Posterior Cruciate Ligament Agenesis Requiring Surgical Reconstruction.

Agenesis of the posterior cruciate ligament (PCL) is a rare disorder often found in conjunction with various other abnormalities within the knee. A 15-year-old adolescent boy presented with an absent PCL, leading to intermittent symptoms. At the age of 20 years, the patient underwent arthroscopically assisted PCL reconstruction. The patient was permitted to weightbear immediately after the procedure and started physical therapy 4 weeks after the procedure. No complications were encountered at the 2-year follow-up.

Effect of posterior shoulder tightness on internal impingement in a cadaveric model of throwing.

PURPOSE: Posterior shoulder tightness is common in throwing athletes, especially those with symptomatic shoulder internal impingement. The role of posteroinferior capsular contracture in the pathoetiologies of throwing-related injuries caused by shoulder internal impingement remains unclear. The purpose of this study was to assess effect of posterior shoulder tightness on internal impingement in a cadaveric model of throwing. METHODS: Seven fresh-frozen cadaveric shoulders were tested with the shoulder abducted to 90° and at maximum external rotation to simulate the late cocking phase of throwing motion. Glenohumeral joint contact pressure and area through internal impingement, humeral head shift, and the maximum humeral rotation angle were measured. Posteroinferior capsular plication was performed to simulate posteroinferior capsular tightness and induce glenohumeral internal rotation deficit. RESULTS: Following generation of simulated posteroinferior capsular tightness with resultant glenohumeral internal rotation deficit, glenohumeral contact pressure was significantly increased (P < 0.05), the impinged area of rotator cuff tendon was significantly decreased (P < 0.05), and the humeral head shifted posteriorly (P < 0.05) during shoulder internal impingement. CONCLUSION: Excessive posteroinferior capsular tightness can cause forceful internal impingement of the shoulder at maximum external rotation position.

The effect of glenohumeral internal rotation deficit due to posterior capsular contracture on passive glenohumeral joint motion.

BACKGROUND: To date, no study has investigated the biomechanical consequences of glenohumeral internal rotation deficit (GIRD) at values seen in symptomatic athletes. Hypothesis/ PURPOSE: The purpose of this study was to determine the biomechanical changes that occur with a full spectrum of GIRD in a cadaveric model with passive loading. We hypothesized that there is a critical percentage of GIRD that will result in a decrease in posterior glenohumeral translation and shift of the humeral head apex at the extreme ranges of motion. STUDY DESIGN: Controlled laboratory study. METHODS: Six specimens were tested using the following conditions: (1) native state ("intact"); (2) after external rotation (ER) stretch ("stretched"); and (3) GIRD of 5%, 10%, 15%, and 20%. For each condition, maximum ER, maximum internal rotation (IR), and total range of motion were measured. Kinematic data were obtained to determine the position of the humeral head apex (HHA), the highest point on the articular surface of the humeral head, relative to the geometric center of the glenoid. The amount of translation was measured in the anterior, posterior, superior, and inferior directions. RESULTS: External rotation significantly increased compared with the intact condition for the stretched and 5% GIRD states, and IR decreased significantly beginning with 5% GIRD. At maximum ER, the HHA shifted significantly in the superior direction compared with the intact condition for all GIRD states, and at maximum IR, the HHA shifted significantly in the inferior direction compared with the intact and stretched conditions starting at 10% GIRD. The amount of posterior translation decreased significantly starting at 10% GIRD, and the amount of inferior translation decreased significantly starting at 20% GIRD. CONCLUSION: Biomechanical changes of passive glenohumeral joint motion occur in the glenohumeral joint with as little as 5% GIRD. CLINICAL RELEVANCE: Biomechanical changes of passive glenohumeral joint motion are noted with as little as 5% GIRD in this cadaveric model, and as the amount of GIRD increases, more substantial effects are noted.

Impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens: a post hoc analysis of clinical trials in type 2 diabetes mellitus.

OBJECTIVE: To explore the impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens in patients with type 2 diabetes mellitus. METHODS: In this post hoc analysis, pooled data from 11 multinational clinical trials involving 1455 patients with type 2 diabetes were used to compare specific insulin treatments in Latino/Hispanic, Asian, African-descent, and Caucasian patients. Insulin treatments included once daily insulin glargine or neutral protamine Hagedorn (BASAL), insulin lispro mix 75/25 twice daily (LMBID), or insulin lispro mix 50/50 three times daily (LMTID). RESULTS: Race/ethnicity was associated with significant outcome differences for each of the insulin regimens. BASAL therapy was associated with greater improvement in several measures of glycemic control among Latino/Hispanic patients compared with Caucasian patients (lower end point hemoglobin A1c, greater reduction in hemoglobin A1c from baseline, and a larger proportion of patients achieving hemoglobin A1c level <7%). In contrast, LMBID therapy was associated with higher end point hemoglobin A1c and a smaller decrease in hemoglobin A1c from baseline in Latino/Hispanic and Asian patients than in Caucasian patients. Furthermore, fewer Asian patients attained a hemoglobin A1c level <7% than did Caucasians patients. For LMTID therapy, hemoglobin A1c outcomes were comparable across patient groups. Fasting blood glucose and glycemic excursions varied among racial/ethnic groups for the 3 insulin regimens. Weight change was comparable among racial/ethnic groups in each insulin regimen. During treatment with LMTID, Asian patients experienced higher incidence and rate of severe hypoglycemia than Caucasian patients. CONCLUSIONS: Latino/Hispanic, Asian, and African-descent patients with type 2 diabetes show different metabolic responses to insulin therapy, dependent in part on insulin type and regimen intensity.

Influence of distinct anatomic subregions of the supraspinatus on humeral rotation.

The supraspinatus, having distinct anterior and posterior subregions, is most commonly considered an abductor of the humerus, but it has also been shown to induce humeral rotation. The objective of this study was to quantify the magnitude and direction of humeral rotation that results from loading the distinct anterior and posterior subregions of the supraspinatus. Fourteen cadaver specimens were tested under four loading conditions based on physiological cross section area of the supraspinatus: (1) anterior only; (2) posterior only; (3) physiologic (each subregion loaded simultaneously); and (4) nonphysiologic (the tendon loaded as a whole). Each specimen was tested at 0, 15, 30, 45, and 60 degrees of glenohumeral abduction in the scapular plane and from 60 degrees of internal to 45 degrees of external rotation in 15 degrees increments. The humeral rotation that occurred with loading from the initial starting rotation position was measured using a rotary variable inductance transducer. In the scapular plane, the anterior subregion of the supraspinatus acts as both an internal and external rotator depending on the initial position of the humerus. The posterior subregion either acted as an external rotator or did not induce rotation. This study demonstrated a distinct functional difference between the anatomic subregions of the supraspinatus. This understanding will help to improve testing methods and the development of repair strategies of the supraspinatus.

Two-year efficacy and safety of AIR inhaled insulin in patients with type 1 diabetes: An open-label randomized controlled trial.

BACKGROUND: Patients with type 1 diabetes require intensive insulin therapy for optimal glycemic control. AIR((R)) inhaled insulin (system from Eli Lilly and Company, Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) may be an efficacious and safe alternative to subcutaneously injected (SC) mealtime insulin. METHODS: This was a Phase 3, 2-year, randomized, open-label, active-comparator, parallel-group study in 385 patients with type 1 diabetes who were randomly assigned to receive AIR insulin or SC insulin (regular human insulin or insulin lispro) at mealtimes. Both groups received insulin glargine once daily. Efficacy measures included mean change in hemoglobin A1C (A1C) from baseline to end point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety assessments included hypoglycemic events, pulmonary function tests, adverse events, and insulin antibody levels. RESULTS: In both treatment groups, only 20% of subjects reached the target of A1C <7.0%. A significant A1C difference of 0.44% was seen favoring SC insulin, with no difference between the groups in insulin doses or hypoglycemic events at end point. Patients in both treatment groups experienced progressive decreases in lung function, but larger (reversible) decrements in diffusing capacity of the lung for carbon monoxide (DL(CO)) were associated with AIR insulin treatment. Greater weight gain was seen with SC insulin treatment. CONCLUSIONS: The AIR inhaled insulin program was terminated by the sponsor prior to availability of any Phase 3 data for reasons unrelated to safety or efficacy. Despite early termination, this trial provides evidence that AIR insulin was less efficacious in lowering A1C and was associated with a greater decrease in DL(CO) and increased incidence of cough than SC insulin in patients with type 1 diabetes.

Effect of rotator cuff muscle imbalance on forceful internal impingement and peel-back of the superior labrum: a cadaveric study.

BACKGROUND: Throwing athletes with shoulder pain have been shown to have decreased rotator cuff muscle strength. Shoulder internal impingement and labral peel-back mechanism, as may occur during the late cocking phase of throwing motion, are thought to cause rotator cuff injury and type II superior labrum anterior and posterior lesions. Therefore, the objective of this study was to assess the effect of rotator cuff muscle force on internal impingement and the peel-back of the superior labrum by quantifying maximum external rotation, glenohumeral contact pressure, and position of the cuff insertion relative to the glenoid. HYPOTHESIS: A change in rotator cuff muscle force will lead to increased external rotation, glenohumeral contact pressure, and overlap of the cuff insertion relative to the glenoid. STUDY DESIGN: Controlled laboratory study. METHODS: Eight fresh-frozen cadaveric shoulders were tested at the simulated late cocking position. Glenohumeral contact pressure, location of the cuff insertion relative to the glenoid, and maximum humeral external rotation angle were measured. The forces of the supraspinatus, subscapularis, and infraspinatus muscles were determined based on published clinical electromyographic data. To assess the effect of cuff muscle imbalance, each muscle force was varied. Horizontal abduction positions of 20 degrees , 30 degrees , and 40 degrees with respect to the scapular plane were tested. RESULTS: Decreased subscapularis strength resulted in a significant increase in maximum external rotation (P <.001) and increased glenohumeral contact pressure (P <.01). The cuff insertion overlapped the edge of the glenoid at 30 degrees and 40 degrees of horizontal abduction for all muscle loading conditions. CONCLUSION: Decreased subscapularis muscle strength in the position simulating the late cocking phase of throwing motion results in increased maximum external rotation and also increased glenohumeral contact pressure. CLINICAL RELEVANCE: Athletes with decreased subscapularis muscle strength, such as fatigue with repetitive throwing, may be more susceptible to rotator cuff tears and type II superior labrum anterior and posterior lesions. Subscapularis muscle strengthening exercises may be beneficial for preventing these injuries.

AIR inhaled insulin versus subcutaneous insulin: pharmacokinetics, glucodynamics, and pulmonary function in asthma.

OBJECTIVE: This study evaluated pharmacokinetic and glucodynamic responses to AIR inhaled insulin relative to subcutaneous insulin lispro, safety, pulmonary function, and effects of salbutamol coadministration. RESEARCH DESIGN AND METHODS: Healthy, mildly asthmatic, and moderately asthmatic subjects (n = 13/group, aged 19-58 years, nonsmoking, and nondiabetic) completed this phase I, open-label, randomized, crossover euglycemic clamp study. Subjects received 12 units equivalent AIR insulin or 12 units subcutaneous insulin lispro or salbutamol plus AIR insulin (moderate asthma group only) before the clamp. RESULTS: AIR insulin exposure was reduced 34 and 41% (both P < 0.01) in asthmatic subjects (area under the curve(0-t'), 24.0 and 21.1 nmol x min x l(-1) in mild and moderate asthma subjects, respectively) compared with healthy subjects (35.2 nmol x min x l(-1)), respectively. Glucodynamic (G) effects were similar in healthy and mildly asthmatic subjects (G(tot) = 38.7 and 23.4 g, respectively; P = 0.16) and were reduced in moderately asthmatic subjects (G(tot) = 10.7 g). Salbutamol pretreatment (moderately asthmatic subjects) improved bioavailability. AIR insulin had no discernable effect on pulmonary function. AIR insulin adverse events (cough, headache, and dizziness) were mild to moderate in intensity and have been previously reported or are typical of studies involving glucose clamp procedures. CONCLUSIONS: This study suggests that pulmonary disease severity and asthma treatment status influence the metabolic effect of AIR insulin in individuals with asthma but do not affect AIR insulin pulmonary safety or tolerability. In view of the potential interactions between diabetes treatment and pulmonary status, it is prudent to await the results of ongoing clinical trials in diabetic patients with comorbid lung disease before considering the use of inhaled insulin in such patients.

Effects of exenatide versus insulin analogues on weight change in subjects with type 2 diabetes: a pooled post-hoc analysis.

BACKGROUND AND OBJECTIVE: In two previously reported multi-center, randomized, open-label, comparator (insulin) controlled trials in patients with type 2 diabetes sub-optimally controlled with metformin and a sulfonylurea, treatment with exenatide and insulin analogue therapy produced similar reductions in glycosylated hemoglobin A(1c) (A1C). However, treatment with exenatide was associated with a reduction in body weight while insulin analogue therapy was associated with weight gain. This analysis further characterizes the relative impact of commonly employed insulin analogues versus exenatide on weight change over a 6-month period. RESEARCH DESIGN AND METHODS: In this pooled post-hoc analysis of two trials, 1047 subjects with diabetes were compared regarding the relative impact of an adjunctive treatment - an insulin analogue (glargine or biphasic insulin aspart) or exenatide (5 mug twice daily for 4 weeks, 10 mug thereafter) - on body weight. RESULTS: While exenatide treatment provided similarly effective glycemic control compared with insulin analogue therapy, it was also associated with weight reduction in the majority of subjects (73.3%, averaging 3 kg decrease by endpoint), with approximately 22% achieving > or =5% weight loss, and 3.2% of subjects achieving > or =10% weight loss. In contrast, by the end of the study most insulin-treated subjects (75.9%) had gained weight (mean 3 kg). Only 2% of insulin-treated subjects achieved > or =5% weight loss, and 0.2% of subjects achieved > or =10% weight loss. CONCLUSIONS: These findings support the use of exenatide as a treatment option in insulin-naïve subjects with type 2 diabetes and who are overweight and sub-optimally controlled by metformin and sulfonylurea. However, these results should be interpreted with caution given the exploratory nature of this post-hoc analysis.

Premeal insulin lispro plus bedtime NPH or twice-daily NPH in patients with type 2 diabetes: acute postprandial and chronic effects on glycemic control and cardiovascular risk factors.

OBJECTIVE: Two insulin regimens were used to explore acute and chronic postprandial changes in glycemia, lipemia, and metabolic markers associated with increased risk of cardiovascular disease. METHODS: An open-label, randomized, two-period crossover study (12 weeks/period) compared a prandial regimen [premeal insulin lispro+bedtime neutral protamine Hagedorn (NPH)] with a basal regimen (twice-daily NPH). There were 30 patients (12 women and 18 men; mean age=61 years) with type 2 diabetes mellitus (mean duration=16 years) who were randomized after a 2-month lead-in with twice-daily NPH treatment. A standard lunch test meal developed according to each patient's caloric needs was administered at the end of each treatment period. RESULTS: Insulin lispro was associated with significantly lower postprandial glucose (area under the curve0-5 h=43.54 vs. 57.65 mM/h; P<.001), elevated insulin concentrations, and acutely altered lipid fractions that included an early decrease followed by an increase in free fatty acids, lower triglycerides, elevated total cholesterol, elevated low-density lipoprotein cholesterol (LDL), and elevated high-density lipoprotein cholesterol. After 12 weeks of treatment, insulin lispro+bedtime NPH reduced hemoglobin A1c (HbA1c; mean+/-SE=7.6+/-0.2 vs. 8.2+/-0.2%; P<.001) without increasing hypoglycemia or insulin dose as compared with twice-daily NPH. Furthermore, treatment with the prandial insulin regimen resulted in lower total cholesterol, lower LDL cholesterol, and lower oxidized LDL. CONCLUSION: Improved postprandial glycemic control, as observed in a regimen containing both prandial insulin lispro and NPH as the basal insulin, is associated with significantly lower HbA1c and acute modulation of lipid fractions after a test meal. These biochemical modifications may potentially have a favorable impact on cardiovascular risk in patients with type 2 diabetes mellitus.

Inhaled insulin delivery--where are we now?

Since 1925, when the concept of treating diabetes with inhaled insulin (INH) was originally published, a number of clinical challenges have been resolved through technological advancements. Efforts by pharmaceutical partnerships or individual companies have resulted in the development of both injection-free devices and novel insulin formulations. Four different INH systems are now in phase 3 of clinical development, and several other INH systems are in earlier stages of clinical study. Clinical data consistently demonstrate that INH therapy is comparable to subcutaneous (SC) therapy in improving glycaemic control in patients with either type 1 or type 2 diabetes, generally without greater risk of overall hypoglycaemia. INH is generally well tolerated and appears to be safe. Adverse-event profiles for INH therapies are similar to SC insulin therapy, with the majority of events being reported as being mild to moderate. Long-term safety studies are ongoing, with emphasis on evaluating the impact of INH therapy on pulmonary function and immune responses. Although small, reversible decreases in pulmonary diffusion capacity (DL(co)) and FEV1 have been reported in response to INH, pulmonary function and structure do not appear to be affected in any clinically significant way. While insulin antibodies are increased in INH therapy, these antibodies have not been correlated with haemoglobin A1c (HbA1c), insulin dosage, hypoglycaemia, pulmonary function or adverse events. Nevertheless, properly controlled, long-term studies will best answer any remaining concerns. From the patient's perspective, INH therapy is preferred by the majority of patients over conventional SC insulin therapy. Studies have shown that patients prefer INH therapy, because it provides greater lifestyle flexibility and social acceptability while at the same time avoiding the pain associated with injection. Thus, after more than 80 years during which the injection route has been the only means of administering insulin, patients and physicians may soon avail themselves of another valuable tool in management of diabetes.

Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model.

Prostate adenocarcinoma is associated with the formation of osteoblastic metastases in bone. It has been hypothesized that osteoclastic bone resorption is a critical component before the development of these osteoblastic lesions in bone. This observation has led researchers to test agents that inhibit osteoclastic activity to prevent or halt the formation of metastatic prostate cancer lesions in bone. Bisphosphonates inhibit osteoclast activity, and previous studies showed that they have the ability to reduce the osteolytic bone resorption associated with multiple myeloma and breast cancer. The objective of this study was to evaluate the efficacy of zoledronate in limiting the formation and/or progression of osteoblastic lesions produced by the injection of known prostate cancer cells (LAPC-9 and PC-3 cells) into the tibia of SCID mice. The mice were treated with either 30- micro g or 150- micro g doses of zoledronate before tumor implantation (pretreatment group), or at weekly intervals after tumor implantation (weekly treatment group), or weekly starting one month after tumor implantation (delayed-treatment group). The zoledronate was very effective in limiting the formation of osteolytic lesions in PC-3 implanted tibias by inhibiting osteoclast activity. Radiographic and histological analysis at weekly intervals revealed that osteolytic lesions developed in the control tibias by 2 weeks, and there was complete destruction of the cortical bone in much of the proximal tibias by 4 weeks. In the treatment groups, there was minimal cortical destruction noted in the weekly treatment groups at both doses, whereas mild cortical erosion was evident in the pretreatment groups, with more cortical destruction noted in the 30- micro g group compared with the 150- micro g group. Tartrate-resistant acid phosphatase (TRAP) staining showed that zoledronate decreased osteoclastic numbers and that there was a dose-dependent response. In tibias implanted with the LAPC-9 cells, the zoledronate was not effective in halting the formation of the osteoblastic lesions. Radiographic and histological analysis revealed that osteoblastic lesions either had formed or were developing in 18 of 18 of the control tibias and 36 of 36 of the treated tibias at 8 weeks regardless of dose or treatment schedule. Furthermore, TRAP staining demonstrated that osteoblastic lesions had formed in the LAPC-9 tibias under conditions in which osteoclast numbers were significantly reduced. These results suggest that osteoclast activity may not be critical for the development of osteoblastic lesions associated with prostate tumor cells. Hence, bisphosphonates may not be ideal agents to prevent the formation of osteoblastic lesions associated with prostate cancer metastases to bone.