Quantitative Tractography-Based Evaluations in Essential Tremor Patients after MRgFUS Thalamotomy.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) targeting the thalamic ventral intermediate nucleus (VIM) is an innovative treatment for drug-refractory essential tremor (ET). The relationship between lesion characteristics, dentate-rubro-thalamic-tract (DRTT) involvement and clinical benefit remains unclear. OBJECTIVES: To investigate whether clinical outcome is related to lesion volume and/or its overlap with the DRTT. To compare the reliability of probabilistic versus deterministic tractography in reconstructing the DRTT and improving VIM targeting. METHODS: Forty ET patients who underwent MRgFUS thalamotomy between 2019 and 2022 were retrospectively analyzed. Clinical outcomes and adverse effects were recorded at 1/6/12 months after the procedure. The DRTT was generated using deterministic and probabilistic tractography on preoperative diffusion-tensor 3 T-images and location and volume of the lesion were calculated. RESULTS: Probabilistic tractography identified both decussating (d-DRTT) and non-decussating (nd-DRTT) components of the DRTT, whereas the deterministic approach only identified one component overlapping with the nd-DRTT. Despite the lesions predominantly intersecting the medial portion of the d-DRTT, with a significantly greater overlap in responder patients, we observed only a non-significant correlation between tremor improvement and increased d-DRTT-lesion overlap (r = 0.22, P = 0.20). The lesion volume demonstrated a significant positive correlation with clinical improvement at 1-day MRI (r = 0.42, P < 0.01). CONCLUSION: Variability in the reconstructed DRTT position relative to the lesion center of mass, even among good responders, suggests that this fiber bundle is unlikely to be considered the sole target for a successful MRgFUS thalamotomy in ET. Indirect individualized targeting allows for more precise and reproducible identification of actual treatment coordinates than the direct method.

Deepening the decisional processes under value-based conditions in patients affected by Parkinson's disease: A comparative study.

Patients affected by Parkinson's disease (PD) display a tendency toward making risky choices in value-based conditions. Possible causes may encompass the pathophysiologic characteristics of PD that affect neural structures pivotal for decision making (DM) and the dopaminergic medications that may bias choices. Nevertheless, excluding patients with concurrent impulse control disorders, results are few and mixed. Conversely, other factors, such as individual differences (e.g., emotional state, impulsivity, consideration for future consequences) and cognitive functioning, in particular executive functions (EFs), are involved, even though few studies investigated their possible role. The present study investigated (1) the differences in value-based DM between 33 patients with PD without impulse control disorders and 33 matched healthy controls, and (2) the relationships among decisional performances, EFs, and individual differences in a group of 42 patients with PD who regularly undertake dopaminergic medications. All participants underwent an individual assessment to investigate value-based DM, cognitive abilities, and individual differences associated with DM. Nonparametric analyses showed the presence of riskier decisions in patients compared with healthy controls, depending on the characteristics of the decisional situation. Moreover, parameters of the decisional tasks involving the number of risky choices were significantly related to the posology of dopaminergic medications, EFs, and individual differences. Findings were discussed, highlighting possible clinical implications.

Long-term Functional, Sexual, and Cosmetic Outcomes in Adult Patients Who Underwent Hypospadias Repair During Childhood at a Highly Specialized Italian Pediatric Hospital.

OBJECTIVE:  This study aims to evaluate long-term functional, sexual, and cosmetic outcomes in adult patients who underwent hypospadias repair during childhood at a national highly specialized pediatric hospital. METHODS:  Medical records of pediatric patients who had undergone surgical repair of hypospadias between 1993 and 2004 at Meyer Children Hospital of Florence were reviewed. Adult patients were contacted by telephone between July and August 2021 and invited to participate. Long-term surgical outcomes were assessed focusing on complications and reinterventions, and 3 validated questionnaires on urinary function, erectile function, and penile cosmetic appearance were administered. RESULTS:  From January 1993 to December 2004, a total of 799 patients with hypospadias underwent repair surgery. Two hundred thirty-nine patients gave consent to be included in the study. Follow-ups occurred between 17 and 28 years after the first surgery. Most patients had anterior localization of hypospadias (210/239) and associated penile curvature (132/239). The most frequent surgery for hypospadias repair was meatal advancement and glanduloplasty incorporated (MAGPI) (88/239), and the most used surgical treatment for penile curvature was the Nesbit technique (49/132). The complication rate was 27% (65/239) in an average time of 4.7 years, and 48 surgical procedures have been performed to treat them. At follow-up, the mean IPSS was 0.96 ± 1.97, the mean IIEF-5 score was 24.10 ± 1.02, and the mean HOSE score was 15.47 ± 0.45. Patients who underwent reintervention reported a lower IPSS than those who underwent only 1 surgery (0.29 vs. 1.16). CONCLUSION:  Hypospadias repair during childhood leads to rather normal urinary and sexual function and penile cosmetic appearance in adolescence and adulthood.

Ecophysiological and nutritional characterisation of two morphotypes of Cakile maritima subsp. maritima Scop. from Puglia region, Southern Italy.

Cakile maritima subsp. maritima Scop. (sea rocket) is a succulent halophyte with significant potential as a nutritious food source, being rich in essential nutrients such as vitamins, minerals, and antioxidants. This annual species exhibits two distinct leaf morphotypes: entire lamina (EL) and pinnatifid lamina (PL). Our understanding of their ecophysiological and nutritional profiles is still limited. The present study investigated the wild EL and PL sea rocket plants from southern Italy during their vegetative stage. The bio-morphological traits (leaf mass area-LMA, dry matter and chlorophyll concentrations), main inorganic ions, key antioxidants (carotenoids, anthocyanins, phenols, flavonoids, glucosinolates, vitamin C as ascorbic and dehydroascorbic acid), and antioxidant activity (by FRAP, DPPH, ABTS assays) were analyzed. Additionally, photosynthetic gas exchange and chlorophyll fluorescence were measured. PL plants showed thicker leaves (higher LMA) and greater accumulation of photo-protective pigments (carotenoids and anthocyanins), despite similar chlorophyll levels. The PL plants also demonstrated higher photosynthetic activity, transpiration rates, and stomatal conductance, with reduced non-photochemical quenching. The EL morphotype had higher cation (K, Mg, Ca, Na) and vitamin C (135.3 mg 100 g-1 FW) concentrations, while no significant disparities were observed between the morphotypes in phenolic concentration (208.5 mg g.a.e. 100 g-1 FW), flavonoids (71.5 mg q.e. 100 g-1 FW), or glucosinolates (61 mg g-1 FW). Interestingly, while the EL type had higher vitamin C, the PL morphotype showed superior antioxidant activity (FRAP, DPPH) and seems to be better adapted to water/nutrient scarcity typical of southern Italy. Both morphotypes offer potential as high-nutritional foods, however, future research should investigate the genotype-specific production of antioxidant compounds in EL and PL plants in response to environmental stresses, including salinity for potential exploitation as a new crop.

Focused ultrasound therapy in movement disorders: management roadmap toward optimal pathway organization.

MRI-guided focused ultrasound (MRgFUS) lesioning is an innovative, safe and effective treatment which provides an innovative development in the field of minimally invasive stereotactic neurosurgery. Based on the application of focused ultrasound energy under full MR planning and thermal imaging control, unilateral lesioning of the thalamus, subthalamic nucleus, and globus pallidus is indicated for the treatment of movement disorders, including essential tremor, Parkinson's disease, and dystonia. We started to apply this technique in February 2019 for the treatment of patients with movement disorders. The authors developed a diagnostic therapeutic care pathway, which is herewith proposed and applied as an explication of standard clinical practice in use. The project was the result of the application of different methods such as Health Technology Assessment (HTA), Strengths, Weaknesses, Opportunities and Threats analysis (SWOT) and Demin -Plan, Do, Check, Act (PDCA) cycle. The aim of this project was to standardize the MRgFUS diagnostic-therapeutic pathway (DTP), describe its application and the appropriateness of different phases (patient selection, intervention phase and follow-up). Here, we described in detail our experience in the DTP application from 2019 up to now in 610 patients with movement disorders.

Modified PATIO technique for urethrocutaneous fistula after hypospadias repair: Experience from a tertiary referral hospital.

INTRODUCTION: Urethrocutaneous fistula (UCF) is a common complication after hypospadias repair with an incidence of 5-10%. Several techniques are described for its repair: small UCFs are frequently corrected by isolation, excision, and closure with apposition of a protective second layer. In 2008 Malone described the PATIO technique: the fistula tract is turned inside out in the urethral lumen preventing contact with passing urine without direct urethral sutures. OBJECTIVE: Aim of our study is to present our outcomes using a modified version of the PATIO technique, with a more reproducible isolation of the tract and without its fixation at the urethral meatus. STUDY DESIGN: We retrospectively reviewed all cases of UCFs corrected with a modified PATIO technique at our center between 2016 and 2020. Data collected from electronical clinical notes were age at UCF closure, location of UCF, presence of meatal stenosis and clinical outcomes. Data are presented as median and IQR. RESULTS: In the study period we performed 425 urethroplasties for distal and mid penile hypospadias. The incidence of UCFs was 7% (30/425) and 25 patients underwent UCF correction with modified PATIO. Median age at repair was 4.5 years (IQR: 2.5-6.2). At a median follow-up of 3 years (IQR: 2-4) recurrence was observed in 5 cases out of 24 with one patient who was lost at follow-up (20.8%). One case was corrected successfully with re-do modified PATIO technique, while 4 are awaiting repair. One cases was lost at follow-up. UFC-recurrence was homogeneously distributed along the study period. DISCUSSION: Risk factors for UCF recurrence are mostly the type of hypospadias, neo-urethral length, and quality of the urethral plate. Among the many existing techniques, we propose a modified version of Malone's PATIO repair. We believe that the use of four stay-suture to isolate the fistula allows a well-defined dissection of the tract along its surface, compared to the use of a single stay-suture. In our experience, there is no need to keep and fix the traction on the fistula tract to the urethral meatus, probably reflecting the efficacy of the fistula closure during the introflection, which is then maintained without traction. Limitations to our study include the retrospective nature of the review, the small sample size of the cohort and the absence of control groups. CONCLUSIONS: Our results appear consistent with literature regarding the efficacy of PATIO principles in treating UCF. Modified PATIO seem to be particularly reproducible, showing encouraging results.

The Optimal Targeting for Focused Ultrasound Thalamotomy Differs between Dystonic and Essential Tremor: A 12-Month Prospective Pilot Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug-resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal. OBJECTIVES: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET. METHODS: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response. RESULTS: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events. CONCLUSIONS: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT.

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

BACKGROUND: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization. CASES: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described. CONCLUSIONS: This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol.

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF). Methods and analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat. Ethics and dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences. Trial registration numbers: NCT05287503, EudraCT 2021-004565-13.

Unraveling Autonomic Dysfunction in GBA-Related Parkinson's Disease.

Background: Patients with Parkinson's disease (PD) and GBA gene mutations (GBA-PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA-PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved. Objectives: To provide instrumental measures of pattern and severity of autonomic dysfunction in GBA-PD and explore their correlation with other non-motor symptoms and implications for clinical practice. Methods: In this cross-sectional study, 21 GBA-PD and 24 matched PD noncarriers underwent extensive assessment of motor and non-motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R-R intervals and blood pressure short-term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post-ganglionic sudomotor dysfunction. Results: Despite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA-PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho-vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA-PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment. Conclusions: Compared to PD noncarriers, GBA-PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA-PD, regardless of clinically overt symptoms.

Characterization of Targeted Phenolic Compounds in Globe Artichoke Heads and Waste from Vegetatively and "Seed"-Propagated Genotypes.

In the globe artichoke, both the edible portion and the waste biomass are recognized as valuable sources of bioactive compounds. For this study, heads with 30 cm-long floral stems including two to three leaves were harvested from five genotypes, which included two traditional vegetative-propagated varietal types ("Brindisino" and "Violetto di Foggia") and three "seed"-propagated hybrids ("Tempo", "Opal", and "Madrigal"). The study aimed to determine the total and individual polyphenolic concentrations (measured spectrophotometrically and using HPLC) and antioxidant activity (AA) in different artichoke parts, namely the "hearts" (H), head waste (HW), stem waste (SW), and leaf waste (LW). "Brindisino" SW exhibited the highest accumulation of luteolin (26,317 mg kg-1 F.W.), while "Tempo" H displayed the highest cynarin content (190 mg kg-1 F.W.). "Tempo" HW and H showed the highest levels of apigenin (640 mg kg-1 F.W.), and the greatest source of chlorogenic acid was found in the HW of "Opal" and the H of "Brindisino" (4300 mg kg-1 F.W.). The hybrids generally exhibited lower total polyphenolic concentrations than the traditional genotypes, particularly evident in the LW. The SW demonstrated the highest concentration of total polyphenols (18,000 mg kg-1 F.W.), followed by the edible H and non-edible HW (12,000 mg kg-1 F.W.), while the LW exhibited the lowest concentration (2000 mg kg-1 F.W.). Interestingly, the AA did not precisely align with the total polyphenolic concentration, showing slight variations between the examined parts and genotypes.

Corrigendum: PMCA-based detection of prions in the olfactory mucosa of patients with sporadic Creutzfeldt-Jakob disease.

[This corrects the article DOI: 10.3389/fnagi.2022.848991.].

Determination of Nitrate and Nitrite in Swiss Chard (Beta vulgaris L. subsp. vulgaris) and Wild Rocket (Diplotaxis tenuifolia (L.) DC.) and Food Safety Evaluations.

Nitrite and nitrate levels in vegetables are a matter of concern due to their toxicity at high levels and nitrate high accumulation. Moreover, there is a lack of knowledge about their levels in some types of widely consumed vegetables such as chard and rocket. In this study, 124 Swiss chard and wild rocket samples were analyzed for determining nitrite and nitrate using validated and accredited analytical methods by ion chromatography with conductivity detection. High nitrite concentrations, up to 219.5 mg kg−1 f.w., were detected in one Swiss chard and three wild rocket samples. One Margin of Safety (MoS) value was <1. Regarding nitrate, in Swiss chard samples the mean concentration (2522.6 mg kg−1) was slightly higher than those reported in the literature for spinach and lettuce. No MoS was <1, but 83% of values were <100. Nitrate concentrations higher than the legal limit were quantified in 11 rucola samples. The verification of 25% of wild rocket samples with nitrate concentration higher than the legal limit confirmed the need for official control. This study also suggests the introduction of legal limits for nitrite/nitrate in Swiss chard and nitrite in wild rocket.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy May Spare Dopaminergic Therapy in Early-Stage Tremor-Dominant Parkinson's Disease: A Pilot Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug-resistant tremor in Parkinson's disease (PD). OBJECTIVE: The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early-stage tremor-dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy. METHODS: We prospectively enrolled patients with early-stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD-FUS) and patients treated with oral dopaminergic therapy (PD-ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12 months after thalamotomy. RESULTS: We included 10 patients in the PD-FUS group and 20 patients in the PD-ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD-ODT group 6 months after thalamotomy. CONCLUSIONS: In early-stage tremor-dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.