The digital thermal hyperemia pattern is associated with the onset of digital ulcerations in systemic sclerosis during 3 years of follow-up.

OBJECTIVES: One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers. METHODS: We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years. RESULTS: No patient with a LTH peak/plateau ratio ≥1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed. CONCLUSIONS: A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort.

Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis.

OBJECTIVES: Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynaud's phenomenon (PRP) and healthy controls. METHODS: Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand. RESULTS: Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction). CONCLUSIONS: We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynaud's phenomenon secondary to SSc.

Cryptosporidiosis and microsporidiosis as causes of diarrhea in kidney and/or pancreas transplant recipients.

INTRODUCTION: Gastrointestinal disorders in solid organ recipients may have various origins including cryptosporidiosis and microsporidiosis. The prevalence of these infections is poorly known in solid organ transplant (SOT) patients in industrialized countries. METHODS: We prospectively assessed the infectious causes of diarrhea in SOT patients. Secondary objectives were to gain further insight into the main characteristics of cryptosporidiosis, and to assess risk factors for this infection. All adult kidney and/or pancreas recipients presenting with diarrhea and admitted to our facility between May 1, 2014 and June 30, 2015 were enrolled. A stool sample was analyzed using a standardized protocol including bacteriological, virological, and parasitological investigations. Data related to clinical symptoms, immunosuppression, and environmental potential risk factors were collected through a self-administered questionnaire and computerized medical records. RESULTS: Out of 73 enrolled patients, 36 had infectious diarrhea (49.3%). Viruses ranked first (17/36), followed by parasites and fungi (11/17). Cryptosporidiosis was the most common parasitic disease (n=6 patients). We observed four microsporidiosis cases. The estimated prevalence of cryptosporidiosis and microsporidiosis in this cohort was 3.7 and 2.40/00, respectively. No significant risk factor for cryptosporidiosis or microsporidiosis, neither environmental nor immunological, could be evidenced. CONCLUSION: Both cryptosporidiosis and microsporidiosis represent a significant cause of diarrhea in kidney transplant recipients.

[Sub acute ischemia of a lower limb in a patient with juvenile peripheral arterial disease and arterial cocaine toxicity]. / Ischémie subaiguë d'un membre inférieur et toxicité artérielle périphérique de la cocaïne chez une patiente présentant une artériopathie juvénile.

A 35-year-old woman was hospitalized for subacute ischemia of the left leg following an intermittent claudication for some weeks. She also presented paleness and coldness of both hands. The radial pulses could not be palpated. Smoking was the only cardiovascular risk factor. Duplex ultrasonography and angiography revealed a left popliteal thrombus combined with low diameter leg arteries and in the upper limbs stenosis of the left radial artery and thrombosis of the right radial artery. Search for a metabolic, embolic or thrombophilic etiology was negative. More minute history taking revealed use of cannabis and recent nasal administration of cocaine. Her condition improved with heparin therapy except for the upper limbs with ischemia of the hands and disabling Raynaud's phenomenon. This report highlights the combined arterial toxicity of drugs often used together by drug addicts. The association of cannabis use and tobacco smoking is not rare in patients with Buerger-like juvenile arteriopathy and cocaine may provoke peripheral vascular disease by embolism or in situ thrombosis. Interrogation of a patient presenting with Buerger-like peripheral arterial disease should insist on detecting use of drugs in association with tobacco smoking.

Site and clinical outcome of deep vein thrombosis of the lower limbs: an epidemiological study.

Clinical outcomes of patients diagnosed with venous thromboembolic disease (VTED) have rarely been assessed on large series of patients from single institutions. This was work based on our practice to routinely screen all suspected pulmonary embolism (PE) and deep venous thrombosis (DVT) patients with bilateral proximal and distal venous US was designed to evaluate survival, recurrence and cancer occurrence in patients diagnosed with symptomatic or asymptomatic DVT and to assess their relationship with the site of the DVT (proximal vs. distal, bilateral vs. unilateral). Our study is based on the cross-matching of the VTED register of the Grenoble University Hospital with the local Cancer Register and community mortality data. Survival analyses were performed with the Kaplan-Meier method; prognostic variables were tested using the log-rank test. A total of 1913 patients with a DVT of the lower limbs from 1993 to 1998 were included (57% women; mean age, 69 years). Of these, 1018 patients were diagnosed with proximal DVT (156 bilateral) and 895 distal DVT (112 bilateral). PE was associated in 760 patients. Patients with PE and no detected DVT were not included. At 2 years, adjusted survival rates were 80% in patients with unilateral-distal DVT, 67% in bilateral-distal, 72% in unilateral-proximal and 65% in bilateral-proximal DVT patients. The cumulated VTED recurrence rates were 7.7% in unilateral-distal DVT, 13.3% when DVT was bilateral-distal, 14% when unilateral-proximal and 13.2% when bilateral-proximal. The rate of new cancer was 6.4% in unilateral-distal DVT, 10.8% when it was bilateral-distal, 6.5% when unilateral-proximal and 6.1% when bilateral-proximal. Based on a large series of unselected patients, our results show that the site of the DVT and principally the bilaterality provides important prognostic information that may be used in the setting up of medical strategies.

["Isolated" thrombi of the aorta: retrospective study of 10 observations]. / Thromboses aortiques "isolées": analyse rétrospective de 10 observations.

INTRODUCTION: Thrombi of the aorta are mostly linked to atheromatous plaques on the aortic wall of patients with classical risk factors for cardiovascular disease. The thrombus rarely appears on sound arteries and in this case is called "isolated". METHODS: We present a retrospective study of ten patients with "isolated" thrombi of the aorta treated between 1995 and 2004 at the Hospital of Grenoble. The following parameters were considered in this analysis: age of the patient when the thrombosis appeared, gender, cardiovascular risk factors, revealing mode of the thrombus, its anatomic location, biological and morphological exploration results and the treatment performed. Patients with atheromatous plaques on the aortic wall were excluded. RESULTS: In eight out of ten cases the clinical presentation of the aortic thrombus is an acute ischemia of a limb. In all of the cases the diagnosis was confirmed by an injected thoraco-abdominal scan apart from one case where the primary diagnosis was made using an arterial echo-Doppler. The search for the thrombophilia can be considered to have been exhaustive in seven cases. For the search of an anti-phospholipid antibody syndrome this has been achieved in eight cases. Two etiologic diagnoses could be placed. The first one revealed during the aortic thrombosis a neoplasia of adenocarcinomic type without any primary identified. The second case was an essential thrombocythemia diagnosed one year after the thrombosis. The eight other cases remained "isolated" after an average 2.5 years follow-up. DISCUSSION: Less than one hundred cases of aortic thromboses could be identified in the literature. The cases developing on a sound artery are difficult to quantify and the word "isolated" thrombus may be sometimes used by default. The hypothesis of an isolated focal atheromatous plaque or of inflammatory pathologies inducing a thrombus can be an example. The biological and morphological explorations have to be exhaustive even if in most of the cases they are not sufficient for the diagnosis. Therapy calls for anti-coagulation but is not standardized. The clinical follow-up appears to be essential since pathological conditions can possibly develop after the event of the thrombosis. It also enables refinement of the actions to be taken especially regarding long-term use of anticoagulants.

[Sneddon syndrome with anti-mitochondrial type M5 antibodies]. / Syndrome de Sneddon avec anticorps anti-mitochondries de type M5.

INTRODUCTION: Antimitochondrial type M5 antibodies (AMA-M5) are among the immunological abnormalities associated with Sneddon syndrome. CASE: A 45 year-old woman, hospitalized for diplopia and with a 20-year history of obstetrical accidents, internuclear ophthalmoplegia and livedo, was diagnosed with Sneddon syndrome associated with primary antiphospholipid syndrome (APS) aggravated by the presence of AMA-M5. DISCUSSION: AMA-M5 are immunological markers of APS to the same extent as antiphospholipid antibodies. This case demonstrates the interest of screening for AMA-M5 in cases of strong clinical suspicion of APS when the anticoagulant lupus test is normal and no anti-cardiolipin, anti-b2 glycoprotein I or antiprothrombin antibodies are found.

[Thrombosis of legs arteries: imputability of anti-phosphatidylethanolamine antibodies?]. / Thromboses artérielles des membres inférieurs: responsabilité des anticorps antiphosphatidyléthanolamine?

BACKGROUND: At the beginning the antiphospholipid antibodies syndrome was associated with systemic lupus erythematosus. But since 1988 it has become a sole entity. Its current definition is based on the criteria established in 1999 by Sapporo and consists of associating the clinical criteria of thrombosis of arteries or peripheral veins and of miscarriage of pregnancy with the biological criteria. Either anti-cardiolipin antibodies or lupus anticoagulant must be present. Anti-phosphatidylethanolamine antibodies are not included in the Sapporo criteria. CASE REPORT: A non smoking, 43 year-old man showed a clinical manifestation of livedo on the thighs, and left knee and foot, associated with a rapidly extending cutaneous necrosis on the left toes. One year earlier his right leg was amputated up to half of the calf following distal gangrene. The gangrene was consecutive to a stent implantation after a significant stenosis of the right superficial femoral artery. The etiological investigations revealed neither thrombophily nor cholesterol embolism nor vasculitis. No sign of underlying neoplasia could be found. These clinical symptoms as well as the anamnesis were strongly suggestive of an antiphospholipid antibodies syndrome. The immunological dosages revealed isolated positive anti-phosphatidylethanolamine antibodies, persistent six weeks later. DISCUSSION: Several cases of clinical manifestations of the antiphospholipid antibodies syndrome have been described, without any anti-cardiolipin antibodies or lupus anticoagulant, but with presence of anti-phosphatidylethanolamine antibodies. In cases of these strong evocative symptoms but no evidence of the classical biological Sapporo criteria, these antibodies should be systematically searched for.

Interaction of anti-HLA antibodies with pig xenoantigens.

BACKGROUND: Many patients with renal failure are condemned to long-term dialysis with little prospect of transplantation because they are highly sensitized with immunoglobulin G (IgG) directed against class I human leukocyte antigens (HLA) of virtually all donors. Xenotransplantation could represent an attractive solution providing their alloantibodies (alloAb) do not recognize porcine motifs. Hitherto there has been no in vivo demonstration of any cross-reactivity and the objective of this work was to investigate this problem using a technique of extracorporeal pig kidney perfusion as a model of clinical xenografting. METHODS: Pig kidneys were perfused ex vivo with plasma from both a group of highly sensitized patients and healthy individuals. Sequential plasma samples were analyzed for the titer of anti-Galalpha1-3Gal antibody (Ab) (major natural xenoreactive Ab) by enzyme-linked immunosorbent assay and anti-HLA class I Ab against a cell panel. At the end of perfusion, kidneys were perfused with a citric acid buffer to elute bound Ab. RESULTS: Galalpha1-3Gal Ab were shown to decrease rapidly in the plasma (in less than 10 min) and then reached a plateau. A fractional decrease in anti-HLA Ab was also found in some of the perfused plasma samples. Anti-Gal Ab were readily detected in all citric acid perfusates and anti-HLA Ab in 8 of 10. The HLA specificities of eluted Ab were mainly concordant with the originally designated specificities for each patient. CONCLUSION: Anti-HLA class I Ab presumably cross-react with pig class I homologues. However, some plasma samples did not cross-react, suggesting that negatively cross-matched pig kidneys could be identified in the pig population for xenotransplantation in these patients. Further studies are required to precisely describe these cross-reactivities and to understand their functional significance in xenotransplantation.

A polymorphism in the major immediate-early gene delineates groups among cytomegalovirus clinical isolates.

Major immediate-early gene exon 4 sequences were determined at codons 161-241 and 254-397 in 25 cytomegalovirus clinical strains and compared with those of reference strains AD169 and Towne. The nucleotide sequences at codon 161-241 segregated into three groups which could be determined by restriction mapping of a 247-nucleotide amplified target. AD169 and Towne belonged to the same group. Clustered variations and group-specific amino-acid motifs found in the deduced peptide sequence of the two immediate-early (IE) exon 4 regions raised a question is to the effects of polymorphism on IE1 function and/or immunogenicity. On the basis of restriction analysis of polymerase chain reaction (PCR) products, virus isolates were also classified into four glycoprotein B (gB) genotypes. Strain distribution in IE1 and gB genotypes showed a lack of concordance of the two grouping methods, and no preferential association was observed between the clinical context or kind of specimen and IE1 or gB groups. These data lead up to further prospective studies which could provide important information on the implication of the MIE gene region in virus pathogenesis and indicate whether linkage unbalance exists in particular clinical contexts between IE1 and gB loci.

Detection of human papillomavirus in squamous intraepithelial lesions by consensus and type-specific polymerase chain reaction.

Polymerase chain reaction (PCR) was used to identify human papillomavirus (HPV) in 216 cervical biopsy specimens from women referred to the gynecological out-patient unit for colposcopy because of an abnormal smear. HPV DNA was screened using type-specific primers for HPV6, 11, 16, 18, 31 and 33 (TS-PCR) as well as a consensus primer located in the E1 region of the HPV genome (C-PCR). TS-PCR specificity was validated by Southern blot analysis. Low-grade (SIL 1) and high-grade (SIL 2) squamous intraepithelial lesions were found in 165 biopsies. HPV16 detection was better with PCR than Southern blot, particularly for SIL 1 and SIL 2. The fact that 10% of HPV16 (all SIL 2) were not detected by C-PCR indicates that both PCR techniques should be performed. C-PCR also detects uncharacterized HPV types (8.6% prevalence in our results), mainly in SIL 1 and SIL 2. HPV16, the most frequently isolated type (prevalence 21%), was associated with SIL 2 in 83% of cases. A low HPV prevalence was found in specimens without dysplastic cells. These results suggest that PCR may be an important tool for identifying women at risk for developing dysplasia or cervical cancer.

[Morphometric analysis of erythrocyte aggregates in vitro: pharmacological application with buflomedil]. / Analyse morphométrique des agrégats érythrocytaires in vitro. Application pharmacologique au Buflomedil.

Erythrocyte aggregation is usually evaluated through indirect measurements such as the sedimentation rate and rheometric measurements of aggregation and disaggregation thresholds. The aim of this study was a preliminary evaluation of a morphometric approach of aggregates in vitro. A sample of blood (on EDTA) was examined under the microscope, and a picture with magnification X 640 was obtained after stabilization of the cellular structure. The digital image was analyzed with a home made dedicated software that allows the measurement of the cellular density and the evaluation of several shape parameters. Ten samples obtained from different donors were analysed within one hour after blood withdrawal and 24 hours later (preservation temperature: 4 degrees C), with and without adjunction of Buflomedil (4 microg/ml). Results showed an important anti-aggregant effect of Buflomedil administrated in these conditions, both on fresh and preserved blood (p<10(-3)). These results illustrate the potential interest of a morphometric approach to erythrocyte aggregation. They show new pharmacological properties of Buflomedil administered in vitro, which have to be confirmed with a therapeutic administration of the compound.

[Adverse effects and medication errors: incidence and role of the organization of drug distribution]. / Effets indésirables et erreurs de médication: incidence et rôle de l'organisation du circuit du médicament.

The true incidence of adverse drug events is controversial and there are few data concerning the percentage of potentially preventable adverse drug events. Over 2 months, in two internal medicine units, we asked the staff to report adverse drug events. All incidents were evaluated: adverse drug events (preventable and non-preventable) and potential adverse drug events (non-intercepted potential adverse drug events and intercepted potential adverse drug events). The severity, the stage in the process at which the error occurred and the type of error were evaluated by a physician reviewer. Over the 240 admissions, the incidence of adverse drug events is 18 per 1000 patient-days. The system design caused 77 per cent of the incidents. The medication errors occurred at all stages from ordering to administration. Adverse drug events resulting in medication errors (n = 22) were more serious than non-preventable adverse drug events (n = 26) (p = 0.003). A prevention strategy by pharmacovigilance centres (Centres Régionaux de Pharmacovigilance) should target all stages of the drug delivery process.

[Neuropsychic side-effects of therapeutic doses of zipeprol]]. / Effets neuropsychiques indésirables du zipéprol à dose thérapeutique.

We report the two first cases of neuropsychic side-effects with zipeprol (non opiate antitussive) given at therapeutic doses. In both cases, the patients showed confusion, whereas, hallucinations occurred only in one case. The anticholinergic activity of zipeprol might explain these effects. These two cases are in agreement with zipeprol central nervous system action.

[Secretan's syndrome: myth or pathomimia?]. / Le syndrome de Secrétan : mythe ou pathomimie ?

UNLABELLED: Secretan's syndrome is a rare condition involving generally trauma-induced hard edema of the dorsal aspect of the hand. The cause is poorly understood but factitious trauma is often suspected. CASE REPORT: A 42-year-old woman presented with a fortuitous edema on the back of the right hand. The minimally depressible edema was associated with moderately intense mechanical pain. Routine laboratory tests were normal. An extensive imaging work-up (bone x-ray of the hand and wrist, bone scintigraphy, computed tomography phlebography, lymphoscintigraphy, magnetic resonance imaging) was equally non-contributive. The diagnosis of self-inflected trauma was suggested by the atypical nature of the edema, the absence of any organic disorder on the tests performed, and the patient's attitude concerning her disease. In this clinical context, the diagnosis of Secretan's syndrome was retained. Outcome was compatible, with secondary development of complex regional pain syndrome. DISCUSSION: Three forms of Secretan's syndrome have been recently described: benign; hyperplastic; and mixed. The cause remains poorly defined. Certain authors report that it is most likely related to pathomimia. Treatment can combine physiotherapy and psychological counseling. CONCLUSION: Secretan's syndrome is a poorly-understood and rarely-described condition that may be underdiagnosed. Physicians specialized in vascular medicine should be aware of this syndrome and its difficult diagnosis by elimination.

[Recurrent deep vein thrombosis and myeloproliferative syndrom: emergence of JAK2 mutation five years after the initial event]. / Thromboses veineuses à répétition et syndrome myéloprolifératif : positivité secondaire d'une mutation JAK2 cinq ans après l'événement initial.

JAK 2 mutation is the molecular event responsible for 95% of polycythemia cases and 50% of thrombocythemia vera and myelofibrosis cases. It can be used as a tool for the diagnosis of myeloproliferative disorders. We report a case illustrating the fact that a negative result does not definitively eliminate the diagnosis. A 40-year old woman, with a medical history of familial deep vein thrombosis, developed thrombosis of the inferior vena cava with extension to the suprahepatic veins and pulmonary embolism. No constitutional or acquired thrombophilia was diagnosed; search for JAK 2 mutation was negative. The patient was treated with fluindione. Five years later, she relapsed with popliteo-femoral and vena cava deep vein thrombosis. The etiological work-up included a PET scan which revealed diffuse uptake in bones and suspected neoplasic bone marrow invasion. Progenitor cell cultures were positive and JAK 2 mutation was confirmed. The bone marrow aspirate had the cytologic appearance of a myeloproliferative disorder. This case illustrates the fact that JAK 2 mutation can be identified several years after onset of a latent myeloproliferative disorder. Cases with a high clinical likelihood should lead to renewed search for this mutation. Secondary discovery of this mutation can be explained by a higher proportion of mutation expressing clones.

Cutaneous iontophoresis of treprostinil in systemic sclerosis: a proof-of-concept study.

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose-limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo-controlled, double-blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc-related DUs.

[Temporary vena caval filters: report on cohort of 72 patients in Grenoble, France]. / Filtres cave temporaires: suivi d'une cohorte de 72 patients au CHU de Grenoble.

Patients with a contra-indication for anticoagulation can benefit from temporary vena caval filters for protection against pulmonary embolism or recurrence. The filter can be removed secondarily, once the contra-indication is overcome, enabling better long-term outcome by reducing the risk of thrombotic and mechanic complications inherent in these devices. However, it has been shown in several studies that effective withdrawal rates were low and could be improved by the establishment of protocols and registries. We report a retrospective study of withdrawal in 72 patients in whom an ALN® vena caval filter was implanted at the Grenoble University Hospital over a period of three years with an intention for secondary retrieval. Seventy percent of the indications were related to the coexistence of thrombotic and hemorrhagic conditions. Fifty-five percent of filters were removed, the remaining 45% shared involved patients who died before retrieval (11%), those lost to follow-up (4%), technical failure of retrieval (6%), withdrawal technically unfeasible (3%), retrieval refused by patients (6%) and medical indications for continuing filtration (15%). Despite an effective follow-up of these patients and 91% success rate of withdrawal, nearly one out of two filters remains in place. A long-term follow-up of these patients is needed to learn more about the outcome of these filters.