Autosomal-dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation.

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population.

OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5 years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5 years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.

Lymphocytosis as a response biomarker of natalizumab therapeutic efficacy in multiple sclerosis.

BACKGROUND: Natalizumab is an effective therapy in relapsing-remitting multiple sclerosis (RRMS), as it reduces lymphocyte transmigration through the blood-brain barrier (BBB) and induces lymphocytosis. OBJECTIVES: To analyse natalizumab-induced lymphocytosis (NIL) as a biomarker of drug efficacy. MATERIALS AND METHODS: We enrolled 50 relapsing-remitting (RR) and progressive-relapsing (PR) natalizumab-treated patients who had received at least 16 infusions and had been tested for lymphocyte count 24 hours before each administration. Clinical, MRI and hematological data were collected. Patients were divided into responders and sub-optimal responders according to the experience of at least one clinical and/or instrumental relapse during the treatment. RESULTS: In 15 (30%) patients, an instrumental/clinical (14) or only instrumental (one) relapse occurred. We found a statistically significant difference in the mean percentage of the lymphocytes between the two groups over the first ten administrations (p=0.04). The comparison between the time-to-relapse in the groups with high and low levels of lymphocytes showed that the group with a low NIL had a greater risk of relapse (p=0.03). CONCLUSIONS: We suggest that NIL could be a biomarker of therapeutic efficacy in patients with RRMS treated with natalizumab, and that the risk of relapse may be higher in patients with a lower-than-expected NIL.

The impact of resveratrol on the outcome of the in vitro fertilization: an exploratory randomized placebo-controlled trial.

BACKGROUND: Resveratrol is a natural polyphenolic compound present in plants and red wine with many potential health benefits. This compound has various anti-inflammatory and anti-tumor properties and can improve cellular mitochondrial activity. This trial was designed to evaluate the effect on the outcome of IVF of Resveratrol supplementation in women > 35 years with good ovarian reserve (AMH > 1.2 ng/ml). Women were randomized to receive or placebo or Resveratrol (150 mg per day) for three months preceding the ovarian stimulation (OS). All patients were stimulated with a starting dose of recombinant FSH ranging between 150 and 300 IU according to age and ovarian reserve. GnRH antagonist flexible protocol was adopted for pituitary suppression. Triggering was performed with urinary hCG (10.000 IU). RESULTS: The study was conducted between January 2019 and December 2022 with aa total of 37 cases and 33 controls were recruited. No statistically significant differences in the number of oocytes retrieved, biochemical pregnancy, clinical pregnancy and live birth rates were observed between women treated with resveratrol and control group. A statistically significant increase in the follicle output rate (FORT) and follicle-to oocyte index (FOI) was observed in women treated with resveratrol-based nutraceutical (0.92 versus 0.77 [p = 0.02], and 0.77 versus 0.64 [p = 0.006], respectively). CONCLUSIONS: Preliminary results from this study indicate that pre-treatment with resveratrol may improve ovarian sensitivity to exogenous FSH, which in turn may decrease the risk of hypo-response to OS in advanced reproductive age women.

Treatment-resistant insomnia treated with pregabalin.

We report a case with refractory insomnia. We diagnosed her case as depression with high levels of anxiety, weakness, with diminished ability to think or concentrate and with a sensory-motor disorder. Although this last symptom was very distressing, it did not satisfy the criteria for RLS (Restless Legs Syndrome). After treatment with paroxetine (20 mg) and zolpidem (10 mg), anxiety and mood deflection were attenuated. Nevertheless, a mild depression, an intermittent awakening (fragmentation of the sleep-wake rhythm) and subsyndromal RLS persisted. Her resistant insomnia was treated with benzodiazepine sleeping drugs (triazolam 0.25 mg, lorazepam 2.5 mg, fluorazepam 30 mg) with only partial insomnia remission, antidepressants (trazodone 150 mg RP, mirtazapine 15-30 mg, agomelatine 50 mg) and antipsychotics (levomepromazine 25 mg, zuclopentixol 25 mg) without results. Her intractable insomnia was markedly responsive to pregabalin without side effects. Our hypothesis is that the therapy with pregabalin may be indicated for resistant insomnia associated with subsyndromal RLS, even when the latter does not satisfy fully all the criteria for diagnosis.

Nerve growth factor and brain-derived neurotrophic factor concentrations in schizophrenia: a review.

There is growing interest in the role of neurotrophins in the pathophysiology of schizophrenia. Neurotrophins are a large family of dimeric polypeptides that promote the growth and the differentiation of developing neurons in the central and peripheral nervous systems as well as the survival of neuronal cells in response to stress. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) concentrations are here reviewed in relation to medication-naive early psychotic patients and in medicated chronic schizophrenic patients. Most data point to decreased plasma and serum NGF and BDNF concentrations in naive drug and in medicated schizophrenic patients compared to healthy controls. Higher BDNF levels were observed in patients with the paranoid subtype of schizophrenia. Low serum BDNF levels were associated with reduction in hippocampal volume (HV) at the onset of schizophrenia. Evidence on the correlation between BDNF levels and positive and negative schizophrenic symptoms were ambiguous. There are contrasting results on a possible correlation between increase in BDNF concentrations and treatment with antipsychotics. Antipsychotic treatment can elevate NGF values, specifically atypical. Growth factors might be good candidates as prognostically and diagnostically useful markers in schizophrenia.

The impact of modern radiotherapy on long-term cardiac sequelae in breast cancer survivor: a focus on deep inspiration breath-hold (DIBH) technique.

INTRODUCTION: One of the most feared side effects of radiotherapy (RT) in the setting of breast cancer (BC) patients is cardiac toxicity. This side effect can jeopardize the quality of life (QoL) of long-term survivors. The impact of modern techniques of RT such as deep inspiration breath hold (DIBH) have dramatically changed this setting. We report and discuss the results of the literature overview of this paper. MATERIALS AND METHODS: Literature references were obtained with a PubMed query, hand searching, and clinicaltrials.gov. RESULTS: We reported and discussed the toxicity of RT and the improvements due to the modern techniques in the setting of BC patients. CONCLUSIONS: BC patients often have a long life expectancy, thus the RT should aim at limiting toxicities and at the same time maintaining the same high cure rates. Further studies are needed to evaluate the risk-benefit ratio to identify patients at higher risk and to tailor the treatment choices.

Major depressive disorder, anhedonia and agomelatine: an open-label study.

Despite a wide range of available antidepressants, the effect of the treatment is often suboptimal and there is a need for more effective and better tolerated drugs. Unlike other antidepressants, agomelatine represents a new approach to depression with an innovative mechanism of action. It is an agonist of melatoninergic receptors MT1 and MT2 and a selective antagonist of 5-HT2c receptors. In this open-label 8-week study we aimed to investigate the efficacy of agomelatine on depressive symptoms in patients with major depression. Secondary endpoints were the effect of agomelatine on anhedonia. Thirty major depressive patients received a flexible dose (25-50 mg; per os, daily) of agomelatine. Depressive (Hamilton Depression Scale) and anxious (Hamilton Anxiety Scale) symptoms, anhedonia (Snaith Hamilton Rating Scale), and sleep quality (Leeds Sleep Evaluation Questionnaire) were assessed. Twenty-four patients (80%) completed 8 weeks of treatment. Significant improvements were seen at all visits on the HAM-D (p<.05), HAM-A(p<.01), SHAPS (p<.05), LSEQ (p<.05). Nine subjects (30%) were responders and 5 (17%) remitters at week 1; 18 (60%) were remitters by the end of the trial. There was no serious adverse event. No aminotrasferase elevations were noted. In line with previous studies, in which agomelatine was associated with early clinical improvement, this study also provides evidence of an early response and the findings of improvements in depression scores. Moreover, this is the first study where agomelatine was effective in the treatment of anhedonia. Additional trials are needed to delineate the place of agomelatine in the contemporary pharmacotherapy for depressive disorders.

Inhibition of prostaglandin synthesis reduces the induction of MyoD expression in rat soleus muscle.

MyoD is a myogenic regulatory factor with a critical role in skeletal muscle development and regeneration. As muscle regeneration comes with an inflammatory process, it has been proposed that the inflammatory cells can play an important role in the induction of muscle fibres regeneration. The aim of the present work was to verify if a cyclooxygenase inhibitory drug (ketoprofen) would alter the normal expression of MyoD in a regenerating rat soleus muscle after an over-load lesion. Using immunohistochemical techniques, the numbers of m-cadherin-positive cells, a selective marker of satellite cells, and MyoD-positive cells were evaluated in functionally overloaded rat soleus muscles 4 days after a gastrocnemius tendon cut. The same study was conducted either with four rats injected with ketoprofen (100 mg/kg b.w./day) or with four rats injected with saline solution. The data obtained showed a very large decrease in the number of MyoD positive/m-cadherin positive cells in the ketoprofen injected group compared to the control group. Although further studies are needed to elucidate the sequence of biochemical events that induce a reduction of MyoD expression due to ketoprofen, the results demonstrate that prostaglandin synthesis is required for the induction of MyoD expression and that ketoprofen can affect this expression, with possible adverse effects on muscle regeneration.

Mapping of a gene for Parkinson's disease to chromosome 4q21-q23.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 1 percent of the population over age 50. Recent studies have confirmed significant familial aggregation of PD and a large number of large multicase families have been documented. Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD, with a Zmax = 6.00 for marker D4S2380. This finding will facilitate identification of the gene and research on the pathogenesis of PD.

Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

Autonomic neuropathy in mixed cryoglobulinemia.

A retrospective, cross-sectional study was performed on a series of HCV-related mixed cryoglobulinemia (HCV-MC) patients to assess autonomic neuropathy (AN) and its relation to peripheral neuropathy (PN). Thirty consecutive patients affected by HCV-MC underwent clinical, neurological and electrodiagnostic examinations. Autonomic nervous system (ANS) involvement was assessed by functional cardiovascular tests and sympathetic skin response (SSR) evaluation. Sural nerve biopsy was performed in 10 patients with PN. All patients received steroids, 15 also received recombinant interferon-alpha2b (RIfn-alpha2b). PN occurred in 27 patients (90.0%) and AN in 4 (13.3 %) all with signs of PN. SSR was the autonomic test more frequently altered. Biopsy disclosed axonal degeneration more evident in the 4 patients with AN. Three out of 4 patients with AN received steroids and rIFN-alpha2b and 1 steroids alone. In our study on HCV-MC, it was concluded that AN can occur also without dysautonomic symptoms, SSR appears to be one of the optional tests to use together with dysautonomic tests to identify AN and finally PN and AN do not seem to be positively influenced by addition of rIFN-alpha2b to steroid treatment.

Perceived insecurity, mental health and urbanization: Results from a multicentric study.

AIMS: This article aims to (1) explore the levels of perceived insecurity in a sample of patients with mood or anxiety disorders and (2) assess whether living in 'big cities' can influence the levels of patients' perceived insecurity and social contacts compared to living in a non-urbanized context. METHODS: A total of 24 Italian mental health centers (MHCs) have been invited to participate. Twenty patients consecutively accessing the MHC have been recruited. All patients have been assessed using validated assessment tools. RESULTS: The sample consisted of 426 patients, mostly female, with a mean age of 45 years. Globally, 52.2% of patients had a diagnosis of mood disorders, and 37.8% had anxiety disorders. Half of the sample declared that the main feeling toward life is uncertainty; higher levels of pessimistic views toward life have been detected in patients living in urban areas. A positive association between negative attitudes toward life and higher levels of depressive and anxiety symptoms, poor social functioning and higher levels of perceived psychological distress has been found. CONCLUSION: Our findings confirm the presence of a common sense of perceived uncertainty among our sample. Such attitude toward life can have a detrimental impact on patients' psychological and physical well-being, contributing to high levels of distress.

Primary cerebral toxoplasmosis: a rare case of ventriculitis and hydrocephalus in AIDS.

We describe the clinical, radiological and neuropathological findings in an adult AIDS patient presenting with ventriculitis and hydrocephalus as the primary manifestations of cerebral toxoplasmosis. Clinical symptoms including fever, headache, changes in mental status and focal neurological deficits were non-specific. Cranial computed tomography showed a subtile ventricular dilatation whereas magnetic resonance imaging disclosed triventricular hydrocephalus due to stenosis of the aqueduct and a periventricular nodular rim of high signal intensity on T2- and proton density-weighted images. This rim also showed a slight enhancement on post-contrast T1-weighted images. Focal intracerebral lesions could not be delineated, neither by neuroimaging nor by pathology. Neuropathological examination showed severe ventriculitis with large ependymal and subependymal necrosis as well as dilatation of the lateral and the third ventricle. The only microorganism demonstrated at histology in the central nervous system was Toxoplasma gondii. We conclude that ventriculitis and hydrocephalus without any focal parenchymal lesion may be the only manifestations of CNS toxoplasmosis. It is important to recognize this unusual form of presentation of cerebral toxoplasmosis in order to perform specific therapy.

Peripheral nervous system involvement in Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a rare congenital malformation of unknown etiology characterized by cutaneous hemangiomas, venous varicosities and bony and soft tissues hypertrophy usually affecting one limb. Several complex anomalies involving various organs and systems have been described, whereas involvement of the peripheral nervous system has rarely been reported in KTS. We describe the case of a 67-year-old woman with KTS and peripheral neuropathy related to the presence of epineurial microscopic arteriovenous anastomoses (AVA) and endoneurial vascular coils in sural nerve biopsy from both hypertrophic and non-hypertrophic limb. The maintenance of AVA has been proposed to be the cause of the hypertrophy. The observation in our patient of AVA in non-hypertrophic limb contrasts with this hypothesis.

Human mesenchymal stem cells are tolerized by mice and improve skin and spinal cord injuries.

INTRODUCTION: We sought to use human mesenchymal stem cells (HMSC) for skin and spinal cord repair in mice. MATERIALS AND METHODS: Human bone marrow obtained from a young healthy donor was used to separate and culture human mesenchymal stem cells (HMSC). Ten mice were included in each of four groups. A full-thickness skin defect was surgically performed on all mice in groups 1 and 2. A transverse complete medullar section was performed in groups 3 and 4. Groups 1 and 3 received HMSC IV infusion and local HMSC polymer implant. Groups 2 and 4 received only the IV HMSC infusion. Five control animals from each group went through the same lesions but they didn't receive treatment. RESULTS: After local administration of HMSC into the fibrin polymer combined with the IV infusion of HMSC, there was no immune rejection; all skin defects healed without scar or retraction at a median time of 14 days. Sixty percent of the animals treated with IV infusion and polymer with HMSC simultaneously had improved neurological activities, while all control mice with spinal cord injury experiments died or perpetuated their paralysis with worsening muscular atrophy and increasing propensity to skin damage. CONCLUSIONS: HMSC are not immunologically reactive and can trespass species defense barriers. Animals treated with these cells repaired injuries better than controls. In this way we propose that universal HMSC from donors can be cultured, expanded, and cryopreserved to be used in human organ or tissue regeneration.

Identification and characterization of a novel member of the dystrobrevin gene family.

A new member of the dystrobrevin gene family was identified using a bioinformatics approach. Sequence analysis indicates that this gene, named DTN-B, is highly homologous to the rabbit A0, the previously described dystrobrevin (DTN), Torpedo 87 kDa and to the C-terminus of dystrophin. The coiled-coil domain, shown to be the site of interaction between dystrobrevins and dystrophin, is highly conserved. Immunostaining studies indicate that DTN-B and DTN expression is absent in affected muscle fibers from DMD patients and carriers.

Lack of sodium channel mutation in an Italian family with paramyotonia congenita.

OBJECTIVE: To conduct the genotype-phenotype correlation in a family in which several individuals share clinical and electrophysiologic features of paramyotonia congenita (PC). BACKGROUND: PC, hyperkalemic periodic paralysis (HyperPP), and potassium-aggravated myotonias form the group of hereditary sodium channelopathies. Each of these disorders is associated with different point mutations in SCN4A, the gene encoding the alpha-subunit of the adult human skeletal muscle sodium channel. However, in HyperPP families, evidence of a causative gene different from SCN4A has been found. METHODS: We conducted direct clinical examination, electrophysiologic (EMG/electroneurographic) and cardiologic studies, as well as laboratory screening in several affected and nonaffected members of the family. We performed the genotype-phenotype correlation by microsatellite linkage and cDNA-mutation analyses of the SCN4A gene. RESULTS: Affected members in this family showed clinical and electrophysiologic features typical of PC. The disease phenotype segregated with the chromosomal region that includes the SCN4A gene. Analysis of the entire cDNA sequence of the SCN4A gene in the index case disclosed a G3826A transition, which results in the Val1276Ile substitution. However, PCR-single-stranded confirmation polymorphism and direct sequencing analysis of the segment coding for Val-1276 on genomic DNA confirmed the G3826A transition in the index case but was negative in 11 affected members of the family; however, neither mutations nor aberrant splicings causative of the PC phenotype in this family were found on SCN4A. CONCLUSION: The existence of a second gene different from SCN4A that can give rise to a clinical PC phenotype can be speculated upon.

Paradoxical sleep rebound without previous debt: the effect of minute doses of clonidine in man.

This report describes an experimental condition in which clonidine administration does not modify paradoxical sleep (PS) directly, but is followed by a secondary rebound. After oral consumption of minute doses of clonidine (CLN), 12 subjects showed no direct effect of CLN, but showed a significant increase of PS production in the following placebo night. Four other subjects experienced a decrease of PS under CLN and no rebound the next night. In addition, these four subjects had mechanisms of slow wave sleep production significantly weaker than the first 12 subjects.

Phenotype heterogeneity among hemizygotes in a family biochemically screened for adrenoleukodystrophy.

We report on two clinically, neurologically normal relatives of a boy affected by adrenoleukodystrophy (ALD); they were found repeatedly to have the biochemical defect of an ALD hemizygote. The assay consisted in the determination of very-long-chain fatty acids in lyophilized and reconstituted plasma. While no evidence of neurologic disease (leukodystrophy or myeloneuropathy) was present in these hemizygotes, adrenocortical insufficiency provoking compensatory high ACTH release was found in both. These findings should be taken into consideration when counseling families in which cases with clinically expressed ALD are represented in several generations.