Robotic-assisted rehabilitation for balance in stroke patients (ROAR-S): effects of cognitive, motor and functional outcomes.

OBJECTIVE: Due to the aging population, the incidence of stroke is steadily increasing. In patients with stroke outcomes, sensory, motor and cognitive problems limit the performance of activities of daily living. The development of new technologies in rehabilitation is improving the quality and efficiency of functional recovery. Hunova robotic platform (Movendo Technology, srl, Genoa, Italy) is a robotic device for functional assessment and rehabilitation of balance. The purpose of this study is to evaluate the effects of rehabilitation with Hunova on cognitive function and balance in older adults with stroke. PATIENTS AND METHODS: This is a randomized, controlled, single-blind study. Twenty-four older adults with stroke outcomes were randomized into the Hunova group (HuG), which performed a specific rehabilitation program for balance using Hunova for 12 sessions in addition to conventional rehabilitation, and the control group (CoG), which performed only conventional rehabilitation. All patients underwent a clinical cognitive, balance, quality of life and fatigue assessment, and an instrumental balance assessment with Hunova at the beginning and end of treatment. RESULTS: Statistical analysis showed significant improvements in most clinical scales in both groups. Comparing the groups, HuG showed greater improvements in executive functions, speed of information processing, attention and discrimination of multiple stimuli, static and dynamic balance and autonomy in daily activities, standing postural sway, and trunk control in static and dynamic conditions. CONCLUSIONS: Data analysis showed that elderly with stroke who underwent balance technology treatment with Hunova in combination with conventional treatment had a greater improvement in cognitive functions, balance and reduced risk of falling.

Preliminary evaluation of cerebral 18F-DOPA PET/CT in the differential diagnosis of brain lesions in inconclusive MR.

AIM: To evaluate the utility of brain 18F-DOPA PET/CT in the differential diagnosis of brain lesions with inconclusive MRI. MATERIAL AND METHODS: Twelve patients were studied, with a total of 16 lesions, without definitive diagnosis after brain MRI. A double acquisition PET/CT brain scan was acquired at 20 and 90min. Visual and semiquantitative assessment was performed with SUVmax calculation of the lesions and calculation of the T/S Ratio (tumor/contralateral striatum) and T/N Ratio (contralateral healthy tumor/parenchyma) for each time. RESULTS: Based on the visual assessment scale and using T/S ratio ≥1 and T/N ratio ≥1.3 to determine malignancy, the values of sensitivity (S), specificity (E) and positive predictive value (PPV) were: visual assessment (S 100%, E 33.3%, VPP 71.4%), T/S Ratio (S 90%, E 100%, VPP 100%) and T/N Ratio (S 100%, E 16.6%, VPP 66.6 %). No lesion showed an increase in SUVmax in late acquisition. 18F-DOPA PET/CT modified treatment in 75% of the patients. CONCLUSION: 18F-DOPA PET/CT is a useful tool in the study of brain lesions with inconclusive MRI. Late imaging (dual-point) has no added value in the final diagnosis. FDOPA has an impact on patient management modifying therapeutic behavior.

68Ga-PSMA-11 PET/CT in patients with occult biochemical recurrence of prostate carcinoma and negative 18F-Choline PET/CT. Preliminary assessment of its clinical use.

OBJECTIVE: To assess the clinical usefulness of 68Ga-PSMA PET/CT studies in patients with occult biochemical recurrence of prostate carcinoma, with negative or inconclusive radiologic and 18 F-Choline PET/CT imaging studies. MATERIAL AND METHODS: Retrospective descriptive study. The first 14 patients with a history of prostate carcinoma, treated with curative intent and presenting suspicion of biochemical recurrence with low PSA values (<3 ng/mL) were selected. Imaging studies, prostate ultrasound, pelvic CT and/or MRI were negative, and all of them had a negative or inconclusive 18F-Choline PET/CT. All patients were referred to 68 Ga-PSMA-11 PET/CT. PROTOCOL: Dose 2.2 M Bq/kg. 20 mg furosemide at start. PET/CT images from skull base to proximal third of thighs at 60 min, and late images at 3 h if needed. RESULTS: The 68 Ga-PSMA-11 PET/CT was able to localize the occult biochemical recurrence in 9 of the 14 patients (64.2%), and it affected the therapeutic attitude in all of them. Four patients (28.5%) obtained a negative or inconclusive 68 Ga-PSMA-11 PET/CT and continued under vigilant approach with PSA controls and imaging studies according to the clinical guidelines. These patients had the lowest PSA values (less than 1 ng/mL). One of the 68 Ga-PSMA-11 PET/CT studies was inconclusive, reporting the presence of a doubtful right iliac adenopathy. CONCLUSION: 68 Ga-PSMA-11 PET/CT allows an early diagnosis, with low PSA values, of occult biochemical recurrence of prostate carcinoma, even in patients with negative 18 F-Choline PET/CT.

Valoración preliminar de la 18F-DOPA PET/TC cerebral en el diagnóstico diferencial de lesiones cerebrales con RM no concluyente.

AIM: To evaluate the utility of brain 18F-DOPA PET/CT in the differential diagnosis of brain lesions with inconclusive MRI. MATERIAL AND METHODS: Twelve patients were studied, with a total of 16 lesions, without definitive diagnosis after brain MRI. A double acquisition PET/CT brain scan was acquired at 20 and 90 minutes. Visual and semiquantitative assessment was performed with SUVmax calculation of the lesions and calculation of the T/S ratio (tumor/contralateral striatum) and T/N ratio (tumor/contralateral healthy parenchyma) for each time. RESULTS: Based on the visual assessment scale and using T/S ratio ≥ 1 and T/N ratio ≥ 1.3 to determine malignancy, the values of sensitivity (S), specificity (E) and positive predictive value (PPV) were: visual assessment (S 100%, E 33.3%, VPP 71.4%), T/S ratio (S 90%, E 100%, VPP 100%) and T/N ratio (S 100%, E 16.6%, VPP 66.6%). No lesion showed an increase in SUVmax in late acquisition. 18F-DOPA PET/CT modified treatment in 75% of the patients. CONCLUSION: 18F-DOPA PET/CT is a useful tool in the study of brain lesions with inconclusive MRI. Late imaging (dual-point) has no added value in the final diagnosis. F-DOPA has an impact on patient management modifying therapeutic behavior.

A new T helper 17 cytokine in hidradenitis suppurativa: antimicrobial and proinflammatory role of interleukin-26.

BACKGROUND: Interleukin (IL)-26 is a signature T helper 17 cytokine described as a proinflammatory and antimicrobial mediator. So far, IL-26 has been reported in several immune-mediated inflammatory diseases, but its involvement in inflammatory skin disorders is poorly known. OBJECTIVES: To investigate the role of IL-26 in hidradenitis suppurativa (HS), through its involvement in antimicrobial activity. METHODS: IL-26 was assessed in patients with HS through gene expression and protein analysis at skin and circulating levels. Ex vivo HS organ skin cultures, together with IL-26 antibody treatment, were performed to determine the IL-26 activity. Peripheral blood mononuclear cells (PBMCs) from patients with HS and healthy controls were either silenced or not with IL-26 small interfering (si)RNA in order to measure its antimicrobial, cytotoxic and phagocytic activities against Staphylococcus aureus. RESULTS: Firstly, we observed that IL-26 is able to modulate the proinflammatory response at the immune cell level. IL-26 was increased in the plasma of patients with HS compared with healthy controls. Subsequently, we explored the bactericidal, cytotoxic and phagocytic activities of PBMCs against S. aureus in patients with HS and healthy controls. These activities were lower in patients with HS than in controls. Remarkably, the killing activities were reduced when healthy control PBMCs were transfected with IL-26 siRNA. However, the transfection did not affect the killing activity of HS PBMCs, supporting the idea that IL-26 lacks efficacy in HS. CONCLUSIONS: Our findings suggest that infection susceptibility in HS might be related to IL-26. Although the role of bacteria remains controversial in HS, this paper supports that there is a defect of antimicrobial response in these patients. What's already known about this topic? Interleukin (IL)-26 is a T helper 17 cytokine described as an antimicrobial and proinflammatory mediator. IL-26 has been reported in immune-mediated inflammatory diseases, but its involvement in inflammatory skin disorders remains unclear. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder characterized by deficiency of IL-20 and IL-22 (a close homologue of IL-26), which causes antimicrobial peptide pauperization leading to severe and recurrent skin infections. What does this study add? IL-26 plasma levels are higher in patients with HS than in healthy control individuals. The antimicrobial activity of IL-26 might be ineffective in patients with HS. What is the translational message? Cutaneous antimicrobial incompetence in HS could be related to IL-26.

PET/TC imaging with somatostatin analogues for assessment of neuroendocrine tumors, initial experience. / PET/TC con análogos de la somatostatina en el estudio de tumores neuroendocrinos, experiencia inicial.

PET with somatostatin analogues (SSA PET/CT) enables the detection of cells with overexpression of somatostatin receptors, especially subtypes 2 and 5; this detection is variable depending on the type of molecule used. This is the basis for its use in the study of neuroendocrine tumours (NETs), which are characterized by an overexpression of these receptors in more than 80% of the subtypes. This PET is now being used in our country supported by the good results published by other groups, that were superior to those of other imaging techniques. We present two of the first cases of SSA-PET/CT with 68Ga-edotreotide (SomaKit TOC®) performed in our centre. SSA-PET/CT was the test that finally determined the clinical management of both patients.

The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Perfusion SPECT, SISCOM and PET (18)F-FDG in the assessment of drug- refractory epilepsy patients candidates for epilepsy surgery.

AIMS: Brain perfusion SPECT (ictal-interictal), SPECT images and subtraction ictal SPECT coregistered to MRI (SISCOM) and (18)F-FDG-PET (interictal), play an important role in the pre-surgical diagnosis of patients with medically refractory epilepsy. This study aimed to establish: the reproducibility of visual ictal-interictal SPECT and SISCOM analysis altogether with the capacity of SPECT, SISCOM and PET to determine the epileptogenic zone. MATERIAL AND METHODS: (99m)Tc-HMPAO SPECT ictal-interictal and SISCOM (Analyze 7.0) were performed on 47 refractory epilepsy patients (24 F, 19-60 yrs). In 13 patients, SISCOM was also performed using a new program (Focus DET). Ictal-interictal SPECT and SISCOM images were analysed independently by two nuclear medicine physicians (observer 1 and 2). Kappa concordance coefficient was used to evaluate the reproducibility. In sixteen patients, SPECT, SISCOM and PET findings were compared with the resected area during the surgery, and surgical outcome using Engel scale or with the stereo EEG-(SEEG). RESULTS: The ictal-interictal SPECT interobserver agreement was 91%, Kappa index 0.86, SISCOM (Analyze 7.0) interobserver agreement percentage was 82%, Kappa index 0.80, Analyze 7.0 showed a higher inconclusive results than visual SPECT analysis. SISCOM FocusDET interobserver agreement was 92%, Kappa index 0.87, with lower inconclusive results than Analyze 7.0. SPECT, SISCOM and PET combined findings identified 87% seizure onset zone: 79% temporal, 26% parieto-temporal and 7% frontal. CONCLUSIONS: Ictal-interictal SPECT and SISCOM showed a high reproducibility in this sample of patients with drug-refractory epilepsy. SPECT,SISCOM and PET combined findings improved detection of epileptogenic zone in comparison with the individual assessment.

Desregulación de la expresión de microRNAs en el carcinoma papilar de tiroides / Deregulation of MicroRNAs Expression in Human Papillary Thyroid Carcinoma

El descubrimiento de los microRNAs (miRNAs) ha demostrado que estos se comportan como una poderosa clase de reguladores de la expresión génica. Al actuar a nivel postranscripcional, los miRNAs son capaces de modular la expresión de al menos un tercio de los RNA mensajeros codificados por el genoma. Aquí resumimos las principales alteraciones en la expresión de los genes para miRNAs identificados en el carcinoma papilar de tiroides. Se discuten también los mecanismos por los cuales la desregulación de estos miRNAs podrían estar involucrados en la transformación de las células foliculares tiroideas. Rev Argent Endocrinol Metab 51:205-212, 2014 Los autores declaran no poseer conflictos de interés.

MicroRNAs (miRNAs) small (~22 nt) single-stranded RNA molecules that are not further translated into proteins. They can act as negative regulators of the protein-coding gene expression and may impact cell differentiation, proliferation and survival. They have been implicated in carcinogenesis. The purpose of this review is to summarize the main alterations of miRNA expression identified in thyroid papillary carcinomas, and discuss the mechanisms by which miRNA deregulation might be involved in thyroid cell transformation. Rev Argent Endocrinol Metab 51:205-212, 2014 No financial conflicts of interest exist.

PATZ1 interacts with p53 and regulates expression of p53-target genes enhancing apoptosis or cell survival based on the cellular context.

PATZ1 is a transcriptional factor functioning either as an activator or a repressor of gene transcription depending upon the cellular context. It appears to have a dual oncogenic/anti-oncogenic activity. Indeed, it is overexpressed in colon carcinomas, and its silencing inhibits colon cancer cell proliferation or increases sensitivity to apoptotic stimuli of glioma cells, suggesting an oncogenic role. Conversely, the development of B-cell lymphomas, sarcomas, hepatocellular carcinomas and lung adenomas in Patz1-knockout (ko) mice supports its tumour suppressor function. PATZ1 role in mouse lymphomagenesis is mainly because of the involvement of PATZ1 in BCL6-negative autoregulation. However, this does not exclude that PATZ1 may be involved in tumorigenesis by other mechanisms. Here, we report that PATZ1 interacts with the tumour suppressor p53 and binds p53-dependent gene promoters, including those of BAX, CDKN1A and MDM2. Knockdown of PATZ1 in HEK293 cells reduces promoter activity of these genes and inhibits their expression, suggesting a role of PATZ in enhancing p53 transcriptional activity. Consistently, Patz1-ko mouse embryonic fibroblasts (MEFs) show decreased expression of Bax, Cdkn1a and Mdm2 compared with wild-type (wt) MEFs. Moreover, Patz1-ko MEFs show a decreased percentage of apoptotic cells, either spontaneous or induced by treatment with 5-fluorouracil (5FU), compared with wt controls, suggesting a pro-apoptotic role for PATZ1 in these cells. However, PATZ1 binds p53-target genes also independently from p53, exerting, in the absence of p53, an opposite function on their expression. Indeed, knockdown of PATZ1 in p53-null osteosarcoma cells upregulates BAX expression and decreases survival of 5FU-treated cells, then suggesting an anti-apoptotic role of PATZ1 in p53-null cancer cells. Therefore, these data support a PATZ1 tumour-suppressive function based on its ability to enhance p53-dependent transcription and apoptosis. Conversely, its opposite and anti-apoptotic role in p53-null cancer cells provides the perspective of PATZ1 silencing as a possible adjuvant in the treatment of p53-null cancer.

Assessment of host defence mechanisms induced by Candida species.

Some species of Candida are opportunistic pathogens that can cause disease in a host immunocompromised by underlying local or systemic pathological processes. C. albicans is the species most often associated with oral lesions, but other species of Candida, including C. glabrata, C. tropicalis and C. parapsilosis, have also been isolated in the saliva of subjects with and without candidiasis. In the present study we evaluated the host defence mechanisms induced by Candida albicans and other Candida species in monocytes and oral epithelial cells in order to establish the existence of a species-specific cellular response. Our results indicated that, during Candida species infection, the epithelial cells actively participate in the host defence by producing antimicrobial peptides and proinflammatory cytokines. Moreover, in infections caused by Candida tropicalis and Candida glabrata, the host defence may be strengthened by the release of perforin and granzyme by polymorphonuclear leukocytes recruited at the site of infection.

Mitochondrial G protein coupled receptor kinase 2 regulates proinflammatory responses in macrophages.

G-protein-coupled receptor kinase 2 (GRK2) levels are elevated in inflammation but its role is not clear yet. Here we show that GRK2 expression is dependent on NFκB transcriptional activity. In macrophages, LPS induces GRK2 accumulation in mitochondria increasing biogenesis. The overexpression of the carboxy-terminal domain of GRK2 (ßARK-ct), known to displace GRK2 from plasma membranes, induces earlier localization of GRK2 to mitochondria in response to LPS leading to increased mt-DNA transcription and reduced ROS production and cytokine expression. Our study shows the relevance of GRK2 subcellular localization in macrophage biology and its potential therapeutic properties in inflammation.

Pax8 has a critical role in epithelial cell survival and proliferation.

The transcription factor Pax8, a member of the Paired-box gene family, is a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well characterized with respect to its role in regulating genes responsible for thyroid differentiation, its involvement in cell survival and proliferation has been hypothesized but remains unclear. Here, we show that Pax8 overexpression significantly increases proliferation and colony-forming efficiency of Fischer rat thyroid line 5 epithelial cells, although it is not sufficient to overcome their hormone dependence. More interestingly, we show that Pax8-specific silencing induces apoptosis through a p53-dependent pathway that involves caspase-3 activation and cleavage of poly(ADP)ribose polymerase. Our data indicate that tumor protein 53 induced nuclear protein 1 (tp53inp1), a positive regulator of p53-dependent cell cycle arrest and apoptosis, is a transcriptional target of Pax8 and is upregulated by Pax8 knockdown. Remarkably, tp53inp1 silencing significantly abolishes Pax8-induced apoptosis thus suggesting that tp53inp1 may be the mediator of the observed effects. In conclusion, our data highlight that Pax8 is required for the survival of differentiated epithelial cells and its expression levels are able to modulate the proliferation rate of such cells.

Betamethasone therapy in ataxia telangiectasia: unraveling the rationale of this serendipitous observation on the basis of the pathogenesis.

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive neurological dysfunction. To date, only supportive care aimed to halt the progressive neurodegeneration is available for the treatment. Recently, an improvement of neurological signs during short-term treatment with betamethasone has been reported. To date, the molecular and biochemical mechanisms by which the steroid produces such effects have not yet been elucidated. Therefore, a review of the literature was carried out to define the potential molecular and functional targets of the steroid effects in A-T. Glucocorticoids (GCs) are capable of diffusing into the CNS by crossing the blood-brain barrier (BBB) where they exert effects on the suppression of inflammation or as antioxidant. GCs have been shown to protect post-mitotic neurons from apoptosis. Eventually, GCs may also modulate synaptic plasticity. A better understanding of the mechanisms of action of GCs in the brain is needed, because in A-T during the initial phase of cell loss the neurological impairment may be rescued by interfering in the biochemical pathways. This would open a new window of intervention in this so far incurable disease.