Group-based exercice training programs for military members presenting musculoskeletal disorders - protocol for a pragmatic randomized controlled trial.

BACKGROUND: Musculoskeletal disorders are a leading cause of morbidity and the most prevalent source of disability among soldiers. Their high prevalence in armed forces and limited ressources have led to problems related to access to physical rehabilitation care. To increase access, supervised group-based exercise programs for the most prevalent musculoskeletal disorders (low back pain, patellofemoral pain, rotator cuff-related shoulder pain or lateral ankle sprain) have been developed at a Canadian Armed forces (CAF) base, but their effectiveness has not been evaluated. The primary objective of this randomized controlled trial is to evaluate the mid- and long-term effects of these group-based training programs on pain severity and functional limitations, in comparison with usual individual physiotherapy care. Secondary objectives include comparing both interventions in terms of health-related quality of life, pain-related fear, and patients' satisfaction. METHODS: One hundred and twenty soldiers with a new medical referral for physiotherapy services for one of the four targeted musculoskeletal disorders will be consecutively recruited. They will be randomly assigned to either group-based training program or usual individual physiotherapy care, and will take part in the assigned 12-week intervention. There will be four evaluation sessions over 26 weeks (baseline, week 6, 12 and 26). At each follow-up, functional limitations, pain severity, health-related quality of life and pain-related fears will be assessed. Patients satisfaction with treatment will also be evaluated at the end of the intervention period. Either two-way repeated measures ANOVA will be used to analyse and compare the effects of the interventions. DISCUSSION: This RCT will determine the effectiveness of group-based training programs compared to usual individual physiotherapy care. This new intervention model could represent an efficient, and more pro-active approach to manage a higher number of soldiers with musculoskeletal disorders. It could improve access to physical rehabilitation care and improve the health of soldiers. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT05235152 ), February 11th 2022.

Membrane-targeted HrpNEa can modulate apple defense gene expression.

Fire blight caused by Erwinia amylovora is the major bacterial disease of tribe Maleae, including apple. Among the proteins secreted by this bacterium, HrpNEa, also called harpin, is known to induce hypersensitive response in nonhost plants and to form amyloid oligomers leading to pore opening in the plasma membrane and alteration of membrane homeostasis. To better understand the physiological effects of HrpNEa in the host plant, we produced transgenic apple plants expressing HrpNEa with or without a secretion signal peptide (SP). HrpNEa expressed with a SP was found to be associated within the membrane fraction, in accordance with amyloidogenic properties and the presence of transmembrane domains revealed by in silico analysis. Expression analysis of 28 apple defense-related genes revealed gene modulations in the transgenic line expressing membrane-targeted HrpNEa. While apple transgenic trees displaying a high constitutive expression level of SP-HrpNEa showed a slight reduction of infection frequency after E. amylovora inoculation, there was no decrease in the disease severity. Thus HrpNEa seems to act as an elicitor of host defenses, when localized in the host membrane.

[Which future in cardiovascular therapy for nitric oxide and its derivatives?]. / Quel avenir en thérapeutique cardiovasculaire pour le monoxyde d'azote et ses dérivés?

Nitric oxide (NO) is involved in the regulation of several physiological processes such as vascular homeostasis. Exogenous NO supply offers major therapeutic interest, especially in the treatment of coronary artery disease, ischemic syndromes and other cardiovascular pathologies. Nevertheless, the administration of NO itself is limited by its short half-life. NO prodrugs have been marketed for decades, e.g. organic nitrates for angina pectoris. These prodrugs display undeniable advantages such as angina crisis relief and preconditioning effect. Nevertheless, they suffer from several drawbacks: toxicity, tolerance, endothelial dysfunction exacerbation. These negative effects are related to massive production of reactive species derived from oxygen or nitrogen, which trigger oxidative and nitrosative stress. New NO donors are under development to overcome those disadvantages, among which the S-nitrosothiols family seems especially promising.

[Renin-angiotensin-aldosterone system: an old system offering new drug targets for the cerebral circulation]. / Système rénine-angiotensine-aldostérone: vieux système mais piste stratégique de régulation de la circulation cérébrale.

In a rat model of human essential hypertension (SHR), the chronic increase in cerebral arteriolar blood pressure is accompanied by remodelling with wall hypertrophy and a fall in diameter. The latter produces an increase in cerebrovascular resistance which maintains cerebral blood flow autoregulation at high systemic blood pressure levels, but accentuates hypoperfusion at low arterial pressures such as those observed during and following cerebral ischemia. Using ACE inhibitors and AT1 blockers we have shown that the normalisation of wall thickness is pressure-dependent but that the normalisation of arteriolar diameter relates to a pressure-independent mechanism involving aldosterone. This raises the possibility of new drug targets for arteriolar remodelling involving intracellular sodium-dependent modulation of protein metabolism.

PAF and haematopoiesis: III. Presence and metabolism of platelet-activating factor in human bone marrow.

Platelet-activating factor (PAF) is a phospholipid compound with major immunoregulatory activities. The present study shows that human bone marrow contains 576 +/- 39 pg PAF/ml (n = 35). Bone marrow-derived PAF exhibits the same biophysical and biological properties that synthetic PAF. PAF concentrations in bone marrow are correlated with the granulocyte (r = 0.4, P = 0.02) but not with the lymphocyte (r = 0.24, P = 0.17) and the monocyte (r = 0.12, P = 0.48) counts. In bone marrow PAF is inactivated by a plasma PAF acetylhydrolase activity (48.0 +/- 2.3 nmol/min per ml, n = 34). Experiments with [3H]PAF indicate that human bone marrow cells actively metabolize this potent molecule by the deacetylation-transacylation pathway. Results of this investigation indicate the permanent presence of significant amounts of PAF in bone marrow suggesting its putative involvement in the processes of bone marrow cell proliferation and maturation.

PAF and haematopoiesis. X. Macrophage colony-stimulating factor and granulocyte macrophage colony-stimulating factor enhance platelet-activating factor acetylhydrolase production by human blood-derived macrophages.

Platelet-activating factor (PAF), a phospholipid autacoid with potent regulatory functions, is synthesized by stimulated monocytes. Macrophages are a source of the plasma acetylhydrolase activity (AHA) which regulates PAF concentrations. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are involved in the differentiation and functions of cells from the monocytic/macrophagic lineage. This work reports that M-CSF and GM-CSF stimulated AHA production by human blood monocyte-derived macrophages in a time- and dose-dependent manner. After 7 days of culture without serum, a 6- and 4-fold increase was found in cells treated with M-CSF (1000 U/ml) and GM-CSF (50 ng/ml), respectively. M-CSF (up to 1000 U/ml) and GM-CSF (up to 10 ng/ml) did not induce PAF production by human blood monocytes. While GM-CSF (10 ng/ml) and interleukin-1 (10 U/ml) stimulated M-CSF production from monocyte-derived macrophages, PAF did not. These results indicate that M-CSF and GM-CSF enhance AHA production by human blood-derived macrophages cultured in low serum concentrations. Clearly the effects of growth factors on AHA production in vivo deserve to be assessed.

Production, metabolism and effect of platelet-activating factor on the growth of the human K562 erythroid cell line.

The human immature K562 erythroid cell line was studied for its capacity to produce and to metabolize the phospholipid molecule platelet-activating factor (PAF). K562 cells produced PAF under calcium ionophore stimulation. Lyso PAF and acetyl-CoA (the acetate donor molecule for the acetylation of lyso PAF into PAF) had no effect on the amounts of PAF produced by ionophore-stimulated cells. The metabolism of PAF and lyso PAF by K562 cells was compared to that of freshly-isolated human bone marrow erythroblasts and blood erythrocytes. K562 cells rapidly metabolized [3H]PAF and [3H]lyso PAF with 1-alkyl analogue of phosphatidylcholine as the major metabolic product. In contrast, blood erythrocytes did not. PAF acetylhydrolase activity levels in K562 cells and bone marrow erythroblasts were similar and higher than in blood erythrocytes. PAF (1-100 nM) stimulated [3H]thymidine incorporation in K562 cells grown in low serum concentration, a non-metabolizable PAF agonist being more potent than PAF to stimulate thymidine incorporation. PAF receptor mRNA was detected in K562 cells by polymerase chain reaction on reverse transcripts. The present study demonstrates that K562 cells produce and metabolize PAF and underlines the putative role of erythroid precursors in the modulation of bone marrow PAF concentrations. The effect of PAF on the growth of K562 cells might be mediated through PAF receptors suggesting a potential role of PAF on the proliferation and functions of human erythroid marrow precursors.

PAF and hematopoiesis. VIII. Biosynthesis and metabolism of PAF by human bone marrow stromal cells.

Human bone marrow stromal cells were studied for their ability to synthesize and to metabolize platelet-activating factor (PAF), a lipidic compound with potent immunoregulatory properties. When stimulated with 2 microM calcium ionophore for 60 minutes, cultures of stromal cells increased their PAF production (3.52 +/- 0.91 ng/1 x 10(6) cells) compared with controls (0.82 +/- 0.13 ng/1 x 10(6) cells). Addition of exogenous lyso PAF (100 nM) and acetyl-CoA (100 microM) during calcium ionophore stimulation did not change the PAF production. The synthesis of PAF was not influenced by the concentration of albumin in the incubation buffer. The PAF from stromal cells exhibited a hexadecyl chain at the sn-1 position of the molecule, as determined by reverse-phase HPLC. While stromal cells contained low amounts of PAF acetylhydrolase activity and did not secrete it in the culture medium, they metabolized exogenous PAF with 1-alkyl-2-acyl-glycero-phosphocholine and neutral lipids as the major metabolic products. The present results are the first to demonstrate the synthesis and metabolism of PAF by human bone marrow stromal cells. These data suggest that they might be a source of the PAF found in the human bone marrow and/or might be important in the regulation of its levels. The role of PAF on the proliferation and functions of human hematopoietic cells deserves investigation.

Hepar lobatum carcinomatosum associated with liver metastases from breast cancer: report of five cases.

BACKGROUNDS AND AIMS: Hepar lobatum carcinomatosum (HLC) is an exceptional acquired hepatic distortion which consists in irregularly lobulated hepatic contours seen in patients with known liver metastases, usually from breast carcinoma. We aimed to describe and analyze five similar cases of HLC resulting from metastatic mammary carcinoma in the liver and associated with rapid hepatic failure. METHODS: Five cases of HLC were investigated. Medical (including blood liver tests), radiological and histological data (2 cases) were collected and retrospectively analyzed. All patients were followed up for metastatic invasive ductal carcinoma of the breast and had a common pattern of treatment with combination of targeted therapies (bevacizumab, AVASTIN) and chemotherapy (paclitaxel, TAXOL). RESULTS: All the patients showed rapid hepatic failure after a mean of 9 courses of bevacizumab/paclitaxel. In all cases, liver imaging revealed liver capsule retraction and an irregular lobular margin. An apparent tumor regression of all liver metastases was showed in two cases. Biopsies were consistent with sinusoidal obstruction syndrome (SOS) and, surprisingly, no tumoral cells were found. CONCLUSION: Although rare, such an unusual pattern of liver metastasis may mimick acute cirrhosis and cause rapid hepatic failure in patients, despite possible apparent tumor regression on imaging. The etiology of this pathology is unclear, and may involve multiple pathogenic factors. Direct or indirect vascular injury plays an important role in the development of HLC.

PAF and hematopoiesis. II. Elevated levels of plasma paf acetylhydrolase after rapid infusion of 5-fluorouracil in cancer patients.

Blood platelet-activating factor (PAF) levels are regulated by a plasma PAF acetylhydrolase. We investigated its levels in cancer patients during the course of a 5-day 5-fluorouracil (5-FU) treatment. PAF acetylhydrolase increased in nine patients with daily bolus infusion of 0.4 g 5-FU per m2 of body surface (81.7 +/- 8.7 nmol PAF/min/ml vs. 66.6 +/- 7.0; P < 0.001 for day 5 as compared to day 1). By contrast PAF acetylhydrolase did not change in seven patients with continuous infusion of 5-FU. The meaning of these results is discussed in respect of the immunoregulatory role of PAF.

PAF and haematopoiesis XII: macrophage colony-stimulating factor (M-CSF) decreases platelet-activating factor (PAF) acetylhydrolase production in macrophagic J774 cells.

Platelet-activating factor (PAF) is a phospholipid mediator with major immunoregulatory activities. Macrophages produce PAF acetylhydrolase activity, which regulates blood PAF concentrations. Macrophage colony-stimulating factor (M-CSF) is involved in the differentiation and functions of cells from the monocytic/macrophagic lineage. We found that murine macrophagic J774 cells metabolized PAF with lyso PAF as the major metabolite product. As in mouse plasma, the metabolism of PAF by J774 cells was not inhibited by PMSF, p-BPB, DTNB and quinacrine, M-CSF (100-5000 U/ml) significantly decreased PAF acetylhydrolase activity of the J774 cell without exhibiting a significant effect on cell growth. Elevated concentrations of M-CSF are found in blood and tissues during inflammatory states. It could be suggested that a decreased PAF catabolism by tissue macrophages in response to M-CSF may induce local elevated PAF concentrations, thus amplifying the inflammatory response.

PAF and haematopoiesis. IV. Modifications of spleen and thymus PAF contents after a single dose of the chemotherapeutic drug 5-fluorouracil in mice.

The spleen and thymus of mice were examined for the presence of PAF after injection of 5-fluorouracil (5-FU) (200 mg/kg). A significant increase of the spleen (P = 0.005) and thymus (P < 0.05) PAF concentrations was noted 48 h after 5-FU infusion. PAF levels in thymus are similar to those of controls from days 4 to 14. By contrast, spleen PAF significantly decreased (0.005 < P < 0.03) from days 7 to 14. Conversely, the 5-FU administration did not modify the spleen and plasma acetylhydrolase activity, suggesting that the variations of PAF levels in thymus and spleen were mainly due to differences of local PAF production. Thus, the chemotherapeutic drug 5-FU modulates in vivo PAF production in haematopoietic organs of mice. Considering the effects of PAF in the processes of B- and T-cell proliferation and functions, these results could be of importance for the role of PAF during human cancer therapy and haematopoiesis in vivo.

Necropsy study on glomerulonephritis in the elderly.

The necropsy reports and clinical observations of 44 cases of glomerulonephritis occurring in patients over 55 years old were reviewed. Two-thirds of the patients died from a rapidly progressive renal disease with focal necrotizing and fibrosing glomerular lesions; half of these exhibited a granulomatous splenic trabeculitis; an associated vasculitis was found in only a minority of these cases. Another important group consisted of cases of acute diffuse glomerulonephritis which, as a rule, occurred in association with a major infection. There were only four cases of chronic sclerosing glomerulonephritis.

Concussions in athletes produce brain dysfunction as revealed by event-related potentials.

We have used event-related potentials (ERP) to assess cerebral activity following mild traumatic brain injuries in 20 college athletes practising contact sports. Concussion victims showed a striking decrease in P300 amplitude, an effect presumed to reflect alterations in attentional-cognitive processes. Moreover, the degree of impairment was strongly related to the severity of post-concussion symptoms. Our data suggest that concussions cause objectively measurable changes in the electrophysiological markers of brain activity and hence in the functions of the structures from which they originate. ERPs may thus constitute a reliable method to accurately monitor the clinical course and recovery of head injuries in athletes.

Kidney transplantation in primary oxalosis.

A 33 year old patient with primary oxalosis was submitted to cadaver kidney transplantation after 15 months treatment by hemodialysis. During the dialysis period, he developed complete heart block which immediately followed bilateral nephrectomy. The transplant functioned correctly and was found to excrete large amounts of oxalate. Death, which supervened 7 months after transplantation, was due to miliary tuberculosis. The patient's own kidneys and various organs examined post mortem showed extensive oxalate deposits, which were mainly observed in the graft, conducting system of the heart, ocular structures, spleen and pancreas. The problems of managing terminal uremia secondary to primary oxalosis are discussed.

Chitinases of Trichoderma atroviride Induce Scab Resistance and Some Metabolic Changes in Two Cultivars of Apple.

ABSTRACT This study reports the combination of a transgene-mediated defense mechanism with a conventionally bred resistance in order to improve apple scab resistance. Two cultivars of apple (Galaxy, scab-susceptible, and Ariane, carrying the Vf resistance gene) were transformed with endochitinase and exochitinase genes derived from the biocontrol fungus Trichoderma atroviride. The obtained transgenic lines were analyzed for the expression of both genes and resistance to two races of the pathogen Venturia inaequalis: the common race 1 and race 6 which overcomes the resistance conferred by the Vf gene. A negative correlation between growth of transgenic lines and endochitinase activity was observed. Reduced growth appeared to be associated with high lignin content and high peroxidase as well as glucanase activity, suggesting that endochitinase activity may disturb the metabolism of the plant. Scab inoculation with races 1 and 6 performed in a growth chamber on 14 lines of normal vigor identified 6 lines with significantly enhanced resistance. Ten lines with reduced vigor were tested in vitro with a bioassay on rooted shoots. All lines expressing high endochitinase activity exhibited a significant reduction of scab symptoms.

[Cerebral magnetic resonance imaging (MRI) in the diagnosis of leptomeningeal carcinomatosis in melanoma patients]. / Imagerie par résonance magnétique (IRM) cérébrale dans le diagnostic des méningites mélanomateuses.

OBJECTIVE: Meningeal involvement is frequent in metastatic melanoma, approximately 30% in autopsy series. Functional signs may be misleading and the neurological examination may be normal. Certain diagnosis requires identification of tumor cells in the cerebrospinal fluid. CSF cytology is however sometimes negative and magnetic resonance imaging (MRI) with gadolinium injection may provide the diagnosis. The aim of this retrospective study was to assess the role of imaging in the diagnosis of leptomeningeal carcinomatosis. PATIENTS AND METHODS: The diagnosis of leptomeningeal carcinomatosis was made in 8 patients between 1992 and 1998. All had signs of neurological function impairment, but the neurology examination was abnormal in only 2. RESULTS: Cytology examination of the cerebrospinal fluid provided the diagnosis of leptomeningeal carcinomatosis in 5 patients. One out of 5 brain CT scans were positive, showing meningeal enhancement confirmed by brain MRI. The spinal tap was not contributive in 2 cases and was not done in 1. In these three cases, the brain CT did not provide any diagnostic element while the brain MRI with gadolinium injection confirmed the diagnosis of leptomeningeal carcinomatosis. DISCUSSION: Forty-one percent of patients with autopsy proven leptomeningeal carcinomatosis have a normal ante mortem spinal tap. Brain MRI with gadolinium injection has better sensitivity than brain CT scan. All patients with nonspecific neurological signs and a normal spinal tap should be explored with a brain MRI.

[Surgical treatment of pilonidal disease. A new simplified technic]. / Le traitement chirurgical de la maladie pilonidale. Une technique nouvelle simplifiée.

A simplified technique for treatment of pilonidal sinus has been employed in 25 patients during the last 3 years. Initial results have been very encouraging as there have been no recurrences up to the present time. Mean duration of hospitalization was 3 days, patients can get out of bed after 24 hours, and work can be resumed after 2 weeks, complete healing requiring one month.

Takotsubo syndrome (TKS): a possible mechanism of sudden unexplained death in epilepsy (SUDEP).

We report a case of Takotsubo syndrome after epilepsy, and review the literature. We identified 59 cases of Takotsubo syndrome after focal or generalised epilepsy. As in Takotsubo syndrome in general, the patients were mostly female (84%), with a mean age of 63 years, and the evolution was generally favourable. There was one death and one stroke, and 4 cases were of relapsing Takotsubo after a new seizure. Takotsubo syndrome may induce cardiac arrhythmias. A near-SUDEP (sudden unexplained death in epilepsy) was reported in one patient. Animal models of SUDEP have shown similar cardiac lesions to those seen in Takotsubo syndrome, and strengthen the hypothesis of a link between these conditions. Takotsubo syndrome after epilepsy may be relatively common; we suggest measurement of serum troponin levels in high-risk patients and cardiac follow-up.