A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder presenting with a spectrum of clinical features caused by mutations in different genes. A 10\u2010year\u2010old girl with CIP, hyposmia and hypogeusia, and her unaffected twin and parents underwent next generation sequencing of SCN9A exons and flanking splice sites. Transcript analysis from whole blood successfully assayed the effect of the mutation on the mRNA splicing by polymerase chain reaction amplification on cDNA and Sanger sequencing. We identified the novel splicing variant c.1108\u20102A>G compound with the p.Arg896Gln (c.2687G>A) missense mutation previously described in a homozygous patient. The new intronic variant was predicted to induce exon 10 skipping. Conversely, SCN9A mRNA assay demonstrated its partial deletion with a loss of 46 nucleotides causing a premature stop codon in position p.Gln369 (NP_002968). Genetic analysis showed that the two variants were biallelic, being the mother and brother heterozygous carriers of the missense mutation, and the father heterozygous for the splicing mutation. Skin biopsy showed lack of Meissner's corpuscles, loss of epidermal nociceptors and normal autonomic organ innervation. We report a novel splicing mutation and provide clues on its pathogenic effect, broadening the spectrum of genotypes and phenotypes associated to CIP

90Y-DOTA-nimotuzumab: synthesis of a promising β⁻ radiopharmaceutical

BACKGROUND: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a beta- emitting radioimmunoconjugate (90Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach.METHODS: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50 fold excess of DOTA and then labelled with 90Y3+. The 90Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the 90Y-DOTA-nimotuzumab stability was evaluated in human plasma.RESULTS: The radioimmunoconjugate 90Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma.CONCLUSIONS: The optimized conditions for a mild and easy preparation of 90Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for beta- radio-guided surgery

Radioguided surgery with \u3b2 radiation: a novel application with Ga68.

Radio Guided Surgery is a technique helping the surgeon in the resection of tumors: a radiolabeled tracer is administered to the patient before surgery and then the surgeon evaluates the completeness of the resection with a handheld detector sensitive to emitted radiation. Established methods rely on \u3b3 emitting tracers coupled with \u3b3 detecting probes. The efficacy of this technique is however hindered by the high penetration of \u3b3 radiation, limiting its applicability to low background conditions. To overtake such limitations, a novel approach to RGS has been proposed, relying on \u3b2- emitting isotopes together with a dedicated \u3b2 probe. This technique has been proved to be effective in first ex-vivo trials. We discuss in this paper the possibility to extend its application cases to 68Ga, a \u3b2+ emitting isotope widely used today in nuclear medicine. To this aim, a retrospective study on 45 prostatic cancer patients was performed, analysing their 68Ga-PSMA PET images to asses if the molecule uptake is enough to apply this technique. Despite the expected variability both in terms of SUV (median 4.1, IQR 3.0-6.1) and TNR (median 9.4, IQR 5.2-14.6), the majority of cases have been found to be compatible with \u3b2-RGS with reasonable injected activity and probing time (5\u2009s)

High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study

Myotonic dystrophy type 1 (DM1, MIM #160900), the most common muscular dystrophy among adults, is a multisystem disorder, which affects, besides the skeletal muscle, several other tissues and/or organs, including the gastrointestinal apparatus, with manifestations that frequently affect the quality of life of DM1 patients. So far, only few, mainly retrospective studies evaluated this specific topic in DM1, so we performed a perspective study, enrolling 61 DM1 patients who underwent an extensive diagnostic protocol, including administration of the Gastrointestinal Symptom Rating Scale (GSRS), a validated patient-reported questionnaire about GI symptoms, laboratory tests, liver US scan, and an intestinal permeability assay, in order to characterize frequency and assess correlations regarding specific gastrointestinal manifestations with demographic or other DM1-related features. Our results in our DM1 cohort confirm the high frequency of various gastrointestinal manifestations, with the most frequent being constipation (45.9%). \u3b3GT levels were pathologically increased in 65% of DM1 patients and GPT in 29.82%; liver ultrasound studies showed steatosis in 34.4% of patients. Significantly, 91.22% of DM1 patients showed signs of altered intestinal permeability at the specific assay. We documented a gender-related prevalence and severity of gastrointestinal manifestations in DM1 females compared to DM1 males, while males showed higher serum GPT and \u3b3GT levels than females. Correlation studies documented a direct correlation between severity of muscle weakness estimated by MIRS score and \u3b3GT and alkaline phosphatase levels, suggesting their potential use as biomarkers of muscle disease severity in DM1

11C-Methionine PET/CT in patients with primary hyperparathyroidism and inconclusive pre-operative imaging work-up: diagnostic accuracy and role of semi-quantitative analysis

Objective: 11C-Methionine PET/CT (C-MET) is a promising method in detecting abnormal parathyroid glands in patients with primary hyperparathyroidism (PHPT). The first aim of the study was to evaluate which is the diagnostic role of C-MET in patients with PHPT and inconclusive pre-operative imaging. Second, we aimed to investigate whether C-MET semi-quantitative parameters may reflect biochemical and histological characteristics of involved glands. Methods: Patients with PHPT, undergoing C-MET after an inconclusive pre-operative imaging and having a parathyroid surgery, were retrospectively included. C-MET visual and semi-quantitative assessment was performed. Parameters, as SUVmax, SUVpeak, SUVmean, functional lesion volume (FLV) and total lesion activity (TLA), were measured for each detected lesion; SUVmean, FLV and TLA were calculated on 40\u201390% thresholds of SUVmax to define SUVmean40-90, FLV40-90 and TLA40-90, respectively. Results were correlated with patients\u2019 clinical-laboratory (calcium and PTH values) and histological data (size and weight of excised glands). Mann\u2013Whitney test was used and P value < 0.05 was considered significant. Results: Thirty-eight patients (36 female, age: 57.69 \ub1 15.13 years) were included. Pre-operative median calcium and PTH values were 11.1 mg/dl [interquartile range (IQR) 10.6\u201311.5] and 154.6 pg/ml (IQR 101.8\u2013227.0), respectively. C-MET showed a parathyroid uptake in 30 out of thirty-eight patients (78.9%). Among 42 nodules excised, C-MET correctly detected the side of the neck (right/left) in 30/42 with sensitivity, specificity and accuracy of 79, 75 and 79%, respectively. C-MET correctly identified the exact position (superior/inferior) in 27/42 with sensitivity, specificity and accuracy of 75, 50 and 71%, respectively. SUVpeak, FLV50-70 and TLA40-70 were significantly (P < 0.05) higher in patients with higher PTH results. The histological size resulted significantly (P < 0.05) higher in abnormal glands with higher SUVmax, SUVpeak, FLV40-80 and TLA40-90, the weight was higher in glands with higher SUVpeak, SUVmean40-50, FLV40-80 and TLA40-90. Conclusions: C-MET showed a good performance in detecting hyperfunctioning parathyroid glands in PHPT patients with inconclusive pre-operative imaging. Semi-quantitative PET-derived parameters closely correlated with PTH as well as with size and weight of the excised gland, thus reflecting some biochemical and histological characteristics of involved glands

Extracellular vesicles in immune system regulation and type 1 diabetes: cell-to-cell communication mediators, disease biomarkers, and promising therapeutic tools

Extracellular vesicles (EVs) are generated by cells of origin through complex molecular mechanisms and released into extracellular environment. Hence, the presence of EVs has been described in multiple biological fluids and in most cases their molecular cargo, which includes non-coding RNAs (ncRNA), messenger RNAs (mRNA), and proteins, has been reported to modulate distinct biological processes. EVs release and their molecular cargo have been demonstrated to be altered in multiple diseases, including autoimmune diseases. Notably, numerous evidence showed a relevant crosstalk between immune system and interacting cells through specific EVs release. The crosstalk between insulinproducing pancreatic b cells and immune system through EVs bidirectional trafficking has yet started to be deciphered, thus uncovering an intricate communication network underlying type 1 diabetes (T1D) pathogenesis. EVs can also be found in blood plasma or serum. Indeed, the assessment of circulating EVs cargo has been shown as a promising advance in the detection of reliable biomarkers of disease progression. Of note, multiple studies showed several specific cargo alterations of EVs collected from plasma/serum of subjects affected by autoimmune diseases, including T1D subjects. In this review, we discuss the recent literature reporting evidence of EVs role in autoimmune diseases, specifically focusing on the bidirectional crosstalk between pancreatic b cells and immune system in T1D and highlight the relevant promising role of circulating EVs as disease biomarkers

Sorveglianza dello sviluppo in soggetti con anomalie del setto pellucido. descrizione di un caso con agenzia isolata.

malformazioni cerebrali, anomalie setto pellucid

Diagnostic role of 11C-methionine PET/CT in patients with multiple myeloma and other plasma cell malignancy: a literature review

In patients with plasma cell malignancy (multiple myeloma and plasmacytoma), whole-body low-dose computed tomography, magnetic resonance imaging, and 18F-FDG PET/CT are widely applied and suggested by international guidelines to assess the disease extension. Recently, 11C-methionine PET/CT has proven to be promising in those patients compared to other diagnostic techniques. We aimed to review current literature on the state of the art of 11C-methionine PET/CT in patients with plasma cell malignancy. PubMed/MEDLINE database was screened to find articles regarding the role of 11C-methionine PET/CT in plasma cell malignancy. Terms (PET OR positron emission tomography) AND methionine AND myeloma were used. Among 23 studies initially retrieved, 7 (overall 258 patients) were included. In all except two studies, 11C-methionine PET/CT was related to 18F-FDG PET/CT (of whom one also with 11C-4′-thiothymidine PET/CT), one study to 11C-choline PET/CT and one compared multiple myeloma and control patients, both having 11C-methionine scan. Overall, 11C-methionine PET/CT resulted able to detect a higher number of positive patients as well as more bone lesions than 18F-FDG and 11C-choline (detection rate: 75.6–90.7%, 55.0–76.7%, and 73.7%, respectively). A stronger correlation with bone marrow histological results was found for 11C-methionine than for 18F-FDG and 11C-choline PET/CT scans. Although additional studies are needed to validate the role of 11C-methionine PET/CT, it seems to be a safety and effective tool in identification of medullary and extramedullary disease in patients with plasma cell malignancy