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.

Antibiotics delivered by an implantable drug pump. A new application for treating osteomyelitis.

Osteomyelitis is usually treated with wide surgical debridement and prolonged intravenous antibiotics. The advent of the implantable drug pump has led us to evaluate this therapeutic modality for the treatment of osteomyelitis. We have previously shown that amikacin retains microbiologic activity in an implantable drug pump over a six-week period when incubated at 37 degrees C. We have also demonstrated in rabbits that high local levels and low systemic levels of antibiotic can be achieved using an implantable drug pump as a delivery system and that this method can be used to sterilize infected wounds. This method was applied in the treatment of osteomyelitis in 14 patients whose duration of symptoms ranged from one month to 22 years. In 13 patients, active drainage had been present for more than six months, and all patients had undergone one or more attempts at eradication of their infection. Prior therapy included surgical debridement alone (one patient), one or more attempts at debridement and extended intravenous antibiotic therapy (13 patients), debridement and local flap procedures (four patients), and extended oral antibiotic therapy (two patients). The bones involved were the tibia (six patients), femur (four patients), and elbow, shoulder, hip, and radius (one patient each). Intra-operative cultures indicated that the infecting organism was Staphylococcus aureus alone (seven patients), S. aureus in combination with gram-negative bacteria (five patients), or gram-negative organisms alone (two patients). Debridement and pump implantation were performed in one stage. On an outpatient basis, the pumps were filled with amikacin in a concentration determined by each patient's serum level. Duration of therapy was based upon cessation of drainage and erythrocyte sedimentation rate. During therapy, serum amikacin levels ranged from less than 2.5 micrograms/ml to 8.2 micrograms/ml. The amikacin concentration in the wound drainage was always greater than the upper limits of what could be measured (greater than 55 micrograms/ml to greater than 5,000 micrograms/ml). There were no cases of ototoxicity and one case of minimal renal toxicity (posttreatment creatinine clearance of 66 ml per minute; normal equal to 70 ml per minute). Length of therapy ranged from 32 to 140 days (mean equal to 63 days). Length of hospitalization ranged from five to 52 days (mean equal to 24 days). Drainage in all patients stopped during therapy, but resumed in three patients after pump removal--in two patients, for brief periods of time, and in one patient, it continues. Twelve patients have posttreatment erythrocyte sedimentation rates less than or equal to 20 mm per hour.(ABSTRACT TRUNCATED AT 400 WORDS)

1-O-hexadecyl-2-acetyl-sn-3-glycerophosphorylcholine (PAF): some effects on the aggregation of human platelets by thrombin or collagen.

1-O-hexadecyl-2-acetyl-sn-3-glycerophosphorylcholine (PAF) was examined as a potential mediator of aggregation induced by thrombin or high concentrations of collagen in indomethacin treated platelet rich plasma by investigating the response to collagen and thrombin of platelets previously desensitized to PAF. No reduction in the response to collagen or thrombin was observed and it was concluded that PAF was not a mediator of non-prostanoid dependent aggregation in platelets exposed to thrombin or collagen.

Antibiotic stability in an implantable pump.

We measured the stability of vancomycin, amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam in an implantable drug pump. Two pumps were filled with the antibiotic being tested and were incubated at 37 degrees for 3 weeks. Samples were taken daily. At 3 weeks the pumps were disassembled and examined microscopically for signs of deterioration. If the pumps were intact, bioassays were used to quantitate the biologic activity of each daily antibiotic sample. Vancomycin degraded the pump. Amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam had no effect on the pump and maintained their biologic activity over the 3-week period.

Northern blotting.

Northern blotting is a way of detecting specific RNA sequences, homologous to a hybridization probe, within a complex RNA sample. In this procedure RNA is first separated by electrophoresis under denaturing conditions (see Chapter 1 ), followed by blotting onto a suitable filter. Specific sequences are then detected by hybridization. The RNA species are both immobilized on the filter and denatured so that when the filter is immersed in a solution containing a labeled nucleic acid probe, the probe binds to RNA of complementary base se?quence (hybridizes), specifically labeling the position on the filter that this RNA sequence has been blotted to from the gel. This defines the size of the RNA molecule complementary to the probe and can be used to compare relative amounts of the RNA species in different samples.

Electrophoresis of RNA denatured with glyoxal or formaldehyde.

The first successful method for electrophoretic analysis of the full size range of cellular RNA molecules was described by Loening (1), and its introduction allowed for major advances, most particularly in the molecular biology of eukaryotic organisms. The method had, nevertheless, two significant disadvantages in that the gels (composed of acrylamide at very low concentrations) were mechanically fragile, and the migration of RNA molecules did not necessarily reflect their size because RNA secondary structure was not disrupted.

Accuracy of cultures of material from swabbing of the superficial aspect of the wound and needle biopsy in the preoperative assessment of osteomyelitis.

The pathogens that were identified on cultures of material obtained by swabbing of the superficial aspect of the wound and needle biopsy were compared with those that were isolated from material that was obtained at débridement from sixty patients who had post-traumatic or postoperative osteomyelitis. The cultures of material that was obtained by superficial swabbing of the wound and needle biopsy were inadequate for prediction of the presence of aerobic organisms. Moreover, the failure to isolate anaerobes from the material obtained by needle biopsy did not rule out the presence of anaerobic organisms. Therefore, tissue for culture of aerobic and anaerobic organisms must be obtained during operative débridement in order to identify all pathogenic organisms. Fungi were isolated from the material obtained by biopsy in two patients. In addition, histological examination of the tissue obtained at biopsy led to the diagnosis of epidermoid carcinoma in two patients in whom this diagnosis had not been suspected before biopsy. Cultures were negative for mycobacteria in all patients. An additional ten patients who had a tibial non-union and latent osteomyelitis were studied. In nine of them, cultures of material obtained by needle biopsy showed no growth. Six of these nine patients had an exacerbation of the osteomyelitis after intramedullary nailing for the non-union. Therefore, the absence of growth of organisms from tissue obtained at needle biopsy does not rule out the possibility that osteomyelitis may be reactivated after intramedullary nailing with reaming.

Posterior fracture-dislocation of the distal part of the fibula. Mechanism and staging of injury.

The Bosworth fracture, a fixed posterior fracture-dislocation of the distal part of the fibula due to external rotation of the supinated foot, is a rare injury. In this report we review the literature, present two new cases, and describe our cadaver studies, showing that the initial stages of the injury are identical to those of a Maisonneuve fracture. The final stages that are unique to this fracture-dislocation are the posterior dislocation and fracture of the fibula and the fracture of the medial malleolus or rupture of the deltoid ligament. The objectives of treatment are reduction of the dislocation, repair and stabilization of the tibiofibular syndesmosis, and restoration of the ankle mortise to its anatomical position.

A new surgical approach to fractures of the lateral tibial plateau.

We are reporting on a previously undescribed surgical approach and postoperative protocol for the treatment of fractures of the lateral tibial plateau in which there is a split pattern and depression of the articular surface. In this approach the anterior horn of the lateral meniscus is incised and detached so that the split fragment can be opened like a book. Detachment and incision of the anterior horn minimizes the need to free the lateral meniscus from its tibial attachment. The postoperative protocol includes continuous passive motion followed by non-weight-bearing in a toe-to-groin plaster cast for three months. Our preliminary results have been encouraging, and arthroscopic examination in the seven knees so studied indicated a healed fracture, restoration of the tibial articular surface, and a healed lateral meniscus.

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.

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.

Open reduction and internal fixation of radial head fractures associated with olecranon fracture or dislocation.

Six fracture dislocations or dislocations of the olecranon associated with radial head fractures were treated with open reduction and internal fixation of the radial head. The olecranon was reduced and if fractured (three cases) was internally fixed. Postoperatively, early active range of motion was achieved in all cases. Twelve to 48 months after surgery, there was an average loss of 18 degrees of elbow extension and 56 degrees of forearm rotation. An average of 132 degrees of flexion was maintained. There was no elbow instability or wrist pain.

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.

Transcondylar fractures of the distal humerus.

We classify transcondylar fractures of the distal humerus into four groups: undisplaced; simple displaced; T-type; and fracture dislocations (Posada's fracture). Our treatment of these fractures is based upon this classification. Undisplaced fractures are treated with immobilization. Displaced fractures are reduced and stabilized with internal fixation. Stabilization of these fractures is difficult because the distal fragments are small and a large portion of their surface is covered with articular cartilage. Transposition of the ulnar nerve allows us to use the cubital tunnel as a point for fixation. We found in our series of 11 patients that undisplaced fractures have the best prognosis. However, all of our patients lost elbow motion, particularly extension. Radiographic signs of post-traumatic arthritis were more pronounced in displaced fractures.

Locked flexible intramedullary nails in treatment of unstable femoral fractures.

Twenty patients with unstable femoral fractures were treated with distally locked flexible intramedullary nails. We present our surgical technique and our results. The method has the following advantages: it prevents rotational malalignment and shortening, it is a closed procedure, no reaming is necessary, there is no increase in c-arm time, and there is minimal increase in operative time. Locked flexible intramedullary nails should be used in patients with unstable femoral fractures who have dense metaphyseal bone. Osteopoenia is a contraindication to this method as it increases the risk of nail penetration into the hip.

Patellar fixation protected with a load-sharing cable: a mechanical and clinical study.

The stability of patellar fracture fixation protected with a load-sharing cable was studied in cadavers. A transverse patellar osteotomy was produced and stabilized with standard patellar fixation with or without a figure-of-eight cable that extends from the proximal pole of the patella to the tibial tubercle. Standard fixation techniques (interfragmentary cancellous screws or modified tension-band wiring) alone failed after significantly fewer cycles of flexion and extension than did the same fixation when supplemented with a load-sharing cable. In the clinical evaluation of the load-sharing cable, 14 consecutive patients with displaced patellar fractures were treated. No immobilization was used and the patients were started on passive and active range of motion and weight-bearing ambulation in the early postoperative period. Thirteen fractures healed uneventfully. The increased stability of patellar fracture fixation protected with a load-sharing cable offers three advantages: (a) adjunctive casting is unnecessary, (b) comminuted fractures can be "pieced" together anatomically with less concern for loss of fixation, and (c) early postoperative passive and active range of motion can be achieved.

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.

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).

Tetanus in a patient with frostbite: a case report.

Tetanus occurs in all ages, it can be associated with puncture wounds, war injuries, burns, ear infections, umbilical stump and post partum infections, and heroin abuse.5 Recently, we treated a patient who developed tetanus following frostbite of both feet. The patient had been previously immunized against tetanus, and was receiving antibiotics when the disease became manifest.