Nerve ultrasound in Friedreich's Ataxia: enlarged nerves as a biomarker of disease severity.

OBJECTIVE: In Friedreich's ataxia research, the focus is on discovering treatments and biomarkers to assess disease severity and treatment effects. Our study examines high-resolution nerve ultrasound in these patients, seeking correlations with established clinical markers of disease severity. METHOD: Ten patients with Friedreich's Ataxia underwent a comprehensive clinical assessment with established scales (SARA, FARS, mFARS, INCAT, ADL 0-36, IADL). Additionally, they underwent nerve conduction studies and high-resolution nerve ultrasound. Quantitative evaluation of nerve cross-sectional area, conducted at 24 nerve sites using high-resolution nerve ultrasound, was compared with data obtained from 20 healthy volunteers. RESULTS: All the patients had a severe sensory axonal neuropathy. High-resolution nerve ultrasound showed significant increase, in cross sectional area, of median and ulnar nerves at the axilla and arm. The cumulative count of affected nerve sites was directly associated with clinical disability, as determined by SARA, FARS, mFARS, ADL 0-36, and INCAT score, while displaying an inverse correlation with IADL. CONCLUSIONS: Our study shows that high-resolution ultrasound reveals notable nerve abnormalities, primarily in the upper limbs of patients diagnosed with Friedreich's Ataxia. The observed correlation between these nerve abnormalities and clinical disability scales indicates the potential use of this technique as a biomarker for evaluating disease severity and treatment effects. SIGNIFICANCE: Nerve Ultrasound is a potential biomarker of disease severity in Friedreich's Ataxia.

Predicting value for incomplete recovery in Bell's palsy of facial nerve ultrasound versus nerve conduction study.

OBJECTIVE: This longitudinal study aims at assessing the predictive value of facial nerve high-resolution ultrasound (HRUS) for incomplete clinical recovery in patients with Bell's palsy, the most common facial nerve disease. METHODS: We prospectively enrolled 34 consecutive patients with Bell's palsy. All patients underwent neurophysiological testing (including facial nerve conduction study) and HRUS evaluations 10-15 days (T1), one month (T2), and three months (T3) after the onset of Bell's palsy. Patients who did not experience complete recovery within three months were also evaluated after six months (T4). We have then compared the accuracy of HRUS with that of the facial nerve conduction study in predicting incomplete clinical recovery at three and six months. RESULTS: At T1, the facial nerve diameter, as assessed with HRUS, was larger on the affected side than on the normal side, particularly in patients with incomplete recovery at T2, T3 and T4. ROC curve analysis, however, showed that the facial nerve diameter at T1 had a lower predictive value than the facial nerve conduction study for an incomplete clinical recovery at three (T3) and six (T4) months. Still, the facial nerve diameter asymmetry, as assessed with HRUS, had a relatively high negative predictive value (thus indicating a strong association between normal HRUS examination and a good prognosis). CONCLUSIONS: Although HRUS shows abnormally increased facial nerve diameter in patients in the acute phase of Bell's palsy, the predictive value of this technique for incomplete clinical recovery at three and six months is lower than that of the nerve conduction study. SIGNIFICANCE: Nerve ultrasound has a low predictive value for incomplete clinical recovery in patients with Bell's Palsy.

Modulation of the spinal N13 SEP component by high- and low-frequency electrical stimulation. Experimental pain models matter.

OBJECTIVE: The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of cervical dorsal horn neurons. Neurophysiological studies in healthy participants showed that capsaicin-induced central sensitization causes an increase of the N13 SEP amplitude. Consequently, in human research, this spinal component may serve as a valuable readout of central sensitization. In this study, we wanted to verify if the sensitivity of the N13 SEP for detecting central sensitization is consistent across different experimental pain models inducing central sensitization and secondary hyperalgesia, namely high and low-frequency electrical stimulation (HFS and LFS). METHODS: In 18 healthy participants, we recorded SEP after bilateral ulnar nerve stimulation before and after secondary hyperalgesia was induced through HFS and LFS applied on the ulnar nerve territory of the hand of one side. The area of secondary hyperalgesia was mapped with a calibrated 128-mN pinprick probe, and the mechanical pain sensitivity with three calibrated 16-64-256-mN pinprick probes. RESULTS: Although both HFS and LFS successfully induced secondary hyperalgesia only LFS increased the amplitude of the N13 SEP. CONCLUSIONS: These findings suggest that the sensitivity of the N13 SEP for detecting dorsal horn excitability changes may critically depend on the different experimental pain models. SIGNIFICANCE: Our results indicate that LFS and HFS could trigger central sensitization at the dorsal horn level through distinct mechanisms, however this still needs confirmation by replication studies.

Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans.

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex.

OBJECTIVE: In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. METHODS: In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. RESULTS: HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. CONCLUSIONS: HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. SIGNIFICANCE: Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans.

Biomarkers and new therapeutic targets in renal cell carcinoma.

OBJECTIVE: Renal Cell Carcinoma (RCC) is the most common malignancy in adult kidneys. The American Cancer Society estimated 62,700 new cases and 14,240 deaths in 2018. Although early detection has improved in recent years, the treatment remains a challenge and reliable biomarkers for poor outcomes become necessary for the prevention of metastases and improve the quality of patients' life during and after treatment. Then, the current status of the search for new RCC biomarkers was discussed, as well as the latest discoveries in the RCC risk and metastatic treatment were discussed in this review. MATERIALS AND METHODS: Extensive research was carried out in the online databases and full-free text articles published in the last 5 years, or more when convenient, were evaluated. Articles were included that addressed the proposed theme and were published in the English language. RESULTS: The present state of knowledge on biomarkers for RCC carcinogenesis and progression is still much to be understood about RCC risk factors and molecular pathways resulting in metastatic progression. Newest RCC target therapies were discussed, mainly in relation to immunological therapy, and vaccines that have been tested in numerous trials with different cancer types. CONCLUSIONS: The development of targeted therapies has revolutionized the treatment of advanced and metastatic cancers or non-responder patients. Combined therapy between classical chemotherapy and adjuvant immunotherapies has been modifying the cancer patients prognosis and bringing the hope of a cure in many cases.

Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy.

BACKGROUND: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. AIM: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. MATERIAL/SUBJECTS AND METHODS: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia®) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. RESULTS: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was -2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was -2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. CONCLUSIONS: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures.

Association of the GSTT1 polymorphism in upper aerodigestive tract cancer with tobacco smoking.

Polymorphisms in genes encoding xenobiotic-metabolizing enzymes might explain differences in the susceptibility to upper aerodigestive tract (UADT) cancers in individuals exposed to tobacco or other carcinogens. The present study aimed to evaluate the association of polymorphisms in the glutathione S-transferase (GST) candidate genes GSTM1, GSTT1, and GSTP1 with the risk of UADT cancers. GST gene polymorphisms were determined in 116 individuals with UADT cancer and 224 healthy controls using polymerase chain reaction-based methods. The GSTT1-null polymorphism was found to be a protective factor for UADT cancer [(odds ratio (OR) = 0.5, 95% confidence interval (CI) = 0.27-0.93)], although this association was not confirmed when adjusted for gender, age, smoking, alcoholism, and self-reported skin color in the multivariate logistic regression model (OR = 0.61, 95%CI = 0.29-1.28). The combined effect of GSTT1-positive genotypes with either the GSTP1 wild-type genotype (Ile/Ile) or the GSTP1 variant genotypes (Ile/Val or Val/Val) increased the risk for UADT cancer (OR = 4.34, 95%CI = 1.06-17.78 and OR = 4.55, 95%CI = 1.12-18.42, respectively). A significant interaction was observed among moderate smokers carrying the GSTT1-positive genotype. In this population, the significant gene-gene and gene-environment interactions of GST polymorphisms may confer a substantial risk to UADT cancers.

Sarcopenia in women with vertebral fragility fractures.

We performed a pilot study with the purpose to evaluate the prevalence of sarcopenia in osteoporotic women with vertebral fractures. Dual-energy X-ray absorptiometry (DXA) was used to measure the whole and regional body composition. Appendicular lean mass (aLM) was calculated as the sum of lean mass in arms and legs. We calculated the skeletal muscle mass index (aLM/h(2)), and we measured bone mineral density and T scores by DXA scan at total-body and at femoral neck. Participants were divided according to the number of vertebral fractures (single or multiple fractures). A total of 67 women were included. Thirty-five women (52.23%) had a vertebral fracture, of them 8 (22.85%) were sarcopenic and 32 women (47.76%) had multiple vertebral fractures, of them 14 (43.75%) were sarcopenic. Our results suggest that sarcopenia is common among osteoporotic women increasing along with the number of vertebral fragility fractures.

Efeito da sibutramina na redução do peso e no perfil metabólico em indivíduos obesos de uma população brasileira / Effects of sibutramine on weight reduction and metabolic profile in obese individuals in a brazilian population

O objetivo deste trabalho é avaliar a eficácia e a segurança da dose de 20 mg/dia de sibutramina em voluntários obesos, com IMC superior a 35, e compará-las com a dose de 10 mg/dia e à mudança de estilo de vida de pacientes com IMC inferior a 35 (a avaliação e a comparação foram realizadas em um período de 24 semanas). Foram submetidos a um estudo transversal 54 voluntários, distribuídos em três grupos de observação: grupo sem tratamento farmacológico (GMEV), grupo com IMC inferior a 35 e uma dose de 10 mg/ dia de sibutramina (G1) e grupo com IMC superior a 35 e dose de 20 mg/ dia de sibutramina (G2). Os parâmetros avaliados foram peso, circunferência abdominal e perfil metabólico. Os grupos submetidos ao tratamento farmacológico demonstraram maior redução do peso (G1: redução média de 9,4% ; G2: redução média de 20,6%) quando comparados a indivíduos sem tratamento farmacológico (GMEV: redução de 3,9%), assim como da circunferência abdominal (redução de 7,1%, 12,8% e 3,1% em G1, G2 e GMEV, respectivamente). Em relação aos achados laboratoriais, foram observados redução da glicemia de jejum (14,8%, 22,9% e 5% em G1, G2 e GMEV, respectivamente), aumento do HDL colesterol (31,2%, 40% e 14,2% em G1, G2 e GMEV, respectivamente) e redução do colesterol total (29,0%, 32,8% e 13,7% em G1, G2 e GMEV, respectivamente). Os resultados deste estudo demonstram que a dose de 20 mg de sibutramina é uma indicação segura e eficaz em pacientes obesos com IMC superior a 35

The aim of this study is to assess the efficacy and safety of an oral daily dose of 20 mg sibutramine in obese volunteers (BMI > 35), in comparison with a dose of 10 mg/day and changed lifestyle in patients whose BMI is less than 35. The testing and comparison were performed over 24 weeks. The 54 volunteers were subjected to a cross-sectional study in three observation groups: a reference group without pharmacological treatment (GMEV), a group with BMI < 35, treated with 10 mg ?day sibutramine (G1), and another with BMI ? 35, on a dose of 20 mg? day (G2). The variables assessed were weight, abdominal circumference and metabolic profile. The groups subjected to the drug treatments exhibited greater weight losses (G1: -9.4% and G2: -20.6%) than the group that took no drugs (GMEV: -3.9%). The abdominal circumference was reduced by 7.1%, 12.8% and 3.1% in G1, G2 and GMEV, respectively. Regarding the biochemical variables, there was a reduction in fasting glucose levels (-14.8%, -22.9% and -5% in G1, G2 and GMEV, respectively); an increase in HDL cholesterol (+31.2%, +40% and +14.2% in G1, G2 and GMEV, respectively) and a reduction in total cholesterol (-29.0%, -32.8% and ?13.7% in G1, G2 and GMEV, respectively). The results of this study show that sibutramine, in doses of 20 mg/ day, is a safe and efficient drug for obesity treatment in patients whose BMI exceeds 35.

In vitro and in vivo MR evaluation of internal gradient to assess trabecular bone density.

Here we propose a new magnetic resonance (MR) strategy based on the evaluation of internal gradient (G(i)) to assess the trabecular bone (TB) density in spongy bone. Spongy bone is a porous system characterized by a solid trabecular network immersed in bone marrow and characterized by a different relative percentage of water and fats. Using a 9.4 T MR micro-imaging system, we first evaluated the relative water and fat G(i) as extracted from the Spin-Echo decay function in vitro of femoral head samples from calves. Indeed, the differential effects of fat and water diffusion result in different types of G(i) behavior. Using a clinical MR 3T scanner, we then investigated in vivo the calcanei of individuals characterized by different known TB densities. We demonstrate, on these samples, that water is more prevalent in the boundary zone, while fats are rearranged primarily in the central zone of each pore. In vitro experiments showed that water G(i) magnitude from the samples was directly proportional to their TB density. Similar behavior was also observed in the clinical measures. Conversely, fat G(i) did not provide any information on spongy-bone density. Our results suggest that water G(i) may be a reliable marker to assess the status of spongy bone.

Vitamin D supplementation in fractured patient: how, when and why.

Vitamin D, through its action on calcium metabolism, is essential for bone physiology. It's also required in a wide range of biological systems to act modulating the proliferation and inducing terminal differentiation of a variety of normal cells. Actually vitamin D deficiency can impact muscle function and increases fall risk in elderly, while severe vitamin D deficiency (< 30 nmol/L) is common in patients with fragility fractures. Vitamin D and calcium supplementation, in addition to antiosteoporosis treatment after surgery or conservative treatment, can ensure optimal recovery and survival, especially in hip fractured patients.

Direct measurement of the 7Be solar neutrino flux with 192 days of borexino data.

We report the direct measurement of the 7Be solar neutrino signal rate performed with the Borexino detector at the Laboratori Nazionali del Gran Sasso. The interaction rate of the 0.862 MeV 7Be neutrinos is 49+/-3stat+/-4syst counts/(day.100 ton). The hypothesis of no oscillation for 7Be solar neutrinos is inconsistent with our measurement at the 4sigma C.L. Our result is the first direct measurement of the survival probability for solar nu(e) in the transition region between matter-enhanced and vacuum-driven oscillations. The measurement improves the experimental determination of the flux of 7Be, pp, and CNO solar nu(e), and the limit on the effective neutrino magnetic moment using solar neutrinos.

Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma.

Bone marrow macrophages of patients with active and nonactive multiple myeloma (MM), monoclonal gammopathies of undetermined significance (MGUS) and benign anemia (controls) were stimulated for 7 days with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and analysed for the expression of endothelial cell (EC) markers by reverse transcription (RT)-PCR, real-time RT-PCR, western blot and immunofluorescence. Their vasculogenic ability was investigated in vitro in a Matrigel assay and in vivo on bone marrow biopsies through dual immunofluorescence and confocal laser microscopy. Active MM macrophages exposed to VEGF and bFGF acquired EC markers and formed capillary-like structures mimicking paired bone marrow ECs (multiple myeloma patient-derived endothelial cells, MMECs), with major responsiveness compared to macrophages from nonactive MM, MGUS or controls. Bone marrow biopsies of active MM harbored 'mosaic' vessels, being formed by MMECs, EC-like macrophages and macrophages themselves. These figures were rare in nonactive MM and absent in MGUS or controls. Our data indicate that macrophages contribute to build neovessels in active MM through vasculogenic mimicry, and this ability proceeds parallel to progression of the plasma cell tumors. Macrophages may be a target for the MM antivascular treatment.

Drop-out rate in eating disorders: could it be a function of patient-therapist relationship?

OBJECTIVE: The factors influencing drop-out in eating disorders (ED) are still unclear. The aim of the present study was to determine whether compliance is strongly related to the patient-therapist relationship. MATERIALS AND METHODS: During 14 months all new patients affected by EDs referring to our Specialist Service Center, were assessed and followed up, they underwent EAT 40, EDI II, and computerized case history for ED. Moreover, we collected data from therapist using the GCI scale, and we recorded as the patient perceived his weight (PPW). RESULTS: We found that out of the 100 patients enrolled, 53 withdraw and when probability was predicted according to a digit model, it was not influenced by EDI-II subscales, age, sex, education, EAT-40 score, duration of the disorder and diagnosis while it significantly decreased when GCI scores increased and decreased when the PPW was altered. CONCLUSION: These results seem to confirm that some psychological factors related to patient-therapist relationship can play a key role for a stable and continuous therapeutic program.

Crosstalk between angiogenesis and lymphangiogenesis in tumor progression.

Extensive studies have identified reliable markers of lymphatic endothelial cells, and mechanisms and molecules that regulate development and growth of the lymphatic vessels. Vascular endothelial growth factors (VEGF)-C and VEGF-D, and their cognate receptor tyrosine kinase, VEGF receptor-3 (VEGFR-3), are critical regulators of lymphangiogenesis. By binding to its endothelial cell surface receptors VEGFR-1 and VEGFR-2, VEGF-A mediates vascular leakage, endothelial proliferation and migration. Angiopoietin-2 (Ang-2) is expressed at sites of blood vessel remodeling and invasion, and factors that induce angiogenesis in vivo, such as VEGF-A, upregulate Ang-2 in endothelial cells. In this review, we summarize the literature concerning the crosstalk between angiogenesis and lymphangiogenesis in tumor progression, that is, involvement of VEGF-C, VEGF-D and VEGFR-3 in angiogenesis, and the role played by VEGF-A and Ang-2 in lymphangiogenesis, respectively.

Simulation of real-time deformable soft tissues for computer assisted surgery.

The simulation of realistic surgical procedures requires specialized optimized algorithms for the models of organs and tissues, which should comply both with accuracy of results and run-time computation. This paper provides a general survey of methods and approaches used for the simulation of soft tissues in Computer Assisted Surgery, discussing the technological challenges to achieve realistic simulation of deformation.An application example is presented, referring to the simulation of a gastroenterology procedure, abdominal paracentesis for the treatment of ascites.

Psychiatric comorbidity in a population of outpatients affected by tinnitus.

The aim of this study was to outline the psychopathological characteristics of a population of outpatients affected by tinnitus and to consider its impact on their mental state and ability to function in major areas of their lives. Seventy-five consecutive tinnitus patients were enrolled on their first visit to the outpatients clinic of the Audiology Department of the 'Federico II' University of Naples, for audiological and psychiatric evaluation. A series of audiometric and vestibular tests was performed for tinnitus rating assessment, and further information was obtained from the patient via a semi-structural interview. For the psychopathological examination, patients underwent the Mini International Neuropsychiatric Interview (MINI), by means of which a multiaxial diagnosis (five axes) was expressed, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). For a better understanding of the personality aspects, the Minnesota Multiphasic Personality Inventory (MMPI) test was administered to a subgroup of 55 subjects whose cultural background permitted their full cooperation. The results of the study show that 58 subjects (77% of the total) met the criteria for psychiatric disorder diagnosis, according to the DSM-IV system: Axis I comprises anxiety, affective and somatoform disorders and psychoses; Axis II comprises personality disorders. Multiple diagnoses were expressed in some subjects. The findings of the examination via MMPI show a high percentage of depression, hysteria, and hypochondria. Although we are not seeking to establish a cause-effect relationship between the unpleasant experience of tinnitus and psychopathological disorders, our findings are consistent with those of other authors. Tinnitus can indeed have severe consequences for the subject's ability to function in many areas of their life. In this paper, the implications of such results for the diagnosis and therapy of tinnitus are discussed.