A Dominant STIM1 Mutation Causes Stormorken Syndrome

Stormorken syndrome is a rare autosomal‐dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca²⁺ depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca²⁺ release‐activated Ca²⁺ channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled‐coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain‐of‐function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca²⁺ levels were elevated in platelets from the patients compared with controls, and store‐operated Ca²⁺ entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near‐maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.     

A prospective study of same day bi-directional endoscopy in the evaluation of patients with occult gastrointestinal bleeding

Objective. Previous studies show conflicting results in the diagnostic yield of oesophagogastroduodenoscopy (OGD) and colonoscopy (bi-directional) in identifying potential bleeding sources (PBS) in patients investigated for occult gastrointestinal bleeding (OGIB). The aims of this study were to evaluate the diagnostic yield of bi-directional endoscopy in patients presenting with OGIB and to assess the factors predictive of a positive yield. Material and methods. Patients with OGIB referred to the gastroenterology unit were prospectively included in the study. Colonoscopy was immediately followed by OGD. Predetermined criteria for the diagnosis of a PBS were used. Potential clinical factors predictive of positive yield were assessed. Results. Of the 219 patients (mean age 65 years, 34% M), 110 (50%) had at least one PBS. Colonoscopy revealed 87 PBS in 73 patients (33%), the most common being adenoma. OGD detected 49 PBS in 48 patients (22%), gastric ulcer being the most common. Of the patients with PBS at OGD, 23% also had a PBS at colonoscopy, including 3 patients with colonic cancers. Patients presenting with either a positive faecal occult blood test (FOBT) or iron-deficiency anaemia (IDA) only had a significantly lower yield for PBS than patients with combined positive FOBT and IDA. The percentages of patients with a PBS increased substantially with age. Conclusions. A PBS was found in only 50% of the patients. Colonoscopy had a slightly higher diagnostic yield, and as expected, resulted in a significantly higher cancer detection rate than OGD. In older patients, colonoscopy should be done irrespective of the findings at OGD. Gastrointestinal-specific symptoms and the use of ASA/NSAIDs were not predictive in finding or localizing PBS.     

Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

相似文献   

Change of diagnosis during the first five years after onset of inflammatory bowel disease: results of a prospective follow-up study (the IBSEN Study)

OBJECTIVE: An exact diagnosis of inflammatory bowel disease (IBD) and further subclassification may be difficult even after clinical, radiological and histological examinations. A correct subclassification is important for the success of both medical and surgical therapeutic strategies, but there is a dearth of information available on the frequency of changes in diagnosis in population-based studies. The objective of this work was prospectively to re-evaluate the diagnosis in an unselected cohort of IBD patients during the first five years after the initial diagnosis. MATERIAL AND METHODS: Patients classified as IBD or possible IBD in the period 1990-94 (the IBSEN cohort) had their diagnosis re-evaluated after 1 and 5 years. Initially, the patients were classified as ulcerative colitis (UC), Crohn's disease (CD), indeterminate colitis (IC) or possible IBD. At the 5-year visit, patients were classified as UC, CD or non-IBD. RESULTS: A total of 843 patients (518 UC, 221 CD, 40 IC and 64 possible IBD) were identified. Clinical information was available for 94% of the patients who survived after 5 years. A change in diagnosis was found in 9% of the patients initially classified as UC or CD. A change to non-IBD was more frequent than a change between UC and CD. A large proportion of patients initially classified as IC or possible IBD were diagnosed as non-IBD after 5 years (22.5% versus 50%). When IBD was confirmed in these groups, UC was more frequent than CD. Two changes in diagnosis during follow-up were observed in 2.8% of the patients; this was more frequent in patients initially classified as IC or possible IBD. CONCLUSIONS: There are obvious diagnostic problems in a minority of patients with IBD; a systematic follow-up is therefore important in these patients.     

Use of a synthetic bone void filler to augment screws in osteopenic ankle fracture fixation

Introduction Sufficiently stable constructs may be difficult to obtain with ankle fractures in patients with severe osteopenic bone. Augmentation of the osteosynthesis with a new synthetic bone void filler may help to solve this problem, and it can improve the clinical outcome.Materials and methods A prospective, open-label study was performed in two surgical clinics in Norway. In 37 of 42 selected patients with Weber type B ankle fractures showing clinical and radiologic signs of osteopenic bone, at least one screw was found to be stripping during open reduction and internal fixation (ORIF). All the stripped screws were augmented with the bone void filler, and tightness was assessed clinically afterwards. All patients were followed up for 2 years. Successful healing of the fracture after 3 months and absence of radiographic movement of the augmented screws were assessed relative to the plate and the bone. Safety was assessed by recording adverse events and abnormal haematology findings.Results All 86 augmented screws were clinically tight after augmentation. After 3 months, all fractures healed, and 1 augmented and 1 non-augmented screw appeared to be radiographically loose. After 2 and 6 months, respectively, deep wound infections occurred in 2 patients (5%), necessitating antibiotic treatment, revision surgery and implant removal. After 2 years, all patients had resumed their normal daily activities, and none of the augmented screws showed signs of loosening.Conclusions Augmentation of bone screws with this new synthetic bone void filler was an effective means of gaining screw anchorage. Screw stabilisation with the new synthetic bone void filler proved to be safe and effective in the ORIF of ankle fractures in patients with osteopenic bone.     

Sliding of the compression hip screw in femoral neck fractures

Backing out of the compression screw in the sliding screw-plate hip osteosynthesis was analyzed in a series of 71 hips with medial femoral neck fractures during an observation period of 12-42 months, with a median of 26 months. In addition to the compression screw device, a parallel cranial lag screw was used. A postoperative primary diastasis in the fracture space of 1-5 mm in 11 cases did not predispose to major sliding of the screws or to healing problems. Thirteen of 27 fractures with late screw telescoping of 4 mm or more showed healing disturbances, 11 late segmental collapses, and 2 nonunions, compared with 7 disturbances, 6 late segmental collapses, and 1 nonunion among 39 cases with screw gliding of 3 mm or less. The difference was significant (p less than 0.05, Mann-Whitney). Five early mechanical failures were excluded from this analysis.     

Knee function following suture of fresh tear of the anterior cruciate ligament

A retrospective consecutive series of 60 patients treated with primary suture of knee ligament injuries is presented. All patients had an anterior ligament (ACL) tear. In 54 patients this injury was combined with a medial compartment tear. Four patients had isolated tears of the ACL. At follow-up after 4 years, 11 patients complained of instability, and in eight of these an anterolateral rotatory instability was demonstrated by the Slocum test. In contrast, only five of 49 patients with subjectively stable knees had positive Slocum tests. Thirty of 47 patients with negative Slocum tests had excellent function, compared with four of 13 patients with positive tests.