Genomic Epidemiology of Salmonella enterica Circulating in Surface Waters Used in Agriculture and Aquaculture in Central Mexico.

Salmonella enterica can survive in surface waters (SuWa), and the role of nonhost environments in its transmission has acquired increasing relevance. In this study, we conducted comparative genomic analyses of 172 S. enterica isolates collected from SuWa across 3 months in six states of central Mexico during 2019. S. enterica transmission dynamics were assessed using 87 experimental and 112 public isolates from Mexico collected during 2002 through 2019. We also studied genetic relatedness between SuWa isolates and human clinical strains collected in North America during 2005 through 2020. Among experimental isolates, we identified 41 S. enterica serovars and 56 multilocus sequence types (STs). Predominant serovars were Senftenberg (n = 13), Meleagridis, Agona, and Newport (n = 12 each), Give (n = 10), Anatum (n = 8), Adelaide (n = 7), and Infantis, Mbandaka, Ohio, and Typhimurium (n = 6 each). We observed a high genetic diversity in the sample under study, as well as clonal dissemination of strains across distant regions. Some of these strains are epidemiologically important (ST14, ST45, ST118, ST132, ST198, and ST213) and were genotypically close to those involved in clinical cases in North America. Transmission network analysis suggests that SuWa are a relevant source of S. enterica (0.7 source/hub ratio) and contribute to its dissemination as isolates from varied sources and clinical cases have SuWa isolates as common ancestors. Overall, the study shows that SuWa act as reservoirs of various S. enterica serovars of public health significance. Further research is needed to better understand the mechanisms involved in SuWa contamination by S. enterica, as well as to develop interventions to contain its dissemination in food production settings. IMPORTANCE Surface waters are heavily used in food production worldwide. Several human pathogens can survive in these waters for long periods and disseminate to food production environments, contaminating our food supply. One of these pathogens is Salmonella enterica, a leading cause of foodborne infections, hospitalizations, and deaths in many countries. This research demonstrates the role of surface waters as a vehicle for the transmission of Salmonella along food production chains. It also shows that some strains circulating in surface waters are very similar to those implicated in human infections and harbor genes that confer resistance to multiple antibiotics, posing a risk to public health. This study contributes to expand our current knowledge on the ecology and epidemiology of Salmonella in surface waters.

[Hyperostosis frontalis interna : etiology and differential diagnosis]. / Hyperostose frontale interne : étiologie et diagnostic différentiel.

Hyperostosis frontalis interna was first described in 1719 in association with obesity and hirsutism, forming Morgagni's syndrome. A high prevalence and a lack of studies demonstrating a strong correlation between these different signs currently question the existence of such a syndrome. Hyperostosis frontalis interna predominates in women. The anomaly exclusively involves the inner table and constantly spares the diploe and the external table. The main differential diagnosis of cranial hyperostosis is made between meningioma, osteoma, Paget's disease and fibrous dysplasia. The clinical implication of hyperostosis as well as its etiology are also debated.

L'hyperostose frontale interne a initialement été décrite en 1719, en association avec une obésité et de l'hirsutisme, formant ainsi le syndrome de Morgagni. Une prévalence élevée et un manque d'études confirmant une corrélation entre ces différents signes remettent actuellement en doute l'existence de ce syndrome. L'hyperostose frontale interne prédomine largement chez la femme. L'affection concerne exclusivement la table interne et épargne constamment le diploé et la table externe. Le diagnostic différentiel principal des hyperostoses crâniennes s'établit entre le méningiome, l'ostéome, la maladie de Paget et la dysplasie fibreuse. L'implication clinique de l'hyperostose ainsi que son étiologie sont également débattues.

Impact of cirrhosis in patients undergoing laparoscopic liver resection in a nationwide multicentre survey.

BACKGROUND: The aim was to analyse the impact of cirrhosis on short-term outcomes after laparoscopic liver resection (LLR) in a multicentre national cohort study. METHODS: This retrospective study included all patients undergoing LLR in 27 centres between 2000 and 2017. Cirrhosis was defined as F4 fibrosis on pathological examination. Short-term outcomes of patients with and without liver cirrhosis were compared after propensity score matching by centre volume, demographic and tumour characteristics, and extent of resection. RESULTS: Among 3150 patients included, LLR was performed in 774 patients with (24·6 per cent) and 2376 (75·4 per cent) without cirrhosis. Severe complication and mortality rates in patients with cirrhosis were 10·6 and 2·6 per cent respectively. Posthepatectomy liver failure (PHLF) developed in 3·6 per cent of patients with cirrhosis and was the major cause of death (11 of 20 patients). After matching, patients with cirrhosis tended to have higher rates of severe complications (odds ratio (OR) 1·74, 95 per cent c.i. 0·92 to 3·41; P = 0·096) and PHLF (OR 7·13, 0·91 to 323·10; P = 0·068) than those without cirrhosis. They also had a higher risk of death (OR 5·13, 1·08 to 48·61; P = 0·039). Rates of cardiorespiratory complications (P = 0·338), bile leakage (P = 0·286) and reoperation (P = 0·352) were similar in the two groups. Patients with cirrhosis had a longer hospital stay than those without (11 versus 8 days; P = 0·018). Centre expertise was an independent protective factor against PHLF in patients with cirrhosis (OR 0·33, 0·14 to 0·76; P = 0·010). CONCLUSION: Underlying cirrhosis remains an independent risk factor for impaired outcomes in patients undergoing LLR, even in expert centres.

ANTECEDENTES: El objetivo de este estudio fue analizar el impacto de la cirrosis en los resultados a corto plazo después de la resección hepática laparoscópica (laparoscopic liver resection, LLR) en un estudio de cohortes multicéntrico nacional. MÉTODOS: Este estudio retrospectivo incluyó todos los pacientes sometidos a LLR en 27 centros entre 2000 y 2017. La cirrosis se definió como fibrosis F4 en el examen histopatológico. Los resultados a corto plazo de los pacientes con hígado cirrótico (cirrhotic liver CL) (pacientes CL) y los pacientes con hígado no cirrótico (non-cirrhotic liver, NCL) (pacientes NCL) se compararon después de realizar un emparejamiento por puntaje de propension del volumen del centro, las características demográficas y del tumor, y la extensión de la resección. RESULTADOS: Del total de 3.150 pacientes incluidos, se realizó LLR en 774 (24,6%) pacientes CL y en 2.376 (75,4%) pacientes NCL. Las tasas de complicaciones graves y mortalidad en el grupo de pacientes CL fueron del 10,6% y 2,6%, respectivamente. La insuficiencia hepática posterior a la hepatectomía (post-hepatectomy liver failure, PHLF) fue la principal causa de mortalidad (55% de los casos) y se produjo en el 3,6% de los casos en pacientes CL. Después del emparejamiento, los pacientes CL tendieron a tener tasas más altas de complicaciones graves (razón de oportunidades, odds ratio, OR 1,74; i.c. del 95% 0,92-0,41; P = 0,096) y de PHLF (OR 7,13; i.c. del 95% 0,91-323,10; P = 0,068) en comparación con los pacientes NCL. Los pacientes CL estuvieron expuestos a un mayor riesgo de mortalidad (OR 5,13; i.c. del 95% 1,08-48,6; P = 0,039) en comparación con los pacientes NCL. Los pacientes CL presentaron tasas similares de complicaciones cardiorrespiratorias graves (P = 0,338), de fuga biliar (P = 0,286) y de reintervenciones (P = 0,352) que los pacientes NCL. Los pacientes CL tuvieron una estancia hospitalaria más larga (11 versus 8 días; P = 0,018) que los pacientes NCL. La experiencia del centro fue un factor protector independiente de PHLF (OR 0,33; i.c. del 95% 0,14-0,76; P = 0,010) pacientes CL. CONCLUSIÓN: La presencia de cirrosis subyacente sigue siendo un factor de riesgo independiente de peores resultados en pacientes sometidos a resección hepática laparoscópica, incluso en centros con experiencia.

Comparative analysis of outcomes after liver resection and liver transplantation for early stages hepatocellular carcinoma in HIV-infected patients. An intention-to-treat analysis.

BACKGROUND: To address the results of resection for hepatocellular carcinoma (HCC) in human immunodeficiency virus (HIV)-carriers, and to compare them against survival after liver transplantation (LT). METHODS: All patients with HIV and HCC listed for LT (candidates = LTc+) or resection (LR+) between 2000 and 2017 in our centre were analysed and compared for overall survival (OS) and disease-free survival (DFS). RESULTS: The LTc + group (n = 43) presented with higher MELD scores and more advanced portal hypertension and HCC stages than LR + group (n = 15). One-, 3- and 5-year intention-to-treat survival rates were: 81%, 60% and 44%, versus 86%, 58% and 58% in the LTc+ and LR + groups, respectively (p = 0.746). Eleven LTc + patients dropped out. After LT, OS was 81%, 68% and 59% (no difference with LR + group; p = 0.844). There tended to be better DFS after LT, reaching 78%, 68% and 56% versus 53%, 33% and 33% in the LR + group (p = 0.062). CONCLUSION: This was the largest series of resections for HCC in HIV + patients and the first intention-to-treat analysis. Although LT and resection do not always concern the same population, they enable equivalent survival. At the price of higher recurrence rate, resection could be integrated in the global armoury of liver surgeons.

Use of aspirin and bleeding-related complications after hepatic resection.

BACKGROUND: The operative risk of hepatectomy under antiplatelet therapy is unknown. This study sought to assess the outcomes of elective hepatectomy performed with or without aspirin continuation in a well balanced matched cohort. METHODS: Data were retrieved from a multicentre prospective observational study. Aspirin and control groups were compared by non-standardized methods and by propensity score (PS) matching analysis. The main outcome was severe (Dindo-Clavien grade IIIa or more) haemorrhage. Other outcomes analysed were intraoperative transfusion, overall haemorrhage, major morbidity, comprehensive complication index (CCI) score, thromboembolic complications, ischaemic complications and mortality. RESULTS: Before matching, there were 118 patients in the aspirin group and 1685 in the control group. ASA fitness grade, cardiovascular disease, previous history of angina pectoris, angioplasty, diabetes, use of vitamin K antagonists, cirrhosis and type of hepatectomy were significantly different between the groups. After PS matching, 108 patients were included in each group. There were no statistically significant differences between the aspirin and control groups in severe haemorrhage (6·5 versus 5·6 per cent respectively; odds ratio (OR) 1·18, 95 per cent c.i. 0·38 to 3·62), intraoperative transfusion (23·4 versus 23·7 per cent; OR 0·98, 0·51 to 1·87), overall haemorrhage (10·2 versus 12·0 per cent; OR 0·83, 0·35 to 1·94), CCI score (24 versus 28; P = 0·520), major complications (23·1 versus 13·9 per cent; OR 1·82, 0·92 to 3·79) and 90-day mortality (5·6 versus 4·6 per cent; OR 1·21, 0·36 to 4·09). CONCLUSION: This observational study suggested that aspirin continuation is not associated with a higher rate of bleeding-related complications after elective hepatic surgery.

Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Locoregional extension of intrahepatic cholangiocarcinoma (ICC) at the time of diagnosis results in a low resectability rate and poor prognosis. The aim of this retrospective study was to assess the efficacy of neoadjuvant chemotherapy for locally advanced ICC. METHODS: All consecutive patients with ICC between 2000 and 2013 were included prospectively in a single-centre database and analysed retrospectively. Patients with locally advanced ICC considered as initially unresectable received primary chemotherapy, followed by surgery in those with secondary resectability. Results of patients who underwent surgery for locally advanced ICC were compared with those of patients with initially resectable ICC treated by surgery alone. RESULTS: A total of 186 patients were included in the study. Of 74 patients with locally advanced ICC, 39 (53 per cent) underwent secondary resection after a median of six chemotherapy cycles. Patients in this group were younger (P = 0·030) and had more advanced disease than those who had surgery alone, and presented more frequently with lymphadenopathy (P = 0·010) and vascular invasion (P = 0·010). Postoperative morbidity and mortality were no different between the groups. The median survival of patients who had surgery after chemotherapy was 24·1 months, and that of patients who had surgery alone was 25·7 months (P = 0·391). CONCLUSION: Patients with locally advanced ICC treated by surgery following neoadjuvant chemotherapy had similar short- and long-term results to patients with initially resectable ICC who had surgery alone. Neoadjuvant chemotherapy as a first-line treatment for locally advanced ICC may be an effective downstaging option, facilitating secondary resectability in patients with initially unresectable disease.

The Cortical Processing of Sensorimotor Sequences is Disrupted in Writer's Cramp.

Evidence for pre-existing abnormalities in the sensory and motor systems has been previously reported in writer's cramp (WC). However, the processing of somatosensory information during motor planning has received little attention. We hypothesized that sensorimotor integration processes might be impaired partly due to a disruption in the parieto-premotor network. To test this assumption, we designed 2 nonwriting motor tasks in which subjects had to perform a 4-finger motor sequence either on the basis of sensory stimuli previously memorized (SM task) or freely generated (SG task). Brain activity was measured by combining event-related functional magnetic resonance imaging and coherency electroencephalography in 15 WC patients and 15 normal controls. The bold signal was decreased in patients in both tasks during sensory stimulation but not during movement execution. However, the EEG study showed that coherency was decreased in patients compared with controls, during the delay of the SM task and during the execution of the SG task, on both the whole network and for specific couples of electrodes. Overall, these results demonstrate an endophenotypic impairment in the synchronization of cortical areas within the parieto-premotor network during somatosensory processing and motor planning in WC patients.

Long-term outcomes of patients with 10 or more colorectal liver metastases.

BACKGROUND: Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients. METHODS: The study population consisted of a multicentre cohort of patients with CLM (N=12 406) operated on, with intention to resect, from January 2005-June 2013 and whose data were prospectively collected in the LiverMetSurvey registry. RESULTS: Overall, the group ⩾10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26-0.48)). Other independent favourable factors were as follows: maximal tumour size <40 mm (HR 0.67 (0.49-0.92)); age <60 years (HR 0.66 (0.50-0.88)); preoperative MRI (HR 0.65 (0.47-0.89)); and adjuvant chemotherapy (HR 0.73 (0.55-0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor. CONCLUSIONS: Liver resection might provide long-term survival in patients with ⩾10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed.

Outcomes of surgical shunts and transjugular intrahepatic portasystemic stent shunts for complicated portal hypertension.

BACKGROUND: Transjugular intrahepatic portasystemic stent shunt (TIPSS), instead of surgical shunt, has become the standard treatment for patients with complicated portal hypertension. This study compared outcomes in patients who underwent TIPSS or surgical shunting for complicated portal hypertension. METHODS: This was a retrospective study of all consecutive patients who received portasystemic shunts from 1994 to 2014 at a single institution. Patients who underwent surgical shunting were compared with those who had a TIPSS procedure following one-to-one propensity score matching. The primary study endpoints were overall survival and shunt failure, defined as major variceal rebleeding, relapse of refractory ascites, irreversible shunt occlusion, liver failure requiring liver transplantation, or death. RESULTS: A total of 471 patients received either a surgical shunt or TIPSS. Of these, 334 consecutive patients with cirrhosis who underwent elective surgical shunting (34) or TIPSS (300) for repeated variceal bleeding or refractory ascites were evaluated. Propensity score matching yielded 31 pairs of patients. There were no between-group differences in morbidity and 30-day mortality rates. However, shunt failure was less frequent after surgical shunting than TIPSS (6 of 31 versus 16 of 31; P = 0·016). The 5-year shunt failure-free survival (77 versus 15 per cent; P = 0·008) and overall survival (93 versus 42 per cent; P = 0·037) rates were higher for patients with surgical shunts. Multivariable analysis revealed that a Model for End-Stage Liver Disease (MELD) score exceeding14 and TIPSS were independently associated with shunt failure. In patients with MELD scores of 14 or less, the 5-year overall survival rate remained higher after surgical shunting than TIPSS (100 versus 40 per cent; P < 0·001). CONCLUSION: Surgical shunting achieved better results than TIPSS in patients with complicated portal hypertension and low MELD scores.

Long-term outcomes of radiofrequency ablation combined with hepatectomy compared with hepatectomy alone for colorectal liver metastases.

BACKGROUND: Combining radiofrequency ablation (RFA) with hepatectomy may enable treatment with curative intent for patients with colorectal liver metastasis (CRLM). However, the oncological outcomes in comparison with resection alone remain to be clarified. METHODS: Patients who underwent a first hepatectomy between 2001 and 2012 for CRLM were enrolled. Short- and long-term outcomes of patients who underwent hepatectomy plus RFA were compared with those of patients who had hepatectomy alone using propensity score matching. RESULTS: Of a total of 553 patients, hepatectomy + RFA and hepatectomy alone were performed in 37 and 516 respectively. Before matching, patients in the hepatectomy + RFA group were characterized primarily by a larger tumour burden. After matching of 31 patients who underwent hepatectomy + RFA with 93 who had hepatectomy alone, background characteristics were well balanced. In the matched cohort, overall and disease-free survival in the hepatectomy + RFA group were no different from those among patients who had hepatectomy alone (5-year overall survival rate 57 versus 61 per cent, P = 0·649; 5-year disease-free survival rate 19 versus 17 per cent, P = 0·865). Local recurrence at the ablated site was observed in four of 31 patients (13 per cent). Although overall local recurrence (ablated site and/or cut surface) was more frequent in the hepatectomy + RFA group (9 of 31 (29 per cent) versus 11 of 93 (12 per cent); P = 0·032), there was no difference in intrahepatic disease-free survival between the two groups (P = 0·705). CONCLUSION: Hepatectomy + RFA achieved outcomes comparable to hepatectomy alone. Combining RFA with hepatectomy should be considered as an option to achieve cure.

Brain structural investigation and hippocampal tractography in medication overuse headache: a native space analysis.

BACKGROUND: Spatial normalization of brain images, a prerequisite for voxel based morphometry analysis, may account for the large variability of the volumetric data in medication overuse headache (MOH); possibly because this disease concerns patients differing on both sex and age, and hence with different brain size and shape. METHODS: The present study aimed at providing a subject-based analysis of macrostructure using a native space volumes segmentation (Freesurfer), and microstructure using a region of interest (ROI: i.e. hippocampus) tractography approach in MOH patients. RESULTS: The results show that MOH patients had decreased volumes of left hemisphere temporal gyri (temporal superior, fusiform) and occipital middle gyrus, together with an increased volume of the left inferior (temporal) lateral ventricle. The left temporal volume was negatively correlated with depression score and medication dependence parameters. Seed-based tractography of the hippocampus revealed a decreased number of reconstructed fibers passing through the left hippocampus. CONCLUSION: To our knowledge, these alterations have not been described with methods involving brain normalization, and they indicate that left hemisphere temporal areas, including the hippocampus, may play a role in MOH pathophysiology. Trial registration number NCT00833209. Registered 29 January 2009.

Nomogram for prediction of prognosis in patients with initially unresectable colorectal liver metastases.

BACKGROUND: Although recent advances in surgery and chemotherapy have increasingly enabled hepatectomy in patients with initially unresectable colorectal liver metastases (CRLM), not all such patients benefit from surgery. The aim of this study was to develop a nomogram to predict survival after hepatectomy for initially unresectable CRLM. METHODS: Patients with initially unresectable CRLM treated with chemotherapy followed by hepatectomy between 1990 and 2012 were included in the study. A nomogram to predict survival was developed based on a multivariable Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan-Meier curve and calibration plots. RESULTS: Of a total of 439 patients, liver and globally completed surgery was achieved in 380 (86·6 per cent) and 335 (76·3 per cent) patients respectively. The 5-year overall and disease-free survival rates were 39·9 and 10·0 per cent respectively. Based on the Cox model, the following five factors were selected for the nomogram and assigned specific scores: node-positive primary, 5; more than six metastases at hepatectomy, 7; carbohydrate antigen 19-9 level at hepatectomy above 37 units/ml, 10; disease progression during first-line chemotherapy, 9; and presence of extrahepatic disease, 4. The model achieved relatively good discrimination and calibration, with a C-statistic of 0·66. The overall survival rate for patients with a score greater than 16 was significantly worse than that for patients with a score of 16 or less (5-year survival rate 4 versus 46·3 per cent respectively; P < 0·001). CONCLUSION: The nomogram facilitates personalized assessment of prognosis for patients with initially unresectable CRLM treated with chemotherapy and with planned resection.

Outcome after associating liver partition and portal vein ligation for staged hepatectomy and conventional two-stage hepatectomy for colorectal liver metastases.

BACKGROUND: Although associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been increasingly adopted by many centres, the oncological outcome for colorectal liver metastases compared with that after two-stage hepatectomy is still unknown. METHODS: Between January 2010 and June 2014, all consecutive patients who underwent either ALPPS or two-stage hepatectomy for colorectal liver metastases in a single institution were included in the study. Morbidity, mortality, disease recurrence and survival were compared. RESULTS: The two groups were comparable in terms of clinicopathological characteristics. ALPPS was completed in all 17 patients, whereas the second-stage hepatectomy could not be completed in 15 of 41 patients. Ninety-day mortality rates for ALPPS and two-stage resection were 0 per cent (0 of 17) versus 5 per cent (2 of 41) (P = 0·891). Major complication rates (Clavien grade at least III) were 41 per cent (7 of 17) and 39 per cent (16 of 41) respectively (P = 0·999). Overall survival was significantly lower after ALPPS than after two-stage hepatectomy: 2-year survival 42 versus 77 per cent respectively (P = 0·006). Recurrent disease was more often seen in the liver in the ALPPS group. Salvage surgery was less often performed after ALPPS (2 of 8 patients) than after two-stage hepatectomy (10 of 17). CONCLUSION: Although major complication and 90-day mortality rates of ALPPS were similar to those of two-stage hepatectomy, overall survival was significantly lower following ALPPS.

Molecular detection of the index case of a subclinical Salmonella Kentucky epidemic on a dairy farm.

Salmonella enterica commonly colonizes the intestinal tract of cattle and is a leading cause of foodborne illness. A previously described investigation into the prevalence of S. enterica on a dairy farm revealed an 8-year-long asymptomatic S. enterica epidemic caused by serotypes Cerro and Kentucky in the lactating herd. To investigate the source of the S. Kentucky strains, the genomes of two S. Kentucky isolates were sequenced; one collected prior to the epidemic (2004) and one collected during the epidemic (2010). Comparative genomic analysis demonstrated significant polymorphisms between the two strains. PCR primers targeting unique and strain-specific regions were developed, and screening of the archived isolates identified the index case of the asymptomatic S. Kentucky epidemic as a heifer that was raised off-site and transported onto the study farm in 2005. Analysis of isolates collected from all heifers brought onto the farm demonstrated frequent re-introduction of clones of the epidemic strain suggesting transmission of pathogens between farms might occur repeatedly.

A proposed new method for assessing the pathological response to chemotherapy in resected colorectal liver metastases.

BACKGROUND: Pathological response (PR) to preoperative chemotherapy for colorectal liver metastases (CLM) is recognised as a prognostic factor of outcome. However, the optimal system to assess this parameter is still debated. This study focuses on current methods and proposes a possibly better method for assessing PR. METHODS: Among 223 patients resected for CLM between 2004 and 2011, after more than three cycles of chemotherapy, the percentage of tumour cells, necrosis and fibrosis, and the tumour regression grade were assessed for each of 802 nodules. Pathological response was evaluated according to validated methods and their combinations. A new method combined the percentage of tumour cells and the size of all nodules as follows: , where n is each separate nodule, % is the percentage of remaining tumour cells within nodule n (%) and s is the size of nodule n (cm).The prognostic value of each method was calculated. RESULTS: After a median follow-up of 47 months (3-106), the cumulative 5-year overall survival rate after liver resection was 59%. The proposed method categorised as follows: 0 residual tumour; 0.1-6-cm residual tumour; >6-cm residual tumour, and necrosis rate >50% stratified prognosis (P=0.0027; P=0.02), while the other methods did not. At multivariate analysis, our method remained an independent predictor of outcome (P=0.001). CONCLUSIONS: Combining the percentage of tumour cells multiplied by the size of each separate tumour seems to be a better method for assessing PR. External validation is required.

Brain functional connectivity and morphology changes in medication-overuse headache: Clue for dependence-related processes?

BACKGROUND: Several imaging studies have identified localized anatomical and functional brain changes in medication-overuse headache (MOH). OBJECTIVE: The objective of this article is to evaluate whole-brain functional connectivity at rest together with voxel-based morphometry in MOH patients, in comparison with episodic migraine (EM) patients and healthy controls (HCs). METHODS: Anatomical MRI and resting-state functional MRI scans were obtained in MOH patients (n = 17 and 9, respectively), EM patients (n = 18 and 15, respectively) and HCs (n = 17 and 17). SPM8 was used to analyze voxel-based morphometry and seed (left precuneus) to voxel connectivity data in the whole brain. RESULTS: Functional connectivity at rest was altered in MOH patients. Connectivity was decreased between precuneus and regions of the default-mode network (frontal and parietal cortices), but increased between precuneus and hippocampal/temporal areas. These functional modifications were not accompanied by significant gross morphological changes. Furthermore, connectivity between precuneus and frontal areas in MOH was negatively correlated with migraine duration and positively correlated with self-evaluation of medication dependence. Gray matter volumes of frontal regions, precuneus and hippocampus were also negatively related to migraine duration. Functional connectivity within the default-mode network appeared to predict anxiety scores of MOH patients while gray matter volumes in this network predicted their depression scores. CONCLUSIONS: Our data suggest that MOH is associated with functional alterations within intrinsic brain networks rather than with macrostructural changes. They also support the view that dependence-related processes might play a prominent role in its development and maintenance.

(68)Ga-labeled bombesin analogs for receptor-mediated imaging.

Targeted receptor-mediated imaging techniques have become crucial tools in present targeted diagnosis and radiotherapy as they provide accurate and specific diagnosis of disease information. Peptide-based pharmaceuticals are gaining popularity, and there has been vast interest in developing (68)Ga-labeled bombesin (Bn) analogs. The gastrin-releasing peptide (GRP) family and its Bn analog have been implicated in the biology of several human cancers. The three bombesin receptors GRP, NMB, and BRS-3 receptor are most frequently ectopically expressed by common, important malignancies. The low expression of Bn/GRP receptors in normal tissue and relatively high expression in a variety of human tumors can be of biological importance and form a molecular basis for Bn/GRP receptor-mediated imaging. To develop a Bn-like peptide with favorable tumor targeting and pharmacokinetic characteristics for possible clinical use, several modifications in the Bn-like peptides, such as the use of a variety of chelating agents, i.e., acyclic and macrocyclic agents with different spacer groups and with different metal ions (gallium), have been performed in recent years without significant disturbance of the vital binding scaffold. The favorable physical properties of (68)Ga, i.e., short half-life, and the fast localization of small peptides make this an ideal combination to study receptor-mediated imaging in patients.

Experimental treatment of Staphylococcus aureus bovine intramammary infection using a guanine riboswitch ligand analog.

Staphylococcus aureus is a leading cause of intramammary infections (IMI). We recently demonstrated that Staph. aureus strains express the gene guaA during bovine IMI. This gene codes for a guanosine monophosphate synthetase and its expression is regulated by a guanine riboswitch. The guanine analog 2,5,6-triaminopyrimidine-4-one (PC1) is a ligand of the guanine riboswitch. Interactions between PC1 and its target result in inhibition of guanosine monophosphate synthesis and subsequent death of the bacterium. The present study describes the investigational use of PC1 for therapy of Staph. aureus IMI in lactating cows. The in vitro minimal inhibitory concentration of PC1 ranged from 0.5 to 4 µg/mL for a variety of Staph. aureus and Staphylococcus epidermidis strains and required a reducing agent for stability and full potency. A safety assessment study was performed, whereby the healthy quarters of 4 cows were infused with increasing doses of PC1 (0, 150, 250, and 500 mg). Over the 44 h following infusions, no obvious adverse effect was observed. Ten Holstein multiparous cows in mid lactation were then experimentally infused into 3 of the quarters with approximately 50 cfu of Staph. aureus strain SHY97-3906 and infection was allowed to progress for 2 wk before starting PC1 treatment. Bacterial counts reached then about 10(3) to 10(4) cfu/mL of milk. Infected quarters were treated with 1 of 3 doses of PC1 (0, 250, or 500 mg) after each morning and evening milking for 7d (i.e., 14 intramammary infusions of PC1). During the treatment period, milk from PC1-treated quarters showed a significant reduction in bacterial concentrations. However, this reduction of Staph. aureus count in milk was not maintained during the 4 wk following the end of the treatment and only 15% of the PC1-treated quarters underwent bacteriological cure. The somatic cell count and the quarter milk production were not affected by treatments. Although bacterial clearance was not achieved following treatment with PC1, these results demonstrate that the Staph. aureus guanine riboswitch represents a relevant and promising drug target for a novel class of antibiotics for the animal food industry.

Effects of improved early-life conditions on health, welfare, and performance of pigs raised on a conventional farm.

Nowadays, most pigs are raised indoors, on intensive farms providing a poor environment. In these conditions, the risk of the occurrence of damaging behaviours is high, with dramatic consequences for animal health and welfare as well as economic losses for farmers. Early-life conditions may predispose individuals to develop damaging behaviours later in life. In contrast, reinforcing affiliative behaviours between piglets before weaning might help to prevent tail-biting episodes. In this field study, we aimed at improving early-life conditions of piglets on a commercial farm by completely suppressing painful procedures and staggering their exposure to weaning stress factors. The alternative early-life management strategy combined housing in free-farrowing pens with temporary crating of the sow, socialisation during the lactation period with whole-life maintenance of the hierarchical groups, and delayed transfer to the postweaning room after sow removal. Control conditions included birth in farrowing crates, tail docking, absence of socialisation during the lactation period, abrupt weaning with immediate transfer to the postweaning room and mixing with non-littermates. We evaluated the health, welfare, and performance of alternatively raised pigs (n = 80) as compared to controls (n = 75). Visits were made throughout the lifespan of individuals to evaluate their growth and health status. Body and tail lesions were scored as proxy measures of aggressiveness and impaired welfare. Blood and bristle samples were periodically collected to evaluate stress, inflammation and immune competence. While the whole-life performance of pigs was similar among groups, the alternative early-life conditions prevented the growth slowdown usually observed after weaning. In addition, alternatively raised pigs displayed more neutrophils, eosinophils and monocytes the day after weaning, as well as higher C-Reactive Protein levels. One week later, their monocytes displayed greater phagocytic capacity. Altogether, these data suggest an enhanced innate immune competence for alternatively raised pigs around weaning. Piglets reared under alternative conditions also exhibited fewer and less severe body lesions than standard pigs, one week after weaning. In contrast, they showed more tail lesions on days 36 and 66 associated with greater levels of acute phase proteins (C-Reactive Protein and haptoglobin). To conclude, alternative early-life management better prepared piglets for weaning. However, the whole-life maintenance of early-established social groups was not sufficient to prevent the occurrence of damaging behaviours in undocked pigs.

Complete DNA sequence analysis of enterohemorrhagic Escherichia coli plasmid pO157_2 in ß-glucuronidase-positive E. coli O157:H7 reveals a novel evolutionary path.

Strains of enterohemorragic Escherichia coli (EHEC) O157:H7 that are non-sorbitol fermenting (NSF) and ß-glucuronidase negative (GUD(-)) carry a large virulence plasmid, pO157 (>90,000 bp), whereas closely related sorbitol-fermenting (SF) E. coli O157:H(-) strains carry plasmid pSFO157 (>120,000 bp). GUD(+) NSF O157:H7 strains are presumed to be precursors of GUD(-) NSF O157:H7 strains that also carry pO157. In this study, we report the complete sequence of a novel virulence plasmid, pO157-2 (89,762 bp), isolated from GUD(+) NSF O157:H7 strain G5101. PCR analysis confirmed the presence of pO157-2 in six other strains of GUD(+) NSF O157:H7. pO157-2 carries genes associated with virulence (e.g., hemolysin genes) and conjugation (tra and trb genes) but lacks katP and espP present in pO157. Comparative analysis of the three EHEC plasmids shows that pO157-2 is highly related to pO157 and pSFO157 but not ancestral to pO157. These results indicated that GUD(+) NSF O157:H7 strains might not be direct precursors to GUD(-) NSF O157:H7 as previously proposed but rather have evolved independently from a common ancestor.