Is Hematopoietic Clonality of Indetermined Potential a Risk Factor for Pulmonary Embolism?

Background Unprovoked pulmonary embolism (uPE) is a severe and frequent condition. Identification of new risk factors is mandatory to identify patients that would benefit from a long-term treatment. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations that drive clonal expansion in the absence of cytopenia. Its prevalence is estimated of 5% in the population above 65 years. Since inflammation and endothelial dysfunction may share a pathophysiological pathway(1), we hypothesized that CHIP, may be a risk factor for uPE. Methods We conducted a pilot retrospective observational study. Patients with iPE between 18 to 65 years old were included. PE was considered as unprovoked, when no transient nor persistant risk factor was present and when thrombophilia testing was negative. We excluded documented atherosclerosis, personal or familial history of VTE and presence of cytopenias. CHIP proportion in uPE patients were analyzed using next generation sequencing of the coding sequence of a custom panel composed by DNMT3A, ASXL1, SF3B1, TET2 and TP 53 . Results Upon 61 patients with uPE consecutively included, a total of 19 somatic mutations were found in 12 patients (20%) IC95% [10 - 20]. 15 mutations were found in DNMT3A gene, 3 in ASXL1 and one in TET2 . There was no diference in terms of age, PE location, DVT presence and risk stratification in CHIP carriers and non carriers. Conclusion We report for the first time, the presence of high rates of CHIP in patients presenting with uPE. Thus, CHIP may be a new risk factor for VTE. These results need to be confirmed in an ongoing prospective case-control study including more patients and using a more diverse gene panel to better determine CHIP incidence in uPE.

[Quality standards for ultrasonographic assessment of peripheral vascular malformations and vascular tumors. Report of the french society for vascular medicine. 2018 Update]. / Standards de qualité pour la pratique de l'examen écho-Doppler dans l'étude des malformations et tumeurs vasculaires. Rapport de la Société française de médecine vasculaire (SFMV) : actualisation 2018.

The quality standards of the French Society of Vascular Medicine for the ultrasonographic assessment of vascular malformations are based on the two following requirements: (1) technical know-how: mastering the use of ultrasound devices and the method of examination; (2) medical know-how: ability to adapt the methods and scope of the examination to its clinical indication and purpose, and to rationally analyze and interpret its results. AIMS OF THE QUALITY STANDARDS: To describe an optimal method of examination in relation to the clinical question and hypothesis. To homogenize practice, methods, glossary, and reporting. To provide good practice reference points, and promote a quality process. ITEMS OF THE QUALITY STANDARDS: The 3 levels of examination; their clinical indications and goals. The reference standard examination (level 2), its variants according to clinical needs. The minimal content of the examination report; the letter to the referring physician (synthesis, conclusion and proposal for further investigation and/or therapeutic management). Commented glossary (anatomy, hemodynamics, semiology). Technical bases. Setting and use of ultrasound devices. Here, we discuss ultrasonography methods of using of ultrasonography for the assessment of peripheral vascular malformations and tumors (limbs, face, trunk).

Allergy to deamidated gluten in patients tolerant to wheat: specific epitopes linked to deamidation.

BACKGROUND: Gluten proteins can be modified by deamidation to enhance their solubility and technological applications. However, severe allergic reactions have been reported after the consumption of food products containing deamidated gluten (DG) in subjects tolerant to wheat. This work aimed to characterize allergen profiles for these patients in comparison with those of patients allergic to wheat and to identify IgE-binding epitopes. METHODS: Sera were obtained from 15 patients allergic to DG and from nine patients allergic to wheat proteins (WP). IgE-binding profiles were characterized both in ELISA and in a humanized rat basophilic leukaemia (RBL) cell model. Epitopes were mapped on γ- and ω2-gliadin sequences by Pepscan, and effect of glutamine/glutamic acid substitutions was studied. RESULTS: Compared to the heterogeneous pattern of allergens detected by IgE from patients allergic to WP, responses of patients allergic to DG were homogeneous. In ELISA, all the sera displayed IgE binding to deamidated γ- and ω2-gliadins and deamidated total gliadins, frequently with high concentrations. These modified proteins induced RBL degranulation with most of the sera from DG-allergic patients. A consensus epitope was found on native γ- and ω2-gliadins (QPQQPFPQ); it was repeated several times in their sequences. The substitution of two or three glutamines of this epitope into glutamic acid at positions Q3 or Q4 and Q8 (QPEEPFPE) increased its recognition the best. CONCLUSION: Allergy to DG is a separate entity from wheat allergy. It can be evidenced by strong IgE binding to deamidated gliadins or peptides of the type QPEEPFPE.

Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16.

Serotonin reuptake inhibitor (SRI) antidepressants such as fluoxetine (Prozac), promote hippocampal neurogenesis. They also increase the levels of the bcl-2 protein, whose overexpression in transgenic mice enhances adult hippocampal neurogenesis. However, the mechanisms underlying SRI-mediated neurogenesis are unclear. Recently, we identified the microRNA miR-16 as an important effector of SRI antidepressant action in serotonergic raphe and noradrenergic locus coeruleus (LC). We show here that miR-16 mediates adult neurogenesis in the mouse hippocampus. Fluoxetine, acting on serotonergic raphe neurons, decreases the amount of miR-16 in the hippocampus, which in turn increases the levels of the serotonin transporter (SERT), the target of SRI, and that of bcl-2 and the number of cells positive for Doublecortin, a marker of neuronal maturation. Neutralization of miR-16 in the hippocampus further exerts an antidepressant-like effect in behavioral tests. The fluoxetine-induced hippocampal response is relayed, in part, by the neurotrophic factor S100ß, secreted by raphe and acting via the LC. Fluoxetine-exposed serotonergic neurons also secrete brain-derived neurotrophic factor, Wnt2 and 15-Deoxy-delta12,14-prostaglandin J2. These molecules are unable to mimic on their own the action of fluoxetine and we show that they act synergistically to regulate miR-16 at the hippocampus. Of note, these signaling molecules are increased in the cerebrospinal fluid of depressed patients upon fluoxetine treatment. Thus, our results demonstrate that miR-16 mediates the action of fluoxetine by acting as a micromanager of hippocampal neurogenesis. They further clarify the signals and the pathways involved in the hippocampal response to fluoxetine, which may help refine therapeutic strategies to alleviate depressive disorders.

Total hip replacement in identical twins with Scheie Mucopolysaccharidosis.

Investigation performed at the Hospital for Special Surgery, New York, USA Scheie Syndrome is an autosomal recessive metabolic storage disease with distinct skeletal findings known as "dysostosis multiplex". This paper reports on identical twins with Scheie Syndrome who required total hip arthroplasty for early osteoarthritis of the hip. The surgical approach and exposure was particularly demanding due to the stiffness imposed by the soft tissues arising from infiltration of glycosaminoglycans. The small femoral head and acetabulum limited the diameter of the acetabular component and subsequently the prosthetic head diameter that could be safely utilized without compromising the thickness of the polyethylene liner. Twenty-two millimeter heads with a standard polyethylene insert were therefore utilized in the two arthroplasties performed in 1998 in the first twin, and a 28 mm head with a highly cross linked polyethylene liner, in the arthroplasty performed on the second twin in 2003. This is a relevant issue considering that these patients required an arthroplasty at a young age. Hip arthroplasty relieved pain, improved ambulation and provided a better range of motion in our two patients. There were no peri-operative complications. Long-term survivorship of total hip replacement in this population is not yet known. (Hip International 2005; 15: 55-8).

Post-traumatic ossification of the Achilles tendon: description of a case.

The presence of small areas of ossification in the Achilles tendon is a relatively frequent finding. It is instead rare to find large, extensive ossifications for more than half of the tendon. The authors describe a case of a man aged 45 years who, in the wake of an unknown lesion of the Achilles tendon, developed clinically symptomatic ossification 9.5 cm in length and 2.3 cm in width. The patient was treated surgically by removal of the ossified portion and repair of the diastasis with a proximal Achilles flap. After 17 months, the patient is asymptomatic, there are no disorders in walking, and he exclusively shows moderate limitation in range of movement of the ankle joint associated with tricipital hyposthenia. Bone metaplasia of the Achilles tendon is a rare event, that can follow trauma or surgery. The size of the area to be removed implies considerable difficulty in repair of the continuity and in recovery of the length of the tendon.

The surgical treatment of fractures of the radial head: a comparison between osteosynthesis and capitellectomy.

Until the mid-eighties, capitellectomy was the treatment of choice for displaced fractures of the radial capitellum. The observation of complications such as instability of the elbow, proximal migration of the radius, valgus and humerus-ulna arthrosis, led us to safeguard the capitellum until the biomechanics of the elbow had been restored. A total of 20 patients treated surgically for Mason type II and III displaced fracture of the radial capitellum were studied retrospectively. The patients were divided into two homogeneous groups, of which group 1 was made up of patients treated by capitellectomy, and group 2 by those treated by osteosynthesis. The patients were seen again at mean follow-up of 44.6 months and submitted to clinical and radiographic evaluation. The clinical results were satisfactory in 80% of cases in group 1 and in 100% of cases in group 2. Radiographic signs of arthrosis were present in 90% of patients who had undergone capitellectomy, and in 20% of those who had undergone osteosynthesis.

[Pulmonary embolism and sibilant types of chronic obstructive pulmonary disease decompensations]. / Embolie pulmonaire et formes sibilantes des décompensations de bronchopneumopathie chronique obstructive.

Pulmonary Embolism (PE) poses an important diagnostic problem in patients with chronic obstructive pulmonary disease (COPD). Indeed PE may aggravate the already precarious respiratory state of these fragile patients. Moreover, these two conditions share common symptoms: dyspnoea, wheezing, pleural pain, haemoptysis, palpitations and signs of right cardiac insufficiency. In two studies, one retrospective and the other prospective, we investigated the incidence of PE in patients with non-infective exacerbations of their COPD. The retrospective study was carried out over two years and involved 50 COPD patients with non-infective respiratory exacerbations. In this population, 10 patients out of 50 (20%) had a documented PE. No predictive factor was identified. The prospective study was conducted over one year and COPD patients admitted to hospital with exacerbations were included in the study if they had a positive D-dimer blood test and no evidence of acute respiratory infection. 31 patients were studied with Doppler ultra-sound examination of the legs and a lung perfusion scan. The presence or absence of PE was determined and the two groups were compared. 9 patients out of 31 (29%) had a documented PE. Six of these nine patients had a deep venous thrombosis (DVT). Two predictive factors of PE were identified: existence of a DVT and a significant fall in PaO(2) from baseline state (DeltaPaO(2) > 22 mmHg). We conclude that PE is a frequent (20 to 30%) of non-infective respiratory decompensation in COPD patients. Faced with an unexplained respiratory exacerbation in these patients, a lung perfusion scan should be routinely undertaken to rule out a PE when the D-dimers are positive.

The surgical treatment of supracondylar fractures of the humerus in children by percutaneous fixation using Kirschner wires: analysis of residual deformities.

The authors report the results of the surgical treatment of supracondylar fractures of the humerus during childhood by closed reduction and percutaneous synthesis using Kirschner wires. A total of 16 patients were considered, who were re-examined at a mean follow-up of 57.9 months (24-84). The fractures were evaluated according to the Gartland classification modified by Wilkins. The results were classified based on Flynn criteria, and the duration of hospitalization and early and late complications such as neurovascular deficit and residual deformities were also taken into consideration. Final results were satisfactory in 94% of cases with no septic, vascular, or nervous complications. We observed remodeling of three fractures with defect in reduction of the distal fragment on a sagittal plane, and the absence of correction in a case of deficit in reduction on the frontal plane. Deformity persisted with no secondary displacement in 5 cases with correct postoperative reduction.

Treatment of popliteal arterial aneurysm using a superficial femoral artery autograft.

The usefulness of aggressive surgical management of popliteal arterial aneurysm is now widely accepted. Reconstruction is usually performed using either prosthesis or saphenous vein autograft. Autografts are preferable but not always possible because of problems of availability and congruence. An alternative conduit for cases involving lesions spanning the articular midline of the knee is the superficial femoral artery. From 1993 to 1998, we used superficial femoral artery autografts to treat a total of 18 aneurysms in 12 patients. All patients were male with a mean age of 66 years (range, 42 to 75). Fourteen aneurysms were treated during elective procedures, including four in combination with aortic repair. The remaining four were treated on an emergency basis. Exposure was achieved via the internal medial route in all cases. Treatment consisted of exclusion or aneurysmorraphy. The mean length of the autograft harvested from the ipsilateral thigh was 10.2 cm (range, 6-18). The harvested graft was replaced by a PTFE prosthesis. Our results show that superficial femoral artery autografts are a suitable alternative for two indications: for patients with small aneurysms located in the middle of the popliteal artery, since autografts provide excellent congruence, and for patients with no other useable donor vein or concurrent deep venous thrombosis.

Primary malignant tumors of the venous system in the lower extremities.

Malignant tumors arising from venous walls in the lower extremity are uncommon. Histologically they are divided into two groups: hemangioendotheliomas of intermediate malignancy and leiomyosarcomas. This report describes a retrospective series of seven primary venous tumors observed in four men and three women with a mean age of 49.8 years (range: 18 to 64 years) who underwent surgical treatment between 1985 and 1995. The tumor was located in the superficial femoral vein in four patients, common femoral vein in two patients, and greater saphenous vein in one patient. A palpable tumor was present in five patients, localized pain in two patients, and metastasis in two patients. The histological diagnosis was leiomyosarcoma in six patients and hemangioendothelioma in one patient. Surgical treatment consisted of complete resection in six patients and partial excision in one patient. Venous reconstruction was performed in two patients and adjuvant radiation therapy in four patients. There was no operative morbidity/mortality. Median survival was 31 months. Four patients with leiomyosarcoma died from metastasis. Two patients with leiomyosarcoma and one with hemangioendothelioma are alive at 9 years, 16 months, and 9 months, respectively. Local recurrence was never observed after complete resection. The prognosis of venous leiomyosarcoma of the lower extremities is poor due to early occurrence of metastasis. Doppler ultrasound and MRI are useful to establish early diagnosis at the nontumoral stage. Improvement in the prognosis of leiomyosarcoma may justify perioperative chemotherapy before and after radical surgical excision.

[Effect of meteorological variations on the emergence of deep venous thrombosis of the leg]. / Influence des variations météorologiques sur la survenue de thrombose veineuse profonde des membres inférieurs.

INTRODUCTION: Recent articles have established a significant relationship between metereology variables and the development of vascular disease. We performed a retrospective study to determine relationships between the development of deep vein thrombosis in the lower limb and certain meteorology variables. MATERIALS AND METHODS: We identified 345 cases of phlebitis in 1995. We studied the distribution of the number of venous thrombosis per day, per month and per season. We compared certain meteorological data (atmospheric pressure, temperature, mean hygrometery) for days with and days without venous thrombosis and the atmospheric variations during the 48 hours prior to venous thrombosis. RESULTS: There was a significant relationship (p < 0.004) between the mean number of cases of phlebitis recorded per day and season with winter predominating. On days when phlebitis occurred, the atmospheric pressure was significantly lower (p < 0.05). The number of thrombotic events was significantly different on days when the variation was greater than 10 hectopascals than on days when the variation was less than 10 hectopascals (p < 0.05). CONCLUSIONS: In our study, deep vein thrombosis of the lower limb was significantly associated with certain meteorology variables. Prospective multicentric studies are needed to confirm these relationships.

Skeletal muscle function in patients with hemophilia A and unilateral hemarthrosis of the knee.

Acute hemarthrosis is a frequent complication of hemophilia A. To test the hypothesis that recurrent hemarthrosis has an adverse effect on neuromuscular function, ten patients with hemophilia A and history of unilateral hemarthrosis of the knee were studied. The uninvolved (U) side was used as the control. The time since diagnosis, factor level, and the number of bleeding episodes in the involved (I) knee averaged 11.6 +/- 6.6 years, 7.7 +/- 5.1%, and 7.0 +/- 7.4, respectively. Neuromuscular function was evaluated on a Cybex 340 isokinetic dynamometer. Knee extensor strength measured at 60 degrees/sec was significantly (p less than .05) lower in the I side (mean = 58Nm) than in the U side (mean = 85Nm). Similarly, lower (p less than .05) total work (I = 479J, U = 656J) and average power output (I = 59W, U = 83W) values were obtained. Adjusting for thigh circumference did not eliminate any of these differences. Testing the extensors at faster angular velocities (180 degrees/sec and 240 degrees/sec) and the flexor muscle groups at the three speeds revealed no differences between I and U. X-rays showed minimal changes. These data show that patients with hemophilia A and history of unilateral hemarthrosis of the knee have neuromuscular dysfunction in the I extremity that precedes the appearance of radiologic evidence of joint pathology. It is suggested that strength training should be started early in the rehabilitation of hemophiliacs.

Subclavian artery revascularization for myocardial ischemia.

A 54-year-old woman had a secondary occlusion of the subclavian artery proximal to the internal mammary artery, which had been used for an anterior interventricular artery bypass, and was the source of recurrent angina. A left carotid-to-subclavian bypass was performed with success. This rare complication underscores the need for careful selection and surveillance of candidates for myocardial revascularization using the internal mammary artery.