The Long Hunt for pssR-Looking for a Phospholipid Synthesis Transcriptional Regulator, Finding the Ribosome.

The phospholipid (PL) composition of bacterial membranes varies as a function of growth rate and in response to changes in the environment. While growth adaptation can be explained by biochemical feedback in the PL synthesis pathway, recent transcriptome studies have revealed that the expression of PL synthesis genes can also be tuned in response to various stresses. We previously showed that the BasRS two-component pathway controls the expression of the diacylglycerol kinase gene, dgkA, in Escherichia coli (A. Wahl, L. My, R. Dumoulin, J. N. Sturgis, and E. Bouveret, Mol Microbiol, 80:1260-1275, 2011, https://doi.org/10.1111/j.1365-2958.2011.07641.x). In this study, we set up a strategy to identify the mutation responsible for the upregulation of pssA observed in the historical pssR1 mutant and supposedly corresponding to a transcriptional repressor (C. P. Sparrow and J. Raetz, J Biol Chem, 258:9963-9967, 1983). pssA encodes phosphatidylserine synthase, the first step of phosphatidylethanolamine synthesis. We showed that this mutation corresponded to a single nucleotide change in the anti-Shine-Dalgarno sequence of the 16S rRNA encoded by the rrnC operon. We further demonstrated that this mutation enhanced the translation of pssA Though this effect appeared to be restricted to PssA among phospholipid synthesis enzymes, it was not specific, as evidenced by a global effect on the production of unrelated proteins.IMPORTANCE Bacteria adjust the phospholipid composition of their membranes to the changing environment. In addition to enzymatic regulation, stress response regulators control specific steps of the phospholipid synthesis pathway. We wanted to identify a potential regulator controlling the expression of the phosphatidylserine synthase gene. We showed that it was not the previously suggested hdfR gene and instead that a mutation in the anti-Shine-Dalgarno sequence of 16S RNA was responsible for an increase in pssA translation. This example underlines the fact that gene expression can be modulated by means other than specific regulatory processes.

Reassessment of the Genetic Regulation of Fatty Acid Synthesis in Escherichia coli: Global Positive Control by the Dual Functional Regulator FadR.

UNLABELLED: In Escherichia coli, the FadR transcriptional regulator represses the expression of fatty acid degradation (fad) genes. However, FadR is also an activator of the expression of fabA and fabB, two genes involved in unsaturated fatty acid synthesis. Therefore, FadR plays an important role in maintaining the balance between saturated and unsaturated fatty acids in the membrane. We recently showed that FadR also activates the promoter upstream of the fabH gene (L. My, B. Rekoske, J. J. Lemke, J. P. Viala, R. L. Gourse, and E. Bouveret, J Bacteriol 195:3784-3795, 2013, doi:10.1128/JB.00384-13). Furthermore, recent transcriptomic and proteomic data suggested that FadR activates the majority of fatty acid (FA) synthesis genes. In the present study, we tested the role of FadR in the expression of all genes involved in FA synthesis. We found that FadR activates the transcription of all tested FA synthesis genes, and we identified the FadR binding site for each of these genes. This necessitated the reassessment of the transcription start sites for accA and accB genes described previously, and we provide evidence for the presence of multiple promoters driving the expression of these genes. We showed further that regulation by FadR impacts the amount of FA synthesis enzymes in the cell. Our results show that FadR is a global regulator of FA metabolism in E. coli, acting both as a repressor of catabolism and an activator of anabolism, two directly opposing pathways. IMPORTANCE: In most bacteria, a transcriptional regulator tunes the level of FA synthesis enzymes. Oddly, such a global regulator still was missing for E. coli, which nonetheless is one of the prominent model bacteria used for engineering biofuel production using the FA synthesis pathway. Our work identifies the FadR functional dual regulator as a global activator of almost all FA synthesis genes in E. coli. Because FadR also is the repressor of FA degradation, FadR acts both as a repressor and an activator of the two opposite pathways of FA degradation and synthesis. Our results show that there are still discoveries waiting to be made in the understanding of the genetic regulation of FA synthesis, even in the very well-known bacterium E. coli.

Complications and Disease Recurrence After Ileocecal Resection in Pediatric Crohn's Disease: A Retrospective Study.

OBJECTIVE: The aim of this retrospective study was to describe the risk of postoperative recurrence (POR) after ileocecal resection, the occurrence of surgical complications, and identify predictors of these adverse postoperative outcomes in pediatric Crohn's disease (CD). PATIENTS AND METHODS: All the children less than 18 years of age with a diagnosis of CD, who underwent primary ileocecal resection for CD between January 2006 and December 2016 in our tertiary center, were considered for inclusion. Factors related to POR were investigated. RESULTS: A total of 377 children were followed for CD between 2006 and 2016. During this period, 45 (12%) children needed an ileocecal resection. POR was diagnosed in 16% (n = 7) at 1 year and 35% (n = 15) at the end of the follow-up, with a median follow-up of 2.3 years (Q1-Q3 1.8-3.3). Median duration of the postoperative clinical remission was 1.5 years (range 0.5-2). Multivariate Cox regression analysis identified only young age at diagnosis as a risk factor for POR.In total, 7 of the 43 patients (16%) developed severe postoperative complications, defined as requiring surgical, endoscopic, or radiological intervention. The only risk factor was intraoperative abscess. CONCLUSION: Only young age at diagnosis was associated with POR. This information could be useful to develop targeted therapeutic strategies for young CD children. At the end of follow-up with a median follow-up of 2.3 years (Q1-Q3 1.8-3.3), there was no surgical POR: endoscopic dilatation for POR should be considered in order to delay or prevent surgery.

Collagenous gastritis in children: A national cohort.

BACKGROUND: Collagen gastritis is a rare disease that manifests in children mainly as isolated gastric involvement associated with martial deficiency anemia. There are no recommendations for the management and follow-up of these patients. We aimed to describe the clinical data, endoscopic findings, and treatments deployed in France's children with collagenous gastritis. METHODS: All French pediatric gastroenterology centers and pediatric centers for rare digestive diseases (Centres de Maladies Rares Digestives) were contacted to collect cases of collagenous gastritis, defined on gastric biopsies and diagnosed before 18 years of age. RESULTS: A total of 12 cases diagnosed (4 males and 8 females) between 1995 and 2022 could be analyzed. The median age at diagnosis was 12.5 years (7-15.2). The most frequent clinical presentation was abdominal pain (6/11) and/or nonspecific symptomatology attributed to anemia (8/10). Anemia was present in all children (11/11; Hb 2.8-9.1 g/dL). Nodular gastritis was present in 10 patients (antrum: 2; fundus: 4; in antrum and fundus: 4). All patients had a basement membrane thickening (from 19 to 100 µm). The treatments received were PPI (11), oral or intravenous martial supplementation (12), budesonide (1), and prednisone (1). Martial supplementation improved anemia in all cases. At discontinuation, nine of 10 patients had a recurrence of anemia. CONCLUSION: Collagenous gastritis is an exceptional condition, clinically manifested in children as abdominal pain and iron deficiency anemia probably of hemorrhagic origin. Patients require long-term follow-up and monitoring of their disease to describe the risk of progression better.

Treatments for pediatric achalasia: Heller myotomy or pneumatic dilatation?

AIM: The treatment of achalasia consists of reducing distal esophageal obstruction by either Heller myotomy surgery or endoscopic pneumatic dilatation. The aim of the present study was to evaluate the short- and middle-term results of these procedures in children. METHODOLOGY: For technical reasons, children under six years old (n=8) were treated by surgery only, whereas patients over six years old (n=14) were treated by either Heller myotomy or pneumatic dilatation. RESULTS: Of the children aged under six years, 75% were symptom-free at six months and 83% at 24 months of follow-up. Of the patients aged over six years, complete remission was achieved by Heller myotomy in 44.5% vs. 55.5% by pneumatic dilatation after six months, and in 40% vs. 65%, respectively, after 24 months. Both pneumatic dilatation and Heller myotomy showed significant rates of failure. CONCLUSION: These results suggest that pneumatic dilatation may be considered a primary treatment in children over six years old. Also, where necessary, Heller myotomy and pneumatic dilatation may be used as complementary treatments.

[Hemorrhagic ascites revealing duodenal duplication]. / Une ascite hémorragique révélant une duplication duodénale.

Duodenal duplication is a rare congenital disorder of the gastrointestinal tract. The presentation is highly variable. We report a case of duodenal duplication presenting with hemorrhagic ascites in a 3-month-old girl. The diagnosis of duodenal duplication can be made preoperatively by resonance magnetic imaging. Surgical resection of the duplication was performed. Microscopic examination of the specimen confirmed the duodenal duplication. To our knowledge, this is the 1st reported case of hemorrhagic ascites caused by duodenal duplication and demonstrated by resonance magnetic imaging.

[Mitochondrial neurogastrointestinal encephalomyopathy]. / Encéphalopathie myoneurogastro-intestinale.

This paper describes MRI aspects of a leukodystrophy due to the Mitochondrial Neurogastrointestinal Encephalomyopathy syndrome in an adolescent girl investigated for nocturnal recurrent emesis leading to major cachexia.

[Rotavirus: an ubiquitous infection?]. / Rotavirus: une infection ubiquitaire?

Rotavirus is the most frequent virus found in childhood gastroenteritis. A rotavirus viremia is observed in 19 to 63 % of cases, for three days at the beginning of infection. Then, rotavirus can reach several organs as liver (hepatitis in 1/3 of case), nervous central system (2 % of encephalitis could be linked to rotavirus), or more infrequently mesenteric lymph nodes, lung or heart. However, the link between rotavirus and systemic manifestations has not been well established. Further studies are necessary to confirm the role of rotavirus in these organ's lesions.

[Medication in infectious acute diarrhea in children]. / Traitement médicamenteux des diarrhées aiguëis du nourrisson et de l'enfant.

Acute infectious diarrhea in children remain still a frequent cause of morbidity. 50 % of them are due to rotavirus. Oral rehydration therapy and early realimentation have drastically reduced their mortality and morbidity. Beside oral or eventually IV rehydration therapy no medication has proven its efficacy based on the main HMO criteria (reduction of over 30 % of the stool output) except racecadotril and loperamide which is contre-indicated for the last one in children less than 2 years old. Other medications such as silicates or some probiotics have shown efficacy on diarrhea duration or stool consistency but not on stool output. They have so no formal indication in infectious diarrhea and should be considered as "comfort" treatment. Antibiotics, beside their indication in shigella, cholera and amibiasis could be used in invasive diarrhea in some debilating conditions or infants less than 3 months.

[When and how should small-bowel capsule endoscopy be used in children?] / Quand et comment utiliser la vidéocapsule endoscopique de l'intestin grêle chez l'enfant ?

Small-bowel capsule endoscopy (CE) has recently been used in children. During the past few years, an intense research activity has defined the advantages and limitations of CE. Its uses have been established in several small-bowel pathologies such as obvious or obscure digestive bleeding, Crohn disease, and hereditary polyposis. Although the absence of biopsy reduces the specificity of CE findings, small-bowel exploration using CE achieves better accuracy in detecting lesions than most radiological examinations. In children, swallowing problems and the risk of retention due to stenosis are the main concerns when using CE: these problems can be solved using endoscopic delivery of the capsule and luminal diameter calibration, respectively. This review focuses on the evidence making CE indispensable to small-bowel exploration.

[Desmoid tumors in an adolescent girl with familial adenomatous polyposis]. / Tumeurs desmoïdes dans le cadre d'une polypose adénomateuse familiale chez une adolescente.

Desmoid tumors (DT) are rare and nonmetastasizing fibroblastic neoplasms, characterized by local invasiveness. They occur sporadically or arise in the context of familial adenomatous polyposis (FAP; 5-10% of cases). Most cases develop sporadically in young adults, but some cases also occur in children. We report the case of an adolescent girl with FAP and DT, and we discuss the therapeutic strategies. An adolescent girl with FAP underwent surgery at the age of 14 years with total proctocolectomy. She had a neo-mutation in the APC gene at codon 1068, which is not usually associated with DT. Three years later, she had painful defecations. Imaging showed two abdominal DT. After a multidisciplinary team meeting, the patient was refused for surgery, and medical treatment with antihormonal agents and nonsteroidal anti-inflammatory drugs was started. Imaging 18 months later showed DT stabilization, but the patient had difficulties to control chronic pains, which required morphine treatment, hypnotic sessions, and transcutaneous electric nerve stimulation. This case highlights the importance of DT screening in patients with FAP, mainly after surgery, regardless of their age and genetic mutation. Progress remains to be made in determining DT risk factors and in developing treatment. DT are still difficult to cure because of their potential for local invasion and local recurrence, and need to be managed by a multidisciplinary team.

Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study.

PURPOSE: The aim of this open-label phase II study was to evaluate the activity of raltitrexed (Tomudex; AstraZeneca, Cergy, France) and oxaliplatin combination therapy in patients with diffuse malignant pleural mesothelioma. PATIENT AND METHODSs: Fifteen pretreated and 55 chemotherapy-naive patients (median age, 60 years; World Health Organization performance status of < or = 2) were enrolled. Most patients (66%) had advanced disease. Patients received raltitrexed 3 mg/m2 followed by oxaliplatin 130 mg/m2 every 3 weeks. RESULTS: Twenty-four patients (34%) were classified as having a poor prognosis. In the overall study population, 14 patients (20%) had a partial response, and 32 patients (46%) had stable disease. The symptomatic response rates were as follows: shortness of breath, 36%; pain, 30%; activity, 23%; appetite, 21%; and asthenia, 20%. Median time to disease progression was 18 weeks (95% confidence interval [CI], 13 to 22 weeks). In chemotherapy-naive patients, median survival was 31 weeks (95% CI, 23 to 40 weeks) from the start of treatment and 49 weeks (95% CI, 40 to 52 weeks) from diagnosis of mesothelioma. In pretreated patients, median survival was 44 weeks (95% CI, 24 to 40 weeks) from the start of treatment and 226 weeks (95% CI, 63 to 292 weeks) from the diagnosis of mesothelioma. Overall 1-year survival was 26% (95% CI, 15.5% to 36.4%), survival was 22% (95% CI, 10.9% to 33.2%) in chemotherapy-naive patients and 40% (95% CI, 15.2% to 64.8%) in pretreated patients. Hematologic toxicity was mild, and there was no alopecia. The most common adverse events were asthenia, nausea/vomiting, and paraesthesia, and no treatment-related deaths were reported. CONCLUSION: The raltitrexed and oxaliplatin combination is an active outpatient regimen in malignant mesothelioma and has an acceptable tolerability profile.

Bone geometry in response to long-term tennis playing and its relationship with muscle volume: a quantitative magnetic resonance imaging study in tennis players.

The benefit of impact-loading activity for bone strength depends on whether the additional bone mineral content (BMC) accrued at loaded sites is due to an increased bone size, volumetric bone mineral density (vBMD) or both. Using magnetic resonance imaging (MRI) and dual energy X-ray absorptiometry (DXA), the aim of this study was to characterize the geometric changes of the dominant radius in response to long-term tennis playing and to assess the influence of muscle forces on bone tissue by investigating the muscle-bone relationship. Twenty tennis players (10 men and 10 women, mean age: 23.1+/-4.7 years, with 14.3+/-3.4 years of playing) were recruited. The total bone volume, cortical volume, sub-cortical volume and muscle volume were measured at both distal radii by MRI. BMC was assessed by DXA and was divided by the total bone volume to derive vBMD. Grip strength was evaluated with a dynamometer. Significant side-to-side differences (P<0.0001) were found in muscle volume (+9.7%), grip strength (+13.3%), BMC (+13.5%), total bone volume (+10.3%) and sub-cortical volume (+20.6%), but not in cortical volume (+2.6%, ns). The asymmetry in total bone volume explained 75% of the variance in BMC asymmetry (P<0.0001). vBMD was slightly higher on the dominant side (+3.3%, P<0.05). Grip strength and muscle volume correlated with all bone variables (except vBMD) on both sides (r=0.48-0.86, P<0.05-0.0001) but the asymmetries in muscle parameters did not correlate with those in bone parameters. After adjustment for muscle volume or grip strength, BMC was still greater on the dominant side. This study showed that the greater BMC induced by long-term tennis playing at the dominant radius was associated to a marked increase in bone size and a slight improvement in volumetric BMD, thereby improving bone strength. In addition to the muscle contractions, other mechanical stimuli seemed to exert a direct effect on bone tissue, contributing to the specific bone response to tennis playing.

[Magnet ingestions in children: a French multicenter study]. / Ingestion de corps étrangers aimantés chez l'enfant: enquête multicentrique française.

Digestive complications related to the ingestion of magnetic foreign bodies in children are increasing, especially in Asia and North America. In France, several case reports have been reported since 2008. We conducted a retrospective multicentric study to evaluate the frequency of ingestion of magnet foreign bodies and to describe the complicated cases that have occurred in France over the last 5 years. We report 40 cases of which 60% were multiple magnet ingestions. Eighty-eight percent of the children of the group who had swallowed multiple magnets needed interventional management by endoscopy (33%) or surgery (58%). Only two children (12.5%) of the group who swallowed one magnet required removal. This problem is not uncommon in France (2% of the 1132 foreign bodies investigated in the Toulouse center over 5 years), which justifies clear information for healthcare professionals and caregivers in order to avoid potential intestinal complications. We suggest interventional management or very close monitoring in the cases of multiple magnet ingestion. Meanwhile, in the majority of confirmed cases of simple magnet ingestions, we propose home monitoring.

Clearance mediated by splenic macrophage membrane receptors for immune complexes in cutaneous vasculitis.

This study concerns 11 patients with immune complex associated cutaneous vasculitis (5 leukocytoclastic vasculitis or Gougerot Ruiter's disease, 3 essential mixed cryoglobulinaemia, 2 Henoch-Schönlein purpura and 1 Waldenström's hypergammaglobulinaemic purpura). By determining the clearance of 51Cr-labeled IgG sensitized erythrocytes we showed a slight modification in the splenic mononuclear phagocyte system. In patients with Gougerot-Ruiter's disease the clearance of the autologous IgG-coated erythrocytes was delayed in 1 patient, and normal in 2 patients. In contact, the 8 other patients showed accelerated rates of IgG-mediated clearance. There was no statistically significant correlation between clearance rate, serum complement component levels and composition and/or levels of circulating immune complexes. Thus, the accelerated clearance rate suggests an enhanced activity of the mononuclear phagocyte system IgG-Fc receptors.

Primary bone oxalosis: the roles of oxalate deposits and renal osteodystrophy.

Primary oxalosis is a rare congenital disorder. The excessive oxalate biosynthesis induces deposits in many organs, particularly in kidney and bone. The late onset of primary oxalosis is reported in a 50-year-old man. His chronic renal failure was treated by maintenance hemodialysis for 3 years. He then developed a diffuse bone disease with osteosclerosis and roentgenographic features of hyperparathyroidism. A parathyroidectomy was performed, with debatable improvement of bone lesions. Laboratory results and histologic and histomorphometric studies before and after parathyroidectomy suggest a double histopathogenetic mechanism for this bone disease: renal osteodystrophy and massive bone oxalate deposits. Such deposits may induce both a heterogeneous osteosclerosis with dense metaphyseal bands and histologic bone lesions similar to those of hyperparathyroidism. The crystalline deposits induce in the bone tissue a granulomatous macrophagic reaction. These macrophages are unable to phagocytize the crystals and may be involved in active bone resorption. Bone lesions of oxalosis occur in patients with chronic renal failure, and hyperparathyroidism has a worsening role.

Combination raltitrexed (Tomudex(R))-oxaliplatin: a step forward in the struggle against mesothelioma? The Institut Gustave Roussy experience with chemotherapy and chemo-immunotherapy in mesothelioma.

The aim of this study was to review the experience of the Institut Gustave Roussy in 163 patients with malignant mesothelioma over a 9-year period. Data from seven consecutive prospective trials, four of chemo-immunotherapy and three of chemotherapy were reviewed. The rationale, methods and results of these trials are summarised and discussed. 98 patients were included in four phase II trials of chemo-immunotherapy whose common denominator was a combination of cisplatin and alpha-interferon. The response rate ranged from 15% to 40%. High-dose weekly cisplatin combined with alpha-interferon yielded the highest response rate but the toxicity of this regimen was considered unacceptable. Neither higher doses of alpha-interferon or the addition of mitomycin C or interleukin-2 to the regimen were able to enhance the activity of this combination. 18 patients were included in a paclitaxel-cisplatin phase II trial. The response rate was only 6% (95% confidence interval (CI): 0-24) and toxicity was also significant. This regimen was, therefore, considered ineffective. Of 17 patients with mesothelioma included in a phase I trial that combined raltitrexed and oxaliplatin, 6 (35%) obtained a partial response. Responses were seen even in cisplatin-refractory mesothelioma. Preliminary results of a subsequent ongoing phase II trial using raltitrexed (3 mg/m(2)) and oxaliplatin (130 mg/m(2)) have confirmed this promising activity with a 30% (9/30) response rate (95% CI: 15-49). The tolerance of this outpatient regimen is acceptable (no significant haematological toxicity and no alopecia) and compares favourably with that of our previous regimens. The final results concerning response and survival are required to confirm the efficacy of this combination. The preliminary results of two studies suggest promising activity with the combination of raltitrexed-oxaliplatin in malignant mesothelioma. The efficacy/toxicity ratio of this combination compares favourably with that of our previous chemotherapy and chemo-immunotherapy regimens.

Angioimmunoblastic lymphadenopathy with malignant transformation during long-term remission of ocular melanoma.

A 52-year-old woman presented with angioimmunoblastic lymphadenopathy five years after undergoing enucleation for ocular melanoma. She was first treated by corticotherapy and azathioprine and had two successive remissions over an 18-month period. Lymph node biopsy performed when lymphadenopathy relapsed for the second time showed focal malignant transformation of angioimmunoblastic lymphadenopathy. Intensive polychemotherapy induced a complete remission. Three months after completion of chemotherapy, the patient presented with hepatic metastases from her melanoma and died shortly thereafter. This is believed to be the first documented association between angioimmunoblastic lymphadenopathy and melanoma. Issues regarding the relationship between angioimmunoblastic lymphadenopathy and nonlymphoid malignancies are raised.

Aggregation to thrombin and collagen of platelets from a Glanzmann thrombasthenic patient lacking glycoproteins IIb and IIIa.

The aim of this study was to investigate the platelets of a Glanzmann thrombasthenic patient, which in citrated PRP failed to respond to various agonists, but aggregated and secreted to high concentrations of thrombin (0.36, 0.72 and 1 U/ml) and collagen (4, 10 and 20 micrograms/ml) when washed and resuspended in a Tyrode-albumin solution (containing 2 mM Ca2+). Aggregation of the patient platelets was not affected by anti-IIb/IIIa monoclonal antibody (P18) which strongly inhibits thrombin or collagen induced aggregation of normal platelets. Washed platelets of this patient did not aggregate to ADP (10-100 microM) in the presence of added fibrinogen (2 mg/ml) nor bind 125I-labelled fibrinogen (40 to 320 micrograms/ml) when thrombin-stimulated. Different anti-IIb/IIIa monoclonal antibodies (P2, P18) when used in binding or crossed immunoelectrophoretic studies showed a complete absence of the IIb-IIIa glycoprotein complex on the patient platelets. Moreover, glycoproteins IIb or IIIa were absent on silver-stained two-dimensional (non-reduced/reduced) polyacrylamide gel separations of the patient platelets and were not detected by Western blots used in combination with anti-PLA1 (antigen present on IIIa), anti-Leka (antigen present on IIb). This study shows that platelets lacking glycoproteins IIb or IIIa can aggregate in response to high concentrations of collagen or thrombin when resuspended in the presence of physiological concentrations of calcium. Results obtained in this study could indicate the existence of other mechanisms (other than the IIb-IIIa glycoprotein complex) involving glycolipids, heparans, proteoglycans, and/or unknown membrane glycoproteins to mediate platelet aggregation of stimulated thrombasthenic platelets.

Day 4 bone marrow aspirate for prediction of resistance to induction chemotherapy in acute myeloid leukemia.

Bone marrow aspirate was performed on day 4 of a 7-day induction chemotherapy regimen using daunorubicin, cytosine arabinoside and thioguanine in 42 patients with acute myeloid leukemia (AML). The mean percentage of remaining abnormal cells in day 4 bone marrow was significantly higher in patients having resistant disease (RD) than in patients entering complete remission (CR). Except for patients with FAB M3 AML, most patients who had more than 40% abnormal cells in their day 4 bone marrow had RD. In addition, patients entering CR despite having more than 40% abnormal cells remaining in their day 4 bone marrow seemed to have short CR.