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Introduction/aims The cutaneous silent period (CSP) reflects the function of A-delta sensory fibers. There are few studies on CSP in nerve entrapment syndromes. This study aims to evaluate the neurophysiological abnormalities of small-diameter sensory fibers in ulnar neuropathy at the elbow (UNE) by means of CSP. Methods We consecutively evaluated UNE patients at one electrodiagnostic laboratory. The CSP was obtained upon stimulating the fifth (D5) and third digits, recording from the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles. Results We enrolled 37 UNE patients (mean age 55.4 ± 11.2 y) and 30 controls (mean age 51.2 ± 11.1 y). The combinations of the D5-APB and D5-FDI mean onset latencies of CSP were significantly more prolonged in patients (83.7 ± 6.8 and 84.5 ± 8 ms, respectively) than in controls (78.2 ± 8.1 and 79.4 ± 7.6 ms, respectively). The D5-FDI duration of CSP was shorter in patients (52.2 ± 8.3 ms) than in controls (55.8 ± 7 ms). The mean of the onset latencies of D5-FDI and D5-APB was related to the clinical severity (P = .013 and .0025, respectively). D5-APB and D5-FDI onset latencies were more prolonged and the duration was shorter in the UNE group with absent ulnar sensory nerve action potentials (SNAPs) and axonal motor damage than in patients with preserved SNAPs and with demyelinating damage. Discussion CSP was able to demonstrate abnormalities of small-diameter myelinated sensory fibers. This damage was directly related to UNE severity and to axonal damage of motor fibers. Absence of a sensory large-diameter fiber response did not exclude preserved residual small fiber conduction.

Extracellular vesicles (EVs) are membrane-released vesicles acting as transporters of proteins, lipids and short/long non-coding RNA (miRNAs and lncRNAs). They are released by normal and pathological cells, including hepatocellular carcinoma (HCC). To date, studies focused on miRNAs and lncRNAs contained in EVs derived from HCC are limited. Our aim was to analyze the transcriptional profile of potential regulating miRNAs and lncRNAs in EVs secreted by HCC tumor cell line (HepG2, n = 6), and from a non-tumorigenic hepatocyte cell line (WRL68, n = 6), to compare their differential expression profile and to identify novel molecular diagnostic markers of HCC. EVs were isolated from the conditioned medium, through differential centrifugations. The expression profile of miRNAs (miR-23a, miR-16-2, miR-181a, miR-373, miR-205, miR-27a, miR-1323, and miR-532) and lncRNAs (HULC, HOTAIR, XIST, MALAT-1, GAS-5, H19) was performed in Real-time PCR, and their transcript was found both in HepG2 and WRL68 EVs. Lower miR-181a, miR-205 and miR-1323 expression were detected in EVs secreted by HepG2 compared to WRL68, while an opposite trend was observed for miR-23a, miR-16-2, miR-373, miR-27a, and miR-532. Several significant correlations were found between miRNA and lncRNA. An in silico analysis was also performed. The results obtained could identified them as new potential diagnostic and prognostic biomarkers of HCC.

Glioblastoma (GBM) is the most common form of malignant brain cancer and is considered the deadliest human cancer. Because of poor outcomes in this disease, there is an urgent need for progress in understanding the molecular mechanisms of GBM therapeutic resistance, as well as novel and innovative therapies for cancer prevention and treatment. The pentose phosphate pathway (PPP) is a metabolic pathway complementary to glycolysis, and several PPP enzymes have already been demonstrated as potential targets in cancer therapy. In this work, we aimed to evaluate the role of sedoheptulose kinase (SHPK), a key regulator of carbon flux that catalyzes the phosphorylation of sedoheptulose in the nonoxidative arm of the PPP. SHPK expression was investigated in patients with GBM using microarray data. SHPK was also overexpressed in GBM cells, and functional studies were conducted. SHPK expression in GBM shows a significant correlation with histology, prognosis, and survival. In particular, its increased expression is associated with a worse prognosis. Furthermore, its overexpression in GBM cells confirms an increase in cell proliferation. This work highlights for the first time the importance of SHPK in GBM for tumor progression and proposes this enzyme and the nonoxidative PPP as possible therapeutic targets.

Background: Glioblastoma (GB) is a devastating primary brain malignancy. The recurrence of GB is inevitable despite the standard treatment of surgery, chemotherapy, and radiation, and the median survival is limited to around 15 months. The barriers to treatment include the complex interactions among the different cellular components inhabiting the tumor microenvironment. The complex heterogeneous nature of GB cells is helped by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. Methods: By using fluorescent multiple labeling and a DEPArray cell separator, we recovered several single cells or groups of single cells from populations of different origins from IDH-WT GB samples. From each GB sample, we collected astrocytes-like (GFAP+), microglia-like (IBA1+), stem-like cells (CD133+), and endothelial-like cells (CD105+) and performed Copy Number Aberration (CNA) analysis with a low sequencing depth. The same tumors were subjected to a bulk CNA analysis. Results: The tumor partition in its single components allowed single-cell molecular subtyping which revealed new aspects of the GB altered genetic background. Conclusions: Nowadays, single-cell approaches are leading to a new understanding of GB physiology and disease. Moreover, single-cell CNAs resource will permit new insights into genome heterogeneity, mutational processes, and clonal evolution in malignant tissues.

Objective The aim of the study was to evaluate the clinical and electrodiagnostic testing in ulnar neuropathy at the elbow and differences according to site (humeroulnar arcade vs. retroepicondylar groove) and injury physiopathology (axonal vs. demyelinating), through prospective multicenter case-control study. Design Cases and controls were matched by age and sex. Ulnar neuropathy at the elbow diagnosis was made on symptoms. Statistical analysis was performed using Mann-Whitney, χ, and analysis of variance tests. Results One hundred forty-four cases and 144 controls were enrolled. Sensory loss in the fifth finger had the highest sensitivity (70.8%) compared with clinical findings. Motor conduction velocity across elbow reached the highest sensitivity (84.7%) in localizing ulnar neuropathy at the elbow recording from at least one of the two hand muscles (first dorsal interosseous and abductor digiti minimi). Abnormal sensory action potential amplitude from the fifth finger occurred more frequently in axonal than in demyelinating forms. Differences between retroepicondylar groove and humeroulnar arcade regarded conduction block and job type. Conclusions Clinical findings have less usefulness than electrodiagnostic testing in ulnar neuropathy at the elbow diagnosis. Motor conduction velocity across elbow recorded from both abductor digiti minimi and first dorsal interosseous increases diagnostic accuracy. Axonal forms have greater clinical and electrodiagnostic testing severity than demyelinating forms, which are more frequent in retroepicondylar groove. Manual workers prevailed in humeroulnar arcade. These findings may be helpful in prognostic and therapeutic approaches.

MiRNAs represent a mechanism that regulates gene expression in many pathological conditions. Exosomes are known to be secreted from all types of cells, and the exosomes-released molecules are crucial messengers that can regulate cellular processes. We investigated the miRNAs content of exosomes released by cancer cells during the invasion . An invasion stimulus has been generated through scratches created on the confluent cells of cancer cell lines: glioblastoma, breast and prostate cancers. Several miRNAs were found to be significantly differentially abundant during the cell invasion , both in common among different cell lines and exclusive. Understanding the language codes among cells involved in invasion can lead to the development of therapies that can inhibit cellular communication, slowing or eventually stopping their activity.

The betaretrovirus Mouse Mammary Tumor Virus (MMTV) is the well characterized etiological agent of mammary tumors in mice. In contrast, the etiology of sporadic human breast cancer (BC) is unknown, but accumulating data indicate a possible viral origin also for these malignancies. The presence of MMTVenv-like sequences (MMTVels) in the human salivary glands and saliva supports the latter as possible route of inter-human dissemination. In the absence of the demonstration of a mouse-man transmission of MMTV, we considered the possibility that a cross-species transmission could have occurred in ancient times. Therefore, we investigated MMTVels in the ancient dental calculus, which originates from saliva and is an excellent material for paleovirology. The calculus was collected from 36 ancient human skulls, excluding any possible mouse contamination. MMTV-like sequences were identified in the calculus of 6 individuals dated from the Copper Age to the 17th century. The MMTV-like sequences were compared with known human endogenous betaretroviruses and with animal exogenous betaretroviruses, confirming their exogenous origin and relation to MMTV. These data reveal that a human exogenous betaretrovirus similar to MMTV has existed at least since 4,500 years ago and indirectly support the hypothesis that it could play a role in human breast cancer.

Introduction Alternatives to the classical medial parapatellar (MPP) approach for total knee arthroplasty (TKA) include the mini-medial parapatellar (MMPP), mini-subvastus (MSV), mini-midvastus (MMV) and quadriceps-sparing (QS) approaches. The best approach has been not fully clarified. The purpose of the present study was to conduct a Bayesian network meta-analysis comparing these approaches. Materials and methods The present analysis was carried out according to the PRISMA extension statement for reporting systematic reviews incorporating network meta-analyses of healthcare interventions. The databases search was performed in October 2019. All clinical trials comparing two or more approaches for primary TKA were considered for inclusion. The baseline comparability was evaluated through the analysis of variance (ANOVA) test. The statistical analysis was performed through the STATA software/MP. A Bayesian hierarchical random-effects model analysis was adopted in all the comparisons. Results Data from 52 articles (4533 patients) were collected. The mean follow-up was 20.38 months. With regard to diagnosis, gender, age and BMI, adequate baseline comparability was detected. The MSV approach ranked better concerning clinical scores (the lowest visual analogic scale, the higher KSS and KSFS) and functional outcomes (the shortest straight leg raise, the greatest degree of flexion and range of motion). Concerning perioperative data, the MSV evidenced the shortest hospital stay, while the MPP the shortest surgical duration and lowest estimated blood loss. Conclusion According to the main findings of the present study, the mini-subvastus approach for total knee arthroplasty demonstrated superior overall compared to the other approaches. Orthopaedic surgeons should consider this approach in the light of the evidence and limitations of this Bayesian network meta-analysis.

Chondroblastoma-like osteosarcoma (CBLOS) is a rare and poorly understood variant of OS. We examined the clinicopathological, immunohistochemical and molecular features of six CBLOSs to highlight the differences with conventional high-grade OS (CHGOS) and CB, including CB with aggressive features.We performed histone 3.3 mutation analysis by gene sequencing and/or immunohistochemistry in all cases, while whole exome sequencing (WES) was performed on two CB-like osteosarcomas and 11 conventional high-grade OS.CBLOSs were predominantly localised at acral sites and involved mainly male subjects with a mean age of 29 years. One patient who had metastases at presentation died of disease, while another patient who developed multiple local recurrences and lung metastases was alive with no evidence of disease (ANED) at 294 months. The remaining patients were ANED after a mean interval of 70.8 months. Histologically, all CBLOS presented aggressive features, including nuclear atypia and infiltrative growth. Immunohistochemistry with H3F3 K36M mutant antibody was negative in all CBLOSs, and none of the five tumours tested by gene sequencing had H3F3B mutations. Conversely, all CBs presented the H3F3B K36M variant and were positive for immunostaining with the H3F3 K36M antibody. Two CBLOSs analysed by WES differed in amount and type of mutation from 11 cases of CHGOS. Moreover, CBLOSs showed lower copy number alteration (CNA) score values than CHGOSs.CBLOS presents a different genetic background and a less aggressive clinical behaviour in comparison with CHGOS. Search of the H3F3B K36M mutation is useful in the differential diagnosis with CB.

Objective The main objective is to investigate the diagnostic accuracy and the relation of touch sensation and subjective sensory symptoms in the medial aspect of the hand dorsum, and neurography of the dorsal ulnar cutaneous nerve (DUCN) in ulnar neuropathy at the elbow (UNE). Secondary objective is to report the electrophysiological occurrence of anatomical variant of sensory innervation of the medial aspect of the hand dorsum from superficial radial nerve (SRN). Design Prospective, cohort study. Setting Electromyography laboratory. Participants Consecutive participants (N=282), those with UNE (n=81) and those without UNE (n=201), were enrolled. Interventions Not applicable. Main Outcome Measures Accuracy and agreement between sensory clinical findings of the medial hand dorsum and neurography of DUCN in UNE diagnosis. Results DUCN neurographic and sensory findings had high specificity and relatively low sensitivity. Normal or abnormal sensory nerve action potential (SNAP) of DUCN matched with normal or abnormal touch sensation of the medial aspect of hand dorsum. Abnormal DUCN SNAP was related to the clinical severity of UNE and to the axonal damage of the ulnar nerve. Anatomical variant of the innervation of hand dorsum from SRN was demonstrated in 31 of 564 hands (6.2%) belonging to 26 of 282 participants (9.2%). If the variant was present, DUCN SNAP of the same side was more frequently absent or of low amplitude. Conclusions The utility of DUCN neurography and sensory findings of the medial aspect of the dorsum of the hand is limited in the diagnosis of UNE. However, if DUCN SNAP is absent or low in amplitude, it is advisable to check the presence of the anatomical variant of the innervation of the medial aspect of the hand dorsum from SRN.

The aim of the study was to demonstrate abnormalities of motor conduction of the tibial nerve across the tarsal tunnel in type 2 diabetes.One hundred twenty-four consecutive patients (mean age = 66.6 yrs, 62.1% male) with distal symmetric diabetic polyneuropathy clinically diagnosed were prospectively enrolled. Nerve conduction studies of deep peroneal, tibial, superficial peroneal, medial plantar, and sural nerves and standard needle electromyography in the lower limbs were performed. Demographic, anthropometric, and clinical findings were collected.Motor conduction velocity of the tibial nerve across tarsal tunnel was slowed in 60.5% of patients; another 4% showed conduction block across tarsal tunnel without reduction of motor conduction velocity. Overall percentage of abnormalities across tarsal tunnel (64.5%) exceeds that of the sensory conduction velocities of proximal sural and superficial peroneal nerves. Abnormal tibial motor conduction velocity across tarsal tunnel represents the most common abnormality among all motor nerve conduction study parameters and significantly correlates with hemoglobin level, diabetic neuropathic index score, and diabetic complications frequency.Tibial conduction abnormalities across tarsal tunnel are the most sensitive motor parameter in distal symmetric diabetic polyneuropathy, second only to conduction abnormalities of sensory/mixed distal nerves of the feet. The use of nerve conduction studies across tarsal tunnel of the tibial nerve may be useful in the electrophysiological protocol to confirm the diagnosis of distal symmetric diabetic polyneuropathy.

Introduction: Increasing evidence demonstrates a crucial role of inflammation in inducing and promoting several cancers. Pro-inflammatory upregulation of cytokines such as IL-6 has been implicated in cervical cancer development and progression through several mechanisms, for example, by inducing platelet production, activation, and aggregation. The aim of the study was to evaluate the effective prognostic impact of inflammatory biomarkers such as platelet count, platelet to lymphocyte ratio (PLR), and IL-6 in cervical cancer patients. Materials and Methods: Between 2016 and 2019, 108 out of 159 patients with cervical cancer have been enrolled. Cutoff level of pretreatment platelet count and PLR was identified by using the ROC curve. IL-6 tumoral and peritumoral expression was analyzed and stratified as low and high (low expression: 0 and +1; marked expression: +2 and +3). Results: Median follow-up duration was 30 months (range 16–44). Patients with higher platelet counts showed worse DFS and OS (DFS p < 0.001; OS p < 0.001). Cumulative rates of DFS and OS in patients with lower PLR were higher than in patients with higher values of PLR (DFS p = 0.032; OS p < 0.001). Survival analysis showed a better prognosis in patients with lower IL-6 expression (DFS p < 0.001; OS p < 0.001). Conclusion: Nowadays, causal relationship between inflammation, innate immunity, and cancer is more widely accepted. However, many of the molecular and cellular mechanisms mediating this relationship remain unresolved. Ongoing inflammatory response was associated with poor outcomes in cervical cancer patients. A higher pretreatment platelet count and PLR value associated with higher IL-6 tumoral expression could be used to predict poor prognosis in cervical cancer patients.

We performed a prospective multicenter case-control study to explore the association between ulnar neuropathy at elbow (UNE) and body and elbow anthropometric measures, demographic and lifestyle factors, and comorbidities. Cases and controls were consecutively enrolled among subjects admitted to four electromyography labs. UNE diagnosis was made on clinical and neurographic findings. The control group included all other subjects without signs/symptoms of ulnar neuropathy and with normal ulnar nerve neurography. Anthropometric measurements included weight, height, waist, hip circumferences, and external measures of elbow using a caliper. The participants filled in a self-administered questionnaire on personal characteristics, lifestyle factors, and medical history. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by fitting unconditional logistic regression models adjusted by center and education level. We enrolled 220 cases (males 61.8%; mean age 51.7 years) and 460 controls (47.4% males; mean age 47.8 years). At multivariable analysis, UNE was associated to male gender (OR = 2.4, 95%CI = 1.6-3.7), smoking habits (>25 pack-years (OR = 2.3, 95%CI = 1.3-4.1), body mass index (OR = 1.05, 95%CI 1.01-1.10), polyneuropathies (OR = 4.1, 95%CI 1.5-11.5), and leaning with flexed elbow on a table/desk (OR = 1.5, 95%CI 1.0-2.2). Cubital groove width (CGW) turned out to be negatively associated with UNE (OR = 0.80, 95%CI = 0.74-0.85). Our study suggests that some personal factors especially anthropometric measures of the elbow may play a role in UNE pathogenesis as the measures of wrist in CTS. We demonstrated that for each millimeter of smaller CGW the risk of idiopathic UNE increases of 25%.

Introduction In this study we collected reference values for the across-tarsal-tunnel conduction of the motor tibial nerve (mTN). Methods The mTN compound muscle action potentials (CMAPs) from the abductor hallucis muscle were obtained by stimulating below/above the malleolus and the popliteal fossa. The effect of weight, height, body mass index (BMI), foot and leg length, sex, and age were evaluated using univariate and multivariate correlation analyses, and predictive equations for each mTN conduction parameter were developed. Results On the basis of data from 185 subjects, there were differences between women and men in all anthropometric parameters and for some nerve conduction values. Through multivariate analysis, age, but not sex, was found to have a significant impact. Height affected both distal and proximal conduction velocity. BMI affected CMAP amplitude. Discussion mTN conduction is influenced by various demographic and anthropometric factors. For all intrinsic factors, height demonstrated the greatest effect on mTN conduction across the tarsal tunnel.

Drug-eluting bioresorbable vascular scaffolds (BVSs) have emerged as a potential breakthrough for the treatment of coronary artery stenosis, providing mechanical support and drug delivery followed by complete resorption. Restenosis and thrombosis remain the primary limitations in clinical use. The study aimed to identify potential markers of restenosis and thrombosis analyzing the vascular wall cell transcriptomic profile modulation triggered by BVS at different values of shear stress (SS). Human coronary artery endothelial cells and smooth muscle cells were cultured under SS (1 and 20 dyne cm

Recent evidence suggests that a loss of expression of caveolin in the stromal compartment (sCav-1) of human invasive breast carcinoma (IBC) may be a predictor of disease recurrence, metastasis and poor outcome. At present, there is little knowledge regarding the expression of sCav-1 at the metastatic sites. We therefore studied sCav-1 expression in IBCs and in their axillary lymph nodes to seek a correlation with cancer metastasis. 189 consecutive invasive IBCs (53 with axillary lymph node metastases and 136 without) were studied by immunohistochemistry, using a rabbit polyclonal anti-Cav-1 antibody. In IBCs sCav-1 was evaluated in fibroblasts scattered in the tumor stroma whereas in lymph nodes sCav-1 was assessed in fibroblast-like stromal cells. For the first time, we observed a statistically significant progressive loss of sCav-1 from normal/reactive axillary lymph nodes of tumors limited to the breast to metastatic axillary lymph nodes, through normal/reactive axillary lymph nodes of tumors with axillary metastatic spread. These data indicate that Cav-1 expressed by the stromal compartment of lymph nodes, somehow, may possibly contribute to metastatic spread in IBC.

Postoperative ileus (POI) impairs patient recovery, prolonging hospital stay after major surgery in ovarian cancer (OvCa) patients. Thus, intraoperative bowel isolation is expected to reduce manipulation-related impairment. The aim of this study was to investigate the impact of intraoperative intestinal isolation bag on POI in OvCa patients submitted to primary surgery. A randomized trial including patients managed with or without isolation bag during OvCa primary surgery was conducted. Patients were selected by consecutive randomization. Primary endpoints were the time between surgery and resumption of bowel motility (as passage of first/continued flatus), assessing of postoperative nausea or vomiting and return to regular diet. Secondary endpoint was the impact of intestinal isolation bag on length of hospitalization in the two groups. Ninety-two patients respecting inclusion criteria were eligible to be enrolled in the study (48 patients as Group 1 and 44 patients as Group 2). Thirty-eight (79.2%) patients, in which intraoperative isolation bag was used, experienced first/continued flatus within 3 days from surgery and they were susceptible to be discharged within 5 days, compared, respectively, to 34.3% of Group 2 (n = 15). Advantages were more evident in patients whose surgery took over 220 min (OR 0.02, CI 95% 0.001–0.57; p

The objective of the study is to investigate the effects of age, height, gender, body mass index (BMI), waist-to-hip ratio (WHR), arm and elbow measures on ulnar nerve conduction. We enrolled 261 "disease-free" subjects. We analyzed motor conduction velocity (MCV) in across elbow (AE) and forearm tracts, and sensory conduction velocity in 4th, 5th digit-wrist tracts (U4, U5) and in dorsal ulnar cutaneous nerve (DUC). We calculated the amplitudes of sensory and motor potentials (CMAPa and SNAPa), % of CMAPa drop AE, MCV drop and distal motor latency (DML). Univariate and multivariate analyses were performed. We estimated the predictive equations. The median nerve was examined for comparison. Age was negatively correlated with all conduction parameters. Forearm and AE MCV, % of CMAPa drop, DML, U4 and U5 SCV also depended upon height. Females had higher U4 and U5 SNAPa than males. BMI showed inverse relationship with U4 and U5 SNAPa. DUC parameters depended upon BMI and arm length. Similar trends were observed for the median nerve. "Normative" ulnar conduction parameters should be adjusted for demographic and anthropometric measures to improve diagnostic sensitivity.

Background Sudden unexplained death (SUD) refers to cases of sudden death where autopsy fails to identify any cardiac or extracardiac underlying cause. Guideline‐directed standard genetic testing identifies a disease‐causing mutation in less than one‐third of cases of SUD. Conversely, whole exome sequencing (WES) may provide the key to solve most cases of SUD even after several years from the subject's death. Methods We report on a case of sudden unexpected death of a 37‐year‐old male, with inconclusive autopsy conducted 14 years ago. A recent reevaluation through WES was performed on DNA extracted from left ventricular samples. A multiple step process including several “in silico” tools was applied to identify potentially pathogenic variants. Data analysis was based on a 562 gene panel, including 234 candidate genes associated with sudden cardiac death or heart diseases, with the addition of 328 genes highly expressed in the heart. WebGestalt algorithms were used for association enrichment analysis of all genes with detected putative pathogenic variants. Results WES analysis identified four potentially pathogenic variants: RYR2:c.12168G>T, TTN:c.11821C>T (rs397517804), MYBPC3:c.1255C>T (rs368770848), and ACADVL:c.848T>C (rs113994167). WebGestalt algorithms indicated that their combination holds an unfavorable arrhythmic susceptibility which conceivably caused the occurrence of the events leading to our subject's sudden death. Conclusion Associating WES technique with online prediction algorithms may allow the recognition of genetic mutations potentially responsible for otherwise unexplained deaths., We report on a case of sudden unexpected death of a 37‐year‐old male, with inconclusive autopsy conducted 14 years ago, where recent reevaluation through whole exome sequencing (WES) and WebGestalt algorithms allowed the recognition of four genetic mutations (RYR2‐K4056N, TTN‐R3941C, MYBPC3‐R419C, and ACADVL‐V283A) potentially responsible for the subject's sudden death.

The role of tourniquet during knee arthroplasty is controversial. The present study compares various tourniquet protocols using a Bayesian network meta-analysis of peri-operative data.The present study was conducted in accordance with the PRISMA extension statement for reporting systematic reviews incorporating network meta-analyses of health interventions. The literature search was conducted in September 2020. All clinical trials investigating the role of tourniquet in knee arthroplasty were considered for inclusion. Methodological quality was assessed using Review Manager 5.3. A Bayesian hierarchical random-effects model analysis was used in all comparisons.Ultimately, pooled data from 68 studies (7413 procedures) were analysed. Significant inconsistency was found in the data relating to total estimated blood lost; no assumption could be made on this outcome. Full-time tourniquet resulted in the shortest surgical duration and lowest intra-operative blood lost, in both cases followed by incision-to-suture. The incision-to-suture protocol achieved the smallest drop in haemoglobin during the first 72 h post-operatively and the lowest rate of blood transfusion, both followed by full-time tourniquet. Hospitalisation was shortest in the absence (no-tourniquet) group, followed by the cementation-to-end group.For knee arthroplasty, longer tourniquet use is associated with the shorter duration of surgery, lower intra-operative blood lost, lower drops in haemoglobin and fewer transfusion units. The shortest average hospitalisation was associated with no tourniquet use.

Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations. Disease implicated variants and predicted deleterious alterations were also chosen. TP53 genetic testing revealed a never reported TP53 deletion arose as de novo mutation in the mother and inherited by the proband. We then performed whole-exome analysis of the trio to uncover inherited variants from the father that potentially worsen the already altered genetic background in the proband. No pathogenic variants were inherited in autosomal recessive, de novo dominant or X-linked recessive manner. Comparing proband and father exome we detected 25 predicted deleterious variants including a nonsense mutation in ERCC3. Those inherited mutations are possible candidate modifiers linked to TP53, explaining the proband accelerated tumor onset compared to the mother and providing a possible explanation of the genetic anticipation event in this Li-Fraumeni family.

Total hip arthroplasty (THA) is one of the most performed intervention in orthopaedics surgery. Currently, there is no unanimous approval concerning the best approach for THA in terms of nerve palsies, dislocations and further revisions. Hence, a Bayesian network meta-analysis was conducted. The present study was conducted according to the PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of healthcare interventions. The literature search was performed in September 2019. The NMA was performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. Data from 10,675 THA were collected. The mean follow-up was 10 months. The anterior approach reported the lowest risk to incur a post-operative dislocation (overall inconsistency P = 0.99). The posterolateral approach reported the lowest risk to incur a nerve palsy (overall inconsistency P = 0.77). The funnel plot revealed a low risk of publication bias. The lateral approach was found to have the lowest risk of resulting in a revision surgery (overall inconsistency P = 0.90). According to our network comparisons, the posterolateral approach for THA represent the favourable exposure with regards to nerve palsy, further dislocations and revision surgeries.

Familial isolated hyperparathyroidism (FIHP) is a rare inherited disease accounting for 1% of all cases of primary hyperparathyroidism (PHPT). It is genetically heterogeneous being associated with mutations in different genes, including MEN1, CDC73, CASR, and recently GCM2. The aim of the study was to further investigate the molecular pathogenesis in Italian FIHP kindreds. We used whole exome sequencing (WES) in the probands of seven unrelated FIHP kindreds. We carried out a separate family-based exome analysis in a large family characterized by the co-occurrence of PHPT with multiple tumors apparently unrelated to the disease. Selected variants were also screened in 18 additional FIHP kindreds. The clinical, biochemical, and pathological characteristics of the families were also investigated. Three different variants in GCM2 gene were found in two families, but only one (p.Tyr394Ser), already been shown to be pathogenic in vitro, segregated with the disease. Six probands carried seven heterozygous missense mutations segregating with the disease in the FAT3, PARK2, HDAC4, ITPR2 and TBCE genes. A genetic variant in the APC gene co-segregating with PHPT (p.Val530Ala) was detected in a family whose affected relatives had additional tumors, including colonic polyposis. We confirm the role of GCM2 germline mutations in the pathogenesis of FIHP, although at a lower rate than in the previous WES study. Further studies are needed to establish the prevalence and the role in the predisposition to FIHP of the novel variants in additional genes.

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.

The inheritance of mutated suppressor genes, such as BRCA1 and BRCA2, is acknowledged as an etiological factor in hereditary breast carcinoma (HBC). Two different molecular mechanisms are possible; the Knudson’s “two hits” or the gene haploinsufficiency. Etiology of sporadic breast carcinoma (SBC) is not known, although data support the possible role of the betaretrovirus Mouse Mammary Tumor Virus (MMTV). This study analyzes the presence of MMTV exogenous sequences in two representative groups of HBC and SBC, excluding any contamination by murine and retroviral material and endogenous betaretroviruses. The 30.3% of 56 SBC contained MMTV sequences, against the 4.2% of 47 HBC (p < 0.001). Cases positive for viral sequences showed the presence of p14, signal peptide of the MMTV envelope precursor. This result was expected based on the fact that HBCs, having a specific genetic etiology, do not need the action of a carcinogenetic viral agent. Moreover, the striking results obtained by comparing two groups of vastly different tumors represent an additional element of quality control: the distinction between HBC and SBC is so well-defined that results cannot be ascribed to mere coincidence. This paper strengthens the hypothesis for a viral etiology for human sporadic breast carcinoma.

BackgroundBladder cancer (BC) is the 9th most common cancer diagnosis worldwide. Low grade (LG) represents 70% of all BCs, characterized by recurrence and rare ability (10-15%) to progress to high grade (HG) and invade. The remaining 30% is high grade (HG), fast invasive BC, which is resistant to therapy. Identifying biomarkers for predicting those tumors able to progress is a key goal for patient outcome improvement. This study focuses on the most promising prognostic markers.Materials and methodsTP53 and FGFR3 mutational status, Survivin, CK19, CK20, E-cadherin and CD44 gene expression analysis were performed on 66 BCs.ResultsSurvivin was found associated to tumor grade (pConclusionWe suggest Survivin, both as a biomarker associated to G3 BCs but negatively related to TP53 mutational status, and as a potential novel therapeutic target.

Background Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate. Methods Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq. Results Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation. Conclusion Collectively, these results support a role of defective cohesin in the development of human colorectal cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1116-0) contains supplementary material, which is available to authorized users.

Objectives To evaluate sensitivity, specificity and predictive values of sensory findings in ulnar neuropathy at the elbow (UNE), differences according to UNE localization and pathophysiology, and relation between the sites of sensory symptoms, abnormal evaluation of sensation and neurographic findings of ulnar sensory nerve. Methods Hand diagram and Semmes-Weinstein monofilaments were used for clinical evaluation in four ulnar hand territories. Sensory neurography was measured in the fourth and fifth digits-wrist segments (U5) and in the dorsal ulnar cutaneous nerve. Results We enrolled 75 idiopathic UNE cases and 180 controls. Symptoms in the fifth digit, reduction of touch sensation and U5 sensory nerve action potential amplitude (SNAPa) had the highest sensitivity, specificity and predictivity in UNE diagnosis. The normal/abnormal sensory clinical findings of the fifth digit matched with normal/abnormal U5 SNAP more than the matching of sensory parameters in the other ulnar hand sites. Sensory anomalies were more frequent in predominantly axonal than demyelinating UNE. There were no differences according to UNE location. Conclusion Sensory anomalies of the fifth digit are constant findings in UNE more than anomalies of the other ulnar nerve hand regions. Significance Probably the fascicles from fifth digit are the most liable to damage at elbow.

Background Tumors develop by progression through a series of stages. Every cell of the tumor microenvironment is constantly changing in the flow of the cancer progression. It has become clear in recent years that stroma is essential for tumor maintenance and growth. Here, we aimed to give a chronological order of gene expression changes given in the dynamical framework of microinvasive breast cancer microenvironment. Methods RNA-seq was performed on seven microinvasive breast cancers. For each of them we microdissected seven different portions of the tumor, four related to the breast epithelium and three to the stroma. Breast epithelium was chronologically subdivided in normal breast epithelium (NBE), carcinoma in situ (CIS), emerging invasive fingers (EIF) and invasive breast cancer (IBC). For each of the breast epithelium subdivisions we collected the adjacent stroma (S): S-NBE, S-EIF and S-IBC. Results The overall differentially expressed genes (DEGs) in all the compartments were analysed and evaluated to understand the pathways involved in tumor progression. Then we analysed the DEGs of the epithelial and stromal portions in comparison with the normal portions. We observed that the stromal cells are necessary for the development and the maintenance of the tumor, especially in tumor progression. Moreover the most important genes involved in the main metabolic pathways were analysed and the communications within the different cell compartments were highlighted. Conclusions As a future perspective, a deeply study of the identified key genes, particularly in the stromal cells, will be crucial to develop an anticancer therapy that is undergoing a conversion from a cancer cell-centric strategy to a stroma-centric strategy, more genomically stable. Electronic supplementary material The online version of this article (10.1186/s12967-019-1936-x) contains supplementary material, which is available to authorized users.

Glioblastoma is the most common and aggressive malignant primary brain tumor. Despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Radiation therapy has a major role as adjuvant treatment for glioblastoma following surgical resection. Many studies have shown that polymorphisms of genes involved in pathways of DNA repair may affect the sensitivity of the cells to treatment. Although the role of these polymorphisms has been investigated in relation to response to radiotherapy, their role as predisposing factors to glioblastoma has not been clarified yet. In the present study, we evaluated the association between polymorphisms in DNA repair genes, namely: XRCC1 rs25487, XRCC3 rs861539 and RAD51 rs1801320, with the susceptibility to develop glioblastoma. Eighty-five glioblastoma patients and 70 matched controls were recruited for this study. Data from the 1000 Genomes Project (98 Tuscans) were also downloaded and used for the association analysis. Subjects carrying RAD51 rs1801320 GC genotype showed an increased risk of glioblastoma (GC vs GG, χ(2) = 10.75; OR 3.0087; p = 0.0010). The C allele was also significantly associated to glioblastoma (χ(2) = 8.66; OR 2.5674; p = 0.0032). Moreover, RAD51 rs1801320 C allele increased the risk to develop glioblastoma also when combined to XRCC1 rs25487 G allele and XRCC3 rs861539 C allele (χ(2) = 6.558; p = 0.0053).

Etiology of human breast cancer is unknown, whereas the Mouse Mammary Tumor Virus (MMTV) is recognized as the etiologic agent of mouse mammary carcinoma. Moreover, this experimental model contributed substantially to our understanding of many biological aspects of the human disease. Several data strongly suggest a causative role of MMTV in humans, such as the presence of viral sequences in a high percentage of infiltrating breast carcinoma and in its preinvasive lesions, the production of viral particles in primary cultures of breast cancer, the ability of the virus to infect cells in culture. This paper demonstrates that MMTV is present in human saliva and salivary glands. MMTV presence was investigated by fluorescent PCR, RT-PCR, FISH, immunohistochemistry, and whole transcriptome analysis. Saliva was obtained from newborns, children, adults, and breast cancer patients. The saliva of newborns is MMTV-free, whereas MMTV is present in saliva of children (26.66%), healthy adults (10.60%), and breast cancer patients (57.14% as DNA and 33.9% as RNA). MMTV is also present in 8.10% of salivary glands. RNA-seq analysis performed on saliva of a breast cancer patient demonstrates a high expression of MMTV RNA in comparison to negative controls. The possibility of a contamination by murine DNA was excluded by murine mtDNA and IAP LTR PCR. These findings confirm the presence of MMTV in humans, strongly suggest saliva as route in inter-human infection, and support the hypothesis of a viral origin for human breast carcinoma.

CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.

Objective Previous studies showed "F-wave inversion" (F-INV) as a sensitive method in the electrodiagnosis of early stage of carpal tunnel syndrome (CTS). This study aimed at evaluating the sensitivity and specificity of F-wave and nerve conduction velocity (NCV) testing in CTS. Methods We consecutively enrolled 244 cases and 108 controls. F-waves analysis included: Fwave minimum and mean latencies, F-wave persistence and chronodispersion, mean-F/CMAP amplitude ratio, F-INV. Specificity and sensitivity of F-waves parameters were calculated in the whole sample of CTS patients and by grouping the patients according to CTS severity. Multivariate logistic regression was also performed using F-INV as a dependent variable. Results In the whole sample the sensitivity of F-mean-INV and of median–ulnar NCV comparative testing was 50.8% and 93.7%, respectively. F-INV sensitivity dropped to 8% in CTS early stage. F-INV could be predicted only by distal motor latency of the median nerve. The sensitivity of all F-wave parameters increased only in the most severe stages of CTS. Conclusions This study does not confirm the electrodiagnostic usefulness of F-INV in early stage of CTS. All F-wave parameters, including F-INV, are much less sensitive than conventional NCV in CTS electrodiagnosis. F-wave does not add further useful information specifically related to CTS.

Objective To assess the associations between carpal tunnel syndrome (CTS) severity and selected anthropometric and obesity indexes. Design We performed a case-control study. Clinical and electrophysiological severity of CTS was classified as mild, moderate, or severe based on validated scales. Body and hand anthropometric characteristics were measured at the time of the electrodiagnostic study. We estimated the relative risk ratios (RRRs) of CTS severity by fitting multinomial logistic regression models adjusted by age and sex. In addition, we fitted multivariable models, including age, sex, wrist ratio, hand ratio, body mass index (BMI), and waist/stature ratio. Setting Electromyography laboratories. Participants Consecutive patients (N=1087), those with CTS (n=340) and those without CTS (n=747), were enrolled. Interventions Not applicable. Main Outcome Measures Associations between CTS severity and selected anthropometric and obesity indexes. Results We observed associations between many anthropometric indexes and CTS severity. Among obesity indexes, the waist/stature ratio, and among hand anthropometric indexes, the wrist/palm ratio, showed the highest RRRs for the clinical and electrophysiological severity scales. The RRRs of severe CTS (adjusted for age and sex) for the wrist/palm ratio were 3.5 for the clinical scale and 2.4 for the electrophysiological scale. The RRRs of severe CTS for the waist/stature ratio were 2.3 for the clinical scale and 2.0 for the electrophysiological scale. In the multivariable models, both BMI and the waist/stature ratio were associated with the outcomes. Conclusions Different configurations of the body and, in particular, the hand and wrist system may influence the occurrence and severity of CTS. Multiple obesity indexes, possibly including the waist/stature ratio, should be considered when investigating the association between body composition and CTS. Future studies should determine whether in obese subjects with CTS the weight and waist circumference loss produces an improvement in CTS symptoms and recovery of distal conduction velocity of the median nerve.

Background Glioblastoma (GBM) is the most frequent and malignant primary brain tumor in adults and despite the progress in surgical procedures and therapy options, the overall survival remains very poor. Glutamate and α-KG are fundamental elements necessary to support the growth and proliferation of GBM cells. Glutamate oxidative deamination, catalyzed by GLUD2, is the predominant pathway for the production of α-KG. Methods GLUD2 emerged from the RNA-seq analysis of 13 GBM patients, performed in our laboratory and a microarray analysis of 77 high-grade gliomas available on the Geo database. Thereafter, we investigated GLUD2 relevance in cancer cell behavior by GLUD2 overexpression and silencing in two different human GBM cell lines. Finally, we overexpressed GLUD2 in-vivo by using zebrafish embryos and monitored the developing central nervous system. Findings GLUD2 expression was found associated to the histopathological classification, prognosis and survival of GBM patients. Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production. In support of these findings, we also demonstrated, with in-vivo studies, that GLUD2 overexpression affects glial cell proliferation without affecting neuronal development in zebrafish embryos. Interpretation We concluded that GLUD2 overexpression inhibited GBM cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons.

Objective: To study the diagnostic properties of hand/wrist and body measures according to validated clinical and electrophysiological carpal tunnel syndrome (CTS) severity scales. Methods: We performed a prospective case-control study. For each case, two controls were enrolled. Two five-stage clinical and electrophysiological scales were used to evaluate CTS severity. Anthropometric measurements were collected and obesity indicators and hand/wrist ratios were calculated. Area under the receiver operating characteristic curves (AUC), sensitivity, specificity, and likelihood ratios were calculated separately by gender. Results: We consecutively enrolled 370 cases and 747 controls. The wrist-palm ratio, waist-hipheight ratio and waist-stature ratio showed the highest proportion of cases with abnormal values in the severe stages of CTS for clinical and electrophysiological severity scales in both genders. Accuracy tended to increase with CTS severity for females and males. In severe stage, most of the indexes presented moderate accuracy in both genders. Among subjects with severe CTS, the wrist-palm ratio presented the highest AUC for hand measures in the clinical and electrophysiological severity scales both in females (AUC 0.83 and 0.76, respectively) and males (AUC 0.91 and 0.82, respectively). Among subjects with severe CTS, the waist-stature ratio showed the highest AUC for body measures in the clinical and electrophysiological severity scales both in females (AUC 0.78 and 0.77, respectively) and males (AUC 0.84 and 0.76, respectively). The results of waist-hip-height ratio AUC were similar. Conclusions: Wrist-palm ratio, waist-hip-height ratio and waist-stature ratio could contribute to support the diagnostic hypothesis of severe CTS that however has to be confirmed by nerve conduction study.

The aims are to evaluate electrodiagnostic testing (EDX) requests and verify if presence, consistency and agreement of referral diagnosis could be predicted by patient demographic findings and referring physician typology, and if there were differences in respect to our previous study performed 16 years ago. The study concerns EDX requests referred to two electromyography labs during the year 2011. Differences between findings of general practitioners (GPs) versus specialists' requests and between this study with the previous were assessed. Multivariate logistic regression was performed to calculate odds ratio to assess the strength of association between presence, consistency and agreement of referral diagnosis with patient demographic findings and referring physician typology. We evaluated EDX requests of 1,586 patients (mean age 56 ± 16.7 years, 58.8 % women), 1,050 (66.2 %) were referred by GPs and 536 (33.8 %) by specialists. The suspected diagnosis was reported in 1,033 (65.1 %) requests, the overall consistency was 79.9 % and agreement was 71.9 %. Presence, consistency and agreement of referral diagnosis were predicted by physician's typology (specialist). Only if the suspected diagnosis was carpal tunnel syndrome, consistency and agreement were high regardless of doctor's typology. The physicians, especially GPs, who reported the referral diagnosis decreased during the past 16 years. A diagnostic test, including EDX, should be considered mainly if it fits into the best diagnostic strategy. The neurophysiologist should decide if EDX is useful, make the best decision on further management, and not submit patients to unnecessary and uncomfortable procedures. This choice of behaviour could be questionable and may lead to ethical and deontological problems.

Summary Study aim This prospective study aim to examine whether clinical findings and electrodiagnostic testing (EDX) in patients with lumbosacral monoradiculopathy due to herniated disc (HD) differ as a function of root involvement level (L5 vs. S1) and HD zone (paramedian vs. intraforaminal). Patients and methods All patients with L4, L5 or S1 monoradiculopathy were prospectively enrolled at four electromyography (EMG) labs over a 2-year period. The diagnosis was based on a congruence between patient history and MRI evidence of HD. We compared the sensitivities of clinical findings and EDX with respect to both root involvement level and HD zone. Multivariate logistic regression was performed in order to verify the association between abnormal EMG, clinical, and neuroradiological findings. Results One hundred and eight patients (mean age 47.7 years, 55% men) were consecutively enrolled. Sensory loss in the painful dermatome was the most frequent finding at physical examination (56% of cases). EMG was abnormal in at least one muscle supplied by femoral and sciatic nerves in 45 cases (42%). Inclusion of paraspinal muscles increased sensitivity to only 49% and that of proximal muscles was useless. Motor and sensory neurography was seldom abnormal. The most frequent motor neurographic abnormalities were a delay of F-wave minimum latency and decrease in the compound muscle action potential amplitude from extensor digitorum brevis and abductor hallucis in L5 and S1 radiculopathies, respectively. Sensory neurography was usually normal, the amplitude of sensory nerve action potential was seldom reduced when HD injured dorsal root ganglion or postganglionic root fibres. Multivariate logistic regression analysis showed that EMG abnormalities could be predicted by myotomal muscular weakness, abnormal deep reflexes, and paraesthesiae. The only clinical and electrophysiological differences with respect to root involvement level concerned deep reflexes and motor neurography of deep peroneal and tibial nerves. Conclusions Only some EDX parameters are helpful for the diagnosis of lumbosacral radiculopathy. EMG was abnormal in less than 50% of cases and its abnormalities could be predicted by some clinical findings. However, neurography is useful as a tool for differential diagnosis between radiculopathy and more diffuse disorders of the peripheral nervous system (polyneuropathy, plexopathy).

OBJECTIVE: To identify optimal cutoff values for body, hand, and wrist measurements in order to correctly identify individuals with carpal tunnel syndrome (CTS), using receiver operating characteristic (ROC) curves. METHODS: We enrolled patients with CTS and control subjects at a 1:2 ratio, regardless of age and sex. The diagnosis of CTS was based on clinical findings and delayed distal conduction velocity of the median nerve. The anthropometric measurements included weight, height, waist circumference, hip circumferences, wrist depth/width, third digit length, and palm length/width. Obesity indicators and hand/wrist ratios were calculated. Area under the ROC curve (AUC), sensitivity, specificity, and likelihood ratios were calculated separately according to sex. To assess the role of multiple anthropometric measurements, we fit multivariable logistic regression models including age, wrist ratio, shape index, body mass index, and waist-to-hip ratio. RESULTS: The study group comprised 1,117 subjects (250 female patients and 474 female controls; 120 male patients and 273 male controls). In women, the accuracy of all anthropometric measures was low (AUC ≤0.64). In men, the accuracy of the hand ratio, shape index, and wrist-to-palm ratio was moderate (AUC = 0.75). The estimates from the multivariable models confirmed the well-known associations between the selected variables and the risk of CTS, but the use of multiple predictors did not dramatically improve the diagnostic performance observed for single anthropometric indexes. CONCLUSION: In clinical practice, the cutoff values for many anthropometric measurements have limited value as tools for the diagnosis of CTS.

Papillary thyroid carcinoma is the most frequent histologic type of thyroid tumor. Few studies investigated the role of c-KIT expression in thyroid tumors, suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and a receptor loss following malignant transformation. We investigated and correlated c-KIT expression levels and two known markers of thyrocytes differentiation, PAX8 and TTF-1, in malignant and benign cytological thyroid samples. Moreover, we performed functional studies on human papillary thyroid carcinoma cell line to associated c-KIT expression to thyrocytes differentiation and tumor proliferation. c-KIT and PAX8 expression resulted higher in benign samples compared to the malignant ones, and the expression levels of these two genes were significantly correlated to each other. We also observed that c-KIT overexpression led to an increase of PAX8 expression level together with a decrease of proliferation. Furthermore, c-KIT overexpressing cells showed a regression of typical morphological features of malignancy. Taken together these results suggest that c-KIT could be involved in the differentiation of thyroid cells and in tumor progression.

Objective Breast cancer is the most common female cancer in Morocco. About 5 to 10% are due to hereditary predisposition and mutations in BRCA1 and BRCA2 genes are responsible for an important proportion of high-risk breast/ovarian cancer families. The relevance of BRCA1 /2 mutations in the Moroccan population was not studied. The main objective of this study is to investigate the spectrum of BRCA1 and BRCA2 germline mutations in early onset and familial breast/ovarian cancer among Moroccan women. Methods We screened the entire coding sequences and intron/exon boundaries of BRCA1 and BRCA2 genes in 40 patients by direct sequencing. Results Nine pathogenic mutations were detected in ten unrelated families, five deleterious mutations in BRCA1 gene and four mutations in BRCA2 gene. Four novel mutations were found: one in BRCA1 (c.2805delA/2924delA) and three in BRCA2 (c.3381delT/3609delT; c.7110delA/7338delA and c.7235insG/7463insG). We also identified 51 distinct polymorphisms and unclassified variants (three described for the first time). Conclusions Our data suggest that BRCA1 and BRCA2 mutations are responsible for a significant proportion of familial breast cancer in Moroccan patients. Therefore full BRCA1 /2 screening should be offered to patients with a family history of breast/ovarian cancer.

To demonstrate whether in distal symmetric polyneuropathy (DSPN) in diabetes there are differences between patients with and without neuropathic pain and whether pain is associated with demographic, clinical and electrophysiological variables.We prospectively enrolled 154 consecutive patients (mean age 67 years, 64% men) in an electromyography (EMG) lab. The differences were calculated between DSPN patients with (no.78) and without neuropathic pain (no.76) relating to age, sex, BMI, type, duration, treatment and complications of diabetes, HbA1c, type and duration of DSPN symptoms, DSPN clinical severity score (with Diabetic Neuropathic Index-DNI), electrophysiological findings of lower limb muscles and nerves.The differences between DSPN patients with and without pain included the presence of symptoms (burning and weakness), DNI score and neurographic findings of all nerves and neurogenic EMG. But in the logistic regression models enter only the following variables: DNI score, neurogenic EMG, and among symptoms “burning-.The presence of pain in DSPN is associated with DSPN clinical severity, neurogenic EMG and presence of “burning- symptom but not with demographic or neurographic findings, or diabetes related variables. Therefore, the neuropathic pain in DSPN does not associate with the degree of involvement of large diameter sensory fibres or diabetes severity.

To report an electrophysiological study on thenar motor neuropathy of the median nerve.Twenty-eight consecutive patients (mean age, 48.8 years; 17 men) with dominant hand thenar muscle weakness without sensory symptoms were enrolled in this study. Electromyography of hand and forearm muscles and neurography of median, ulnar, radial, and palmar nerves, including distal motor latency recording from the second interosseous-lumbrical muscles, were performed.Complete denervation of the abductor pollicis brevis muscle was observed in one case and delayed median abductor pollicis brevis-distal motor latency was observed in the others. Other neurographic findings were normal.Thenar motor neuropathy may have different pathogeneses. It may be considered a variant of carpal tunnel syndrome involving the motor branch only or more likely due to chronic direct compression of the branch, because it preferentially affects males, dominant hand, and persons doing manual work. In both cases, anatomic origin and variations in the course of the branch may favor thenar motor neuropathy.

Objective Carpal tunnel syndrome (CTS) has a high prevalence in agricultural workers, especially those engaged in vineyards. We postulated that vineyard CTS was electrophysiologically different from CTS of other subjects. We performed a retrospective cross-sectional electrophysiological study of two cohorts of consecutive patients with CTS, the first consisting of vineyard workers and the second, of other unselected types of workers, housewives and pensioners. Methods Thirty-three vineyard workers (mean age 46.8 years, 42% women) and 205 patients with other occupations (mean age 53.7 years; 66% women) were enrolled. All patients underwent sensory and motor neurography of the median and ulnar nerves. Differences in demographic and electrophysiological findings between groups were calculated and multiple linear regression analysis was performed to eliminate the influence of potential confounding factors (age, sex, BMI, clinical severity of CTS) on the results of univariate difference analysis. Results Univariate analysis showed that DML was longer and compound muscle action potential amplitude of the median nerve, recorded from the abductor pollicis brevis muscle, was smaller in vineyard workers than in the other CTS patients. These differences remained significant after adjusting the results for confounding factors. Conclusions The vineyard workers showed a different pattern of CTS than the other patients: thenar motor fibres were more affected, presumably due to chronic compression on the thenar branch. This suggests an association between “common” CTS and thenar mononeuropathy. Significance Occupational physiologists should clarify the mechanisms of neuromuscular engagement in particular jobs and ergonomists design suitable working tools, because many “individual” risk factors are difficult to change, but workplace-related risk factors can be modified.

Diabetes mellitus is a main risk factor for vascular diseases. Vascular injury induced by diabetes mellitus is characterized by endothelial dysfunction attributable to an increased oxidative stress. So far, the molecular mechanisms involved in the vasculotoxic effects of diabetes are only partially known. We examined the effect of diabetes mellitus on oxidative stress and Rac-1 activation, a small G -protein involved in the activation of NADPH oxidase. Our results show that oxidative stress in vessels of different murine models of diabetes mellitus and in endothelial cells treated with high glucose is associated with an increased Rac-1/PAK binding and Rac-1 translocation from cytosol to plasma membrane, thus demonstrating an enhanced Rac-1 activity. More important, selective Rac-1 inhibition by an adenoviral vector carrying a dominant negative mutant of Rac-1 protected from oxidative stress and vascular dysfunction induced by diabetes mellitus. Our study demonstrates that Rac-1 plays a crucial role in diabetes-induced vascular injury, and it could be a target of novel therapeutic approaches to reduce vascular risk in diabetes mellitus. © 2006 American Heart Association, Inc.

The pathogenetic hypotheses of Raynaud’s phenomenon include increased activation of sympathetic noradrenergic nerves controlling muscle tone of digit arteriolar walls. Because acral sympathetic fibres contain vasoactive adrenergic and cholinergic fibres for sweat glands, we tested cholinergic sympathetic fibre function in primary Raynaud’s phenomenon (PRP) patients by sympathetic skin response (SSR). Twenty-six consecutive patients (19 women, 7 men, mean age 37.8 years) with PRP were enroled prospectively. SSR was obtained by random electrical stimulation of the left ulnar nerve at the wrist recording from the palm (PSSR), third (M3SSR) and fifth fingers (U5SSR) on the right side. For each subject latency of shortest response, area of largest response and grand mean latencies and areas of 12 consecutive responses were calculated. The differences between patients and a control group (15 women, 6 men, mean age 38.9 years) were calculated. SSR habituation was also compared between patients and controls. PSSRs were recorded in all patients and no difference in any PSSR parameter was found between patients and controls. U5SSRs and M3SSRs were absent in two patients. Grand mean area and mean of largest M3SSRs and U5SSRs were significantly lower in patients than in controls. Grand mean latency and mean of shortest M3SSRs and U5SSRs were significantly slower in patients than in controls. M3 and U5SSRs habituated less in patients than in controls. Dysregulation of cholinergic sympathetic fibres innervating the fingers was found in PRP. Abnormal peripheral mechanisms may be the cause. Since SSR habituation was also not normal, even central mechanisms may be implicated.

The BRCA1 tumor suppressor gene is found mutated in familial breast cancer. Although many of the mutations are clearly pathological because they give rise to truncated proteins, several missense variants of uncertain pathological consequences have been identified. A novel functional assay to screen for BRCA1 missense variants in a simple genetic system could be very useful for the identification of potentially deleterious mutations. By using two prediction computer programs, Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen), seven nonsynonymous missense BRCA1 variants likely disrupting the gene function were selected as potentially deleterious. The budding yeast Saccharomyces cerevisiae (S. cerevisiae) was used to test these cancer-related missense mutations for their ability to affect cell growth and homologous recombination (HR) at the HIS3 and ADE2 loci. The variants localized in the BRCA1 C-Terminus (BRCT) domain did not show any growth inhibition when overexpressed in agreement with previous results. Overexpression of either wild-type BRCA1 or two neutral missense variants did not increase yeast HR but when cancer-related variants were overexpressed a significant increase in recombination was observed. Results clearly showed that this genetic system can be useful to discriminate between neutral and deleterious BRCA1 missense variants. Hum Mutat 0, 1–11, 2008. © 2008 Wiley-Liss, Inc.

Background The association between carpal tunnel syndrome (CTS) and high body mass index (BMI) and some hand measures is well known. No study has been specifically focused on waist circumference (WC) and waist-to-hip-ratio (WHR). The aim of this prospective case–control study is to evaluate the association between CTS and WC, WHR and other body and hand anthropometric measures. Methods We consecutively enrolled one “idiopathic” CTS case for two controls in 3 outpatient electromyography labs. The main anthropometric measures were BMI, WC, WHR, wrist ratio (WR) and hand ratio (HR). We performed univariate and multivariate analyses. Results Female cases and controls were 250 and 474 and male cases and controls were 120 and 273, respectively. At univariate analysis there were differences in many anthropometric measures between cases and controls. At multivariate logistic regression analyses high BMI, WC and WHR and abnormal HR and WR were independent risk factors for CTS. Crossing two categories between BMI, WC and WHR, the overweight subjects, especially females, were at risk only if they had very high WC or high WHR. The risk increased if they were obese. Conclusions High WC/WHR doubles the risk of CTS, the risk further increased if overweight/obese subjects have also very high WC or high WHR. The obese subjects were always at risk regardless of WC and WHR values. Metabolic causes of this association with CTS were hypothesised. BMI is not the only and most powerful body predictor of “idiopathic” CTS, but also WHR and WC should be considered. These measures may not be interchangeable and it may be desirable to consider the utility of their joint use.

BRMS1 is regarded as a metastasis suppressor gene for its ability to reduce metastatic potential of human and murine breast cancer cells as well as human melanoma cells. However, BRMS1 association to human tumor progression is not clearly understood. In the present study we analyzed BRMS1 mRNA expression in tumor progression and its potential prognostic value for breast carcinoma. BRMS1 mRNA expression level was quantified by real-time PCR in 47 tumoral, in 14 peritumoral and in 15 metastatic microdissected cellular populations from 47 breast cancer patients with 10-year follow up. We found BRMS1 expression to be higher in carcinoma cells than in matching normal epithelial cell populations in 10 out of 14 cases (p = 0.0005), while lymph-nodal carcinoma cells showed lower BRMS1 expression in 9 out of 15 cases (p = 0.001). Using both in vivo (human mammary breast carcinomas) and in vitro systems (breast cancer cell lines) we were able to demonstrate that BRMS1 overexpression was not a bias effect induced by cell proliferation rate. BRMS1 expression levels did not correlate with standard breast cancer prognostic factors but BRMS1 higher expression was associated with patient shorter disease-free and overall survival. Our findings are apparently inconsistent with the concept of BRMS1 as a metastasis suppressor gene. One possible explanation is that epithelial cells increase their BRMS1 expression as a compensatory response to tumor formation or metastasis progression, which is elevated in proportion to tumor aggressiveness, whereas those cells of the primary tumor that cannot upregulate BRMS1 escape to form metastasis.