The use of BoneWelding? technology in spinal surgery: an experimental study in sheep

The innovative BoneWelding^? technology, where ultrasound energy bonds bioresorbable implants to bone, was tested for its feasibility in spine surgery and its local thermal effects. The three tested concepts consisted of implementation of a resorbable plating system, two converging polymer pins and suture anchors to the cervical vertebral bodies. Bioresorbable polylactide implants (PLDLLA 70/30) were inserted ventrally into the third and fourth vertebral body of seven sheep, of which six were sacrificed at 2 months and one sheep immediately after temperature measurements during implant insertion. Polymer screws were used as controls. Qualitative, semi-quantitative histological, and quantitative histomorphometrical evaluation showed excellent anchorage of the implants, new mineralized bone at the implant-bone interface, no inflammatory cell reaction or thermal damage to the adjacent bone in response to the novel insertion technology. The application of two converging pins, parallel inserted polymer pins, or fusion of the implant to the polymer plates did not affect the overall excellent tissue tolerance of the technology. Temperature increase during insertion was noticed but never exceeded 47°C for less than 1 s. The BoneWelding^? technology was proven to be safe and easy to apply.     

A Phase II,open-label,randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens

Objectives To assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) in patients with metastatic colorectal cancer who had failed one or two previous chemotherapeutic regimens that included oxaliplatin and/or irinotecan. Methods This was a Phase II, multicentre, open-label, randomised, two-arm, parallel-group study comparing AZD6244 with capecitabine monotherapy. Patients received either 100 mg twice daily oral AZD6244 free-base suspension every day or 1,250 mg/m² twice daily oral capecitabine, for 2 weeks, followed by a 1-week rest period, in 3-weekly cycles. The primary endpoint was the number of patients experiencing disease progression events. Results Sixty-nine patients were randomised in the study (34 and 35 patients in the AZD6244 and capecitabine groups, respectively). Disease progression events were experienced by 28 patients (∼80%) in both the AZD6244 and capecitabine treatment groups. Median progression-free survival was 81 days and 88 days in the AZD6244 and capecitabine groups, respectively. Ten patients in the AZD6244 treatment arm had a best response of stable disease. For capecitabine, best response was a partial response in one patient, with stable disease in a further 15 patients. The most frequently observed adverse events reported with AZD6244 were acneiform dermatitis, diarrhoea, asthenia and peripheral oedema, compared with hand-foot syndrome, diarrhoea, nausea and abdominal pain with capecitabine. Conclusions AZD6244 showed similar efficacy to capecitabine in terms of the number of patients with a disease progression event and of progression-free survival. AZD6244 is currently undergoing evaluation in Phase II trials in combination with other chemotherapeutic agents.     

ELECTRODERMAL ACTIVITY OF UNDERSOCIALIZED AGGRESSIVE CHILDREN: A PILOT STUDY

Electrodermal activity of 11 children with conduct disorder (CD) and 11 normal children were compared during periods of rest, moderate tone and loud bell stimulation. The CD group was best differentiated from controls by lower reactivity to the first bell, while on tonic measures they showed normal values. The electrodermal profile of the CD children thus resembled that of adult sociopaths on phasic measures only. The possibility of using electrodermal measures for predicting outcome and for differential diagnosis is raised.     

Investigation of neuromuscular blocking agents at Richter Ltd

Investigation of new neuromuscular blocking agents was started 30 years ago in Richter Ltd. This paper presents the results obtained by Richter's scientists. 2 compounds out of 100 bisquaternary ammonio steroid having androstane skeleton were selected for further pharmacological study. One of these agents, pipecuronium bromide (Arduan) elicited long-lasting block of neuromuscular transmission without cardiovascular side effects in both animal experiments and clinical studies. Arduan is a powerful competitive antagonist of acetylcholine, since it can bind pre- and postsynaptic (N1) receptors of the transmitters. It has no remarkable cumulative effect. Neostigmine rapidly and completely antagonized the neuromuscular blockade caused by pipecuronium. Arduan was introduced into clinical practice. The second compound, RGH-4201 (Duador) evoked a neuromuscular block of short duration. It showed slight atropin-like cardio-vagolytic effect in animal experiments. In the clinical studies, however, the cardiovascular side effects were found to be too strong. Therefore, it was not introduced in clinical practice.     

Myosin: a noncovalent stabilizer of fibrin in the process of clot dissolution

Myosin modulates the fibrinolytic process as a cofactor of the tissue plasminogen activator and as a substrate of plasmin. We report now that myosin is present in arterial thrombi and it forms reversible noncovalent complexes with fibrinogen and fibrin with equilibrium dissociation constants in the micromolar range (1.70 and 0.94 microM, respectively). Competition studies using a peptide inhibitor of fibrin polymerization (glycl-prolyl-arginyl-proline [GPRP]) indicate that myosin interacts with domains common in fibrinogen and fibrin and this interaction is independent of the GPRP-binding polymerization site in the fibrinogen molecule. An association rate constant of 1.81 x 10(2) M(-1) x s(-1) and a dissociation rate constant of 3.07 x 10(-4) s(-1) are determined for the fibrinogen-myosin interaction. Surface plasmon resonance studies indicate that fibrin serves as a matrix core for myosin aggregation. The fibrin clots equilibrated with myosin are stabilized against dissolution initiated by plasminogen and tissue-type plasminogen activator (tPA) or urokinase (at fibrin monomer-myosin molar ratio as high as 30) and by plasmin under static and flow conditions (at fibrin monomer-myosin molar ratio lower than 15). Myosin exerts similar effects on the tPA-induced dissolution of blood plasma clots. Covalent modification involving factor XIIIa does not contribute to this stabilizing effect; myosin is not covalently attached to the clot by the time of complete cross-linking of fibrin. Thus, our in vitro data suggest that myosin detected in arterial thrombi binds to the polymerized fibrin, in the bound form its tPA-cofactor properties are masked, and the myosin fibrin clot is relatively resistant to plasmin.     

Occurrence and course of suicidality during short-term treatment of late-life depression

BACKGROUND: Elderly persons (> or =65 years) have the highest rate of suicide; still, little is known about the occurrence, course, and responsivity of suicidal ideation during treatment of depression in late life and how suicidality affects treatment response. METHODS: This study was undertaken to determine (1) how suicidal ideation changes during short-term depression treatment and (2) whether treatment response differs among 3 groups of patients based on their levels of suicidality at baseline and during treatment (those with a recent suicide attempt or current suicidal ideation [high-risk group; n = 46], those with recurrent thoughts of death [moderate-risk group; n = 143], or those with no suicide attempt, suicidal ideation, or thoughts of death [low-risk group; n = 206]). This is a secondary analysis of pooled data from 3 treatment studies of late-life major depression. Participants were 395 elderly persons with a current major depressive episode, treated as inpatients or outpatients under protocolized conditions with paroxetine hydrochloride or nortriptyline hydrochloride, with or without interpersonal psychotherapy. Changes in suicidal ideation over time, rate of responses, and time to response in each group were compared. RESULTS: Suicidal ideation decreased rapidly early in the course of treatment, with more gradual change thereafter. At the beginning of treatment, 77.5% of the patients reported suicidal ideation, thoughts of death, or feelings that life is empty. After 12 weeks of treatment, suicidal ideation had resolved in all treated patients; 4.6% still reported thoughts of death. However, 6-week (P =.001) and 12-week (P =.02) rates of response were significantly lower in high-risk patients than in low- and moderate-risk patients. High- and moderate-risk patients needed a significantly (P<.001) longer time to respond than low-risk patients (median time to response, 6 and 5 vs 3 weeks). CONCLUSIONS: While suicidal ideation resolves rapidly, the resolution of thoughts about death is more gradual. Suicidal elderly persons with depression require special attention during depression treatment because they have a lower response rate and need a longer time to respond.     

Increased prevalence of platelet glycoprotein IIb/IIIa PLA2 allele in ischaemic stroke associated with large vessel pathology

Introduction: Platelet glycoprotein IIb/IIIa is a membrane receptor with a central function in the platelet adhesion and ultimately in the thrombus formation. Two major variants of the gene encoding the IIIa subunit, called PLA1 (A1) and PLA2 (A2), have been identified in the general population. There are indications that the A2 allele can also be associated with acute thrombosis or stroke. The purpose of this study was to study the distribution of the A2 allele in different vascular subtypes of stroke disease. Materials and methods: A total of 638 consecutive patients were analyzed and classified as having large vessel pathology (n=168) or a small vessel infarct (n=210). Localization of the vascular occlusions was deducted from analysis of the magnetic resonance imaging (MRI) scan results in stroke patients. The remainder patients were listed into a mixed vascular pathology group (n=167). Patients with other or poorly characterized stroke etiology were excluded from the study (n=93). Results: In the small vessel and mixed vascular pathology groups, the PLA2 allele frequency was similar to that in the controls. By contrast, PLA2 allele frequency was approximately two-fold higher in patients with large vessel pathology (23.3%) than in the stroke-free control subjects (11.7%, p<0.0005). Multivariate logistic regression analysis of data confirmed this association with an odds ratio (OR) of 2.9 (95% confidence interval [CI]: 1.6–4.9, p<0.0005). Conclusions: These data suggest that the PLA2 allele is more frequent in brain infarcts associated with large-vessel occlusion.     

Aboral pouch with preserved duodenal passage--new reconstruction method after total gastrectomy

A new reconstruction method--the aboral pouch with preserved duodenal passage--has been introduced after total gastrectomy. After removal of the stomach, preparation of the Roux loop and construction of the esophago-jejunostomy, a jejuno-duodenostomy is performed approximately 50 cm away from the esophageal anastomosis between the Roux limb and the duodenal stump. Right below this second anastomosis, the Roux limb is closed with a stapling device to provide a unidirectional food passage through the duodenum. The aboral pouch is constructed as a side-to-side anastomosis between the Roux limb under the stapled segment and the aboral end of the Y limb. The advantages of the reservoir-constructing methods and the interposition methods are combined in this new reconstruction type. Our experiences of 17 cases having undergone this reconstruction method are presented.