Open reduction internal fixation after displacement of a previously nondisplaced acromial fracture in a multiply injured patient: case report and review of literature.

SUMMARY: A twenty-eight-year-old multiple trauma patient had a nondisplaced acromion fracture that was not detected until after it had displaced. Open reduction internal fixation was performed without complication and the patient achieved excellent shoulder abduction strength. Nondisplaced acromion fractures may displace if not protected. Open reduction internal fixation of displaced acromion fractures should be considered if deltoid muscle strength is important to the patient.     

Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) can cause severe organ damage due to enhanced platelet aggregation by ultra-large von Willebrand factor (VWF) multimers. Thus inhibition of VWF by the anti-VWF ARC1779 might potentially be beneficial for TTP patients. This prospective trial tested the safety, pharmacokinetics and pharmacodynamics of the anti-VWF aptamer ARC1779 added to plasma exchange therapy (PEX) in patients with acute TTP. Seven patients received bolus primed continuous i.v. infusions of ARC1779 (1-2 μg/kg/min) in addition to PEX until remission of TTP was induced or for 14 days. Mean steady state ARC1779 plasma concentrations of 9.9 μg/ml reduced VWF activity to 5% (mean baseline activity was 125% in TTP patients compared to a reference plasma). PEX reduced ARC1779 levels by 50%, but steady state concentrations were restored rapidly with a mini-bolus. After discontinuation of PEX, ARC1779 alone further increased platelet counts in one patient. Stopping ARC1779 was associated with an immediate drop of platelet counts in this patient. This suggests that ARC1779 can block the progression of TTP in patients with severe ADAMTS13 is deficiency. ARC1779 was generally well tolerated without any signs of bleeding. Pharmacokinetics and pharmacodynamics of ARC1779 were well predictable and in agreement with those observed in a previous trial with healthy volunteers. Based on its mechanism of action and the observed effect on platelet counts, ARC1779 used as an adjunctive to PEX may help accelerate recovery from organ dysfunction.     

Routine removal of external fixators without anesthesia

OBJECTIVE: To examine the degree of discomfort experienced by patients with routine removal of all external fixators without anesthesia. DESIGN: Retrospective review. SETTING: Outpatient clinic and hospital. PATIENTS: A total of 106 consecutive patients for whom removal of external fixators was indicated. INTERVENTION: External fixators were removed without anesthesia. MAIN OUTCOME MEASUREMENTS: Visual Analog Pain Scale (VAS) following external fixator removal and patients' reported willingness to repeat the procedure without anesthesia. RESULTS: Patients with pin site inflammation had a significantly higher VAS (4.82 vs. 2.92, P < 0.0001). The chi test revealed that pin site inflammation was less common with wrist spanning fixators than with lower extremity and pelvic fixators. No correlation existed between age, site of fixator, closed head injury, use of olive wires, or the duration of fixation and VAS. In all, 95 of 106 patients (89.6%) responded yes when asked if they would undergo removal of their fixator again without anesthesia. Despite the association between inflamed pin sites and a higher VAS, in 84% (37/44) of the cases with inflamed pin sites, the patient would choose to undergo fixator removal without anesthesia again. CONCLUSIONS: Removal of external fixators without anesthesia is well tolerated by the great majority of patients. Inflammation at pin sites is associated with a higher degree of discomfort during external fixator removal. Despite the higher pain score, most patients with pin-site inflammation report that they would repeat the procedure without anesthesia.     

Electrical alternans and hemodynamics in the anesthetized guinea pig can discriminate the cardiac safety of antidepressants

INTRODUCTION: The arrhythmogenic risk of fluoxetine, citalopram, and venlafaxine were evaluated through preclinical assays measuring hERG, blood pressure and electrical alternans over their respective clinical unbound concentration ranges. METHODS: Anesthetized guinea pigs were instrumented with jugular and carotid cannulae for drug infusion and blood pressure monitoring respectively; a thoracotomy was performed for placement of a monophasic action potential probe on the left ventricle and for placement of pacing wires on the left ventricular apex. Drugs were infused as a 5-min loading dose immediately followed by a 10-min maintenance dose to achieve clinically relevant plasma concentrations; blood samples were taken at the end of each maintenance dose. Ventricular pacing was performed twice at baseline and at each dose level as follows: 50 preconditioning-beats at S1=220 (or 240) ms immediately followed by 30 test-beats at S2=200 ms. This S1-S2 protocol was repeated for S2=190 to 140 ms. HERG and calcium current measurements were recorded in HEK-293 cells stably expressing hERG potassium currents and freshly isolated guinea pig cardiac myocytes using the whole-cell configuration of the patch clamp technique. RESULTS: Physiologically relevant inhibition (IC(20)) of hERG occurred at concentrations 22-fold (fluoxetine), 9-fold (citalopram), and 11-fold (venlafaxine) beyond their respective clinically effective concentration (C(eff)). At the highest achievable levels, fluoxetine (20-fold C(eff)) and citalopram (28-fold C(eff)) significantly decreased heart rate and/or blood pressure as well as increasing electrical alternans by 5 and 18 ms respectively. Venlafaxine increased blood pressure at only 1.3-fold C(eff), but did not increase electrical alternans at the highest achievable dose (3.1-fold C(eff)). DISCUSSION: These data suggest that evaluating other dose limiting side effects in relation to a drug's therapeutic range may be crucial for accurate assessment of arrhythmia liability.     

Architecture of blood vessels in human fetal gastric corpus: a corrosion casting study.

Vascular architecture of the gastric corpus was investigated in 16-24 wk human fetuses using a corrosion casting technique and the scanning electron microscopy. The general distribution of blood vessels seen in adults has already been established in the fetus, with three major vascular plexuses located in the serosa, submucosa and mucosa. The serosal plexus, supplied and drained by large extramural vessels, contained anastomosing, arcade-like arrays of arteries and veins with their branches piercing the muscularis and communicating with the compact submucosal plexus. Vertical arterioles and capillaries were sent by submucosal arteries to supply a very dense capillary plexus which surrounded the gastric pits and consisted of wide, sinusoidal vessels showing morphological manifestations of angiogenesis by intussusceptive growth. The plexus was drained by vertical venules emptying into submucosal veins. In contrast to the richly vascularized upper half of the mucosa, the lower half showed a relative paucity of blood vessels, probably due to the thinness of the fetal mucosa allowing an effective diffusion of oxygen and nutrients from the upper half. Neither arteriovenous anastomoses, nor end-arteries were found in the fetal stomach. Results of this study support one of the two existing models of mucosal vascularization in the human stomach: i.e. the model postulating the presence of short and long arterioles and two distinct, albeit interconnected capillary networks in the upper and lower zones of the mucosa respectively. In human fetuses, the latter network is absent; it probably develops by remodelling of the preexisting vertical capillaries in the last phase of pregnancy, prior to the onset of gastric gland function.     

Ofatumumab Combined With Fludarabine and Cyclophosphamide (O-FC) Shows High Activity in Patients With Previously Untreated Chronic Lymphocytic Leukemia: Results From a Randomized,Multicenter, International,Two-Dose,Parallel-Group Phase II Trial

IntroductionChemoimmunotherapy regimens are the treatment standard for fit patients with chronic lymphocytic leukemia (CLL). Ofatumumab is a human monoclonal antibody that binds to a unique membrane-proximal epitope composed of both the large- and small-loop domains of CD20. Overall response rates (ORRs) of 47%-58% have been observed with single-agent ofatumumab in patients with fludarabine-refractory CLL. We evaluated the efficacy and tolerability of 2 doses of ofatumumab combined with fludarabine and cyclophosphamide (O-FC) in previously untreated patients with CLL in an international, randomized, parallel-group phase II trial.Patients and MethodsPatients with active CLL were randomized to ofatumumab 500 mg (group A) or 1000 mg (group B) day 1, with fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² days 2-4, course 1; days 1-3, courses 2-6; administered every 4 weeks for 6 courses. For both groups, first dose of ofatumumab was 300 mg. The primary endpoint was complete response (CR) rate (1996 NCI-WG criteria) assessed by an Independent Review Committee (IRC), measured from the start of treatment up to 3 months after the last course.ResultsThere were 61 patients enrolled and randomized on this study (Table 1). Seventy-one percent and 57% of patients in groups A (n = 31) and B (n = 30), respectively, completed all 6 courses of O-FC treatment. The CR rate by IRC evaluation was 32% (95% CI, 17%-51%) for group A and 50% (95% CI, 31%-69%) for group B; the ORR was 77% (95% CI, 59%-90%) and 73% (95% CI, 54%-88%), respectively (Table 1). The CR rate and ORR for patients who received all 6 courses of O-FC were 56% and 92%, respectively. Follow-up is ongoing for progression-free and overall survival. No grade 3-4 infusion-related reactions on the day of ofatumumab infusion were reported. During treatment and up to 30 days following the last dose, the most common (> 10% of patients) grade 3-4 adverse events (AEs) reported by investigators were infections in 11 patients (group A, n = 4; group B, n = 7), including febrile neutropenia in 3 patients in each group, and hematologic AEs, including neutropenia in 29 patients (group A, n = 11; group B, n = 18), anemia in 8 patients (group A, n = 2; group B, n = 6), and thrombocytopenia in 9 patients (group A, n = 2; group B, n = 7). Grade 3-4 hemolytic anemia occurred in 2 patients in group A and 1 in group B. In group A, a patient died 50 days from last dose during follow-up (febrile neutropenia). In group B, a patient died 19 days from last dose during treatment (dyspnea; etiology unknown), and another patient died 186 days from last dose (neutropenia following alternative treatment for progressive CLL).ConclusionsThe O-FC regimen is active in previously untreated patients with CLL at the ofatumumab doses investigated. AEs with the O-FC regimen were manageable with no unexpected toxicities. The 1000 mg dose of ofatumumab is currently being evaluated in combination with chemotherapy in other studies for patients with CLL. Abstract 8 - Table 1. Patient Characteristics and Response