Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin.

AIMS: To show that albiglutide, a glucagon-like peptide-1 receptor agonist, is an effective and generally safe treatment to improve glycaemic control in patients with type 2 diabetes mellitus whose hyperglycaemia is inadequately controlled with pioglitazone (with or without metformin). METHODS: In this 3-year, randomized, double-blind, placebo-controlled study, 310 adult patients on a regimen of pioglitazone (with or without metformin) were randomly assigned to receive additional treatment with albiglutide [30 mg subcutaneous (s.c.) once weekly, n = 155] or matching placebo (n = 155). The primary efficacy endpoint was change from baseline to week 52 (intention-to-treat) in glycated haemoglobin (HbA1c). RESULTS: The model-adjusted change from baseline in HbA1c at week 52 was significantly better with albiglutide than with placebo (-0.8%, 95% confidence interval -1.0, -0.6; p < 0.0001). Change from baseline fasting plasma glucose was -1.3 mmol/l in the albiglutide group and +0.4 mmol/l in the placebo group (p < 0.0001); a significantly higher percentage of patients reached the HbA1c goals with albiglutide (p < 0.0001), and the rate of hyperglycaemia rescue up to week 52 for albiglutide was 24.4 versus 47.7% for placebo (p < 0.0001). Albiglutide plus pioglitazone had no impact on weight, and severe hypoglycaemia was observed rarely (n = 2). With few exceptions, the results of safety assessments were similar between the groups, and most adverse events (AEs) were mild or moderate. The 52-week incidence rates for gastrointestinal AEs for albiglutide and placebo were: 31.3 and 29.8%, respectively (diarrhoea: 11.3 and 8.6%; nausea: 10.7 and 11.3%; vomiting: 4.0 and 4.0%). CONCLUSIONS: Albiglutide 30 mg administered once weekly as an add-on to pioglitazone (with or without metformin) provided effective and durable glucose lowering and was generally well tolerated.

Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions.

BACKGROUND: The role of bone morphogenetic proteins (BMPs) in osseous repair has been demonstrated in numerous animal models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions. The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone. MATERIALS AND METHODS: One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, partially blinded, multi-center clinical trial between February, 1992, and August, 1996, and were followed at frequent intervals over 24 months. Each patient was treated by insertion of an intramedullary rod, accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft. Assessment criteria included the severity of pain at the fracture site, the ability to walk with full weight-bearing, the need for surgical re-treatment of the nonunion during the course of this study, plain radiographic evaluation of healing, and physician satisfaction with the clinical course. In addition, adverse events were recorded, and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit. RESULTS: At 9 months following the operative procedures (the primary end-point of this study), 81% of the OP-1-treated nonunions (n = 63) and 85% of those receiving autogenous bone (n = 61) were judged by clinical criteria to have been treated successfully (p = 0.524). By radiographic criteria, at this same time point, 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had healed fractures (p = 0.218). These clinical results continued at similar levels of success throughout 2 years of observation, and there was no statistically significant difference in outcome between the two groups of patients at this point (p = 0.939). All patients experienced adverse events. Forty-four percent of patients in each treatment group had serious events, none of which were related to their bone grafts. More than 20% of patients treated with autografts had chronic donor site pain following the procedure. CONCLUSIONS: rhOP-1 (BMP-7), implanted with a type I collagen carrier, was a safe and effective treatment for tibial nonunions. This molecule provided clinical and radiographic results comparable with those achieved with bone autograft, without donor site morbidity.

Septic arthritis.

Hematogenous septic arthritis causes pain and effusion and begins with inoculation of the joint with bacteria from the intravascular space. The degradation of ground substance by enzymes released and activated by the acute inflammatory response, toxins and enzymes produced by the bacteria, and T lymphocytes stimulated during the delayed immune response, leads to destruction of the articular cartilage. Whether a given patient will develop a septic joint or a less severe form of infection is dependent upon characteristics of the bacterial strain and of the individual's host defenses. Management consists of systemic antibiotic therapy and decompression of the joint. Synovectomy, salicylate administration, and continuous passive motion are adjuvant therapies that have not as yet not been proved to be of benefit.

Bone repair techniques, bone graft, and bone graft substitutes.

This paper reviews the techniques and materials (bone graft and bone graft substitutes) that currently are used to treat nonunions and bone defects. The techniques reviewed are intramedullary nailing, plating, distraction osteogenesis, and electric stimulation. Bone graft and bone graft substitutes reviewed are as follows: vascularized bone transfers; autogenous bone graft; autogenous bone marrow; dimineralized bone matrix; growth factors; calcium sulphate; calcium phosphates; and allograft. The goal of management of fractures, nonunions, and segmental bony defects, is the return of function as quickly and completely as possible. Techniques and management strategies constantly are evolving to accomplish this goal. This paper reviews the history, indications, and limitations of bone repair techniques, methods of bone grafting, and materials available as bone graft substitutes.

The use of dynamic external fixation to obtain tibiocalcaneal fusion after Boyd's amputation.

Two patients sustained severe injuries of the foot and ankle, which were managed with Boyd's amputation. A large-pin dynamic external fixator was used to obtain fusion between the calcaneus and distal tibia. Boyd's amputation preserves limb length and prevents posterior migration of the heel pad (both are disadvantages of Syme's amputation). Use of a dynamic external fixator may result in reliable and rapid consolidation of the fusion (thus overcoming the disadvantage associated with Boyd's amputation).

Distal femur as a donor site of autogenous cancellous bone graft.

We performed a prospective clinical study and a cadaveric study to evaluate the morbidity associated with harvesting cancellous bone from the distal femoral metaphysis for use in the lower extremity. Thirty patients underwent harvest of distal femoral cancellous bone: 13 for acute trauma and 17 for reconstructive procedures. The distal femoral condyle is approached through a 6-cm midlateral, longitudinal incision. A small cortical window is created, bone graft is harvested, and the cortical window is replaced. All patients were kept nonweight bearing on the extremity for a minimum of 6 weeks. Patients were followed for an average of 10 months (range 3-32 months) and no patient was lost to follow-up before allowing full weight bearing. There were no donor site would or neurovascular problems and no femur fractures. A cadaveric study was also performed in which bone was harvested from the distal femur, the bone was quantified, and the knees were tested in compression (axial loading). The bone-harvested knees failed in the same load range as the contralateral control knees did. The distal femoral metaphysis has many advantages compared with the iliac crest in cases when cancellous bone is needed for the lower extremity. Harvesting distal femoral bone is associated with little morbidity if performed correctly, and if the patient remains nonweight bearing for 6 weeks.

Intracapsular fractures of the proximal femur.

Intracapsular fractures in the geriatric population are the result of progressive osteopenia, resulting in weakening of the bone. Minor trauma results in fracture of the weakened femoral neck. Most commonly, this process occurs in patients whose osteopenia is secondary to senile osteoporosis. The fact that the femur is osteopenic means that fixation may be difficult to achieve. However, reduction is relatively easy to obtain because of the absence of communication and the minimal displacement.

Bacterial resistance mechanisms as therapeutic targets.

In the 50 years since antimicrobial agents were first introduced, bacteria have acquired a wide variety of mechanisms which have enabled them to resist the effects of these drugs. One way of overcoming this problem is to administer an antibiotic with an agent which counteracts the mechanism of resistance to that antibiotic; an example of such an approach which has already been successfully implemented is the combination of a beta-lactam antibiotic with a beta-lactamase inhibitor. This review describes antibiotic resistance mechanisms which might lend themselves to an inhibitor approach and the potential therapeutic applications of such a strategy.

Identification of two laccase genes in the cultivated mushroom Agaricus bisporus.

A cDNA library was constructed in lambda gt11 using mRNA from 11-d-old mycelium of Agaricus bisporus. Three clones containing laccase sequence were identified using an affinity-purified anti-laccase antibody. From one of these clones, a 333 bp sequence was used to identify further cDNA clones (including one which is close to full length) and a genomic clone. The coding sequences found were of two similar but not identical versions with differences at 36 out of 520 residues of deduced amino acid sequence. The laccase genes each encode a sequence expressed as a 2.3 kb mRNA, specifying a 520 residue polypeptide including a 19 amino acid residue signal peptide that is absent from the N terminus of the mature (extracellular) protein. The coding sequence of lcc1 is interrupted by 14 short introns. The lcc1 and lcc2 genes are not allelic as they do not segregate in uninucleate spores derived from a four-spored basidium. Comparison of the deduced amino acid sequences with that of the other fungal laccases that have been cloned, and with the very similar ascorbate oxidases from higher plants shows that whilst some sequence is absolutely conserved at and around the amino acid residues involved in copper binding, the overall sequence similarities are low.

High-level mupirocin resistance in Staphylococcus aureus: evidence for two distinct isoleucyl-tRNA synthetases.

Mupirocin resistance in Staphylococcus aureus results from changes in the target enzyme, isoleucyl-tRNA synthetase (IRS). Twelve strains of S. aureus comprising four susceptible (MICs < or = 4 micrograms/ml), four intermediate level-resistant (MICs between 8 and 256 micrograms/ml), and four highly resistant (MICs > or = 512 micrograms/ml) isolates were examined for their IRS content and the presence of a gene known to encode high-level mupirocin resistance. Ion-exchange chromatography of cell extracts showed a single IRS active peak in mupirocin-susceptible strains, with 50% inhibitory concentrations (IC50s) of 0.7 to 3.0 ng of mupirocin per ml. In strains showing intermediate mupirocin resistance, similar single IRS activity peaks were observed, but these were less sensitive to inhibition, and the mupirocin IC50s for them were 19 to 43 ng/ml. Strains that were highly resistant to mupirocin displayed two distinct peaks; one was similar to that found with susceptible strains (IC50, 0.9 to 2.5 ng/ml), but an additional peak with an IC50 of 7,000 to 10,000 ng/ml was also observed. A strain cured of the plasmid encoding high-level mupirocin resistance lacked the resistant IRS peak. Restriction digests, produced by endonuclease NcoI, of total bacterial DNA isolated from the highly resistant strains hybridized with a mupirocin resistance gene probe, whereas DNA isolated from the intermediate level-resistant and susceptible strains did not. These results demonstrate that two different IRS enzymes were present in highly mupirocin-resistant S. aureus strains. In strains expressing intermediate levels of resistance, only a chromosomally encoded IRS which was inhibited less by mupirocin than IRS from fully susceptible strains was detected.

The structure of laccase protein and its synthesis by the commercial mushroom Agaricus bisporus.

Agaricus bisporus secretes abundant laccase activity into the medium during mycelial growth. SDS-PAGE analysis of extracellular laccase protein, purified from compost extract, showed a predominant band of 65 kDa molecular mass, together with lesser amounts of smaller polypeptides. The main polypeptide was purified electrophoretically. Amino acid sequence analysis of the N-terminal region of the main polypeptide was used to specify the sequence of a 15-residue chemically synthesized peptide (N-terminal peptide). Rabbit antibodies were raised against pure laccase, electrophoretically purified main polypeptide and the synthetic N-terminal peptide. Electrophoretically purified main polypeptide antibody was further purified by affinity chromatography on laccase-CNBr-Sepharose. Western blot analysis showed that the antigenic behaviour of laccase in compost extract, culture filtrate from malt-extract culture, and the purified enzyme from both sources, differed. The patterns of bands revealed are most simply explained by generation of (proteolytically) partially cleaved enzyme molecules in the culture medium, possibly combined with differences in extent of glycosylation. [35S]Methionine incorporation and immunoprecipitation were used to follow laccase synthesis in cultures grown on malt extract. After short-term labelling, a single polypeptide of 68 kDa apparent molecular mass was immunoprecipitated from both mycelial extracts and the culture medium. When poly(A)-containing RNA from malt-extract-grown mycelium was translated in vitro in rabbit reticulocyte lysate, a single polypeptide of about 57 kDa molecular mass was immunoprecipitated, consistent with the previously measured carbohydrate content of 15% for the pure enzyme. After treatment with N-glycanase, the polypeptide showed an increase in mobility during SDS-PAGE consistent with a reduction in molecular mass of about 5 kDa, indicating about equal amounts of N- and O-linked carbohydrate. C-terminal labelling of pure laccase was attempted by transpeptidation with carboxypeptidase Y. Although some minor bands were labelled, the main polypeptide was not, indicating that the C-terminus of the enzyme may be blocked.

Treatment of acutely infected arthroplasties with incision, drainage, and local antibiotics delivered via an implantable pump.

Twelve patients with acutely (symptomatic less than ten weeks) infected arthroplasties were treated with minimal debridement and intraarticular antibiotic, amikacin, delivered via an implantable pump. The infection was suppressed in ten cases. Intraarticular levels of amikacin were obtained in eight cases. These levels ranged from greater than 150 micrograms/ml to 1688 micrograms/ml. The systemic level of amikacin remained below 10 micrograms/ml in all but one case. Duration of hospitalization averaged 19 days. There were no significant toxic side effects to amikacin.