PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism.

We analyzed the PINK1 gene in 58 patients with early-onset Parkinsonism and detected the homozygous mutation W437X in 1 patient. The clinical phenotype was characterized by early onset (22 years of age), good re- sponse to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinson’s disease and 3 further relatives were reported affected, according to an autosomal dominant transmission

Tiroidectomia totale con impiego del dissettore ad ultrasuoni: risultati di uno studio prospettico randomizzato

In the last years, the introduction and employment in surgery of the dissectors of last generation (ultrasounds, radiofrequency, etc.) have contributed to a remarkable improvement and simplification of the performances and the surgical techniques. The present study has the aim to verify, on the basis of the experience made in the last two years and through a careful comparisons with operations performed in the usual way, the advantages of employment of ultrasonic dissector in thyroid surgery and if besides such advantages it is possible to obtain real and substantial reductions of the complications. To such aim a randomized perspective study has been lead, confronting two groups of 60 patients, submitted to total thyroidectomy in Chair of General Surgery and Surgical Physiopathology of the University of Palermo - Complex Operating Unit of General Surgery. In all patients have been considered age, sex, histological diagnosis, length of the incision, time (from the incision until suture of skin), entity of the bleeding, hospital stay, post-operative consequences and total costs of thyroidectomy. The elaboration of the obtained data shows the advantages following to the use of the dissectors of last generation: reduction of the times, reduction of the complications, better tolerance of the operation by patients, better rationalization of the resources

Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit.

Objective of the study was to test the efficacy, safety, and tolerability of two single doses of Epoetin alfa in patients with Friedreich's ataxia. Ten patients were treated subcutaneously with 600 IU/kg for the first dose, and 3 months later with 1200 IU/kg. Epoetin alfa had no acute effect on frataxin, whereas a delayed and sustained increase in frataxin was evident at 3 months after the first dose (+35%; P < 0.05), and up to 6 months after the second dose (+54%; P < 0.001). The treatment was well tolerated and did not affect hematocrit, cardiac function, and neurological scale. Single high dose of Epoetin alfa can produce a considerably larger and sustained effect when compared with low doses and repeated administration schemes previously adopted. In addition, no hemoglobin increase was observed, and none of our patients required phlebotomy, indicating lack of erythropoietic effect of single high dose of erythropoietin. © 2010 Movement Disorder Society

New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma.

The tyrosine kinase inhibitor (TKI) sorafenib continues to be the anchor drug in the treatment of advanced stage hepatocellular carcinoma (HCC). Other TKIs as well as immune checkpoint inhibitors (ICIs) have also been approved, however the response rates remain poor and heterogeneous among HCC patients, largely due to antitumor drug resistance. Studies aimed at identifying novel biomarkers and developing new strategies to improve the response to current treatment and to overcome drug resistance, are urgently needed. Germline or somatic mutations, neoantigens, and an immunotolerogenic state against constant inflammatory stimuli in the liver, are crucial for the anti-tumor response. A pharmacogenetic approach has been attempted considering germline polymorphisms in genes encoding for proteins involved in drug-targeted pathways. Single gene and comprehensive multi-gene somatic profiling approaches have been adopted in HCC to identify tumor sensitivity scores and immunogenic profiles that can be exploited for new biomarkers and innovative therapeutic approaches. However, the high genomic heterogeneity of tumors and lack of molecularly targeted agents, hamper the discovery of specific molecular markers of resistance to therapy. Adoptive cell therapy with chimeric antigen receptor redirected T (CAR-T) cells targeting specific tumor-associated antigens (TAAs) was proposed recently. The specificity of the chosen TAA, an efficient homing of CAR-T cells to the tumor site, and the ability of CAR-T cells to survive in the tumor microenvironment are central factors in the success of CAR-T therapy. The current review describes the principal systemic treatments for HCC and the molecular evidence regarding potential predictive host and somatic genetic markers, as well as the emerging strategy of liquid biopsy for disease monitoring. Novel immunotherapeutic approaches for HCC treatment, including the use of ICIs and CAR-T, as well as strategies to overcome drug resistance, are discussed

Growth hormone response to arginine test distinguishes multiple system atrophyfrom Parkinson's disease and idiopathic late-onset cerebellar ataxia

OBJECTIVE: Multiple system atrophy (MSA) is difficult to distinguish from idiopathic Parkinson's disease (PD) and idiopathic late-onset cerebellar ataxia (ILOCA). This study aimed to evaluate GH response to three different GH stimulation tests in order to establish a reliable test to differentiate these degenerative disorders. DESIGN: Twelve patients with MSA, 10 with PD, eight with ILOCA and 30 healthy controls entered the study. They were submitted to clonidine, arginine, and GH-releasing-hormone (GHRH) + arginine tests in a random manner on three different nonconsecutive days. The peak serum GH response was used as a primary variable for analysis of stimulation tests. By ROC analysis, the optimum cut-off level was considered as the cut-off with the maximal sum of sensitivity and specificity. RESULTS: After clonidine administration, GH peak was significantly lower in patients with MSA than in those with ILOCA (P < 0.05) and in the controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the clonidine test distinguished patients with MSA from those with PD with a sensitivity and specificity of 78%. Moreover, this test distinguished patients with MSA from those with ILOCA with a sensitivity of 100% and a specificity of 75% at a cut-off level of 5 mU/l, and with a sensitivity of 75% and a specificity of 100% at the cut-off level of 7.6 mU/l. After arginine administration, the GH peak was significantly lower in patients with MSA than in those with ILOCA (P = 0.001) and in controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the arginine test distinguished patients with MSA from those with PD with a sensitivity and a specificity of 100%. At a GH peak cut-off value of 3.6 mU/l the arginine test distinguished patients with MSA from those with ILOCA with a sensitivity and specificity of 100%. After GHRH + arginine administration, a significant GH increase was found in all groups of patients and controls. CONCLUSIONS: The GH response to arginine administration is impaired in MSA. Therefore, the arginine test showed the highest diagnostic accuracy to distinguish MSA from both PD and ILOCA, and could be used in the clinical practice of these neurodegenerative diseases

Rashba spin precession in quantum Hall edge channels

Quasi--one dimensional edge channels are formed at the boundary of a two-dimensional electron system subject to a strong perpendicular magnetic field. We consider the effect of Rashba spin--orbit coupling, induced by structural inversion asymmetry, on their electronic and transport properties. Both our analytical and numerical results show that spin--split quantum--Hall edge channels exhibit properties analogous to that of Rashba--split quantum wires. Suppressed backscattering and a long spin life time render these edge channels an ideal system for observing voltage--controlled spin precession. Based on the latter, we propose a magnet--less spin--dependent electron interferometer.Comment: 7 pages, 6 figure

Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects.

Pelizaeus-Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus-Merzbacher-Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression. This observation underlines the interest of determining both free T3 and free T4 serum concentrations to screen for MCT8 mutations in young patients (<3 y) with a severe Pelizaeus-Merzbacher-Like disease presentation or older severe mentally retarded male patients with "hypomyelinated" regions

Physical activity in the prevention of peripheral artery disease in the elderly

Aging is a well-known cardiovascular risk factor and cardiovascular diseases (CVD) are estimated to be the most common cause of death in the elderly. Peripheral arterial disease (PAD) represents an important clinical manifestation of CVD leading to increase morbidity and mortality, especially in elderly population. The correct management of PAD population includes the prevention of cardiovascular events and relief of symptoms, most commonly intermittent claudication. Progressive physical activity is an effective treatment to improve walking distance and to reduce mortality and cardiovascular events in patients with PAD, however the ability to effectively engage in physical activity often declines with increasing age. The maintenance and increase of reserve functional capacity are important concepts in the elderly population. Ultimately, the goal in participation of physical activity in the healthy elderly population is maintenance and development of physical functional reserve capacity. Therefore, for individuals suffering of PAD, appropriate physical activity in the form of supervised exercise may serve as a primary therapy. Although there are few direct comparisons of therapeutic exercise programs vs. pharmacological or surgical interventions, these increases in walking distance are greater than those reported for the most widely used agents for claudication, pentoxyphylline, and cilostazol. Despite a reduction in mortality and improvement of quality of life caused by physical activity in the PAD population, the molecular, cellular, and functional changes that occur during physical activity are not completely understood. Therefore, this review article aims at presenting an overview of recent established clinical and molecular findings addressing the role of physical activity on PAD in the older population

A randomized clinical trial of lithium in multiple system atrophy.

The aim of our study was to test the safety and tolerability of lithium in multiple system atrophy (MSA). The study was randomized, placebo-controlled, and double-blind. The primary endpoint of the study was safety and tolerability. An interim analysis, performed 1 year after the first patient was randomized, showed a higher proportion of trial abandon (P < 0.01) and a higher number of adverse events (P < 0.02) in the lithium group. The trial was stopped by the Data Monitoring Committee. Overall, lithium was not well tolerated, and we do not encourage future studies with lithium in MSA patients