appear independently of neuroleptic treatment. In our prospective study, we assessed the incidence of AC in a cohort of DLB as compared with that in patients with Parkinson disease (PD). METHODS: In total, 614 patients with PD and 236 DLB were recruited and followed during 2005-2013. AC was diagnosed as sudden akinetic state unresponsive to dopaminergic rescue drugs, dysphagia and serological alterations without recovery for 48 h or more requiring hospital admission. Exposure to neuroleptics was specifically evaluated, because of the high implicit risk in DLB. RESULTS: 24 patients with PD (3.9%) and 16 patients with DLB (6.8%) developed AC. 77 (32.6%) DLB and 32 (5.2%) PD were exposed to typical neuroleptics, but only 8 DLB and 3 PD presented with AC. Disease duration before AC was lower in DLB than in PD group (p<0.01). Outcome was fatal in 8 patients with (50%) DLB and 3 (12.5%) PD (p=0.05). When age and use of neuroleptics were adjusted for into a Cox proportional hazards model predicting time to AC, the HR of patients with DLB was 13.0 (95% CI 4.23 to 39.9; p<0.001). CONCLUSIONS: AC in DLB can appear independently of neuroleptic treatment, occurs earlier and is more frequently fatal than in PD.

Recurrent and fatal akinetic crisis in genetic-mitochondrial parkinsonisms.

BACKGROUND AND PURPOSE: Akinetic crisis (AC) is the most severe and possibly lethal complication of parkinsonism. It occurs with an incidence of 3‰ Parkinson's disease patients per year, but it is not known whether genetically determined parkinsonism is more or less susceptible to this complication. METHODS: In a cohort of 756 parkinsonian patients the incidence and outcome of AC was prospectively assessed. A total of 142 of the parkinsonian patients were tested for genetic mutations because of familial parkinsonism, and 20 patients resulted positive: in four the mutation definitely involved mitochondrial functions (POLG1, PINK1), two presented with LRRK2 mutation, nine presented with GBA mutation and five presented with Park 4 different mutations. RESULTS: Akinetic crisis occurred in 30 patients for an incidence of 2.8‰ persons/year and was lethal in seven (23%), not dissimilarly from known incidences of this complication. Yet six of 30 patients were carriers of genetic mutations, one GBA, one LRRK2, one POLG1 and three PINK1. In POLG1 and PINK1 carriers, the syndrome was recurrent and was fatal in three. Incidence of AC was 3.0‰ in familiar parkinsonism, 21.2‰ in genetic parkinsonisms. CONCLUSIONS: Our preliminary findings suggest that the incidence of AC is remarkably increased in carriers of these genetic mutations.

Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

BACKGROUND AND AIMS: Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. METHODS: To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. RESULTS: The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. CONCLUSION: The results of the study suggest that in a homogeneous area, AB is not interfering with diagnosis of AD or DLB.

PARP1 allows proper telomere replication through TRF1 poly (ADP-ribosyl)ation and helicase recruitment.

Telomeres are nucleoprotein structures at eukaryotic chromosome termini. Their stability is preserved by a six-protein complex named shelterin. Among these, TRF1 binds telomere duplex and assists DNA replication with mechanisms only partly clarified. Here we found that poly (ADP-ribose) polymerase 1 (PARP1) interacts and covalently PARylates TRF1 in S-phase modifying its DNA affinity. Therefore, genetic and pharmacological inhibition of PARP1 impairs the dynamic association of TRF1 and the bromodeoxyuridine incorporation at replicating telomeres. Inhibition of PARP1 also affects the recruitment of WRN and BLM helicases in TRF1 containing complexes during S-phase, triggering replication-dependent DNA-damage and telomere fragility. This work unveils an unprecedented role for PARP1 as a "surveillant" of telomere replication, which orchestrates protein dynamics at proceeding replication fork.

ECG monitoring of post-stroke occurring arrhythmias: an observational study using 7-day Holter ECG.

Post-stroke arrhythmias represent a risk factor for complications and worse prognosis after cerebrovascular events. The aims of the study were to detect the rate of atrial fibrillation (AF) and other cardiac arrhythmias after acute ischemic stroke, by using a 7-day Holter ECG which has proved to be superior to the standard 24-h recording, and to evaluate the possible association between brain lesions and arrhythmias. One hundred and twenty patients with cryptogenic ischemic stroke underwent clinical and neuroimaging assessment and were monitored with a 7-day Holter ECG. Analysis of the rhythm recorded over 7 days was compared to analysis limited at the first 24 h of monitoring. 7-day Holter ECG detected AF in 4% of patients, supraventricular extrasystole (SVEB) in 94%, ventricular extrasystole (VEB) in 88%, short supraventricular runs (SVRs) in 54%, supraventricular tachycardia in 20%, and bradycardia in 6%. Compared to the first 24 h of monitoring, 7-Holter ECG showed a significant higher detection for all arrhythmias (AF p = 0.02; bradycardia p = 0.03; tachycardia p = 0.0001; SVEB p = 0.0002; VEB p = 0.0001; SVRs p = 0.0001). Patients with SVRs and bradycardia were older (p = 0.0001; p = 0.035) and had higher CHA2DS2VASc scores (p = 0.004; p = 0.026) respectively, in the comparison with patients without these two arrhythmias. An association was found between SVEB and parietal (p = 0.013) and temporal (p = 0.013) lobe lesions, whereas VEB correlated with insular involvement (p = 0.002). 7-day Holter ECG monitoring proved to be superior as compared to 24-h recording for the detection of all arrhythmias, some of which (SVEB and VEB) were associated with specific brain areas involvement. Therefore, 7-day Holter ECG should be required as an effective first-line approach to improve both diagnosis and therapeutic management after stroke.

Protracted benefit from paradoxical kinesia in typical and atypical parkinsonisms.

Paradoxical kinesia (PK) is the sudden resolution of a previously stabilized akinesia in an advanced idiopathic Parkinson's disease (IPD) patient facing an immediate threat. We are reporting the effect of PK, as a consequence of a life threatening event (earthquake), in a group of 14 patients with parkinsonism and dementia in Hoehn/Yahr (H/Y) stage 3-5. All the patients presented an extraordinary motor response during the earthquake that has recently stricken the Italian city of L'Aquila. All of them were able to safely escape unaided and, in some cases, to assist their families, despite they suffered before from severe night time akinesia and gait difficulties with postural instability requiring assistance. In five patients, the improvement of motor disabilities, particularly of freezing, lasted for 2-5 months.

Symptomatic REM sleep behaviour disorder.

Rapid eye movement (REM) sleep behaviour disorder (RBD) precedes or accompanies many neurodegenerative disorders. In synucleinopathies, including dementia with Lewy bodies, Parkinson's disease and multiple system atrophy, the prevalence of RBD varies from 19% to almost 77% in different reports. In tauopathies, including Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy and frontotemporal dementia, the prevalence is rare, ranging from 0% to 27%. RBD has however also been described in amyotrophic lateral sclerosis, limbic encephalitis, Guillain-Barré syndrome, Tourette's syndrome, autism, epilepsy and post-traumatic stress disorder. The present paper reviews the current literature on symptomatic RBD and on RBD induced by drug administration, antidepressants, tricyclics and newer drugs, which are often described as precipitating factors for RBD. Controversial findings, flaws in categorisation and hypothetical aetiological mechanisms are also discussed.

The role of liver transplantation in the treatment of hereditary hemorrhagic telangiectasia: a short literature review.

The liver is involved in up to 73% of patients suffering from hereditary hemorrhagic telangiectasia (HHT), but only some of them become symptomatic. Although management is often conservative, sometimes a more aggressive approach is required. The role of surgery is still undefined. Open ligation, banding, or closure of the arteriovenous malformation feeding artery have been proposed but rejected, as they are followed by an unacceptably high incidence of complications, derived from ischemia of the biliary tree. Orthotopic liver transplantation (OLT) has been successfully attempted in 28 patients with cardiac, biliary, or portal hypertension as well as mixed clinical presentations. Twenty-four were alive at time of data collection. Cardiovascular and pulmonary functions have improved after the operation in most cases. Intrahepatic relapse of the hallmark lesion of the disease (telangiectasia and arterovenous malformation) has been recently described in two cases. OLT represents a valuable therapeutic option for hepatic-based HHT, provided early diagnosis and referral to a specialized unit.

Visual hallucinations in Parkinson's disease: clues to separate origins.

Our paper discusses two experimental studies suggesting that Visual Hallucinations (VH) in Parkinson's Disease (PD) may have separate origins. The first is a prospective 8years study evaluating the appearance of VH, visual abnormalities assessed by Visual Evoked Potentials (VEPs) and REM sleep Behaviour Disorder (RBD), in 80 PD patients treated with l-Dopa and Dopaminoagonists (DA). In chronically treated, cognitively unimpaired, PD patients VH were statistically related (p=0.001) to RBD occurrence and high DA doses. Visual abnormalities were significantly reduced by l-Dopa or DA intake, and were statistically unrelated to VH. The second study involved PD patients placed in a Virtual Reality Environment, to decontextualize visual input. When motor symptoms worsened and VEP abnormalities developed patients consistently described hallucinatory dysperceptions of the virtual environment. The two studies therefore show that VH can occur in two seemingly distinct conditions, one is related to chronic treatment and to a sleep disorder frequently observed in PD, the other is probably related to a hypodopaminergic state. Our studies support a recently proposed integrative model of VH, and show that the neural circuits purported to explain VH must include the retinal dopaminergic system and the REM sleep regulatory system.

Novel Approaches for the Treatment of Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein (LDL) cholesterol.The extent of underdiagnosis and undertreatment of individuals with FH is largely unknown.The LDL-lowering capacity of statins in combination with other lipid-lowering drugs is maximally around 50-60%. FH patients have a strongly elevated LDL-C and in most cases maximal current treatment is not sufficient to reach the desired LDL targets.Therefore, FH patients have a large residual cardiovascular risk despite the use of statins and there is a medical need for new additional drugs to further lower LDL-C in patients with FH to improve their prognosis.PCSK9 inhibitors have shown great efficacy in lowering lipids with very few side effects. No synergism between statins and PCSK9 inhibition was observed in many trials, allowing clinicians to select a statin dose before considering the initiation of PCSK9-inhibitor therapy.In patients with FH, who are at risk for markedly accelerated atherosclerosis and premature cardiovascular death, also treatment with lomitapide or mipomersen has the potential to reduce the risk of atherosclerotic cardiovascular disease and premature mortality.These new drugs will be probably reserved for the most severely affected FH patients and could help clinicians to reduce their residual cardiovascular risk.

Disputes in the Treatment of Diabetic Nephropathy: The Dual Blockade of Renin-Angiotensin System.

The prevention and the treatment with drugs interacting with the renin-angiotensin system (RAAS) are one of the greatest successes of the pharmacological research in the last years. Many trials demonstrated the efficacy of ARBs and ACEi in preventing or reducing the progression of albuminuria, the loss of kidney function and the mortality in diabetic population.The rationale for applying a dual RAAS blockade is based on data showing that ACEi mono-therapy produces an incomplete RAAS blockade with angiotensin I and renin accumulation and the subsequent angiotensin II 'escape' production by non-ACE pathways. The use of ARBs and ACEi in combination could lead to a stronger RAAS block and consequently to a more effective nephroprotection. Years ago, some studies performed in small groups of patients with diabetic nephropathy confirmed the effectiveness of this pharmacological approach.In contrast recent important trials, like ONTARGET, ALTITUDE and VA NEPHRON-D failed to demonstrate the effectiveness of this therapeutic strategy, suggesting that probably not all the diabetic patients with nephropathy should be considered equal as regard the response to this therapy. These 3 long-term studies showed that the dual blockade of RAAS may bring cardiovascular and renal adverse events, even in presence of a reduction of albuminuria. Dual blockade of RAAS is not currently feasible in patients with diabetic nephropathy, but we consider that the effort to try to apply a complete RAAS blockade should be pursued and that probably through an accurate selection of patients in the future we could reconsider this kind of therapy.

Dopamine transporter single-photon emission computerized tomography supports diagnosis of akinetic crisis of parkinsonism and of neuroleptic malignant syndrome.

Akinetic crisis (AC) is akin to neuroleptic malignant syndrome (NMS) and is the most severe and possibly lethal complication of parkinsonism. Diagnosis is today based only on clinical assessments yet is often marred by concomitant precipitating factors. Our purpose is to evidence that AC and NMS can be reliably evidenced by FP/CIT single-photon emission computerized tomography (SPECT) performed during the crisis. Prospective cohort evaluation in 6 patients. In 5 patients, affected by Parkinson disease or Lewy body dementia, the crisis was categorized as AC. One was diagnosed as having NMS because of exposure to risperidone. In all FP/CIT, SPECT was performed in the acute phase. SPECT was repeated 3 to 6 months after the acute event in 5 patients. Visual assessments and semiquantitative evaluations of binding potentials (BPs) were used. To exclude the interference of emergency treatments, FP/CIT BP was also evaluated in 4 patients currently treated with apomorphine. During AC or NMS, BP values in caudate and putamen were reduced by 95% to 80%, to noise level with a nearly complete loss of striatum dopamine transporter-binding, corresponding to the "burst striatum" pattern. The follow-up re-evaluation in surviving patients showed a recovery of values to the range expected for Parkinsonisms of same disease duration. No binding effects of apomorphine were observed. By showing the outstanding binding reduction, presynaptic dopamine transporter ligand can provide instrumental evidence of AC in Parkinsonism and NMS.

Short-term dynamics of circulating T cell receptor V beta repertoire in relapsing-remitting MS.

To understand the short-term dynamics of the circulating T cell receptor V beta (TCRBV) repertoire in relapsing-remitting multiple sclerosis (MS), we monitored the TCRBV profiles of untreated MS patients and healthy controls. Expansions of TCRBV genes in MS patients were significantly more frequent than in controls (P<0.001), were predominantly oligoclonal (80%) and were significantly correlated with immune responses to myelin basic protein (MBP) (P<0.02) and with inflammatory disease activity detected by magnetic resonance imaging (MRI) (P<0.05). Autoreactive T cell responses against myelin antigens may be implicated in perturbations of TCR repertoire in untreated MS patients, detectable even in the absence of clinically evident manifestations.

Decreased integrin gene expression in patients with MS responding to interferon-beta treatment.

Interferon-beta (IFN-beta) ameliorates disease course in a subset of patients with MS. The reasons for heterogeneity of clinical responses, however, are unclear. We assessed possible effects of IFN-beta on the gene expression of the leukocyte adhesion molecules VLA-4 and LFA-1 during the first year of treatment of 50 patients with relapsing-remitting MS who showed differential clinical responses. We observed a significant reduction of VLA-4 (P=0.002) and LFA-1 (P=0.03) mRNA expression compared to baseline in first-year clinical responders (n=22). In contrast, first-year IFN-beta non-responders (n=28) had unchanged levels of VLA-4 and LFA-1. In vitro treatment of PBMC with IFN-beta indicated a direct effect on transcription of the integrins' genes. Transcriptional downmodulation of adhesion molecules during IFN-beta treatment may contribute to its mode of action in MS.

RANTES production and expression is reduced in relapsing-remitting multiple sclerosis patients treated with interferon-beta-1b.

RANTES (regulated upon activation, normal T-cell expressed and secreted), a CC chemokine, appears to play a role in the pathogenesis of relapsing-remitting multiple sclerosis (RR-MS), enhancing the inflammatory response within the nervous system. We have demonstrated that RANTES production is increased in RR-MS compared to controls. Interferon-beta-1b (IFN-beta-1b) treatment reduces RANTES production in sera and peripheral blood adherent mononuclear cell (PBAM) supernatants both in relapse and remission. IFN-beta-1b also reduces RANTES expression in PBAM. Our results suggest that RANTES modulation might represent one of the mechanisms of action of IFN-beta-1b in RR-MS.

Purchasing infant shoes: attitudes of parents, pediatricians, and store managers.

Questionnaires designed to collect data about the purchase of shoes for normal infants were completed by 104 parents in a university ambulatory unit, 127 practicing pediatricians, and 36 shoe store managers. Infants received their first pair of walking shoes at an average age of 8.1 months (range: 4 to 12 months) and at an average cost of $14.56 (range: $2 to $43). Most of these shoes had laces (95%), high tops (87%), hard soles (74%), and special arch supports (50%). Of the 104 children, 73 had shoes before they were walking (average cost: $13.21) and 35 wore walking shoes before they were even standing (average cost: $12.68). Parents obtained much more information about shoes from friends and relatives than from physicians. Those parents who obtained most of their information from salespersons spent the most for shoes. The average cost of shoes recommended by store managers was $18.74. Although 77% of pediatricians felt that inexpensive canvas sneakers are adequate, only 28% of the salespersons and 37% of the parents believed that wearing sneakers is healthy.