Temporal summation of the nociceptive withdrawal reflex involves deactivation of posterior cingulate cortex.

BACKGROUND: Temporal summation of pain sensation is pivotal both in physiological and pathological nociception. In humans, it develops in parallel with temporal summation of the nociceptive withdrawal reflex (NWR) of the lower limb, an objective representation of the temporal processing of nociceptive signals into the spinal cord. METHODS: To study the contribution of cortical and subcortical structures in temporal summation of pain reflex responses, we compared the fMRI signal changes related to the temporal summation threshold (TST) of the NWR with that related to the single NWR response. We studied 17 healthy subjects using a stimulation paradigm previously determined to evoke both the TST of the NWR (SUMM) and the NWR single response (SING). RESULTS: We found a significant activation in left (contralateral) primary somatosensory cortex (SI), bilateral secondary somatosensory cortex (SII), bilateral insula, anterior cingulate cortex (ACC) and bilateral thalamus during both SUMM and SING conditions. The SUMM versus SING contrast revealed a significant deactivation in the posterior cingulate cortex (PCC) and bilateral middle occipital gyrus in SUMM when compared to SING condition. CONCLUSIONS: Our data support the hypothesis that temporal summation of nociceptive reflex responses is driven through a switch between activation and deactivation of a specific set of brain areas linked to the default mode network. This behaviour could be explained in view of the relevance of the pain processing induced by temporal summation, recognized as a more significant potential damaging condition with respect to a single, isolated, painful stimulation of comparable pain intensity. SIGNIFICANCE: The study demonstrated that TST of the NWR involves a selective deactivation of PCC.

Stop-event-related potentials from intracranial electrodes reveal a key role of premotor and motor cortices in stopping ongoing movements.

In humans, the ability to withhold manual motor responses seems to rely on a right-lateralized frontal-basal ganglia-thalamic network, including the pre-supplementary motor area and the inferior frontal gyrus (IFG). These areas should drive subthalamic nuclei to implement movement inhibition via the hyperdirect pathway. The output of this network is expected to influence those cortical areas underlying limb movement preparation and initiation, i.e., premotor (PMA) and primary motor (M1) cortices. Electroencephalographic (EEG) studies have shown an enhancement of the N200/P300 complex in the event-related potentials (ERPs) when a planned reaching movement is successfully stopped after the presentation of an infrequent stop-signal. PMA and M1 have been suggested as possible neural sources of this ERP complex but, due to the limited spatial resolution of scalp EEG, it is not yet clear which cortical areas contribute to its generation. To elucidate the role of motor cortices, we recorded epicortical ERPs from the lateral surface of the fronto-temporal lobes of five pharmacoresistant epileptic patients performing a reaching version of the countermanding task while undergoing presurgical monitoring. We consistently found a stereotyped ERP complex on a single-trial level when a movement was successfully cancelled. These ERPs were selectively expressed in M1, PMA, and Brodmann's area (BA) 9 and their onsets preceded the end of the stop process, suggesting a causal involvement in this executive function. Such ERPs also occurred in unsuccessful-stop (US) trials, that is, when subjects moved despite the occurrence of a stop-signal, mostly when they had long reaction times (RTs). These findings support the hypothesis that motor cortices are the final target of the inhibitory command elaborated by the frontal-basal ganglia-thalamic network.

Acquired peripheral neuropathy: a report on 20 children.

Guillain-Barré syndrome (GBS) is an inflammatory polyneuropathy characterized by acute onset, rapid progression, symmetric muscular weakness, pain, and paresthesias. The incidence of GBS in the pediatric age group is 0.8 cases per 100,000; 50%-70% of the cases are preceded by respiratory or gastrointestinal infectious episodes or vaccination. The etiopathogenesis of GBS has been hypothesized to involve a direct immune-mediated mechanism against the peripheral nerves. A series of 20 patients managed in the Department of Pediatrics of the University of Catania between 2003 and 2011 and evaluated according to epidemiologic, clinical, and therapeutic features is reported.

Primary headaches in children: clinical findings on the association with other conditions.

The aim of the present study is to report on the frequency of some comorbidities in primary headaches in childhood. Two hundred and eighty children (175 males and 105 females; ratio 1.7:1), aged 4 to 14 years, affected by primary headaches were consecutively enrolled in this study. In direct interviews, parents and children gave information about the association of their headaches with different conditions including asthma and allergic disorders, convulsive episodes, sleep disorders and increased body weight, affections some time associated in the literature to headache as comorbidities . In addition, anxiety and depression, attention deficit/hyperactivity disorder, tics, learning disabilities and obsessive-compulsive disorders, using psycho-diagnostic scales were evaluated. Two hundred and eighty children matched for age, sex, race and socio-economic status, were used as controls. No significant association of primary headaches was found with asthma and allergic disorders, convulsive episodes, sleep disorders and increased body weight. Overall behavioral disorders were more common in children who experienced headache than in controls. A significant association of primary headache was found with anxiety and depression (p value < 0.001), but not with the other psychiatric disorders. Primary headaches in children are not associated with most of the psychiatric and systemic conditions herein investigated. On the contrary, there was a significant association with anxiety and depression, as frequently reported in adults.

High frequency of OPA1 mutations causing high ADOA prevalence in south-eastern Sicily, Italy.

Optic atrophy type 1 (OPA1) gene mutation causes autosomal dominant optic atrophy (ADOA, MIM #165500). Prevalence of ADOA ranges from 1:50,000 in most populations to 1:12,000 in Denmark. Seventy members of nine families were analysed for the presence of OPA1 gene mutations by polymerase chain reaction (PCR) and direct sequencing. We identified three OPA1 gene mutations in 48 patients with variable signs of optic atrophy. Two mutations, c.784-21_784-22insAluYb8 and c.876_878delTGT, were found in two different families. The third mutation, c.869G>A, was found in 28 patients from seven families. The haplotype analysis data suggested that the c.869G>A mutation is a founder mutation. Our main result suggests a higher ADOA prevalence in south-eastern Sicily than previously found in Denmark. This is because of not only the founder effect but also to the presence of three different mutations in the geographical area of the study. Our hypothesis is that a combination of social pressure because of blindness and migration factors is involved. In fact, in Siracusa, a provincial capital in south-eastern Sicily, St. Lucy, the patron saint of the blind was born and died.

Krabbe leukodystrophy in a selected population with high rate of late onset forms: longer survival linked to c.121G>A (p.Gly41Ser) mutation.

Krabbe leukodystrophy (KD) is a neurodegenerative lysosomal disorder caused by mutations in the galactocerebrosidase (GALC) gene. Different clinical forms are described based on the age at onset. In reported series, the early infantile form (EIKD) accounts for more than 90% of the cases. The rarer late onset forms (LOKD) become manifest later than 6 months up to the adult age. We report clinical, imaging, mutational analysis and geographic data in a large cohort of individuals with Krabbe disease examined over a 30-year period. Retrospective analyses of disease onset and long-term follow-up were conducted in 26 KD patients. Molecular analysis was performed in 12 patients and their families. Nine cases had EIKD, and 17 LOKD, accounting for two thirds of our series. No correlation was found between enzymatic activity, onset age and disease progression. Despite common geographical origin, only in a few cases could parental consanguinity be proven. The p.Gly41Ser mutation was associated with longer survival. A wide spectrum of LOKD is found despite similar genotype. Although current knowledge about onset age, residual enzyme activity and molecular analysis still fail to allow the identification of patient candidates for treatment, this information is valuable for long-term outcome prediction and could lead to reconsideration of inclusion criteria for bone marrow transplant (BMT) or other future therapeutic approaches.

Pontocerebellar hypoplasia: clinical, pathologic, and genetic studies.

BACKGROUND: Mutations in genes encoding subunits of the tRNA-splicing endonuclease (TSEN) complex were identified in patients with pontocerebellar hypoplasia 2 (PCH2) and pontocerebellar hypoplasia 4 (PCH4). OBJECTIVE: We report molecular genetic findings in 12 Italian patients with clinical and MRI findings compatible with PCH2 and PCH4. METHODS: We retrospectively selected a cohort of 12 children from 9 Italian families with MRI of hypoplastic pontocerebellar structures and clinical manifestations suggesting either PCH2 or PCH4 and submitted them to direct sequencing of the genes encoding the 4 subunits of the TSEN complex, namely TSEN54, TSEN34, TSEN15, and TSEN2. RESULTS: In a cohort of 12 children, we detected the common p.A307S mutation in TSEN54 in 9/12 available patients from nine unrelated families. We also detected a novel c.1170_1183del (p. V390fs39X) in compound heterozygosity with the common p.A307S in a child with a severe PCH4 phenotype. In another severely affected patient, the second mutant allele was not identified. Two sibs without mutations in the TSEN complex were unlinked to the PCH3 locus. In addition to typical clinical and neuroradiologic features of PCH2, both children were affected by a tubulopathy resembling Bartter syndrome. CONCLUSIONS: We confirm that the common p.A307S mutation in TSEN54 is responsible for most of the patients with a PCH2 phenotype. The presence of a heterozygous in/del variant correlates with a more severe phenotype as PCH4. In addition, we describe a new clinical form of PCH in 2 sibs with clinical and MRI features of PCH2.

Neurological manifestations in individuals with pure cutaneous or syndromic (Ruggieri-Happle syndrome) phenotypes with "cutis tricolor": a study of 14 cases.

BACKGROUND: The term cutis tricolor describes the combination of congenital hyper- and hypo-pigmented skin lesions in close proximity to each other in a background of normal complexion. This phenomenon has been reported so far: (i) as pure cutaneous trait, (ii) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome--RHS), (iii) as a distinct type (cutis tricolor parvimaculata); (iv) in association with other (e. g., vascular) skin disturbances. AIM: The aim of this study was to define the spectrum of neurological abnormalities in cutis tricolor. METHODS: A retrospective and prospective 14-year study of clinical, electroencephalographic (EEG), neuroradiological (MRI), cytogenetic and ZFHX1B gene studies of 14 individuals (8 M, 6 F; aged 2-28 years) with cutis tricolor (4 pure cutaneous; 10 syndromic) was undertaken. RESULTS: Neurological involvement was recorded in 71.4% (10/14) of the patients [100% (10/10) in RHS and null (0/4) in cases with isolated skin manifestations] and included psychomotor delay (n=8), seizures (n=9), EEG abnormalities (n=6), a behavioural phenotype (n=4), non-specific brain abnormalities (n=6). Genetic analyses excluded ZFHX1B mutations and revealed a 19qter deletion (n=1). CONCLUSIONS: Even though we could not exclude the ascertainment and referral biases, we concluded that cutis tricolor may be a marker of underlying neurological involvement particularly in subjects with a syndromic (RHS) phenotype.

The scatter factor signaling pathways as therapeutic associated target in cancer treatment.

Receptor tyrosine kinases (RTKs) are key regulators of critical cellular processes such as proliferation, differentiation, neo-vascularization, and tissue repair. In addition to their importance in the regulation of normal physiology, aberrant expression of certain RTKs has also been associated to the development and progression of many types of cancer. c-Met and RON are two RTKs with closely related sequences, structural homology, and similar functional properties. Both these receptors, once activated by their respective ligands, the Hepatocyte Growth Factor/Scatter Factor (HGF/SF1) and the Macrophage Stimulating Protein/Scatter Factor 2 (MSP/SF2), can induce cell migration, invasion and proliferation. Soon after its discovery in the mid-1980s, c-Met attracted a great interest because of its role in modulating cell motility. Moreover, the causal role for c-Met activating mutations in human cancer propelled an intensive drug discovery effort throughout academic institutions and pharmaceutical companies. While c-Met is now a well-accepted target for anticancer drug design, less is known about the role of RON in cancer and less has been done to target this receptor. In this review we will discuss the biological relevance of c-Met and RON, their deregulation in human cancers and the progress, so far, in identifying c-Met and RON signaling inhibitors. Finally, we will focus on the development of therapeutic strategies and drug efficacy studies based on interfering the scatter factor signaling pathways.

Acute disseminated encephalomyelitis: a long-term prospective study and meta-analysis.

BACKGROUND: There are only a few series in the literature on acute disseminated encephalomyelitis (ADEM) in children. OBJECTIVES AND METHODS: the aims of this study were to perform (i) a prospective clinical/imaging study (1992-2009) on ADEM in children consecutively referred to our institution in Catania, Italy, and (ii) to undertake a systematic review and meta-analysis of published ADEM pediatric cohorts (>10 cases). RESULTS: We identified 17 patients with ADEM (incidence <10 years of age=1.1 per 100 000 person-years). 15 previously published cohorts were compared with our cohort: (i) systematically reviewed (750 cases); and (ii) meta-analyzed (492/750 cases). The 17 patients had the following characteristics: (a) male-to-female ratio, 1.4 (vs. 1.2-1.3 in previous cohorts); (b) mean age at presentation, 3.6 years (vs. 7.1 years in previous cohorts); (c) specific preceding triggering factor, 88% (vs. 69-79% in previous cohorts); (d) the most common initial signs were ataxia, seizures, headache, and thalamic syndrome; (e) brain imaging revealed >3 lesions in 100% (vs. 92% in previous cohorts); (f) the outcome was good in 94% (vs. 70-75% in previous cohorts); and (g) 12% relapsed once (vs. 18% in previous cohorts). CONCLUSIONS: ADEM is generally a benign condition that mosly affects boys more than girls and rarely recurs.

Recurrent peptic ulcer disease in a pediatric patient with type 1 neurofibromatosis and primary ciliary dyskinesia.

Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder with characteristic features of skin and central nervous system involvement. Gastrointestinal complications are rare, especially during childhood. In adults, only two cases of peptic ulcer have been reported in neurofibromatosis, both due to Zollinger-Ellison syndrome. Peptic ulcer disease (PUD) may be primary or secondary in nature and it may be life threatening in the acute phase due to the risk of perforation. A case of recurrent gastrointestinal hemorrhage in a child with systemic neurofibromatosis and primary ciliary dyskinesia (PCD) is presented. The upper gastrointestinal endoscopy revealed the presence of multiple gastric ulcers. The ulcers scarred after the long-term administration of a proton pump inhibitor (PPI), but recurred after the suspension. Laboratory and imaging studies excluded Zollinger-Ellison syndrome and other known causes of PUD, suggesting a potential role of neurofibromatosis itself and primary ciliary dyskinesia in developing of recurrent PUD. As early diagnosis of PUD is vital for patient survival, this case report highlights the possible association of neurofibromatosis and PCD with this condition, responsive to PPI therapy and the potential need of gastric protection before complications arise.

Natural killer cell cytotoxicity is enhanced by very low doses of rIL-2 and rIFN-alpha in patients with renal cell carcinoma.

Very low doses of recombinant interleukin-2 (rIL-2) and interferon-alpha (rIFN-alpha) induce, in patients with advanced renal cell carcinoma (RCC) clinical response rate and median survival time comparable to other protocols, other than immunological response in terms of expansion of NK cells and cT lymphocytes. The aim of this pilot study was to verify whether very low dose immunotherapy can enhance NK cell cytotoxicity against tumoral target cells. Eight patients with advanced and 13 patients with localised disease received 4-week cycles of rIL-2 (total dose per week 7 MIU/m(2), s.c.) and rIFN-alpha (total dose per week 3.6 MUI/m(2), i.m.) according to the scheme proposed by Buzio et al. Neutrophils, monocytes, eosinophils, NK cells (CD56+bright, CD56+dimmer, CD3-CD56 +), NK-T cells (CD3+CD56+), Th-lymphocytes, cT-lymphocytes, HLA-DR+ and CD25+ lymphocytes and NK cell cytotoxicity were evaluated before and after cycle. The treatment led to the significant expansion of eosinophils (P < 0.001), NK cells (P < 0.001), CD56+bright (P < 0.001), CD56+dimmer (P < 0.001), Th-lymphocytes (P = 0.001), cT-lymphocytes (P = 0.014), HLA-DR+ (P = 0.007) and CD25+(P = 0.002) cells. Neutrophils significantly decreased (P = 0.001), whereas no significant effect was observed on monocytes (P = 0.22) or NK-T cells (P = 0.20). Patients with localised disease responded significantly better to treatment than metastatic patients in terms of the expansion of CD56+bright (P = 0.038), DR+ (P = 0.021), CD25+ (P = 0.006) and Th-lymphocytes (P = 0.014). The NK cell cytotoxicity was significantly increased by the immunotherapy in the whole population (P = 0.021) and similarly in the two groups of patients (P = 0.860); a reverse relation, even if not significant, was seen between the variation of NK-T cells and NK cells cytotoxicity (r = -0.39; P = 0.074).

ENT Wegener's granulomatosis can hide severe central nervous system involvement.

The clinical manifestations of localised or early systemic forms of Wegener's granulomatosis (WG) do not require immediate treatment to save the patient's life and/or the function of a vital organ. The organs mainly involved are the ear, nose, throat (ENT) and lung, and the results of antineutrophil cytoplasmic antibody (ANCA) assays are frequently negative. We here describe three cases of the ANCA-negative early systemic form of WG with prevalent ENT involvement complicated by severe central nervous system (CNS) disease; in two cases, the only symptom was a mild headache. We conclude that, although apparently mild, the localised and early systemic forms of WG can hide CNS involvement and may require immediate treatment. This complication should be suspected and investigated in the case of patients with localised or early systemic disease especially in the presence of ENT involvement and negative ANCA assays.

Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterised by the development of multiple nervous system tumours, ocular abnormalities, and skin tumours. Although classically considered a disease of adults, initial signs and/or symptoms may be evident in childhood and are often unrecognised. OBJECTIVES: The aim of this study was to identify the earliest clinical presentations of NF2 and to characterise the clinical course and outcome in children with NF2. METHODS: We have performed a retrospective (years 1990-1998) and prospective (years 1998-2004) study of 24 patients (10 males, 14 females; currently aged 4 to 22 years) fulfilling the revised (Manchester) NF2 criteria seen at the Universities of Catania and Rome, Italy. RESULTS: Causes of referral prior to a definitive diagnosis of NF2 were: 1) Ophthalmologic problems: early onset lens opacities (n = 3); strabismus (n = 3) and amblyopia (n = 3) (due to underlying cranial nerves and/or brain tumours); 2) Otolaryngology problems: hearing loss and tinnitus (n = 2) in early teens disregarded or treated as ear infections; hoarse (n = 1) or bitonal (n = 1) voice; 3) Neurological dysfunction: seizures secondary to intracranial meningioma (n = 1) or vestibular schwannomas (VS) (n = 1), neurological dysfunction related to brainstem and/or spinal cord tumours (n = 7), isolated and multiple cranial nerve deficits (n = 10), and peripheral neuropathy secondary to schwannomas (n = 4); 4) Skin manifestations: schwannomas misdiagnosed as neurofibromas because of associated café-au-lait spots (n = 2); café-au-lait spots (n = 8) and skin tumours (n = 3). A family history was relevant in 20 % of the patients. Molecular genetic analysis of the NF2 gene revealed typical truncating mutations in all the 5 familial cases and in 2/10 sporadic cases analysed. CONCLUSIONS: Children with NF2 often first come to medical attention because of ocular, subtle skin, or neurological problems the significance of which is realised when they later present with more classical symptoms due to bilateral VS or other intracranial tumours. The clinical course at this young age is highly variable, depending on tumour burden, early surgical intervention, surgical outcome after tumour resection, and complications.

[A 'lucky' patient]. / Un caso 'fortunato'

A 72-year-old male diabetic patient admitted to our operative unit of nephrology and dialysis underwent hemodialytic treatment because of rapidly progressive renal failure. A moderate hypertensive state was associated to nephrotic proteinuria and microematuria. Renal angiography showed a severe stenosis of the right renal artery and a smaller left kidney. Right renal artery stenting induced a significant reduction in serum creatinine (Cr) and the patient discontinued with the dialytic treatment.

Application of fuzzy functions for visual presentation of medical data.

While interpretation of medical data is very often an ambiguous process, computers usually display results of recommendations, provided by both human experts and computer algorithms, as concrete data. This study proposes a visual presentation of relative degrees of uncertainty along with "standard" concrete medical data. A medical parameter (mean arterial pressure) is dynamically evaluated during surgery for being too low or too high. Fuzzy membership functions are utilized to display degrees of deviation in the form of a clear and concise pie chart. Thus, in the Operating Room the anesthesiologist can be provided with an easy statistical assessment of uncertainty of existing recommendations.

Multiple sclerosis in children under 10 years of age.

Despite the consistent amount of information accumulated in recent years on multiple sclerosis (MS) in childhood, many clinicians still view this condition as an exclusively young adult-onset disease and do not consider that it may occur and manifest even during infancy and pre-school age, suggesting that the number of MS cases in the paediatric age group may have been underestimated. Thus, the need to have practical parameters for therapeutic, counselling and educational purposes in such settings as caring for patients whose onset of disease is at very early ages may increasingly arise for practising clinicians. In addition, the clinical and radiographic criteria for the diagnosis of MS have not been validated in a paediatric MS population; accordingly, inclusion age at onset (such as for research purposes) is generally over 10 years. To highlight the peculiarities that characterise MS when it begins at this young age we have reviewed the literature and summarised our preliminary results with the national registry of the Italian Society of Paediatric Neurology (SINP) Study Group on Childhood MS in the group of MS patients with the earliest onset of disease (i.e., <10 years of age).

Congenital muscular dystrophy with adducted thumbs, ptosis, external ophthalmoplegia, mental retardation and cerebellar hypoplasia: a novel form of CMD.

At least six different forms of congenital muscular dystrophy are associated with structural changes of the central nervous system, and three of these have been mapped: merosin-deficient congenital muscular dystrophy on chromosome 6q2, Fukuyama congenital muscular dystrophy on chromosome 9q31, and muscle eye brain disease on chromosome 1p32. Walker-Warburg syndrome, congenital muscular dystrophy with calf hypertrophy, pontocerebellar hypoplasia, and normal eyes, and congenital muscular dystrophy with severe mental retardation and cerebellar cysts are nosologically distinct and have been excluded from the known congenital muscular dystrophy loci with structural changes of the central nervous system. Here, we describe a novel congenital muscular dystrophy syndrome which is phenotypically distinct from the recognized forms of congenital muscular dystrophy with brain involvement. Two siblings, a boy and a girl, were born to consanguineous parents from Sicily. Both children were born with adducted thumbs and toe contractures. They were floppy from birth, walked late, showed profound generalized muscle weakness including facial muscles, elevated creatine kinase levels of 200-700U/l, and histological changes compatible with muscular dystrophy. In addition, both showed ptosis, external ophthalmoplegia, mild mental retardation, and mild cerebellar hypoplasia on MRI. Immunocytochemistry showed normal expression of muscle membrane proteins including laminin alpha 2, laminin beta 2, and alpha-dystroglycan. Linkage analysis excluded the candidate loci on chromosomes 6q2, 9q31, and 1q32. The gene locus for congenital muscular dystrophy 1B, MDC 1B, on chromosome 1q42 was also excluded. Adducted thumbs are a distinct clinical sign that has not been reported in congenital muscular dystrophy before and should facilitate recognition of further patients with this disorder.