Search

Background: Heart failure affects approximately 6.2 million adults in the United States and has an estimated national cost of $30.7 billion annually. Despite advances in treatment, heart failure is a leading cause of hospital readmissions. Nonadherence to treatment plans, lack of education, and lack of access to care contribute to poorer outcomes., Local Problem: For patients with heart failure, the mean readmission rate is 21% nationally and 23% in New York State. Before the pilot heart failure program began, the 30-day readmission rate in the study institution was 28.6%., Methods: A multidisciplinary team created a heart failure self-care pilot program that was implemented on a hospital telemetry unit with 47 patients. Patients received education on their disease process, medications, diet, exercise, and early symptom recognition. Patients received a follow-up telephone call 48 to 72 hours after discharge and were seen by a cardiologist within a week of discharge., Results: The 30-day readmission rate for heart failure decreased by 16.6% after implementation of the pilot program, which improved patient adherence to their medication and treatment plan and resulted in a reduction of readmissions., Discussion: Patients in the pilot program represented diverse backgrounds. Socioeconomic factors such as the lack of affordable, healthy food choices and easy access to resources were associated with worse outcomes., Conclusions: The evidence-based heart failure program improved knowledge, early symptom recognition, lifestyle modification, and adherence to medication, treatment plan, and follow-up appointments. The multidisciplinary team approach to the heart failure program reduced gaps in care and improved coordination and transition of care., (©2022 American Association of Critical-Care Nurses.)

Objective: Respiratory failure represents a significant source of morbidity and mortality for surgical patients. High-frequency percussive ventilation (HFPV) is emerging as a potentially effective rescue therapy in patients failing conventional mechanical ventilation (CMV). Use of HFPV is often limited by concerns for potential effects on hemodynamics, which is particularly tenuous in patients immediately after cardiac surgery. In this manuscript we evaluated the effects of HFPV on gas exchange and cardiac hemodynamics in the immediate postoperative period after cardiac surgery, in comparison with CMV., Methods: Twenty-four consecutive cardiac surgery patients were ventilated in immediate postoperative period with HFPV for two to four hours, then they switched to a CMV using the adaptive support ventilation mode for weaning. Arterial blood gases were performed during the first and second hour on HFPV, and at 45 minutes after initiation of CMV. Respiratory settings and invasive hemodynamic data (mixed venous oxygen saturation, central venous pressure, systemic and pulmonary blood pressure, cardiac output and index) were collected utilizing right heart pulmonary catheter and arterial lines during HFPV and CMV. Primary outcome was improvement in the ratio between partial pressure of oxygen to fraction of inspired oxygen (P/F ratio) and changes in hemodynamics., Results: Analysis of data for 24 patients revealed a significantly better P/F ratio during the first and second hour on HFPV, compared with a P/F ratio on CMV (420.0 ± 158.8, 459.2 ± 138.5, and 260.2 ± 98.5 respectively, p < 0.05), suggesting much better gas exchange on HFPV than on CMV. Hemodynamics were not affected by the mode of the ventilation., Conclusions: Improvement in gas exchange, reflected in a significantly improved P/F ratio, wasn't accompanied by worsening in hemodynamic parameters. The significant gains in the P/F ratio were lost when patients were switched to conventional ventilation. This data suggest that HFPV provides significantly better gas exchange compared with CMV and can be safely utilized in postoperative cardiac patients without any significant effect on hemodynamics., Competing Interests: All authors contributed to the conception or design of the work, the acquisition, analysis, or interpretation of the data. All authors were involved in drafting and commenting on the paper and have approved the final version. This work was performed at New York Methodist Hospital, Brooklyn, New York, USA, now known as New York-Presbyterian Brooklyn Methodist Hospital.

Leptomeningeal carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases. The clinical presentation may differ and the diagnosis may be difficult especially when cancer has not yet been diagnosed. We report a case of LC, where the clinical picture and a specific change in cerebrospinal fluid suggested the diagnosis of a prion disease.

This paper deals with an unusual case of Alzheimer's disease with early onset, no family history, myoclonus, tonic generalized seizures and pseudo-periodic spikes on EEG. The demise occurred after 8 years of progressive cognitive deterioration; the pathological examination showed "Pick-like" atrophy, neurofibrillary tangles, senile plaques, congophilic angiopathy and cerebellar amyloid plaques. The genetical research could not support the hypothesis of a mutation of Presenilin 1 and 2 genes. Anyway, the peculiarity of the phenotype is worthy to be described even in the absence of specific molecular findings.

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, no therapies are available at the moment but clinical trials are ongoing. For that reason it is very important to know the natural history of the disease. We report the results of the natural history of clinical features and quality of life (QoL) in patients with CMT2. Twenty patients were enrolled. At recruitment and at follow-up (2 years), all patients underwent neurological evaluation, QoL and disability assessments. The study-end evaluation took place 20-28 months after the baseline evaluation. During the 2-year follow-up period, CMT2 patients showed a mild reduction of strength of distal muscles of upper limbs and proximal muscles of lower limbs, a worsening sensory function and a mild increase in walking disability. However, there was no relevant worsening of QoL, except for a mild deterioration of one mental health domain.

Purpose: The hypothesis addressed by this study is that a glutamine synthetase (GS) deficiency in neoplastic astrocytes is a possible molecular basis associated with seizure generation in glioblastoma multiforme (GBM)., Methods: Quantitative Western blot analysis of GS was performed in 20 individuals operated for malignant glioma., Results: The levels of GS in patients with GBM and epilepsy were significantly lower (range 0.04-1.15; mean 0.35 +/- 0.36; median 0.25) than in non-epileptic GBM individuals (range 0.78-3.97; mean 1.64 +/- 0.99; median 1.25; P = 0.002). No relationship has been found between histological features (i.e. necrosis, gliosis, stroma, inflammatory cells, giant cells, and haemosiderine) and GS expression or epilepsy., Discussion: Even though the epileptogenesis in glioma is multifactorial, it is conceivable that a down-regulation of GS may have an important pro-epileptogenic role in GBM, through the slowing of glutamate-glutamine cycle. This study suggests that seizures in GBM are coupled with a highly localized enzyme deficiency. The manipulation of GS activity might constitute a novel principle for inhibiting seizures in patients with glioma epilepsy.

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are mammalian neurodegenerative diseases that occur as sporadic, inherited, or iatrogenic forms. Human TSEs exhibit a wide spectrum of phenotypic variability, which is influenced by (1) the conformation of the pathologic prion protein, or PrP(Sc); (2) the polymorphic codon 129 of the prion protein gene (PRNP), involving synonymous or nonsynonymous expression of Met or Val; and (3) the site of formation or entry of the self-replicating PrP(Sc). Brain deposition of PrP(Sc) occurs in a phenotype-specific regional pattern, either as extracellular amyloid plaques and plaque-like aggregates, or as fine granular immunoreactivity at intracellular sites and presynaptic and postsynaptic locations, including dendrites. We previously demonstrated PrP(Sc) deposition in ciliated dendrites of olfactory sensory neurons in sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease. PrP(Sc) immunoreactivity was not limited to the olfactory neuroepithelium. But additionally involved the central olfactory pathway. More recently, we have found that the pathology of the olfactory pathway occurs early in the disease course, either in the myoclonic or classic sCJD or in the ataxic variant. Intriguingly, in the ataxic or cerebellar variant, mainly observed in patients with the Met/Val polymorphism (2) carrying PrP(Sc) type 2, olfactory involvement is accompanied by pathologic changes in the dorsal motor nucleus of the vagus and other brainstem nuclei. These findings suggest that different molecular events and distinct routes of PrP(Sc) spread contribute to the prominent heterogeneity of sCJD, conceivably providing support to the olfactory pathogenesis theory of neurodegenerative diseases.

Background: Autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy type 4H (CMT4H) manifests early onset, severe functional impairment, deforming scoliosis, and myelin outfoldings in the nerve biopsy. Mutations in the FGD4 gene encoding the Rho-GTPase guanine-nucleotide-exchange-factor frabin were reported in five families., Objective: To characterize a novel mutation in FGD4 and describe the related phenotype., Methods: A 20-year-old woman born of healthy consanguineous parents and affected with early-onset peroneal muscular atrophy underwent standard clinical, electrophysiologic, and pathologic (sural nerve biopsy) investigations. Mutational analysis of FGD4 was performed by direct sequencing of genomic DNA. Transcriptional analysis was done by reverse transcriptase PCR on leukocyte RNA., Results: The proband disclosed a moderately severe, scarcely progressive CMT, markedly slowed nerve conduction velocities, and a demyelinating neuropathy characterized by prominent myelin outfoldings. Mutational analysis disclosed a c.1762-2a>g transition in the splice-acceptor site of intron 14, which was predicted to cause a truncated frabin (p.Tyr587fsX14)., Conclusions: The report confirms genetic heterogeneity of FGD4, demonstrates that CMT4H has variable functional impairment, and suggests that frabin plays a crucial role during myelin formation.

Background and Aims: Flow mediated dilation (FMD) of peripheral conduit arteries is a well-established tool to evaluate endothelial function. The aims of this study are to apply the FMD model to cerebral circulation by using acetazolamide (ACZ)-induced intracranial vasodilation as a stimulus to increase common carotid artery (CCA) diameter in response to a local increase of blood flow velocity (BFV)., Methods and Results: In 15 healthy subjects, CCA end-diastolic diameter and BFV, middle cerebral artery (MCA) BFV and mean arterial blood pressure (MBP) were measured at basal conditions, after an intravenous bolus of 1g ACZ, and after placebo (saline) sublingual administration at the 15th and 20th minute. In a separate session, the same parameters were evaluated after placebo (saline) infusion instead of ACZ and after 10 microg/m(2) bs and 300 microg of glyceryl trinitrate (GTN), administered sublingually, at the 15th and 20th minute, respectively. After ACZ bolus, there was a 35% maximal MCA mean BFV increment (14th minute), together with a 22% increase of mean CCA end-diastolic BFV and a CCA diameter increment of 3.9% at the 3rd minute (p=0.024). There were no MBP significant variations up to the 15th minute (p=0.35). After GTN administration, there was a significant increment in CCA diameter (p<0.00001)., Conclusions: ACZ causes a detectable CCA dilation in healthy individuals concomitantly with an increase in BFV. Upon demonstration that this phenomenon is endothelium dependent, this experimental model might become a valuable tool to assess endothelial function in the carotid artery.

We report on the first association of celiac disease, polyarteritis nodosa and HBV infection in a patient who developed a neuropathy. On admission his general and neurological conditions were severely compromised. Haematological test revealed HBV infection and high levels of antibodies to tissue transglutaminase, endomysium, gliadin. EMG showed sensory-motor asymmetric axonal neuropathy. A sural nerve biopsy revealed fibre loss, axonal degeneration with asymmetrical distribution and fascicular ischaemia. A duodenal biopsy was consistent with celiac disease. The patient was treated with immunosuppressive and antiviral therapy, and gluten-free diet with good result. Celiac disease can be related to a higher risk of autoimmune disorders and may have contributed to the development of multineuropathy in this patient.

Background/aims: Up to more than 50% of cryptogenetic stroke patients and patients with migraine with aura (MA) are found to have a right-to-left shunt (RLS), which is usually due to a patent foramen ovale. Moreover, both MA and stroke are cardinal features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Notch3 mutations have been suggested to induce an abnormally high incidence of atrial septal defects in a family harbouring an Arg141Cys pathogenetic mutation. We sought to determine the prevalence of RLS in CADASIL patients with different Notch3 mutations, both with and without migraine as a clinical feature., Methods: Subjects with a molecular diagnosis of CADASIL were tested for the presence of an RLS by means of contrast-enhanced transcranial Doppler (TCD). The diagnosis of migraine was made according to the 2004 International Headache Classification., Results: Sixteen CADASIL patients were tested; 6 had MA. Four patients displayed an RLS on contrast-enhanced TCD examination. Three of these patients had MA. Both patients with Arg141Cys displayed a large RLS., Conclusion: We conclude that RLS is not necessarily linked to CADASIL as a comorbidity factor. Nevertheless, there could be a relation between RLS and specific Notch3 mutations, such as Arg141Cys., (2008 S. Karger AG, Basel.)

Cerebral developmental venous anomalies (DVAs) are generally considered as anatomical variants of the venous system without clinical importance. We report the case of a 15-year-old girl with recurrent episodes of migraine-like headache who presented with subacute vertigo and ataxia associated with intense occipital pain. Magnetic resonance imaging (MRI) showed a DVA with signal modifications of the surrounding brain parenchyma in the left cerebellar hemisphere. The patient's ataxia regressed completely within about 2 months. On a follow-up MRI 4 years later the venous malformation and the parenchymal abnormalities were unchanged. We attribute the patient's focal neurological dysfunction to regional changes in the brain parenchyma, possibly secondary to venous hypertension. Our report provides evidence that also uncomplicated DVAs can become symptomatic and supports the role of the venous congestion within the DVA territory in pathogenesis of some brain parenchymal abnormalities associated with DVAs.

Objective: To assess which are the clinical examination tests that are more related to quality of life (QoL), depression, and disability in CMT patients., Design: Large prospective multicenter study through the use of validated clinical, disability, and QoL measurements. Correlations between clinical pattern and disability/QoL and depression were studied., Setting: Departments of Neurology., Patients and Participants: 211 CMT patients (60% females, mean age 42.5 years)., Interventions: None., Measurements and Results: Sensory function was related to both mental and physical aspects of patient's QoL. Ability to walk on toes and heels was related to physical aspects of QoL/disability but also to bodily pain. Strength of forearm/hand intrinsic muscles was related to disability and physical aspects of QoL., Conclusions: Some clinical tests may be better outcome measures than others because they are related to aspects of life highly relevant to the patients. This information may be useful in clinical practice and in clinical trials to infer the patient's QoL.

The Italian CMT study group performed a multicentre, multidimensional, longitudinal 2-year follow-up study using validated measurements of neurological impairment, disability and quality of life. The aim of the study was to evaluate the natural history of clinical features, disability and QoL in patients with CMT1A. On clinical examination, CMT1A patients showed a significant reduction in muscle strength and sensory function during the 2-year follow-up period. However, there was no worsening of QoL or disability, nor was depression observed. The discrepancy between the evolution of clinical features and the evolution of QoL and disability may be due to the development of compensatory strategies that help patients cope with the slow progression of the disease. Our observations provide information which may be useful when designing clinical trials in CMT.

Quality of life (QoL), as defined by the Short Form 36, has previously been shown to be abnormal in patients with Charcot-Marie-Tooth disease (CMT), both for Physical Composite Scores (PCS) and Mental Composite Scores (MCS). We have now extended these observations in a multicenter evaluation of 89 patients with Charcot-Marie-Tooth disease type 1A, the most common form of CMT. Both the PCS and MCS were abnormal also in this cohort, compared with the Italian population at large. In particular, the ability to ambulate independently as well as toe and heel walk correlated well with QoL measures in our patients.

Point mutations in mtDNA-encoded tRNA genes frequently cause isolated myopathies but rarely cause the facioscapulohumeral phenotype. We report on a patient affected with chronic progressive weakness of facioscapulohumeral/peroneal muscles whose muscle biopsy showed a mitochondrial myopathy. mtDNA direct sequencing and RFLP analysis revealed a heteroplasmic transition T12313C which disrupts a conserved site in the T Psi C stem of the tRNA(Leu(CUN)) gene and fulfills the accepted criteria of pathogenicity. A partial deletion of the nuclear DNA D4Z4 region with residual repeat sizes of 25 kb was also found in the patient and in her mother. This is the first reported case of mitochondrial myopathy/facioscapulohumeral muscular dystrophy (FSHD) "double trouble".

Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.

Background: Limb ataxia is classically attributed to cerebellar hemispheric lesions, although isolated lesions of the inferior cerebellar peduncle (ICP) in the medulla may also cause this sign. It is still unclear why only some patients with acute cerebellar infarcts in the posterior inferior cerebellar artery (PICA) territory present with limb ataxia. The proximal intracranial posterior circulation (P-PC) territory includes structures fed by the intracranial vertebral arteries (ICVAs): the medulla, supplied by small ICVAs branches, and posterior inferior portion of the cerebellum, fed by PICA. ICP and PICA territory cerebellar infarcts most often occur independently but occasionally occur together., Objective: To identify structures responsible for limb ataxia in acute P-PC brain infarcts, correlating clinical and topographical findings., Methods: Sixteen patients (8 women) were included, aged 30-82 years (mean 62 years), with isolated acute strokes in the P-PC territory., Results: The cases reported here indicate that limb ataxia in acute P-PC territory infarcts may be associated with damage to the ICP in the dorsolateral medulla, regardless of a hemispheric cerebellar lesion. In fact, among the nine patients with PICA stroke, limb ataxia was observed only in the two patients who also presented damage to the dorsolateral medulla involving the ICP. Of the seven patients with isolated dorsolateral medullary infarct, only five patients with ICP damage had limb ataxia., Conclusions: When correlating limb ataxia and acute P-PC infarcts, it is important to take into account the entire ICVA territory.

Background: Recently, mutations affecting different domains of dynamin-2 (DNM2) were associated alternatively with autosomal dominant centronuclear myopathy or dominant intermediate (demyelinating and axonal) Charcot-Marie-Tooth disease (CMT) type B., Objective: To assess the etiologic role of DNM2 in CMT., Methods: We performed a mutational screening of DNM2 exons 13 through 16 encoding the pleckstrin homology domain in a large series of CMT patients with a broad range of nerve conduction velocities and without mutations in more common genes., Results: We identified two novel DNM2 mutations that cosegregated with purely axonal CMT in two pedigrees without clinical evidence of primary myopathy., Conclusion: Patients with axonal Charcot-Marie-Tooth disease type 2 neuropathy without mutations in more common genes should undergo investigation for DNM2 pleckstrin homology.

The term "mitochondrial diseases" (MD) refers to a group of disorders related to respiratory chain dysfunction. Clinical features are usually extremely heterogeneous because MD may involve several tissues with different degrees of severity. Muscle and brain are mostly affected, probably because of their high dependence on oxidative metabolism. Muscle can be the only affected tissue or involved as a part of a multi-system disease; ragged red fibers, accumulation of structurally altered mitochondria and cytochrome-c-oxidase (COX) negative fibers are the main pathological features. In mitochondrial encephalopathies, central nervous system (CNS) structures are affected according to different patterns of distribution and severity. Characteristic lesions are neuronal loss, vasculo-necrotic changes, gliosis, demyelination and spongy degeneration. In accordance with either grey matter or white matter involvement two main groups of diseases may be distinguished. Neuronal loss and vasculo-necrotic multifocal lesions are the common features of grey matter involvement; demyelination and spongy degeneration occur when white matter is affected, often associated with less severe lesions of the grey structures. Grey matter lesions are prevalent in MERRF, MELAS, Alpers and Leigh syndromes. White matter involvement is always seen in Kearns-Sayre syndrome and was recently described in mtDNA depletion syndrome linked to dGK mutations and in the rare conditions associated with complex I and II deficiency. In this review we describe the main histopathological features of muscle and CNS lesions in mitochondrial diseases.

Objective: To describe a novel molecular and pathological phenotype of Creutzfeldt-Jakob disease. Patient A 69-year-old woman with behavioral and personality changes followed by rapidly evolving dementia., Results: Postmortem examination of the brain showed intracellular prion protein deposition and axonal swellings filled with amyloid fibrils. Biochemical analysis of the pathological prion protein disclosed a previously unrecognized PrP(Sc) tertiary structure lacking diglycosylated species. Genetic analysis revealed a wild-type prion protein gene. The prion agent responsible for this atypical phenotype was successfully passaged to bank voles., Conclusion: To our knowledge, our results define a new human prion disorder characterized by intracellular accumulation of a novel type of pathological prion protein.

The neurofilament light chain (NF-L) is a major constituent of intermediate filaments and plays a pivotal function in the assembly and maintenance of axonal cytoskeleton. Mutations in the NF-L gene (NEFL) cause autosomal dominant neuropathies that are classified either as axonal Charcot-Marie-Tooth (CMT) type 2E (CMT2E) or demyelinating CMT type 1F (CMT1F). The pathophysiological bases of the disorder(s) are elusive. We performed a mutational analysis of NEFL in a series of 177 index cases with CMT and without mutations in the genes for peripheral myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22) and connexin 32 (GJB1); the motor nerve conduction velocity (MNCV) at the median nerve was below 38 m/s in 76 cases and above 38 m/s in 101. We identified five new pedigrees with four mutations in the head and rod domains of NF-L, including a novel Leu268Pro substitution and a novel del322Cys&#95;326Asn deletion. Several examined affected members exhibited marked variability in the severity of disease and age at onset. Nerve conduction alterations were consistent with an axonal neuropathy often associated with demyelinating features, such as prolonged distal latencies (DL). Pathological examination of sural nerve biopsies in the probands detected in four cases a chronic axonal neuropathy dominated by focal accumulations of NF with axonal swellings (giant axons) and significant secondary demyelination; in the fifth case no NFs accumulations were evident but many myelinated fibres consisted exclusively of microtubules with few or absent NF. The pathological phenotype correlated with the pattern of nerve conduction alterations and indicated that NEFL mutations cause a profound alteration of the cytoskeleton possibly related to defective targeting of NF.

Objective: To evaluate the muscle biopsy findings from 240 patients who had isolated muscle pain., Methods: Histopathology, immunohistochemistry for dystrophin, dystrophin-related proteins, major histocompatibility complex type I, and biochemical analysis of glycolytic and mitochondrial respiratory chain enzymes were performed on muscle biopsies. An attempt was made to correlate pathologic data and clinical findings (sex, age, quality and distribution of symptoms, serum CK levels, and EMG recording)., Results: We have described five groups of patients based on muscle biopsy findings: 51.6% had heterogeneous myopathic abnormalities; only 19% of them had a specific myopathic picture, i.e., central nuclei myopathy, central core disease, myopathy with tubular aggregates or with trabecular fibers or abnormalities of fiber typing; 20% had signs of respiratory chain dysfunction but only one patient had a probable mitochondrial disease; 7% had a neurogenic pattern; 2.4% had a metabolic myopathy (phosphorylase or phosphofructokinase deficiency); and 19% had normal muscle biopsy. No clear-cut correlation between muscle biopsy and clinical data was observed except for those patients with a metabolic myopathy., Conclusions: The probability that a patient complaining only of muscle pain and with a normal neurologic examination has a definite muscle pathology is 2%. Only patients with sole exercise-related muscle pain and sCK seven times higher than the normal value are strongly suspected of having a metabolic myopathy. A rigorous selection of patients is needed before performing a muscle biopsy.

The purpose of this study was to assess the variables that influence quality of life (QoL) and disability in patients with Charcot-Marie-Tooth disease (CMT). We performed a prospective multicentre study using validated clinical disability and QoL measurements. Multivariate analysis was performed using QoL as a dependent variable and duration of symptoms, age, gender and CMT type, depression and disability measurements as independent variables. We enrolled 211 patients. QoL was highly significantly deteriorated with respect to the Italian normative sample. The physical aspect of QoL was mainly related to disability but it does not increase with the age, probably because of an adaptation between expectation and reality. The mental QoL is influenced by depression (hence we have to consider this aspect approaching CMT patients). Moreover, we observed that women complained of more severe symptoms than men. Finally, some CMT subtypes are related to more severe bodily pain symptoms than others. Multiperspective assessment of CMT showed new aspects of this disease, mainly regarding (1) differences between men and women and (2) the crucial role of pain and depression.

Some evidence suggests that endothelial dysfunction, including altered expression of cell adhesion molecules contributes to pathophysiology of nervous system disorders in the course of HIV infection. In this immunohistochemical study we investigated and compared the expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1) in peripheral nerve blood vessels from patients with distal sensory polyneuropathy (DSP) and control patients with other axonal neuropathies. Similar quantitative pattern of immunoreactivity was found in patients with DSP and controls. E-selectin and PECAM-1 immunostained vessels tended to increase in number only in patients with major CD4 cell depletion. The vascular endothelium of the peripheral nerve in HIV-infected subjects with DSP shows no changes facilitating the migration of infected or activated monocytes/macrophages into the nerve. These phenomena probably do not play a critical role in the development of axonal damage in DSP.

We describe four patients, from four different families, affected by a mild myopathy or asymptomatic elevated serum creatine kinase levels, in whom toluidine blue-stained semithin sections of muscle specimens revealed inclusions of different size and shape. The inclusions did not stain by routine histochemical studies. The sarcoplasmic or endoplasmic reticulum calcium 1 (SERCA1) ATPase and/or calsequestrin reactivity of inclusions, by immunohistochemistry, and the SERCA1- and calsequestrin-increased expression, by immunoblot, suggested that inclusions were constituted by an excess of proteins normally present in the terminal cisternae of sarcoplasmic reticulum. Our cases, both sporadic and familial, represent a new type of surplus protein myopathy.

The ataxic form of chronic inflammatory demyelinating polyradiculoneuropathy (ataxic-CIDP) has been recently described as a subtype of chronic ataxic neuropathy, distinguished by steroid responsiveness and relative preservation of myelinated fibres at sural nerve biopsy. We report on a case of progressive, predominantly sensory, steroid-responsive neuropathy with clinical, laboratory, electrophysiological and pathological features of this uncommon form of CIDP. Moreover, the present case displays peculiar hyperpyrexia-triggered relapses leading to transitory severe tetraparesis, bilateral facial drooping, dysphonia, dysphagia and dyspnoea, which leave clinicians with some unresolved questions.

A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.

Background: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients., Objective: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families., Methods: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations., Results: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation)., Conclusions: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin.

Autosomal dominant Charcot-Marie-Tooth disease type 1B (CMT1B) is caused by heterozygous mutations in the extracellular domain of P0. Here, we investigated clinically, electrophysiologically and pathologically a pedigree with a novel mutation in the intracellular domain of P0 (P0ic). The mutational analysis included denaturing high performance liquid chromatography (DHPLC) and nucleotide sequencing. Two patients from subsequent generations were homozygous for an Asp195Tyr mutation in the intracellular domain of P0 (P0ic), whereas two healthy individuals with minimal electrophysiological changes were heterozygous for the same mutation. The authors conclude that mutations of P0ic may undergo a gene dosage effect manifesting semidominant inheritance.

Axon-derived neuregulins (NRGs) are a family of growth factors whose binding to ErbB tyrosine kinase receptors promotes the maturation, proliferation and survival of Schwann cells (SCs). Correct NRG/ErbB signaling is essential for the homeostasis of axonal-glial complexes and seems to play a role in peripheral nerve repair. The potential involvement of ErbB receptors in human peripheral neuropathies has not been clarified. Therefore, we assessed the immunoreactivity for EGFR (ErbB1), ErbB2, and ErbB3 in nerve biopsies from patients with different forms of Charcot-Marie-Tooth disease, type 1, (CMT1), as compared to others with inflammatory neuropathies and controls. The most notable changes consisted in the overexpression of ErbB2 and ErbB3 by SCs of nerves from CMT1A patients. These findings are consistent with an impairment of SC differentiation and expand the molecular phenotype of CMT1A. The upregulation of these receptors may play a role in the inhibition of myelination or in the promotion of recurrent demyelination and axonal damage., (Muscle Nerve, 2006.)

Peripheral neuropathy has emerged as the most common neurologic complication of human immunodeficiency virus (HIV) infection. It will continue to play an Important role in HIV Infection given the fact that HIV-infected Individuals are living longer, are at risk of long-term metabolic complications, and face an Increasing exposure to potentially neurotoxic antiretroviral drugs. We review the various types of peripheral neuropathy that have been associated with HIV infection, including distal symmetrical polyneuropathy, toxic neuropathy from antiretroviral drugs, diffuse infiltrative lymphocytosis syndrome, inflammatory demyelinating polyneuropathies, multifocal mononeuropathies, and progressive polyradiculopathy.

Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are sporadic and genetic neurodegenerative conditions characterized by brain accumulation and deposition of protein aggregates. In AD, the key pathogenic event is linked to the formation of a 4-kDa amyloid beta (Abeta) peptide, generated by sequential cleavages of the amyloid precursor protein (APP). In CJD and other prion diseases, the process is initiated by conformational changes of the cellular prion protein, or PrP(C), into a beta-sheet rich isoform, named PrP(Sc), which acquires protease-resistance and detergent insolubility. Once generated, Abeta and PrP(Sc) are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Abeta and PrP(Sc) is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Abeta, PrP(Sc) is also infectious, and this feature poses public health concerns, as in the case of iatrogenic and variant CJD (vCJD). Several lines of evidence suggest that Abeta and PrP(Sc) are the main factors responsible for death of selected neuronal populations in brains of AD and prion disease's victims. Therefore, in addition to symptomatic treatment of dementia, therapeutic efforts are currently aimed at testing the efficacy of disease-modifying, anti-amyloid therapies. Experimental and clinical therapeutic interventions include passive and active immunization against amyloidogenic peptides, non immunological strategies, as well as drugs enhancing the nonamyloidogenic protein processing. In this review, we focus on molecular mechanisms of AD and prion diseases, and on novel treatment approaches.

The authors describe 12 neuroleptic-treated patients with dementia of various etiologies who showed CSF elevation of phosphorylated 14-3-3zeta and normal tau protein levels. This contrasted with elevated amounts of 14-3-3 gamma, epsilon, and unphosphorylated zeta coupled to high tau protein levels in Creutzfeldt-Jakob disease and negative 14-3-3 assay in drug-free patients with dementia. Characterization of CSF 14-3-3 isoforms and determination of tau protein level can help to distinguish different etiologies of dementia.

Sarcoplasmic masses contain disorganized myofibrillar material and are a striking feature of myotonic dystrophy. However their significance is still unclear. Using immunocytochemistry we studied the expression of cytoskeletal proteins (desmin and vimentin), dystrophin, markers of myogenic differentiation (foetal myosin, neural cell adhesion molecule, bcl-2, insulin-like growth factor-I, fibroblast growth factor, retinoblastoma protein and myoD1), cell cycle regulators (Cdk2, p16, p27 and p57) and muscle proteases (ubiquitin, micro and m calpain and cathepsin D) in muscle biopsies from four patients with myotonic dystrophy. Sarcoplasmic masses were strongly positive for desmin, neural cell adhesion molecule, bcl-2, insulin-like growth factor I, retinoblastoma protein and p57, weakly positive for dystrophin and p16 and negative for vimentin, fibroblast growth factor, myoD1, Cdk2 and p27. Immunoreactivity for foetal myosin was detected only in a few fibres (< 1%). Our data suggest that the late myogenic differentiation programme is activated in sarcoplasmic masses although these areas do not reach complete maturation.

The authors report in patients with Val102/fs null mutation a possibly age dependent variability of clinical and electrophysiologic phenotype, segmental conduction abnormalities mainly in ulnar nerves at the elbow, and excessive myelin foldings and thickenings. The authors hypothesize that myelin thickenings at the paranodal region, in concurrence with compression at usual entrapment sites or minor repetitive trauma, may induce segmental conduction abnormalities.