Emerging therapy in arthritis: Modulation of markers of the inflammatory process.

The induction of tolerance has been proposed as a therapeutic strategy for arthritis aiming to decrease progression of the pathology, probably by promoting suppressor mechanisms of the autoimmune response. This work aimed to confirm whether the treatment with vitamin D3 could synergize oral tolerance induced by hydrolyzed collagen peptides, in our experimental model of antigen induced arthritis in New Zealand rabbits. Clinical observation of the phenomenon indicates that simultaneous treatment with hydrolyzed collagen peptides and vitamin D3 was beneficial when compared with no treatment, for arthritic animals, and for arthritic animals that received treatment with only hydrolyzed collagen peptides or vitamin D3. Treatment with hydrolyzed collagen peptides caused diminished proinflammatory cytokine levels, an effect synergized significantly by the simultaneous treatment with vitamin D3. The anatomical-pathological studies of the animals that received both treatments simultaneously showed synovial tissues without lymphocytic and plasma cell infiltrates, and without vascular proliferation. Some of the synovial tissue of the animals of these groups showed a slight decrease in Galectin-3 expression. We propose that simultaneous oral treatment with vitamin D3 and hydrolyzed collagen peptides could increase the immunoregulatory effect on the process of previously triggered arthritis. We used articular cartilage hydrolysate and not collagen II because peptides best expose antigenic determinants that could induce oral tolerance. Oral tolerance may be considered in the design of novel alternative therapies for autoimmune disease and we have herein presented novel evidence that the simultaneous treatment with vitamin D3 may synergize this beneficial effect.

Characterization of Hybrid Bioactive Glass-polyvinyl Alcohol Scaffolds Containing a PTHrP-derived Pentapeptide as Implants for Tissue Engineering Applications.

Hybrid foam (BG-PVA) with 50 % Bioactive glass (BG) and 50 % polyvinyl alcohol (PVA) was prepared by sol-gel process to produce scaffolds for bone tissue engineering. The pore structure of hydrated foams was evaluated by 3-D confocal microscopy, confirming 70% porosity and interconnected macroporous network. In this study, we assessed the putative advantage of coating with osteostatin pentapeptide into BG-PVA hybrid scaffolds to improve their bioactivity. In vitro cell culture experiments were performed using mouse pre-osteoblastic MC3T3-E1 cell line. The exposure to osteostatin loaded-BG-PVA scaffolds increase cell proliferation in contrast with the unloaded scaffolds. An in vivo study was selected to implant BG-PVA scaffolds, non-coated (Group A) or coated (Group B) with osteostatin into non critical bone defect at rabbit femur. Both groups showed new compact bone formation on implant surface, with lamellae disposed around a haversian canal forming osteons-like structure. We observed signs of inflammation around the implanted unloaded scaffold at one month, but resolved at 3 months. This early inflammation did not occur in Group B; supporting the notion that osteostatin may act as anti-inflammatory inhibitor. On the other hand, Group B showed increased bone formation, as depicted by many new trabeculae partly mineralized in the implant regenerating area, incipient at 1 month and more evident at 3 months after implantation. PVA/BG hybrid scaffolds present a porous structure suitable to support osteoblast proliferation and differentiation. Our in vitro and in vivo findings indicate that osteostatin coating improves the osteogenic features of these scaffolds.

Trauma and amyotrophic lateral sclerosis: a case-control study from a population-based registry.

BACKGROUND AND PURPOSE: Published reports on the association between amyotrophic lateral sclerosis (ALS) and trauma are controversial suggesting the need for a new case-control study done in a large population. METHODS: A case-control study was undertaken in Italy to assess this association. Cases were patients with newly diagnosed ALS from four population-based registries. For each case, two hospital controls were selected, matched for age, sex, and province of residence, one with a neurological (non-degenerative) disease and one with a non-neurological disease (other than orthopedic or surgical). Traumatic events (defined as accidental events causing injuries requiring medical care) were recorded with details on type, site, timing, severity, and complications. The risks were assessed as odds ratios (ORs) with 95% confidence intervals (CI), crude and adjusted for age, sex, education, interviewee (patient or surrogate), physical activity, smoking, alcohol, and coffee. RESULTS: The study population comprised 377 patients in each of the three groups. One or more traumatic events were reported by 225 cases (59.7%), 191 neurological controls (50.7%), and 179 non-neurological controls (47.5%) (P < 0.01) (OR 1.63; 95% CI 1.25-2.14) (P < 0.01). The ORs were 3.07 (95% CI 1.86-5.05) for patients reporting 3+ traumatic events and 2.44 (95% CI 1.36-4.40) for severe traumatic events. The ORs remained significant when the analysis was limited to events that occurred 5+ and 10+ years before ALS onset, to incident ALS, and direct informant. CONCLUSION: Antecedent trauma, repeated trauma, and severe trauma may be risk factors for ALS.

Incidence of ALS in Lombardy, Italy.

OBJECTIVE: To assess the incidence and trends of ALS in a large population at risk. METHODS: This study was performed in nine provinces of Lombardy in Northern Italy (population 4,947,554). Patients with newly diagnosed ALS were enrolled during the period 1998 to 2002 through a prospective regional register. For each patient, the main demographic and clinical information was collected by the caring physicians and reviewed by a panel of experts according to the original and revised El Escorial diagnostic criteria. Overall, age- and sex-specific and standardized annual incidence rates were calculated for the entire population and for each year and province separately. RESULTS: We studied 517 patients (M:F ratio 1.3) aged 18 to 92 years (mean 63.6). Onset of symptoms was bulbar in 29% of cases. ALS was definite in 45%, probable in 27%, probable laboratory supported in 3.5%, possible in 15%, and suspected in 10%. Mean disease duration at diagnosis was 10.6 months. The standardized incidence rate was 2.09 per 100,000/year (95% CI: 1.17 to 3.18). The rate, which was 2.43 in men and 1.76 in women, tended to increase up to ages 65 to 74 and to decrease thereafter. The rate was unchanged over time and presented moderate variations across provinces. The incidence rate of definite ALS was 0.93 (spinal-onset ALS 1.35; bulbar-onset ALS 0.74) and was consistently higher in men with spinal-onset ALS vs men with bulbar-onset ALS and women. CONCLUSIONS: The incidence of ALS varied according to age, sex, and site of onset. No temporal and geographic clusters were detected over a 5-year period.

Prevalence and characteristics of peripheral neuropathy in hepatitis C virus population.

OBJECTIVE: To assess the prevalence of peripheral neuropathy (PN) and its correlation with cryoglobulinemia (CG) in an unselected, untreated referral hepatitis C virus (HCV) population. PATIENTS AND METHODS: Two hundred and thirty four patients (120 women and 114 men) with untreated HCV infection were consecutively enrolled by seven Italian centres. Clinical neuropathy was diagnosed when symptoms and signs of peripheral sensory or motor involvement were present. Median, ulnar, peroneal, and sural nerves were explored in all patients and distal symmetric polyneuropathy was diagnosed when all explored nerves or both lower limb nerves were affected. Mononeuropathy and mononeuropathy multiplex were diagnosed when one nerve or two non-contiguous nerves with asymmetrical distribution were affected. Screening for CG was done in 191 unselected patients. RESULTS: Clinical signs of PN were observed in 25 of the 234 patients (10.6%). Electrophysiological PN was found in 36 (15.3%). CG was present in 56/191 patients (29.3%). The prevalence of CG increased significantly with age (p<0.001) and disease duration (p<0.05). PN was present in 12/56 (21%) patients with CG and 18/135 (13%) without CG (p=NS). PN increased significantly with age (p<0.001) and logistic regression analysis confirmed age as the only independent predictor of PN (OR 1.10 for each year; 95% CI 1.04 to 1.15; p<0.001). CONCLUSIONS: Electrophysiological examination detected subclinical neuropathy in 11 patients (4.7%). Statistical analysis showed that CG was not a risk factor for PN whereas PN prevalence increased significantly with age.

Survival of patients with amyotrophic lateral sclerosis in a population-based registry.

OBJECTIVE: To evaluate the survival of patients with amyotrophic lateral sclerosis (ALS) in an Italian population and to assess the effects of selected prognostic indicators on survival. BACKGROUND: Median survival of ALS patients has been reported to range between 12 and 23 months from diagnosis and between 23 and 36 months from onset of symptoms. Although several negative prognostic factors have been identified, the overall picture still needs clarification. METHODS: We included patients enrolled in an Italian ALS Regional Register (population 4,529,003) during the calendar year 1998. The diagnosis was confirmed by an ad hoc committee using the original El Escorial criteria. Each case was regularly followed up until death or December 31, 2002, whichever came first. Survival was assessed with the Kaplan-Meier method in the whole sample, by level of diagnostic certainty, and by selected prognostic indicators (age, sex, bulbar or spinal onset, and disease duration). Multivariate analysis was done with the Cox proportional hazard function. RESULTS: The sample comprised 79 patients (33 female; 46 male) aged 28-85 years (mean age 64.4 years). Onset of symptoms was bulbar in 30% of cases. Mean symptom duration at diagnosis was 13.3 months. ALS was definite in 43%, probable in 29%, possible in 6%, and suspected in 22%. By December 31, 2002, 56 cases (71%) had died. The cumulative probability of surviving after diagnosis was 78% at 12 months, 56% at 24 months, and 32% at 48 months. Median survival from onset was 39.2 months and from diagnosis 30.6 months. Multivariate analysis confirmed definite ALS at diagnosis and older age as adverse prognostic factors. CONCLUSIONS: Survival of ALS patients in the present sample was slightly longer than previously reported. Better palliative care and supportive treatment may explain the difference. Older age and the presence of definite ALS at diagnosis are poor prognostic predictors.

Predictors of epilepsy surgery outcome: a meta-analysis.

The potential efficacy of temporal and extratemporal resection in patients with partial epilepsy uncontrolled by anti-epileptic drugs is undisputed. However, there are still uncertainties about which patients will benefit most. A systematic review of the available literature has been undertaken by four pairs of reviewers to assess the overall outcome of epilepsy surgery and to identify factors better correlated to seizure outcome. A Medline search for studies on epilepsy surgery published since 1984 was performed. Studies were included if they had a well-defined population and design, a sample size of at least 30 patients, an MRI performed in least 90% of cases, an expected duration of follow-up of at least one year, and a post-operative outcome measured as seizure remission. A good outcome was considered as seizure control or seizure-free status for at least one year or Engel class I. Based on the review of 47 articles meeting all the eligibility criteria, febrile seizures (odds ratio, OR, 0.48; 95% confidence interval, CI, 0.27-0.83), mesial temporal sclerosis (OR 0.47; 95% CI 0.35-0.64), tumors (OR 0.58; 95% CI 0.42-0.80), abnormal MRI (OR 0.44; 95% CI 0.29-0.65), EEG/MRI concordance (OR 0.52; 95% CI 0.32-0.83), and extensive surgical resection (OR 0.24; 95% CI 0.16-0.36) were the strongest prognostic indicators of seizure remission (positive predictors); by contrast, post-operative discharges (OR 2.41; 95% CI 1.37-4.27) and intracranial monitoring (OR 2.72; 95% CI 1.60-4.60) predicted an unfavorable prognosis (negative predictors). Firm conclusions cannot be drawn for extent of resection, EEG/MRI concordance and post-operative discharges for the heterogeneity of study results. Neuromigrational defects, CNS infections, vascular lesions, interictal spikes, and side of resection did not affect the chance of seizure remission after surgery. Despite a number of limitations, the results of the review provide some insight into the selection of the best surgical candidates in clinical practice but raise concerns on the quality of published reports, and may serve as the basis for the identification of better standards to assess surgical outcome in observational studies.

Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2).

A previous study in proximal myotonic myopathy (PROMM/DM-2) and myotonic dystrophy type 1 (DM-1) using brain positron emission tomography demonstrated a reduced cerebral blood flow in the frontal and temporal regions associated with cognitive impairment. The objective was to investigate further cognitive and behavioural aspects in a new series of patients with DM-1 and PROMM/DM-2. Nineteen patients with genetically determined PROMM/DM-2 and 21 patients with moderately severe DM-1 underwent neuropsychological testing and neuropsychiatric interviews. DM-1 and PROMM/DM-2 patients had significantly lower scores on tests of frontal lobe function compared to controls. Neuropsychiatric interviews demonstrated an avoidant trait personality disorder in both patient groups. Brain single photon emission computed tomography showed frontal and parieto-occipital hypoperfusion. The results suggest that there is a specific cognitive and behavioural profile in PROMM/DM-2 and in DM-1, and that this profile is associated with hypoperfusion in frontal and parieto-occipital regions of the brain.

Validity of hospital discharge diagnoses for the assessment of the prevalence and incidence of amyotrophic lateral sclerosis.

INTRODUCTION: As amyotrophic lateral sclerosis (ALS) is a rare neurological disorder, many sources must be investigated for complete case ascertainment. Hospital discharge diagnoses (HDDs) are a source of administrative data for patients hospitalized for a given disease. The accuracy of HDDs was tested, to assess whether they could be used to trace patients with amyotrophic lateral sclerosis (ALS). METHODS: All the HDDs referring to patients with motor neuron disease (MND) (ICD-9 code 335.2) were identified from primary hospital discharge diagnoses made during the years 1994-95 in six target provinces of the Lombardy region in Northern Italy (total population 2922920). The medical records of the patients were reviewed and each patient was then accepted or rejected according to whether he/she did or did not satisfy the El Escorial criteria for the diagnosis of ALS. The ALS discharge diagnoses filed in the study period in the neurology departments of all the regional hospitals were the 'gold standard'. Newly diagnosed patients registered during the year 1998 in the same provinces served for the calculation of the incidence of the disease. Sensitivity, specificity and positive predictive value were calculated. Data were presented separately for all the patients and those who were indicated as first hospital admissions. RESULTS: During the study period a total of 1012122 hospital discharge records were coded in the six index provinces. The ICD-9 code 335.2 was reported in 408 of these (0.04%). These discharge diagnoses were made in 267 patients, 245 of whom were resident in Lombardy at the time of hospital admission. The hospital records of 237 cases were examined. In 95 of these the medical records showed a diagnosis other than ALS. Other motor neuron diseases were listed for 50 patients. Thirteen additional cases were traced through neurology department files. The sensitivity of the HDDs was 91.6%, the specificity 99.9%, the positive predictive value 65.4%. The corresponding values for first-hospitalized patients were 97.7, 99.9, and 37.3. The overall ALS incidence rate obtained from the HDDs was 2.1 per 100000 (95% CI 1.3-3.3). he corresponding rate calculated after exclusion of the false positives and inclusion of the false negatives was 0.8 (95% CI 0.1-2.1) and that obtained using the 1998 cases registered in the same areas was 1.6 (95% CI 0.7-2.7). CONCLUSIONS: The incidence of ALS is overestimated when HDDs are used for the estimate. Nevertheless, with improved quality, administrative data could be useful for the estimate of prevalence and incidence.

Proximal myotonic myopathy: report on italian families and literature review.

Despite the more recent genetic classification of the novel myotonic dystrophies into at least two distinct myotome dystrophy (DM) loci (DM1, DM2/PROMM/PDM), the clinical characteristics of these dominant myotonic syndromes often blur. The multisystemic nature of these disorders leads to a spectrum of symptoms and signs th.it emphasize the similarities and differences between these diseases. This review focuses en the clinical, laboratory, and genetic findings in 3q-linked and unlinked Italian families with proximal myotonic myopathy (PROMM). From a neuromuscular and cardiac point of view, we present follow-up data fom 25 patients studied serially over a 6-year period. We also present data on central nervous system involvement following neuropsychologic arid neuroimaging studies in this same period of time.

[Asymptomatic bilateral occipital calcifications. A possible atypical form of Sturge-Weber-Krabbe syndrome?]. / Calcificazioni occipitali bilaterali asintomatiche. Una possibile forma atipica di sindrome di Sturge-Weber-Krabbe?

Sturge-Weber-Krabbe syndrome is a rare congenital neuro-cutaneous disease which is characterized, in its full clinical expression, by facial naevus flammeus and epilepsy with mental retardation. Different atypical cases in which one or more symptoms are missing and clinical course is benign, have been reported in the literature in recent years. In the present paper a possible case of this syndrome radiologically diagnosed, without neurological and cutaneous symptoms, is reported; the importance of a more comprehensive study of this complex disorder, with particular attention to the incomplete forms, is stressed.

[Thyrotoxic periodic paralysis and Graves' disease. Description of an HLA-CW7-positive case]. / Paralisi periodica tireotossica e morbo di Graves. Descrizione di un caso HLA-CW7 positivo.

Thyrotoxic periodic paralysis is an uncommon complication of hyperthyroidism, more frequent in Oriental populations and in male than in female subjects. Electron microscopic investigations have shown characteristic degenerative changes of muscle fiber. In this study the sequence of pathophysiologic events proposed by the literature is illustrated and a case of thyrotoxic periodic paralysis in a HLA-CW7 positive patient affected by Graves' disease is reported.

Natural history of hepatic haemangiomas: clinical and ultrasound study.

Hepatic haemangiomas are the most common benign tumours of the liver and commonly present as incidental findings on sonographic examination of the abdomen. Since little is known of the natural course of these tumours, we performed a clinical and sonographic follow up of 123 haemangioma patients. Our prospective study investigated clinical and sonographic findings in 158 haemangiomas for periods of 12 to 60 months. Ninety nine haemangiomas measured less than 2 cm and had an echogenic pattern; 40 were between 2 cm and 5 cm with a mainly echogenic structure; 19 measured greater than 5 cm and showed a mixed echo pattern. At the first examination only eight patients, all with giant haemangiomas, presented symptoms which could be attributed to the tumour. During follow up only one haemangioma changed in shape and size. One patient who was symptom free at the first examination experienced right upper abdominal quadrant pain during follow up. No deterioration occurred in any of the patients with symptoms at the first examination, and all had a satisfactory quality of life. No complications arose during the follow up period. This study shows that in adults haemangiomas remain stable in size and echo patterns rarely change. Only haemangiomas greater than 5 cm may cause symptoms. Prolonged clinical and sonographic follow up of small and medium sized haemangiomas is not warranted.

Effect of hemodialysis and hemodiafiltration on uremic neuropathy.

This study was undertaken to compare the effect of 1 year hemodialysis (HD) or hemodiafiltration (HDF) treatment on peripheral neuropathy. Thus 21 of 42 patients on chronic HD (1-1.3 m2 cuprophane dialyzer, Qb 300 ml/min) were switched to HDF (1.3 m2 polysulfone dialyzer, Qb 400 ml/min, substitution volume 9-13 liters, ultrafiltration rate 60-70 ml/min), while the remaining patients were considered as a control group. Treatment time was scheduled both in HD and HDF to maintain adequate BUN levels in relation to protein catabolic rate. However, HDF provided a significantly greater weekly inulin (MW 5,000) clearance than HD (5.8 +/- 1.2 vs. 1.6 +/- 0.2 ml/min; p less than 0.001). HD and HDF groups were comparable for age, time on dialysis and starting electroneurographic parameters, which were on average within the normal range. After 1 year follow-up, creatinine, hematocrit, calcium, phosphate, PTH, BUN, protein catabolic rate and residual GFR were comparable in the two groups, whereas beta 2-microglobulin was significantly reduced in HDF patients (29 +/- 6.7 vs. 38.8 +/- 13.9 mg/l in HD patients, p less than 0.01). During the 1-year treatment, electroneurographic parameters did not change in HDF patients, whereas a significant decrease of ulnar motor nerve conduction velocity, ulnar muscle action potential amplitudes, median sensory nerve conduction velocity and peroneal muscle action potential amplitudes was detected in HD patients. We conclude that HDF might prevent the worsening of the electroneurographic indices occurring during chronic HD treatment, as it provides a more effective removal of middle and larger molecules than HD. The use of a more biocompatible membrane in HDF might further contribute to this favorable effect on uremic neuropathy.