Shoulder arthroplasty using mini-stem humeral components and a lesser tuberosity osteotomy.

PURPOSE: To determine whether lesser tuberosity osteotomy (LTO) and mini-stem humeral components (MSHCs) can be safely and effectively used together in total and hemi-shoulder arthroplasty (TSA/HHA). METHODS: This is a retrospective review of consecutive patients who underwent anatomic TSA/HHA utilizing combined LTO/MSHC with minimum 2-year follow-up. Six-week and final radiographs, range of motion, pain scores, and selected outcome measures were assessed. RESULTS: Seventy five shoulders with mean follow-up of 27.8 months (24-50 months) were analyzed. Sixty-seven (89.3%) shoulders had uneventful LTO healing. There were five (6.67%) LTO failures, one (1.33%) fibrous union, and two (2.67%) osteotomies that had displaced > 4 mm at 6 weeks; four of the five failures required open repair, including one converted to reverse TSA. The other failure, the fibrous union, and the two displaced osteotomies were without clinical deficits and elected for non-operative management. One patient required intraoperative conversion to a long stem due to concern that metaphyseal bone integrity was compromised, in part, by the LTO. Four (5.33%) stems subsided, with one of them also being frankly loose and requiring revision, while the other three were asymptomatic, not requiring treatment. No other stems were judged to be loose. Mean ASES, SANE, VAS, forward flexion, external rotation, and internal rotation all improved significantly (p < 0.001 for all). CONCLUSIONS: LTO/MSHC use is appropriate for TSA/HHA, achieving pain relief and functional improvement. Component loosening appears uncommon at early follow-up. Long-stem components should be available in case the metaphyseal bone is compromised. When performed properly, LTO/MSHC use is a safe and effective surgical strategy.

A pilot study to examine the feasibility of insulin glargine in subjects with impaired fasting glucose, impaired glucose tolerance or new-onset type 2 diabetes.

OBJECTIVE: People with early type 2 diabetes and pre-diabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) are at risk of hyperglycaemia-related complications, including cardiovascular disease. Insulin, traditionally reserved as late treatment in type 2 diabetes, may also be a useful therapy in this population. We examined the short-term efficacy and tolerability of insulin glargine (glargine) in individuals with early or pre-type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicentre, double-blind, placebo-controlled, randomized, parallel group, 12-day study, subjects with IGT/IFG (n=9), newly diagnosed type 2 diabetes (n=9) or normal glucose tolerance (n=3) (confined to a clinical research unit taking a prescribed diet) were randomized to once-daily glargine (n=16) or placebo (saline; n=5) at bedtime. Dose was titrated to achieve target fasting blood glucose (FBG) 80-95 mg/dL. RESULTS: Over the treatment period, mean FBG decreased in glargine-treated subjects (from 100.0+/-18.8 to 85.6+/-18.4 mg/dL), but was unchanged in placebo-treated subjects (from 112.5+/-10.6 to 111.3+/-17.5 mg/dL). Mean eight-point blood glucose value decreased by 9.7 mg/dL in the glargine group, but increased by 8.1 mg/dL in the placebo group. Mean post-exercise blood glucose was similar before and after glargine treatment, but increased after placebo treatment. Five subjects receiving glargine experienced 16 mild symptomatic hypoglycaemia episodes; however, no hypoglycaemia occurred during exercise. Mean body weight decreased in both the glargine (-0.44 kg) and placebo (-0.25 kg) groups, in line with dietary restrictions. CONCLUSIONS: The results of this pilot study suggest that glargine can be used by people with IFG, IGT or new-onset type 2 diabetes for management of hyperglycaemia with low risk of hypoglycaemia. However titration of insulin in people on dietary restrictions should be more cautious as they may be more prone to hypoglycaemia. Further studies are warranted to determine the clinical benefits of this approach.

Effects of the carbohydrase inhibitor miglitol in sulfonylurea-treated NIDDM patients.

OBJECTIVE: To examine the effects of the carbohydrase inhibitor miglitol (BAY m 1099) on the metabolic profiles of non-insulin-dependent diabetes mellitus (NIDDM) patients suboptimally controlled on maximal daily doses of sulfonylurea (SFU) agents. RESEARCH DESIGN AND METHODS: Multicenter, double-blind, randomized, placebo-controlled 14-week clinical trial with six-week, single-blind placebo lead-in and run-out periods. NIDDM volunteers (192) with fasting plasma glucose (FPG) 140-250 mg/dl and hemoglobin A1c (HbA1c) 6.5-12.0% after at least 4 weeks of treatment with SFU at maximal dose were stratified by baseline HbA1c (above and below 9.0%) and then randomly assigned within strata to placebo (n = 63), 50 mg miglitol 3 times a day (n = 61), or 100 mg miglitol 3 times a day (n = 68). Efficacy was assessed by HbA1c, FPG, insulin, and lipid concentrations, and by plasma glucose and serum insulin responses to a standard meal. RESULTS: In the 50 and 100 mg miglitol treatment groups, the mean changes from baseline in HbA1c (with placebo values subtracted) were 0.82 and 0.74%, respectively, and were highly significant (P = 0.0001 in each case). Mean peak plasma glucose levels after a standard test meal were comparably lowered by 57 mg/dl with the 50 mg miglitol dose, and by 64 mg/dl with the 100 mg miglitol dose compared with placebo (P = 0.0001 for each), with associated reductions in integrated serum insulin response (P < 0.05). No significant drug-associated changes in FPG, insulin, or cholesterol levels were noted, but fasting triglyceride levels were lowered significantly with the 50 mg miglitol dose. Miglitol's side effects were limited to flatulence, loose stools, and abdominal discomfort, which were dose-related, rapidly resolved on drug discontinuation, and led to withdrawal from the study of 5 and 15% of patients taking 50 and 100 mg miglitol, respectively. CONCLUSIONS: Miglitol may be indicated as effective adjuvant therapy in NIDDM patients with suboptimal metabolic control despite conventional treatment with diet and maximal daily doses of SFU. The dose of 50 mg miglitol 3 times a day may be preferable to 100 mg miglitol 3 times a day because of comparable efficacy and substantially reduced side effects.

Long-term titrated-dose alpha-glucosidase inhibition in non-insulin-requiring Hispanic NIDDM patients.

OBJECTIVE: To assess the long-term safety and effectiveness of a titrated dose of the alpha-glucosidase inhibitor miglitol (BAY m 1099) in Hispanic NIDDM patients. RESEARCH DESIGN AND METHODS: A 1-year double-blind randomized placebo-controlled study in which diet-treated or diet plus sulfonylurea-treated Hispanic NIDDM patients received either placebo (n = 131) or miglitol in doses of 50, 100, 150, 200 mg t.i.d. (n = 254), up-titrated and down-titrated based on tolerability. Efficacy parameters included changes from baseline in HbA1c, fasting and 2-h postprandial plasma glucose and serum insulin, fasting serum lipids, and urinary albumin-to-creatinine ratio (ACR). Safety assessments consisted primarily of tabulation of adverse events and intercurrent illnesses, and of periodic laboratory determinations. RESULTS: Reductions from baseline in HbA1c levels at the 6-month (primary efficacy) endpoint were significantly greater by 0.83% in the miglitol group than in the placebo group. HbA1c reductions in the miglitol treatment group significantly exceeded those in the placebo group by 0.63, 0.73, and 0.92% at 3, 9, and 12 months of treatment, respectively. Reductions in 120-min postprandial glucose and insulin levels were significantly greater in the miglitol group than in the placebo group at all postbaseline visits. There was little difference between treatments for changes in fasting insulin or lipid levels. Miglitol-associated reductions versus placebo in fasting plasma glucose (P = 0.0587 at 6 months) and in ACR (P = 0.0541 at 1-year) were nearly statistically significant. These efficacy results were not notably different between the 6-month endpoint, at which time the mean miglitol dose was 100 mg t.i.d., and the 1-year visit, when the mean miglitol dose was 149 mg t.i.d. Notable adverse events seen significantly more often in the miglitol group than in the placebo group were flatulence and diarrhea (or soft stools). The incidence of these gastrointestinal adverse events appeared to be dose dependent. CONCLUSIONS: Miglitol treatment of non-insulin-requiring Hispanic NIDDM patients at doses from 50 to 200 mg t.i.d. produced statistically and clinically significant reductions of HbA1c, primarily associated with reduction of glucose and insulin levels in the postprandial period, which were sustained over a year of treatment. Adverse events related to the drug's mechanism of action were common, but generally well tolerated. Doses above 100 mg t.i.d. were not associated with notably enhanced efficacy in most patients.

Chronic treatment of African-American type 2 diabetic patients with alpha-glucosidase inhibition.

OBJECTIVE: To evaluate the long-term efficacy, safety, and tolerability of the alpha-glucosidase inhibitor miglitol in the treatment of African-American patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 345 African-American type 2 diabetic patients (mean age 55.6 years, BMI 31.9 kg/m2, duration of diabetes 4.9 years, baseline HbA1C 8.7%) treated with either diet alone or sulfonylurea were randomized to 1 year of double-blind treatment with either placebo (n = 117) or miglitol (n = 228) at doses of 50 or 100 mg t.i.d., titrated based on tolerability. The primary efficacy criterion was change from baseline in HbA1C at the 6-month visit. Secondarily efficacy parameters included changes from baseline in plasma glucose and serum insulin (both fasting and 120 min after a standardized test meal), fasting lipids, and urinary albumin-to-creatinine ratio. Safety and tolerability evaluations were primarily based on reporting of adverse events and symptoms and on periodic laboratory analyses. RESULTS: Miglitol treatment was associated with a mean placebo-subtracted reduction in HbA1C from baseline of 1.19% at 6 months. Fasting and 120-min postprandial plasma glucose levels were reduced in parallel to HbA1C, in association with miglitol treatment. Significant reductions versus placebo in 120-min postprandial insulin levels, in LDL cholesterol, and in fasting triglycerides, were also seen in the miglitol group at individual study time points. Softer, more frequent stools and flatulence were significantly more common in the miglitol group. Urinary tract infections, hematuria, and herpes simplex infections were significantly more common in the placebo group. CONCLUSIONS: Miglitol treatment appears to be at least as efficacious in the African-American type 2 population as in the U.S. type 2 population at large, with comparable tolerability. alpha-Glucosidase treatment may be an important therapeutic option in these patients in view of their greater risk for microvascular complications and the accumulating body of evidence that better glucose control reduces the risk of these complications.

Advantages of alpha-glucosidase inhibition as monotherapy in elderly type 2 diabetic patients.

The objective of this study was to determine the safety, efficacy, and tolerability of the alpha-glucosidase inhibitor miglitol vs. the sulfonylurea glyburide in the treatment of elderly patients with type 2 diabetes mellitus, inadequately controlled by diet alone. This was a double-blind, randomized, placebo-controlled, 1-yr trial of miglitol 25 mg TID and 50 mg TID compared with placebo and a titrated dose of glyburide in a parallel group comparison study conducted in 30 out-patient sites across the United States. Four hundred eleven (411) diet-treated patients age 60 yr or greater were randomized to receive either placebo TID (n = 101), miglitol 25 mg TID (n = 104), miglitol 50 mg TID (n = 102), or a once-daily dose of glyburide titrated based on fasting plasma glucose (FPG) (n = 104), for a period of 56 weeks. Efficacy was assessed by glycated hemoglobin (HbA1c), fasting and post-meal glucose, insulin, and lipid levels, and by 24-h urinary excretion of glucose and albumin. Safety and tolerability were assessed by tabulation of adverse events, periodic laboratory determinations, and home blood glucose monitoring. HbA1c treatment effects (placebo-subtracted change in HbA1c from baseline) at the 1-yr endpoint were -0.49%, -0.40%, and -0.92% in the miglitol 25 mg TID, miglitol 50 mg TID, and glyburide groups, respectively (P < 0.05- 0.01 vs. placebo). Postprandial insulin levels were significantly greater than placebo and miglitol in the glyburide group (P < 0.01). Hypoglycemia, weight gain, and both routine and serious cardiovascular events were more frequent in the glyburide group (P < 0.05-0.01 vs. placebo or miglitol groups). Diarrhea (or soft stools) and flatulence were more common in both miglitol groups than in the other two groups in a dose-dependent manner, but resulted in relatively few study dropouts. Treatment with miglitol offers the elderly type 2 diabetic patient significant reductions in daylong glycemia as measured by HbA1c. The greater HbA1c reductions seen with once-a-day glyburide occurred at a cost of significant increases in weight, insulin levels, and the incidences of clinical and subclinical hypoglycemia, which did not occur in the miglitol groups. alpha-glucosidase inhibitors are a useful and relatively safe therapeutic option in the elderly patient with type 2 diabetes.

Discordant xenograft rejection in an antibody-free model.

Newborn pigs prevented from suckling colostrum were shown to have less than 0.05 micrograms/ml total immunoglobulin present in their serum. Rabbit heart xenografts transplanted heterotopically into the neck of such pigs were hyperacutely rejected, with a mean survival time of 92 +/- 14 min (mean +/- SD). Pigs which had been allowed to suckle and whose serum contained 10-15 mg/ml maternal immunoglobulin hyperacutely rejected rabbit heart xenografts in 109 +/- 62 min. Histological studies showed no Ig binding but complement component 3 (C3) binding to rabbit hearts placed in immunoglobulin-negative pigs. Prolongation of rabbit heart xenograft survival was achieved by administering cobra venom factor (1 mg/kg) to the pigs pretransplant. These data show hyperacute xenograft rejection in the absence of antibody and suggest that its cause is activation of complement by the alternative pathway.

Orthotopic liver transplantation at Addenbrooke's Hospital Cambridge 1968 to 1991.

Liver grafting is now established as the optimal treatment for patients with end-stage parenchymal liver disease. Twenty-three years of experience at a single center is presented. The 1-year actuarial patient survival rate for all cases transplanted in Cambridge has now risen from 10% in 1968 to 1970 to 80% in 1990 to 1991. Increasing numbers of patients are being referred for transplantation with an ever-increasing range of indications being developed. Many inborn errors of metabolism can now be cured by liver grafting. There is still, however, considerable scope for improvement in many areas of patient treatment from operative and postoperative care to long-term immunosuppressive management. Much remains to be done to minimize early sepsis- and rejection-related deaths and late immunosuppression-related morbidity.

Early abdominal complications following heart and heart-lung transplantation.

In the first 11 years of the heart and heart-lung transplantation programme at Papworth Hospital, Cambridge, 356 patients underwent heart transplantation, and 73 patients received both heart and lungs. Out of 429 patients 41 (9.5 per cent) developed abdominal complications within the first 30 days, and 20 of the 41 required surgery. The complications included pancreatitis (10), peptic ulceration (8), and pseudo-obstruction (8), in addition to colonic perforation and small bowel obstruction. When laparotomy was performed it was well tolerated. This paper supports the view that successful management of abdominal complications following transplantation requires prompt diagnosis and treatment. Where doubt exists in the presence of an acute abdomen, laparotomy is the appropriate way to establish a definitive diagnosis.

Immunofluorescent localization of pig complement component 3, regardless of the presence or absence of detectable immunoglobulins, in hyperacutely rejected heart xenografts.

Rabbit heart xenografts transplanted into the neck of newborn pigs were all hyperacutely rejected within two hours regardless of the presence or absence of detectable endogenous immunoglobulins (Ig). Cryostat tissue sections were prepared from the rejected rabbit hearts and incubated with sheep polyclonal antibodies against pig complement component 3 (C3), pig IgG and pig IgM. Specific immunoreaction was visualized by fluorescein-conjugated antibodies to sheep IgG. C3 was localized mainly on the surfaces of vascular endothelial as well as myocardial cells, and the localization was not dependent upon the presence of pig immunoglobulins within the same tissue. Both pig IgG and IgM were detected only in the heart xenografts transplanted into suckled pigs, whereas no trace of immunoglobulin was found in those transplanted into circulating antibody-free presuckled pigs. Treatment with cobra venom factor (which inhibits complement activity) prior to transplantation prolonged xenograft survival and completely abolished C3 immunostaining. The results provide new evidence at the histochemical level that the alternative pathway of complement is involved in hyperacute xenograft rejection of the species combination (rabbit to pig) used in this study.

Graft-versus-host disease in solid organ transplantation.

Graft-versus-host disease is well recognized in bone marrow transplantation, but has only recently been described in solid organ transplantation. Two such cases in liver graft recipients, proven by the demonstration of donor type HLA antigens in the peripheral blood and marrow on tissue typing, are described in this paper. The literature on this subject is reviewed and the treatment discussed. It is postulated that there is an order of risk of development of graft-versus-host disease depending on the amount of viable lymphoid tissue included with the transplanted organ as follows: small bowel greater than heart-lung greater than liver greater than kidney greater than heart. It seems likely that this condition has been substantially underdiagnosed in the past and that greater awareness of the possibility of graft-versus-host disease in solid organ recipients will lead to the recognition of further cases and allow appropriate treatment to be promptly instituted.

Liver transplantation in patients with situs inversus.

Seven patients with situs inversus abdominis and one with situs inversus totalis underwent liver transplantation; all are alive at follow-up of between 7 months and 5 years. Two patients required retransplantation within the first 3 weeks (for primary non-function and thrombotic infarction). Seven had additional abnormalities associated with the polysplenia-biliary atresia syndrome. Liver transplantation in these patients involved selection of relatively small donor organs or use of reduced-size grafts. Delayed abdominal wall closure was necessary in two patients and all required a modification of the 'piggy-back' technique of suprahepatic vena caval anastomosis to overcome recipient venous anomalies. Biliary drainage by Roux-en-Y choledochojejunostomy was the preferred technique. Although technically challenging, situs inversus is not a contraindication to liver transplantation and patients should expect full recovery.