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Honey bees are unintentionally exposed to a wide range of chemicals through various routes in their natural environment, yet research on the cumulative effects of multi-chemical and sublethal exposures on important caste members, including the queen bee and brood, is still in its infancy. The hive's social structure and food-sharing (trophallaxis) practices are important aspects to consider when identifying primary and secondary exposure pathways for residential hive members and possible chemical reservoirs within the colony. Secondary exposures may also occur through chemical transfer (maternal offloading) to the brood and by contact through possible chemical diffusion from wax cells to all hive members. The lack of research on peer-to-peer exposures to contaminants and their metabolites may be in part due to the limitations in sensitive analytical techniques for monitoring chemical fate and dispersion. Combined application of automated honey bee monitoring and modern chemical trace analysis techniques could offer rapid progress in quantifying chemical transfer and accumulation within the hive environment and developing effective mitigation strategies for toxic chemical co-exposures. To enhance the understanding of chemical fate and toxicity within the entire colony, it is crucial to consider both the intricate interactions among hive members and the potential synergistic effects arising from combinations of chemical and their metabolites.

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A core component of nearly all bacteria, the cell wall is an ideal target for broad spectrum antibiotics. Many bacteria have evolved strategies to sense and respond to antibiotics targeting cell wall synthesis, especially in the soil where antibiotic-producing bacteria compete with one another. Here we show that cell wall stress caused by both chemical and genetic inhibition of the essential, bifunctional penicillin-binding protein PBP1a prevents microcolony formation and activates the canonical host-invasion two-component system ChvG-ChvI in Agrobacterium tumefaciens. Using RNA-seq, we show that depletion of PBP1a for 6 hours results in a downregulation in transcription of flagellum-dependent motility genes and an upregulation in transcription of type VI secretion and succinoglycan biosynthesis genes, a hallmark of the ChvG-ChvI regulon. Depletion of PBP1a for 16 hours, results in differential expression of many additional genes and may promote a stress response, resembling those of sigma factors in other bacteria. Remarkably, the overproduction of succinoglycan causes cell spreading and deletion of the succinoglycan biosynthesis gene exoA restores microcolony formation. Treatment with cefsulodin phenocopies depletion of PBP1a and we correspondingly find that chvG and chvI mutants are hypersensitive to cefsulodin. This hypersensitivity only occurs in response to treatment with ß-lactam antibiotics, suggesting that the ChvG-ChvI pathway may play a key role in resistance to antibiotics targeting cell wall synthesis. Finally, we provide evidence that ChvG-ChvI likely has a conserved role in conferring resistance to cell wall stress within the Alphaproteobacteria that is independent of the ChvG-ChvI repressor ExoR.

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Marine pollutants bioaccumulate at high trophic levels of marine food webs and are transferred to humans through consumption of apex species. Yellowfin tuna (Thunnus albacares) are marine predators, and one of largest commercial fisheries in the world. Previous studies have shown that yellowfin tuna can accumulate high levels of persistent organic pollutants, including Transporter Interfering Chemicals (TICs), which are chemicals shown to bind to mammalian xenobiotic transporters and interfere with their function. Here, we examined the extent to which these same compounds might interfere with the activity of the yellowfin tuna (Thunnus albacares) ortholog of this transporter. To accomplish this goal we identified, expressed, and functionally assayed tuna ABCB1. The results demonstrated a common mode of vertebrate ABCB1 interaction with TICs that predicts effects across these species, based on high conservation of specific interacting residues. Importantly several TICs showed potent inhibition of Ta-ABCB1, such as the organochlorine pesticides Endrin (EC50 = 1.2 ± 0.2 µM) and Mirex (EC50 = 2.3 ± 0.9 µM). However, unlike the effects observed on mouse ABCB1, low concentrations of the organochlorine pesticide TICs p,p'-DDT and its metabolite p,p'-DDD co-stimulated verapamil-induced Ta-ABCB1 ATPase activity possibly suggesting a low transport activity for these ligands in tuna. These results provide a mechanistic basis for understanding the potential vulnerability of tuna to these ubquitous pollutants.

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PURPOSE: This study investigates the performance of a cardiac-based seizure detection algorithm (CBSDA) that automatically triggers VNS (NCT01325623). METHODS: Thirty-one patients with drug resistant epilepsy were evaluated in an epilepsy monitoring unit (EMU) to assess algorithm performance and near-term clinical benefit. Long-term efficacy and safety were evaluated with combined open and closed-loop VNS. RESULTS: Sixty-six seizures (n=16 patients) were available from the EMU for analysis. In 37 seizures (n=14 patients) a ≥ 20% heart rate increase was found and 11 (n=5 patients) were associated with ictal tachycardia (iTC, 55% or 35 bpm heart rate increase, minimum of 100 bpm). Multiple CBSDA settings achieved a sensitivity of ≥ 80%. False positives ranged from 0.5 to 7.2/h. 27/66 seizures were stimulated within ± 2 min of seizure onset. In 10/17 of these seizures, where triggered VNS overlapped with ongoing seizure activity, seizure activity stopped during stimulation. Physician-scored seizure severity (NHS3-scale) showed significant improvement for complex partial seizures (CPS) at EMU discharge and through 12 months (p<0.05). Patient-scored seizure severity (total SSQ score) showed significant improvement at 3 and 6 months. Quality of life (total QOLIE-31-P score) showed significant improvement at 12 months. The responder rate (≥ 50% reduction in seizure frequency) at 12 months was 29.6% (n=8/27). Safety profiles were comparable to prior VNS trials. CONCLUSIONS: The investigated CBSDA has a high sensitivity and an acceptable specificity for triggering VNS. Despite the moderate effects on seizure frequency, combined open- and closed-loop VNS may provide valuable improvements in seizure severity and QOL in refractory epilepsy patients.

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Deregulation of the microRNA miR124a by DNA methylation has been implicated in various malignancies, but no study reported its methylation status in Hodgkin lymphoma (HL). We evaluated the methylation of the three loci encoding for miR124a using methylation-specific PCR in 64 HL patients and 15 reactive lymph nodes obtained from patients with nonmalignant diseases. Results were correlated with clinicopathological parameters. Methylation rates of miR124a-1, miR124a-2, and miR124a-3 in HL were 17, 50, and 28%, respectively. None of the nontumoral samples showed aberrant hypermethylation in any of the miR tested. In HL cases, we found that miR124a-1 methylation correlates with high-risk International Prognostic Score (IPS) (score >3, p = 0.04) and that miR124a-2 methylation was more frequent in children (82.3%, p = 0.006) and men (63.9%, p = 0.01). Methylation of miR124a-3 was associated with advanced Ann-Arbor stages (p = 0.007). The survival analysis showed that methylation of at least one of the miR124a genes was associated with shortened event-free survival in univariate (p = 0.03) and multivariate (p = 0.02) analyses. These results suggest that miR124a methylation is associated with aggressive HL disease and may be an interesting factor for predicting treatment response.

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OBJECTIVE: To gain insight into the long-term impact of vagus nerve stimulation (with VNS Therapy) in children with drug-resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow-up period of up to 24 months. METHODS: The primary objective was to assess change in seizure frequency of the predominant seizure type (defined as the most disabling seizure) following VNS device implantation. Treating physicians collected data from patient records from baseline to 6, 12, and 24 months of follow-up. RESULTS: The analysis population included 347 children (aged 6 months to 17.9 years at the time of implant). At 6, 12, and 24 months after implantation, 32.5%, 37.6%, and 43.8%, respectively, of patients had ≥ 50% reduction in baseline seizure frequency of the predominant seizure type. The responder rate was higher in a subgroup of patients who had no change in antiepileptic drugs (AEDs) during the study. Favorable results were also evident for all secondary outcome measures including changes in seizure duration, ictal severity, postictal severity, quality of life, clinical global impression of improvement, and safety. Post hoc analyses demonstrated a statistically significant correlation between VNS total charge delivered per day and an increase in response rate. VNS Therapy is indicated as adjunctive therapy in children with focal, structural epilepsies, who for any reason are not good candidates for surgical treatment following the trial of two or more AEDs. Children with predominantly generalized seizures from genetic, structural epilepsies, like Dravet syndrome or Lennox-Gastaut syndrome, could also benefit from VNS Therapy. SIGNIFICANCE: The results demonstrate that adjunctive VNS Therapy in children with drug-resistant epilepsy reduces seizure frequency and is well tolerated over a 2-year follow-up period. No new safety issues were identified. A post hoc analysis revealed a dose-response correlation for VNS in patients with epilepsy.

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Major depressive disorder is a common global disease that causes a significant societal burden. Most interventional studies of depression provide a limited assessment of the interventions on mortality and suicide risks. This study utilizes data from an observational registry of patients with major depressive disorder to determine the impact of intervention (vagus nerve stimulation or standard pharmacological/non-pharmacological therapy) and a latent factor, patient trajectory toward response, on mortality, suicide and suicidal ideation. A total of 636 patients were available for an intent-to-treat analysis of all-cause mortality, suicide and suicidal ideation. Patients treated with vagus nerve stimulation in addition to standard therapies experienced lower, but not statistically significant, all-cause mortality (vagus nerve stimulation 4.93 per 1,000 person-years vs. 10.02 per 1,000 patient years for treatment as usual) and suicide rates (vagus nerve stimulation 0.88 per 1,000 person-years vs. 1.61 per 1,000 patient years for treatment as usual). Treatment with vagus nerve stimulation produced a statistically lower relative risk of suicidal ideation 0.80, 95% confidence interval (0.68,0.95). Further, patients that responded to either treatment saw a 51% reduction in relative risk of suicidal behavior; relative risk and 95% confidence interval of 0.49 (0.41,0.58). In summary, we find that treatment with adjunctive vagus nerve stimulation can potentially lower the risk of all-cause mortality, suicide and suicide attempts.

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The etiology of osteochondritis dissecans (OCD) of the capitellum is unknown but has generally been attributed to repetitive microtrauma or ischemia. We present a case report of a handball player with OCD of the capitellum. Preoperatively, he complained of elbow pain. CT imaging showed the injury. This patient was treated with mosaicplasty harvested from the lateral femoral condyle. He returned to his full former sports activities within 6months of surgery. The continuity of the cartilage layer between the osteochondral graft and the capitellum was shown on CT arthrogram images at 12months after surgery. We believe that mosaicplasty gives successful results with end-stage OCD of the capitellum.

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OBJECTIVE: The aim of this study was to evaluate the contribution of the BRCA1 and BRCA2 promoter methylation in the pathogenesis of sporadic breast cancer in Tunisian patients. METHODS: Breast carcinoma tissues (n=117) and available paired normal breast tissues (n=65) from Tunisian women who had no family history were investigated for the methylation status of BRCA1 and BRCA2 promoters using methylation-specific PCR. Breast specimens from women without carcinoma (16 fibroadenomas and 5 mastopathies) were used as control. RESULTS: Hypermethylation of BRCA1 and BRCA2 promoters was detected respectively in 60.7% and 69.2% of the carcinoma tissues, and in only 7.7% and 4.6% of the paired normal breast tissues. None of the fibroadenomas and mastopathies showed hypermethylation. Correlations were found between BRCA1 and BRCA2 hypermethylation and decrease in their mRNA expression (p=0.02 and p=0.009, respectively). Moreover, BRCA1 methylation correlates with patients age (p=0.01) and triple negative (ER-, PR-, HER2-) tumors (p=0.01). Patients with methylated BRCA1 and/or BRCA2 had a significant prolonged survivals compared to those with unmethylated tumors (p=0.002). CONCLUSION: Our results suggest an important role of BRCA1 and BRCA2 promoter methylation in breast cancer development in the Tunisian population.

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Dirofilariasis is a zoonosis affecting dogs and cats. It was transmitted to man by mosquito bites. Human dirofilariasis is rare. We report a case of 4-year-old girl presented with a subcutaneous palmar nodule of the hand. Surgical excision shows a nodule encircling the forth flexor tendon. The histological examination established the diagnosis by the presence of an adult worm identified as Dirofilaria repens. Surgical excision was curative.

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The authors report a case of shoulder bilateral posterior fracture dislocation in a 42-year-old man with osteogenesis imperfecta history. The importance of the communition, the large size of articular surface involved and the poor quality of the bone indicate a bilateral total shoulder arthroplasty. At midterm outcome, a good range of motion of both shoulders was registered.

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AIMS OF THE STUDY: The aim of this study was to investigate whether the Simian Virus 40 (SV40) is implicated in human breast carcinomas (BC). EXPERIMENTAL DESIGN: SV40 presence was investigated by PCR assays targeting the Tag, the regulatory, and the VP1 regions in 109 invasive breast ductal carcinomas from Tunisian women. We also examined the relationship between the presence of SV40 and promoter methylation status of 15 tumor-related genes. Immunohistochemistry was used to investigate the expression of Tag, estrogen and progesterone receptors, HER2, and P53. RESULTS: SV40 DNA sequences were detected in 22% of tumors and in only 1.8% of the matched non-tumoral tissues. Using immunohistochemistry, SV40 was detected in the tumor cells. Hypermethylation frequencies were 78% for RASSF1A, 66% for SHP1, 61% for HIN1 and BRCA1, 47% for P16 and ER, 42% for CDH1 and APC, 40% for BLU, 35% for DAPK, 34% for RARbeta2, 27% for GSTP1, 17% for TIMP3, 14% for CCND2, and 8% for hMLH1. Interestingly, the frequencies of RASSF1A, SHP1, BRCA1, and TIMP3 methylation, and the mean of the methylation index (MI) were significantly higher in SV40-positive than in SV40-negative cases (P-values ranging from 0.043 to 0.003). Moreover, SV40 presence correlates with P53 protein accumulation (32.7% vs. 13.3%; P=0.015) and HER2 low expression (3.7% vs. 28%; P=0.008). We also found SV40 more frequently in patients over 50 years than in younger patients (34.8% vs. 12.3%; P=0.006). CONCLUSIONS: This study is the first to demonstrate the presence of SV40 in human BC and provides data supporting a role for this virus in the pathogenesis of these tumors.

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The involvement of a retrovirus homologous to the mouse mammary tumor virus (MMTV) in the pathogenesis of human breast cancer (BC) has long been assumed, but has never been proven. Previous studies have reported the detection of MMTV-like env sequences in variable proportions that did not exceed 40% of BC cases in several countries. However, these viral sequences have been found in higher proportion (74%) in Tunisian diagnosed with BC during the seventies. This study is an attempt to evaluate the current prevalence of MMTV-like env gene in BC in Tunisian women. We used semi-nested PCR that amplify a 190-bp MMTV-like env sequence, followed by direct sequencing to screen a series of 122 cases of BC randomly selected. The findings were correlated to clinicopathological data and immunohistochemical expression status of progesterone and oestrogen receptors, HER2, and P53. Specific MMTV-like env sequences were found in 17 (13.9%) cases of breast carcinomas, whereas the same sequences were not detected in matched normal breast tissues. The presence of the viral sequences correlates inversely with progesterone receptor expression (6.8% versus 20.3%; P=0.03) and HER2 overexpression (3.1% versus 17.7%; P=0.04). This present study confirms the presence of MMTV-like env sequences in BC in Tunisian women but describes an important decrease in the prevalence of the viral sequences compared with previous studies. This reduction may be due to some changes in the virological characteristics or exposure to the virus.

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BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) exhibits heterogeneous clinical features and a marked variable response to treatment. PATIENTS AND METHODS: We investigated the prognostic significance of the methylation status of DAPK, GSTP1, P14, P15, P16, P33, RB1, SHP1, CDH1, APC, BLU, VHL, TIMP3, and RASSF1A genes in 46 DLBCL specimens from Tunisian patients. Methylation status of each gene was correlated with clinicopathological parameters including the International Prognostic Index (IPI), the germinal center immunophenotype, and response to treatment and survival. Overall survival (OS) and disease-free survival (DFS) rates were calculated by the Kaplan-Meier method and differences were compared with the log-rank test. RESULTS: Hypermethylation of SHP1 was associated with elevated lactate dehydrogenase level (P = 0.031). P16 and VHL were frequently hypermethylated in patients with high IPI scores (P = 0.006 and 0.004) and a performance status of two or more (P = 0.007 and 0.047). In addition, hypermethylation of P16 was significantly associated with advanced clinical stages and B symptoms (P = 0.041 and 0.012). Interestingly, hypermethylation of DAPK was significantly correlated with resistance to treatment (P = 0.023). With regard to survival rates, promoter hypermethylation of DAPK, P16, and VHL were significantly associated with shortened OS (P = 0.003, 0.001, and 0.017, respectively) and DFS (P = 0.006, 0.003, and 0.046, respectively). In multivariate analysis, hypermethylation of DAPK remains an independent prognostic factor in predicting shortened OS (P = 0.001) and DFS (P = 0.024), as well as the IPI and the germinal center status. CONCLUSIONS: This study demonstrates that DLBCLs with hypermethylated P16, VHL, DAPK, and SHP1 commonly show a biologically aggressive phenotype and worse prognosis. Interestingly, hypermethylation of DAPK was found to be an independent prognostic factor that may be used in conjunction with the conventional prognostic factors such as the IPI and the germinal center status.

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PURPOSE: The cause of Sjögren's syndrome is unclear. Several studies suggested the role of Epstein-Barr virus (EBV) in the pathogenesis of this syndrome, but this always remains a subject of numerous controversies. The purpose of this study was to evaluate the prevalence of EBV in Sjögren's syndrome in Tunisia. METHODS: A series of 31 paraffin-embedded biopsies of salivary glands from patients with Sjögren's syndrome were studied in comparison with 19 control glands. EBV was investigated by PCR, EBERs in situ hybridization and by immunohistochemistry for the detection of LMP1, EBNA2 and ZEBRA. RESULTS: EBV DNA was detected by PCR in 3 of 22 PCR beta-globin positive Sjögren's syndrome cases (13.6%) and in 2 of 17 PCR beta-globin positive control glands (11.7%); in situ hybridization positivity was noted in rare lymphocytes in the 3 EBV positive cases of Sjögren's syndrome, but not in control glands; immunohistochemical study was negative in all cases. CONCLUSION: EBV infection does not appear to play a significant role in the pathogenesis of Sjögren's syndrome in Tunisia.

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Epstein-Barr virus (EBV) is detected in Hodgkin's lymphoma (HL) at variable frequencies, depending on various factors including the geographic location. The prevalence of EBV is high among HL diagnosed in the region of the center of Tunisia. The aim of the current work was to define the genotypic features of EBV in a series of EBV-positive HL in this area, in comparison to those of EBV found in association with benign lymphoadenopathies. A 30 bp and a 69 bp deletion within the LMP1 gene were detected in 41% and 11% of HL cases, respectively. In reactive lymph nodes, the 30 bp deletion was found in 43% of the cases. Type A EBV was detected in 84% of HL cases and in 96% of reactive lymphoadenopathies, and type B EBV was detected in others. No significant association was found between histological type of HL, age of the patients, or stage at diagnosis, and the molecular configuration of LMP1. However, LMP1 deletions were found more frequently among male patients. The significance of these results is discussed.

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OBJECTIVE: To study the lymphoid clonality on Tunisian B-cell lymphomas cases by polymerase chain reaction (PCR)-based techniques using DNA from paraffin-embedded tissues. MATERIAL AND METHODS: Here we conducted a retrospective PCR clonality study on 73 cases of B-cell lymphomas and 12 reactive lymphoid tissues. The quality of DNA extracted was tested by beta-globin PCR. Consensus primers directed at the FRIII-VH and FRII-VH regions of the immunoglobulin heavy chain (IgH) gene were used to detect clonality. RESULTS: The results showed that 52 of 73 (71%) B-cell lymphomas exhibited good quality of amplifiable DNA. Clonality was found in 77% of cases using the set of primers FRIIIa/LJH/VLJH and in 65.5% using the set of primers FRIIa/LJH/VLJH. Lymphomas derived from pregerminal centre showed a high rate detection of clonal IgH gene rearrangement (100%) compared to other group of tumors derived from germinal centre or postgerminal centre (74.5%). None of the polyclonal controls gave a clonal pattern. CONCLUSION: This is the first large series of PCR clonality study of IgH gene rearrangements on B-cell lymphoma from Tunisia. Our results were similar to other reports in terms of sensitivity and specificity of these techniques and confirm the interest of that PCR for detecting clonal IgH gene rearrangements in lymphoma.

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