The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Over-the-counter-drugs for the treatment of mood and anxiety disorders--the views of German pharmacists.

INTRODUCTION: Depression, anxiety, agitation and sleep disorders are highly prevalent in the general population, but few persons receive psychiatric care. METHODS: Our aim was to study the views of 690 German pharmacists on "over-the counter" (OTC) drugs for these indications. RESULTS: They reported dispensing OTC medication to an average of 12 customers per day, and this corresponded to almost one quarter of the medications provided for these indications. Herbal drugs and complex homeopathic formulations were used most frequently. Patients preferring OTC substances were described as being younger, with shorter durations of illness and less severe symptoms, and more skeptical regarding psychopharmacology. While genuine pharmacological effects were considered as most relevant, pharmacists were highly aware of placebo and interpersonal factors. Symptoms, comorbidity and advice on drug intake were prominent topics during pharmacy consultations. CONCLUSION: German pharmacists report dispensing large amounts of OTC drugs for anxiety, agitation, sleep disturbances or depression. It is unclear whether this constitutes a rational and cost effective method to deal with mild courses of high prevalence diseases or must be seen critically.

Phase stability and elastic properties of Cr-V alloys.

V is the only element in the periodic table that forms a complete solid solution with Cr and thus is particularly important in alloying strategy to ductilize Cr. This study combines first-principles density functional theory calculations and experiments to investigate the phase stability and elastic properties of Cr-V binary alloys. The cluster expansion study reveals the formation of various ordered compounds at low temperatures that were not previously known. These compounds become unstable due to the configurational entropy of bcc solid solution as the temperature is increased. The elastic constants of ordered and disordered compounds are calculated at both T = 0 K and finite temperatures. The overall trends in elastic properties are in agreement with measurements using the resonant ultrasound spectroscopy method. The calculations predict that addition of V to Cr decreases both the bulk modulus and the shear modulus, and enhances the Poisson's ratio, in agreement with experiments. Decrease in the bulk modulus is correlated to decrease in the valence electron density and increase in the lattice constant. An enhanced Poisson's ratio for bcc Cr-V alloys (compared to pure Cr) is associated with an increased density of states at the Fermi level. Furthermore, the difference charge density in the bonding region in the (110) slip plane is highest for pure Cr and decreases gradually as V is added. The present calculation also predicts a negative Cauchy pressure for pure Cr, and it becomes positive upon alloying with V. The intrinsic ductilizing effect from V may contribute, at least partially, to the experimentally observed ductilizing phenomenon in the literature.

Graft patency and clinical outcome of femorodistal arterial reconstruction in diabetic and non-diabetic patients: results of a multicentre comparative analysis.

OBJECTIVE: in diabetic patients with critical limb ischaemia (CLI) an inferior success rate following infrainguinal bypass surgery is quite often suggested. The aim of this retrospective analysis was, therefore, to evaluate the graft patency and, particularly, the clinical outcome at 1 year in diabetic compared with non-diabetic patients. MATERIAL AND METHODS: two hundred and eleven patients (diabetics 94; non-diabetics 117) with femorodistal reconstruction for CLI were studied. Groups were comparable with regard to the Fontaine classification, the distribution of vascular risk factors, graft material, distal anastomosis site, and the angiographic runoff grading. RESULTS: diabetes did not adversely affect graft function. For diabetics and non-diabetics primary cumulative patency rate at 1 year was found to be 66 and 56%, respectively (p=0.10) and a virtually identical limb salvage rate of 85 and 83% was achieved (p=0.76). With regard to healing of ischaemic foot ulcers a trend against diabetics was noted with a healing rate of 81% compared to 96% in non-diabetics at 1 year (p=0.067); gangrenous foot lesions could be equally remedied in 94% and in 87% among patients with and without diabetes (p=0.44). The survival rate of diabetics, however, was significantly lower with 78% at 1 year compared with 95% in non-diabetic patients (p=0.0004). CONCLUSIONS: our preliminary results support the view that infrainguinal bypass grafting can be safely done even in diabetics. Despite increased mortality in this group, liberal indication for reconstructive vascular surgery seems to be justified by favourable patency rates and clinical outcome in selected patients.

[Natural history and indications for surgery in carotid stenosis]. / Spontanverlauf und Operationsindikation bei Carotis-Stenosen.

Atherosclerotic stenoses of the internal carotid artery are often the underlying cause for ischemic stroke. Several studies show a strong correlation between the grade of stenosis and stroke risk. When cerebral symptoms occur in patients with a carotid artery stenosis of 60% or more the risk of stroke within the following 12 months is over 10%. Large randomised studies show that patients with a high grade carotid artery stenosis benefit clearly from carotid endarterectomy. Surgical treatment reduces stroke risk by more than 70% in these patients. Symptomatic patients with stenoses less than 40% do not benefit by endarterectomy even when surgical complication rate is low. The benefit of carotid endarterectomy is proven for asymptomatic stenoses, too. In asymptomatic patients, however, an operative procedure is justified only when surgical complication rate is 3% or less.

Extraanatomic bypass in the treatment of prosthetic vascular graft infection manifesting in the groin.

BACKGROUND: Infection of an alloplastic vascular graft is a serious complication and often involves the groin. We propose a therapeutic concept using extraanatomic bypass to avoid the septic groin in case of an infected alloplastic vascular reconstruction. PATIENTS AND METHODS: The course of 25 patients (18 men, 7 women, mean age 61 years) with a grade III inguinal infection following placement of an aortic or femoro-distal synthetic graft made of Dacron or PTFE was analysed. The treatment consisted of excision of the infected graft material and extraanatomic reconstruction with ringed PTFE grafts in all patients. Mean follow-up after the extraanatomic procedure was 21 months (1-91 months). RESULTS: Direct surgical exploration definitely secured graft infection in almost three-quarters of the cases. The most common organism isolated was Staphylococcus aureus (13/22 = 59%). At the time of infection 60% of the patients had critical limb ischemia necessitating vascular reconstruction simultaneously with total or partial excision of the infected graft. Complications of the extraanatomic bypass occurred in 7 cases (overall morbidity 28%). Postoperatively, one patient required major amputation. Hospital mortality was 8%. Primary patency and secondary patency rates of extraanatomic grafts amounted to 78.0% (+/- 10.0 SD) and 84.1% (+/- 8.7 SD) respectively after two years. Limb salvage rated 78.4% (+/- 11.6 SD) after 2 years, the 2-year-survival rate was 73.8% (+/- 9.3 SD). CONCLUSIONS: According to the favourable long-term limb salvage and survival rates, we support simultaneous vascular reconstruction by extraanatomic bypass and explanation of the infected graft material in case of grade III inguinal infection of alloplastic vascular reconstructions.

[Hyperglycemia and ketoacidosis associated with olanzapine]. / Hyperglykämie und Ketoazidose unter Olanzapin.

Two psychotic patients developed hyperglycaemia several weeks after starting olanzapine. In one case the elevated glucose concentrations returned to normal soon after withdrawal of olanzapine. In the second case severe ketoacidosis with lethal outcome occurred.

Knitted double-velour Dacron prostheses in aortobifemoral position--long-term performance of different coating materials.

BACKGROUND: The purpose of this prospectively randomized study was to evaluate intraoperative as well as long-term performance of different coating materials for knitted Dacron aortobifemoral prostheses. PATIENTS AND METHODS: Between 1989 and 1992 a total of 150 consecutive patients who underwent aortobifemoral bypass were randomized for three different coating materials: gelatine (Unigraft; n = 49), collagen (Hemashield; n = 50) and human albumin (USCI; n = 51). Intra- and perioperative data such as duration of operation, clamping time, blood loss, and early complications were obtained as well as yearly follow-up examinations up to five years. Frequency of late complications, graft patency, and patient survival were observed. RESULTS: No statistically significant difference of intraoperative data could be obtained. In every group 6% of patients presented with anastomotic aneurysm in the groin. Primary patency rates were Unigraft 92%, Hemashield 91%, USCI 92% (no significant difference, n.s.), secondary patency rates after 5 years were Unigraft 98%, Hemashield 95%, USCI 94% (n.s.). CONCLUSIONS: Overall superiority of one particular type of prosthesis could not be stated. In order to prevent sudden graft failure associated with progressive arteriosclerotic disease or from late anastomotic aneurysm regular follow-up examinations should follow aorto-bifemoral bypass.

The influence of the state of the vertebral arteries on the peri- and postoperative risk in carotid surgery.

OBJECTIVES: To assess the significance of the vertebral arteries (VA) as a prognostic factor within the framework of carotid surgery. DESIGN: Prospective observational study. MATERIALS: A total of 1338 operations were performed on 1182 patients. Three hundred and six of the patients had angiographically confirmed unilateral (299) or bilateral (seven) involvement of the VA. In 31 cases it was not possible to assess the VA. METHODS: Life table analysis. RESULTS: Thirty-day mortality rate was 1.6% (21 out of 1338) for all reconstructions of the internal carotid artery. In addition to three fatal strokes, 22 hemispheric events were noted (1.6%, 22/1338). Follow-up varied between 1 and 96 months (mean 34, S.E.M. 0.76, median 29) and covered a total of 3361 patient years. The cumulative 5-year survival rate was 69%. Irrespective of age, cardiac events were the leading cause of death. In patients with VA involvement, both the 30-day stroke and mortality rate (p < 0.01) and the long-term survival rate (p < 0.01) were significantly poorer. CONCLUSION: Concomitant vertebral artery disease increases the morbidity and mortality of carotid surgery, presumably due to reduced collateral perfusion during cross-clamping. However, the overall risk of surgery remains acceptable.

[How can the prognosis of acute mesenteric artery ischemia be improved? Results of a retrospective analysis]. / Wie kann die Prognose der akuten Mesenterialarterienischämie verbessert werden? Ergebnisse einer retrospektiven Analyse.

AIM: Acute mesenteric ischemia is difficult to diagnose and is combined with a high mortality. In a retrospective analysis it was investigated how to improve the poor prognosis of the disease. PATIENTS AND METHODS: Between January 1988 through December 1994 a total of 46 patients were operated on for acute mesenteric ischemia. Mesenteric artery occlusion was present in three quarters of the cases (n = 35). These were analysed according to symptoms, diagnosis, mechanism of occlusion, operative procedure and prognosis. Distribution of gender was almost balanced (19 women, 16 men) with a median age of 70.5 years. RESULTS: Embolic arterial occlusion was predominant (n = 22). Most frequently, the superior mesenteric artery was exclusively concerned (n = 22). Serum levels of lactate and leucocytes were preoperatively elevated in over 90% (median values: lactate 53 U/l, leucocytes 15050/ml). In 16 patients diagnosis was made on the ground of clinical parameters and/or angiography, but 19 patients were not diagnosed until operation. 19 patients were operated within 6 hours, 12 patients within 24 hours after admission (> 24 hours: n = 4). Vascular reconstructive procedures only, such as thrombectomy and/or aortomesenteric bypass were performed in 9 cases, in a further 7 cases combined with bowel resection. Bowel resection alone was done in 7 patients, 12 patients had only diagnostic laparotomy. 13 patients survived, 10 of them had been treated with vascular reconstruction. CONCLUSION: Acute mesenteric ischemia ought to be suspected in every patient with uncertain abdominal pain, because only early diagnosis can improve prognosis. Measurement of serum lactate is diagnostically helpful, although not proving. In case of elevated lactate levels and uncertain abdominal symptoms angiography of the mesenteric vessels should be performed early. At operation, blood flow in the mesenteric arteries should be restored whenever possible.

[Post-traumatic arteriovenous fistula between splenic artery and vein as a rare cause of acute myocardial ischemia]. / Posttraumatische arteriovenöse Fistel zwischen Arteria und Vena lienalis als seltene Ursache akuter Myokardischämie.

Arteriovenous fistulas of the portal system are rare. Congenital fistulas have to be differentiated from acquired fistulas; the latter are of posttraumatic or iatrogenic origin. The case presented demonstrates a history of diffuse abdominal pain and the first description of myocardial ischemia caused by a posttraumatic splenic arterioportal fistula. After diagnostic and therapeutic difficulties, the definitive treatment consisted in resection of the fistula system including the pancreatic tail.

In vitro cytotoxic effect of difluoromethylomithine increased nonspecifically by peptide coupling.

Difluoromethylomithine (DFMO)-peptide conjugates were synthesized as prodrugs to improve the cytotoxic efficacy of DFMO. All conjugates inhibited cell growth in different cell lines more effectively than DFMO itself. The best cytotoxic effect was achieved in all cell lines by DFMO-Glu-His-Phe-Arg-Trp-Gly-OMe, where the carrier peptide is a melanotropin hormone fragment. Although this conjugate is capable of displacing labeled melanotropin from its receptor, its cytotoxic effect on the receptor-positive human melanoma cell line has not been proven to be receptor-mediated. The differences in the cytotoxicities of the congeners seem to be influenced, at least in part, by the nature of the carrier molecule.

[Acute peripheral arterial occlusion]. / Der akute periphere Arterienverschluss.

Acute embolic occlusion of a normal artery is best treated by simple "Fogarty" maneuver. This procedure is mostly successfully performed even by less experienced surgeons. However, if atherosclerotic disease is the underlying cause for acute occlusion of the vessel, an experienced vascular surgeon and the use of interventional techniques is demanded. In this case, deficits in both experience and technical equipment in the operating room frequently lead to avoidable limb loss.

[Service intervention for prevention of recurrence]. / Service-Eingriffe zur Rezidiv-Prophylaxe.

The decision for or against a service procedure after arterial reconstructions in older patients needs some knowledge about life expectancy, natural course of the lesion and the risk of the procedure. There is no clear definition of a "failing reconstruction". The natural course of pathological lesions of arterial reconstructions is almost unknown. Especially in very old patients there are no general rules for service procedures.