Acute back pain - Role of injection techniques and surgery: WFNS spine committee recommendations.

Objective: Lower back pain is a significant cause of morbidity, and despite a range of interventions available, there is a lack of consensus on the most efficacious treatments. The aim of this systematic review is to formulate a list of recommendations for the role of spinal injections and surgery in the treatment of acute back pain. Methods: A systematic literature search from 2012 to 2022 was conducted on Pubmed, Medline, and Cochrane Central Register of Controlled Trials for papers focusing on the role of injections and surgery for the management of acute lower back pain. Inclusion criteria included randomised controlled trials, as well as prospective and retrospective studies reporting primary outcomes (pain improvement (VAS score) and back-specific functional status) and secondary outcomes (post-procedure complications). These data were reviewed, presented, and voted on by an expert panel consisting of 14 attending spine surgeons from 14 countries at the consensus meeting of the World Federation of Neurosurgical Societies (WFNS) Spine Committee. A two-round consensus-based Delphi method was used to generate consensus, and topics with >66% agreement were categorized as having reached consensus. Results: 100 studies met inclusion criteria. Of these, 20 were selected by the committee for full text review and presented at the consensus meeting. The committee voted on 8 statements and achieved consensus on the following 7 statements: (1) Epidural steroid injections (ESIs) show significant benefit to discogenic back pain; (2) A lateral approach is superior to a midline approach for ESIs; (3) Short-term (<1 week) effect of ESIs is similar between steroids; (4) ESIs have a variety of potential complications; (5) CT or fluoroscopy guidance can be used for lumbar medial branch blocks; (6) Lumbar medial branch radiofrequency ablations can be performed on patients with recurrent pain after a successful ESI, and (7) Acute lower back pain is usually self-limiting, resolves in <6 weeks, and does not require surgical intervention. Conclusion: Given significant treatment heterogeneity, we provide the latest, evidence-based recommendations for management of acute lower back pain. ESIs are effective at short-term pain relief, and surgical intervention should be reserved for patients failing conservative measures.

Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.

Ubiquitin binds the amyloid ß peptide and interferes with its clearance pathways.

Several lines of evidence point to a compromised proteostasis associated with a reduction of the Ubiquitin Proteasome System (UPS) activity in patients affected by Alzheimer's Disease (AD) and suggest that the amyloid ß peptide (Aß) is an important player in the game. Inspired also by many reports, underlining the presence of ubiquitin (Ub) in the amyloid plaques of AD brains, here we set out to test whether Ub may bind the Aß peptide and have any effect on its clearance pathways. By using an integrated array of MALDI-TOF/UPLC-HRMS, fluorescence, NMR, SPR, Microscale Thermophoresis (MST) and molecular dynamics studies, we consistently demonstrated that Aß40 binds Ub with a 1 : 1 stoichiometry and K d in the high micromolar range. In particular, we show that the N-terminal domain of the Aß peptide (through residues D1, E3 and R5) interacts with the C-terminal tail of Ub (involving residues K63 and E64), inducing the central region of Aß (14HQKLVFFAEDVGSNK28) to adopt a mixed α-helix/ß-turn structure. ELISA assays, carried out in neuroblastoma cell lysates, suggest that Aß competitively binds Ub also in the presence of the entire pool of cytosolic Ub binding proteins. Ub-bound Aß has a lower tendency to aggregate into amyloid-like fibrils and is more slowly degraded by the Insulin Degrading Enzyme (IDE). Finally, we observe that the water soluble fragment Aß1-16 significantly inhibits Ub chain growth reactions. These results evidence how the non-covalent interaction between Aß peptides and Ub may have relevant effects on the regulation of the upstream events of the UPS and pave the way to future in vivo studies addressing the role played by Aß peptide in the malfunction of proteome maintenance occurring in AD.

Protocol for the evaluation of a chronic care model experience in Rome.

INTRODUCTION: Chronic diseases are the leading cause of death and disability in almost all over the world; in Europe causing over 9 million deaths per year according to WHO estimates. A promising health organization model for chronic disease management is represented by the Chronic Care Model (CCM). In the 12th district of the ASL Roma 2 since 4 years was implemented a CCM for the management of patients affected by diabetes and/or at high cardiovascular risk. OBJECTIVE: Aim of this study is to evaluate the effectiveness of the Chronic Care Model (CCM) for the management of chronic disease in terms of mortality reduction, avoidable hospitalizations reduction and improvement of clinical parameters. MATERIALS AND METHODS: A retrospective cohort study will involve patients of 12th district of the ASL Roma 2 affected by diabetes and at high cardiovascular risk assisted through the CCM. Their health outcomes will be compared with those of patients in the same clinical conditions, residents in the same district but not assisted with CCM. The sample will be composed by adults (> 18 years) with a diagnosis of diabetes mellitus type 2 (DM2) or metabolic syndrome and / or arterial hypertension (IT) and two or more risk factors. Outcomes will be mortality from all causes and from causes related to DM and IT, preventable hospitalizations as defined in the Prevention Quality Indicators (PQI) by the Agency for Healthcare Research and Quality, and 10 clinical parameters. The data sources will be the records of causes of death (RENCAM), the hospital discharge records (SDO) and information systems for primary healthcare. CONCLUSION: Data from the experience of CCM in Tuscany seem promising especially in the evaluation of patient satisfaction and clinical outcomes particularly on cardiovascular and neurological complications and long-term mortality.

Covalent modifications of the amyloid beta peptide by hydroxynonenal: Effects on metal ion binding by monomers and insights into the fibril topology.

Amyloid ß peptides (Aß) and metal ions are associated with oxidative stress in Alzheimer's disease (AD). Oxidative stress, acting on ω-6 polyunsaturated fatty acyl chains, produces diverse products, including 4-hydroxy-2-nonenal (HNE), which can covalently modify the Aß that helped to produce it. To examine possible feedback mechanisms involving Aß, metal ions and HNE production, the effects of HNE modification and fibril formation on metal ion binding was investigated. Results indicate that copper(II) generally inhibits the modification of His side chains in Aß by HNE, but that once modified, copper(II) still binds to Aß with high affinity. Fibril formation protects only one of the three His residues in Aß from HNE modification, and this protection is consistent with proposed models of fibril structure. These results provide insight into a network of biochemical reactions that may be operating as a consequence of oxidative stress in AD, or as part of the pathogenic process.

Epidemiological and clinical features of migraine in the pediatric population of Northern Italy.

AIM: The aim of this article is to analyze the epidemiological and clinical features of migraine in a pediatric headache center. METHODS: A retrospective study was performed over six years. Hospital record databases were screened for the diagnosis of migraine with aura (MA) or without aura (MO), based on the ICHD-II criteria. STATISTICAL ANALYSIS: Fisher's test or Mann-Whitney U test, significance at p < 0.05. RESULTS: Migraine was diagnosed in 495 children (29.7% MA, 70.3% MO). The majority of diagnoses were made between ages 9 and 14 years. After stratification for age into five groups, we observed an increase of diagnoses in females, with a peak after the age of 15 years, and an increase of MA. In both groups, the attacks were usually severe, infrequent (<1-3/month) lasting <2 hours, and associated with nausea/vomiting, photophobia, phonophobia (more frequent in MO). Osmophobia was reported in 24.7% of the patients with MO. Dizziness was more frequent in patients with MA. Visual auras were the most common occurrence (87.1%). Confusional state was observed in 10.88% of the patients. A positive family history of headache was observed in >88% of the patients. CONCLUSION: We describe the characteristics of pediatric migraine based on the ICHD-II criteria, showing a likely significant loss of diagnoses using the ICHD-III beta. The incidence of migraine increases with age. MO occurs more commonly and shows more frequent attacks and a higher prevalence of associated symptoms, in particular osmophobia. Although males are prevalent in the entire sample, the proportion of females is higher among patients with MA in all of the age groups. Phenotype and sexual prevalence of migraine acquire adult characteristics and become more frequent in females from the onset of puberty.

Malignant teratoma in Klippel-Feil syndrome: a case report and review of the literature.

INTRODUCTION: Klippel-Feil syndrome is characterized by a congenital fusion of cervical vertebrae. Intracranial teratomas are nongerminomatous germ cell tumors and they account for 0.3 to 0.9% of all intracranial tumors. Teratomas with malignant transformation refer to lesions which give rise to malignant cancer of somatic type. The association between tumors of dermoid origin and Klippel-Feil malformation is extremely rare. Only 23 other cases have so far been reported, and only one case of dermoid tumor with areas of dedifferentiation on squamous cell carcinoma has been described. CASE PRESENTATION: We report the case of a 72-year-old white man with a 2-year history of gait and balance disturbances. A brain magnetic resonance imaging revealed a fourth ventricle neoplastic process with infiltrative features. He was operated through a suboccipital craniectomy with a C1 laminotomy and bilateral vertebral artery transposition. At 6-months follow-up, magnetic resonance imaging showed an early regrowth of the fourth ventricle tumor, with the same radiological features. CONCLUSIONS: Patients with Klippel-Feil malformation could develop posterior fossa dermoid tumors. The malignant potential of such tumors must be considered and surgery is recommended. Particular attention must be focused on the histopathological analysis in order to identify possible foci of malignant transformation.

The insulin degrading enzyme activates ubiquitin and promotes the formation of K48 and K63 diubiquitin.

We report an ATP-dependent ubiquitin conjugation with IDE which, in turn, promotes Ub-Ub linkages in tube tests. We propose a novel function for IDE as a non-canonical ubiquitin activating enzyme.

Research priorities in Italian diabetes nursing care: findings from a Delphi study.

AIM: Defining a set of research priorities for diabetes nursing care in the Italian context. DESIGN: A two-step study design based on a modified Delphi technique was undertaken in 2013. METHODS: In the first stage of research, five systematic reviews of literature were performed. Among them 865 recommendations in diabetes nursing care emerged, and 217 (25.1%) were categorized at level IV or lower, thus based on a lack of knowledge and therefore a potential research area. Homogeneous recommendations among the 217 emerged and were categorized by two researchers independently: 96 final recommendations were identified and transformed into items embodied into a questionnaire. A Likert scale ranging from 1 (very low) to 5 (very high) was used to collect the consensus regarding priority. For that purpose a sample of 200 nurses was randomly considered. Potential participants were invited to cooperate via email through a letter reporting aims and methods. In the first round 85 nurses participated; in the third and final round, only 13 nurses took part. RESULTS: Participants have identified 14 research priorities categorized into three main areas: 1) education strategies' effectiveness (n=7); 2) models of care delivery and advanced nursing education effectiveness (n=4); and 3) in specific clinical issues (n=3). CONCLUSIONS: More research on patient education and on models of care delivery and advanced nursing education should be included in any future Italian agenda.

Clinical analysis following lumbar interspinous devices implant: where we are and where we go.

STUDY DESIGN: Retrospective study. OBJECTIVES: We present our experience with patients treated with interspinous devices who are affected by neurogenic intermittent claudication (NIC) or lumbar disc herniation (LDH) where the interspinous system has been inserted following microdiscectomy. METHODS: This study included patients (n = 100) with NIC secondary to lumbar spinal stenosis (group 1), and patients (n = 100) with LDH (group 2) in whom the interspinous device has been implanted following radicular decompression in a period spanning 6 years. The latter have been compared with a homogenous group of patients (n = 100) where no interspinous system has been implanted following microdiscectomy (group 3). Clinical findings have been observed preoperatively and 3, 6, 12 months and every year post-operatively using dedicated questionnaires (Zurich Claudication Questionnaire, Visual Analog Scale and Oswestry Disability Index). RESULTS: Six years following surgical treatment, 85% of the patients of group 1 presented good improvement of symptoms and 90% of the patients referred satisfaction for surgery. Only few cases needed reoperation. In one case, the device was removed and in two cases, we changed the surgical strategy. Overall, patients of group 2 presented significantly less lumbar disc recurrences compared with group 3 (P < 0.05) and better clinical outcome when compared with the same group (P < 0.01). CONCLUSION: According to our features, interspinous systems showed significant and clinically meaningful improvements in pain and disability for up to 6 years. Furthermore, interspinous devices have shown better clinical outcome and less lumbar disc recurrences when associated with standard microdiscectomy. These data, however, need further studies and a longer period of follow-up.

IL-1ß induces GFAP expression in vitro and in vivo and protects neurons from traumatic injury-associated apoptosis in rat brain striatum via NFκB/Ca²âº-calmodulin/ERK mitogen-activated protein kinase signaling pathway.

Reactive astrogliosis, a feature of neuro-inflammation is induced by a number of endogenous mediators including cytokines. Despite interleukin-1 beta (IL-1ß) stands out as the major inducer of this process, the underlying mechanism and its role on neuronal viability remain elusive. We investigated in human astrocytoma cells and the rat brain striatum, the role of the nuclear factor-kB (NF-kB) intracellular Ca(2+) concentration ([Ca(2+)]i) calmodulin (CaM) and extracellular regulated mitogen-activated protein kinases (ERK1/2) in IL-1ß-induced expression of glial fibrillary acidic protein (GFAP) and neuronal apoptosis associated to a brain trauma. Cell data showed that IL-1ß (1 ng/ml) increased NF-kB, pERK1/2 and GFAP expression. Nevertheless, further increase in IL-1ß levels reversed progressively these responses. Preventing ERK1/2 activation with 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthiol]-butadiene antagonized IL-1ß-induced GFAP expression while inhibiting selectively nuclear translocation of NF-kB with caffeic-acid phenethyl-ester down-regulated both ERK1/2 and GFAP expression induced by IL-1ß. The GFAP response was also prevented by antagonizing selectively increase in [Ca(2+)]i, CaM activity or inducible nitric oxide synthase expression with respectively ryanodine plus 2-aminoethoxydiphenyl-borate, N-(6-aminohexyl)-5-chloro-1-naphthalensulfonamide hydrochloride and N-[(3-(aminomethyl)-phenyl]methyl]-ethanimidamide dihydrochloride. Data in vivo supported these findings and showed that GFAP expression induced by IL-1ß (50 ng/ml) correlated with attenuated glial scar formation and reduced neuronal apoptosis. Our data identified the NF-kB/Ca(2+)-CaM/ERK signaling pathway as a novel in vivo key regulator of IL-1ß-induced astrogliosis which may represent a potential target in neurodegeneration.

Endoscopic mucosal resection in high- and low-volume centers: a prospective multicentric study.

BACKGROUND: Endoscopic mucosal resection (EMR) is an effective therapeutic technique well-standardized worldwide for the treatment of gastrointestinal neoplasm limited to the mucosal layer. To date, no study has compared technical and clinical differences based on the number of EMRs performed per year. This study aimed to compare EMR technical success, complications, and clinical outcome between low-volume centers (LVCs) and high-volume centers (HVCs). A total of nine endoscopic centers were included in the study. METHODS: This prospective study investigated consecutive patients with sessile polyps or flat colorectal lesions 1 cm or larger referred for EMR. RESULTS: A total of 427 lesions were resected in 384 patients at nine endoscopic centers. Males accounted for 60.4% and females for 39.6% of the patients. Most of the EMRs (84.8%) were performed in HVCs and only 15.2% in LVCs. All the lesions were resected in only one session. Argon plasma coagulation was performed on the margins of piecemeal resection in 15.7% of the patients in HVCs only. Complete excision was achieved for 98.6% of the lesions in HVCs and 98.8% of the lesions in LVCs. The complication rate was 4.4% in HVCs and 4.6% in LVCs (p = 0.94). Delayed bleeding occurred in 2.5% of the HVC cases and 3.1% of the LVC cases. Perforation occurred in 1.9% of the HVC cases and 1.5% of the LVC cases (p = 1.00). Recurrences were experienced with 15% of the lesions: 15.5% in HVCs and 14% in LVCs (p = 0.79). CONCLUSIONS: The study showed that EMR can be performed also in LVC.

miR-204 targets Bcl-2 expression and enhances responsiveness of gastric cancer.

Micro RNAs (miRs) are small non-coding RNAs aberrantly expressed in human tumors. Here, we aim to identify miRs whose deregulated expression leads to the activation of oncogenic pathways in human gastric cancers (GCs). Thirty nine out of 123 tumoral and matched uninvolved peritumoral gastric specimens from three independent European subsets of patients were analyzed for the expression of 851 human miRs using Agilent Platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by qPCR. miR-204 falls into a group of eight miRs differentially expressed between tumoral and peritumoral samples. Downregulation of miR-204 has prognostic value and correlates with increased staining of Bcl-2 protein in tumoral specimens. Ectopic expression of miR-204 inhibited colony forming ability, migration and tumor engraftment of GC cells. miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil. Altogether, these findings suggest that modulation of aberrant expression of miR-204, which in turn releases oncogenic Bcl-2 protein activity might hold promise for preventive and therapeutic strategies of GC.

Expression of RXFP1 in skin of scleroderma patients and control subjects.

OBJECTIVES: Relaxin (RLX) is involved in extracellular matrix and collagen remodelling. The therapeutic role of the circulating isoform RLX-2 as an anti-fibrotic factor in systemic sclerosis (SSc) has been investigated. Several RLX family peptide receptors (RXFPs) are recognized in humans: RLX-2 is a ligand for RXFP1/LGR7 and RXFP2/LGR8. The aim of this study was to define the pattern of expression of LGR7 in different types of human skin cells and to compare normal skin with lesional and unaffected skin from patients with limited SSc (lSSc). METHOD: We analysed RXFP1 immunolocalization on skin biopsies and cultured fibroblasts from lSSc patients and control subjects. Western blot analysis was carried out on fibroblast lysates. RESULTS: RXFP1 showed cytoplasmic localization on skin cells from control subjects and non-lesional skin from lSSc patients: keratinocytes, gland epithelial cells, endothelium, smooth muscle cells, and fibroblasts. Immunogold electron microscopy confirmed a diffuse epithelial cytoplasmic localization of RXFP1. A substantially lower RXFP1 expression was observed in scleroderma skin, with a lack of staining in most cells. Occasional weak reactivity was observed in cultured scleroderma fibroblasts, while control fibroblasts showed a diffuse cytoplasmic immunoreactivity of RXFP1, confirmed by Western blot analysis. CONCLUSIONS: The decreased cellular expression of RLX-2 receptor RXFP1 in scleroderma skin might represent a pro-fibrotic factor and contribute to the substantial inefficacy of RLX treatment in SSc, as reported in the literature. The pathophysiology of the decrease in RXFP1 may be linked to high RLX-2 serum levels previously detected in SSc, but it has yet to be elucidated.

[Vibrio spp. infections of clinical significance and implication for public health]. / Infezioni da Vibrio spp. di interesse clinico e problematiche di Sanitå Pubblica.

Vibrio spp. infections still are a Public Health concern. Vibrio spp. can be found in marine, estuarine, and freshwater environments, and can be able to cause diseases in fish, shellfish, mammals, as well as in humans. Since '80 to date, the number of species within the genus increased from 21 to more than 100. The most important is Vibrio cholerae, the etiological agent of the cholera, responsible of seven pandemics; serotypes O1 and O139 can produce cholera toxin, while serotypes non-O1/non-O139 are generally associated with sporadic cholera cases and extraintestinal infections. Vibrio parahaemolyticus is an important cause of gastroenteritis associated with contaminated seafood consumption, whereas Vibrio vulnificus and V. alginolyticus can be related to wound infections or seafoodborne primary septicemia in immunocompromised patients. Disease prevention is mainly based on the application of proper individual or collective preventive measures.

Mast cells in canine mammary gland tumour: number, distribution and EPOR positivity.

Erythropoietin (EPO)-mediated mitogenic and anti-apoptotic effects involve all the cells expressing functional receptors for EPO (EPOR), as demonstrated by in vitro and in vivo studies. EPO shows pleiotropic effects and acts as an endogenous mediator of adaptive tissue response to metabolic stress protecting tissues from different injuries. Recently, the EPO/EPOR complex has been identified in several neoplastic cell lines and solid tumours. In this study, the authors investigated the mast cells (MCs) number, distribution and their immunoreactivity for EPOR in normal, dysplastic and neoplastic canine mammary gland. The results showed that MCs were more numerous in displastic glands compared with normal and neoplastic glands. As far as the EPOR immunoreactivity is concerned, we did not observe MCs reaction on cancer, in contrast with previously published data where epithelium of neoplastic gland showed an increase in EPOR expression along with the neoplastic progression. Overall, our results might be suggestive for MCs role in oncogenesis and offer new insight regarding to the expression of EPOR in mammary gland cancer in dog.