Olanzapine and haloperidol in first episode psychosis: two-year data.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

Measurement of perioperative flexion-extension mechanics of the knee joint.

Perioperative knee mechanics currently are evaluated Perioperative knee mechanics currently are evaluated by measuring range of motion. This is an incomplete measurement, however, because the torque applied to achieve the motion is not measured. We hypothesized that a custom goniometer and force transducer could measure the torque required to passively flex a knee through its full range of motion. This measurement was done in the operating room immediately before and after surgery in 20 knees having total knee arthroplasty and 9 having surgery on another limb. Surgery changed the mechanics of 8 knees, whereas unoperated knees remained unchanged. This measurement technique is safe, easy, and repeatable. It improves on the current standard of perioperative knee measurement and can be applied to investigate the effects of surgery and rehabilitation on ultimate knee motion.

The significance of stem-cement loosening of grit-blasted femoral components.

This study analyzed 15 patients who underwent revision for loosening at the stem-cement interface. The femoral components were from the same manufacturer and had grit-blast roughened surfaces. An apparent radiographic deficiency in the cement mantle was present in at least one zone in 1 3 patients. In 9 of 12 patients with localized osteolysis, the osteolysis developed in a zone with an apparent radiographic cement mantle defect. Loosening occurred due to tension failure of the stem-cement interface followed by axial subsidence and movement into relative retroversion. Motion between the stem and the cement mantle fueled an abrasive wear mechanism between the roughened metal surface and the cement mantle, generating excessive metal and cement particles that gained access to endosteal bone via defects in the cement mantle and resulting in localized osteolysis. Although the roughened surface played a central role in these failures, it is unlikely the layer of polymethylmethacrylate (precoat) played a role in the mechanism of failure. In some cases, debonding occurred as a result of tension failure of the metal-precoat interface. In others, tension failure occurred within the cement mantle, leaving the precoat and some cement from the mantle on the stems. There was no difference in the mechanism of failure of stems with precoat proximally compared to stems with precoat proximally and distally. One stem had no precoat; findings in this patient were indistinguishable from the others. The significance of debonding depends on the surface roughness of the stem. Debonding carries a poorer prognosis with a rougher stem surface because of abrasive wear with the generation of numerous metal and cement particulates, which can lead to rapid osteolysis if there are cement mantle defects. Stems with a higher metal-cement bond strength may require a higher quality cement mantle for long-term success.

Fixation, polyethylene wear, and pelvic osteolysis in primary total hip replacement.

A multicenter retrospective review was performed analyzing 1081 primary total hip replacements in 944 patients using the Harris Galante-I cementless acetabular component with screw fixation. All patients were followed up for a minimum of 5 years with a mean followup of 81 months. Linear polyethylene wear averaged 0.11 mm/year (range, 0-0.86 mm/year). Pelvic osteolysis was seen in 25 patients (2.3%). Migration of the acetabular component was seen in four hips. A subgroup of patients was reanalyzed at a minimum followup of 10 years. The mean linear polyethylene wear rate remained 0.11 mm/year. In this group, only one socket had migrated. There was an association between wear rate and age. On average, younger patients had higher wear rates. The risk for having pelvic osteolysis develop and the need for revision surgery also was age-related. Twenty-two percent of hip replacements (15 hips) in patients younger than 50 years of age at the time of their index operation had pelvic osteolysis develop. In contrast, for patients older than 50 years of age at the time of surgery only 7.8% (eight hips) had osteolysis of the pelvis develop. For patients older than 70 years of age at the time of primary total hip replacement, none had pelvic osteolysis develop.

Risk factors for dislocation during the first 3 months after primary total hip replacement.

The prevalence of dislocation of a total hip replacement during the first 3 postoperative months was determined for a series of 315 patients who underwent a unilateral primary total hip operation. All operations were performed by 1 surgeon using a standardized posterior approach with a complete capsulectomy. All of the patients had a femoral component made by 1 manufacturer that had the same 28-mm modular head, the same femoral neck diameter, and the same offset for each size implant. One cementless acetabular component was used for all patients. All of the patients followed the same postoperative rehabilitation program. Of 315 patients, 14 sustained a dislocation, resulting in a prevalence of 4%. There were 13 posterior dislocations and 1 anterior dislocation. Because the surgeon, the surgical approach, the femoral component design, and the rehabilitation protocol were identical for all of these patients, the only variables that could affect the risk of dislocation were the size of the acetabular component and the femoral neck length, the type of fixation of the femoral component, the orientation of the acetabular component, and the characteristics of each patient. The patient characteristics that were studied included age; gender; height; weight; preoperative diagnosis; and a category termed cerebral dysfunction, which included a state of confusion during the hospital stay, a prior history of excessive alcohol consumption, or both of these conditions. Statistical analysis demonstrated 1 variable that was associated with a higher dislocation rate, the presence of cerebral dysfunction. There was a trend toward increased age as a risk factor. None of the other patient or component variables were found to be significant risk factors.

Results of a method of leg-length equalization for patients undergoing primary total hip replacement.

The postoperative leg-length discrepancy was determined radiographically for a consecutive series of 351 patients (408 hips) who underwent bilateral or unilateral primary total hip replacement using a single method of leg-length equalization by preoperative planning with overlay templates. The method of equalization was performed by a measurement of the femoral head and neck segment to be resected from a reference point at the superior aspect of the dislocated femoral head. The amount of femoral bone resected was determined preoperatively by determining the dimensions of the acetabular component thickness and the femoral component head and neck height that would be replacing this resected bone and adjusting this distance for any preexisting leg-length discrepancy. Using this leg-length equalization method, the length of the modular femoral head neck was chosen preoperatively, rather than using soft tissue tension across the prosthetic hip joint to determine whether the leg lengths were equal. Postoperative leg lengths were determined radiologically from a measurement from the acetabular teardrop to the lesser trochanter. Ninety-seven percent of the patients had a postoperative leg-length discrepancy that was less than 1 cm, and 86% had a leg-length difference that was 6 mm (1/4 inch) or less. The average postoperative discrepancy for these 351 patients was 1 mm.

Prediction of postoperative knee flexion in Insall-Burstein II total knee arthroplasty.

Postoperative knee flexion in patients undergoing Insall-Burstein-II total knee arthroplasty at 2 years was evaluated regarding two basic questions: what groups of patients gain or lose the most flexion and what groups of patients have the best or worst postoperative flexion. Thirteen preoperative variables (maximum flexion, flexion arc, tibiofemoral angle, quadriceps strength, extensor lag, Knee Society score, Knee Society patient assessment, gender, age, height, weight, diagnosis, and surgeon) and four postoperative variable (leg length change, tibiofemoral angle, distance from patella to the joint line, and the tibial prosthesis anteroposterior translation on a lateral radiograph) were used in an attempt to explain postoperative flexion. The analysis was performed on 164 consecutive Insall-Burstein-II total knees in which the data were gathered prospectively on a time oriented medical record database. A regression tree analysis was used to identify several groups of patients, characterized by preoperative factor values, who had markedly above average performance on postoperative flexion. The preoperative factors identified include preoperative flexion, flexion arc, tibiofemoral angle, extensor lag, diagnosis, and age. The only postoperative variable of significance was tibiofemoral angle. Among the potential determinants of postoperative flexion that failed to appear predictive were the Knee Society scores and surgeon. Preoperative flexion is known to be a critical determinant of postoperative flexion in total knee replacement. However, in the current study, preoperative flexion accounted for only half of the difference between the best (122 degrees) and the worst (88 degrees) group, as determined with regression tree analysis.

Cellular profile and cytokine production at prosthetic interfaces. Study of tissues retrieved from revised hip and knee replacements.

The tissues surrounding 65 cemented and 36 cementless total joint replacements undergoing revision were characterised for cell types by immunohistochemistry and for cytokine expression by in situ hybridisation. We identified three distinct groups of revised implants: loose implants with ballooning radiological osteolysis, loose implants without osteolysis, and well-fixed implants. In the cemented series, osteolysis was associated with increased numbers of macrophages (p = 0.0006), T-lymphocyte subgroups (p = 0.03) and IL-1 (p = 0.02) and IL-6 (p = 0.0001) expression, and in the cementless series with increased numbers of T-lymphocyte subgroups (p = 0.005) and increased TNF alpha expression (p = 0.04). For cemented implants, the histological, histochemical and cytokine profiles of the interface correlated with the clinical and radiological grade of loosening and osteolysis. Our findings suggest that there are different biological mechanisms of loosening and osteolysis for cemented and cementless implants. T-lymphocyte modulation of macrophage function may be an important interaction at prosthetic interfaces.

Deep venous thrombosis prophylaxis for knee replacement: warfarin and pneumatic compression.

A prospective study of the prevalence of proximal deep venous thrombosis in total knee replacement patients who had prophylaxis for thrombosis with a combination of low-dose warfarin and intermittent pneumatic compression was done. Two hundred and ninety-seven patients who underwent 377 consecutive total knee replacements were studied. All patients were treated with low-dose warfarin and intermittent pneumatic compression using thigh-high sleeves. Surveillance for proximal thrombosis was done by duplex ultrasonography. Proximal thrombosis was detected in 19 patients, for a prevalence of 5%. There were 3 patients who had a major bleeding complication, for a prevalence of 0.9% for the 337 procedures performed. Although there was no concurrent control group of patients treated with another means of prophylaxis to compare with these patients, the low prevalence of proximal thrombosis and the low risk of major bleeding complications that was found compares well with recent reports on the effectiveness and safety of low-molecular-weight heparin.

Factor V Leiden and the risk of proximal venous thrombosis after total hip arthroplasty.

Deep vein thrombosis (DVT) remains a major cause of morbidity in patients undergoing total hip arthroplasty (THA). Despite postoperative DVT prophylaxis, 20-50% of THA patients still develop DVT. Currently, there is no accurate way of predicting which patients will develop DVT despite standard prophylaxis. The presence of factor V Leiden is the most common cause of inherited DVT risk. It has been postulated that patients who have factor V Leiden and are subjected to thrombogenic stressors such as THA would have an increased risk of thrombosis. The factor V Leiden genotype of 36 patients who developed proximal DVT after surgery and 45 control patients who had THA but did not develop DVT was determined. All patients had had prophylaxis against thrombosis using intermittent pneumatic compression alone or in combination with warfarin or aspirin. Surveillance for proximal DVT was performed on all patients prior to discharge by duplex ultrasound. The 2 groups were similar in age, sex, and type of operation. Three of 36 study patients who had developed DVT (8%) and 2 of 45 control patients who had not developed DVT (4%) were heterozygotes for factor V Leiden; these prevalences were not statistically different. Heterozygosity for factor V Leiden is not associated with DVT prophylaxis failure in patients undergoing THA.

Referral patterns of hip pain in patients undergoing total hip replacement.

This study was undertaken to determine the most common referral patterns of hip pain in patients scheduled to undergo primary and revision total hip replacement. The exact location of pain from the hip was recorded prospectively for 323 patients (358 hips) who had primary total hip replacement and for 94 patients who had revision of a loose total hip. Seventy-three percent of patients with primary hip disease had pain in the groin, and 27% had groin pain that referred to the knee. Eighty-nine percent of 57 patients who had femoral component loosening had thigh or knee pain, and all of the 34 patients who had a loose acetabular component with a well-fixed femoral implant had pain in the hip region without distal radiation of pain. These results indicate that in patients who have a painful total hip, thigh pain is highly suggestive of femoral component loosening and pain located around the hip region that does not radiate distally is associated with isolated acetabular component loosening.

Fatigue fracture of a forged cobalt-chromium-molybdenum femoral component inserted with cement. A report of ten cases.

Ten patients who had had a total hip replacement with a forged cobalt-chromium-molybdenum femoral prosthesis (Precoat or Precoat Plus) inserted with cement were seen with a fatigue fracture of the stem an average of fifty months (range, nineteen to seventy-four months) postoperatively. The average age of the patients was sixty-one years (range, forty-three to seventy-three years), and the average weight was ninety-six kilograms (range, seventy to 130 kilograms). Eight patients had had a primary total hip replacement, and two had had a revision; all of the acetabular components had been inserted without cement. Radiographs that had been made before the fracture were available for four of the eight hips that had had a primary replacement; all four had radiographic evidence of debonding of the cement mantle from the proximal end of the stem. This probably caused exaggerated cantilever bending stresses on the proximal aspect of the stem as the distal end of the stem was well fixed. The radiographs of both hips that had had a revision demonstrated a non-union of the greater trochanter, which had resulted in separation at the cement-bone interface at the proximal portion of the femur before the fracture. Scanning electron micrographs of five of the ten fractured prostheses demonstrated a fatigue fracture that began near the anterolateral corner of the prosthesis, through characters that had been etched on the implant with a laser. Metallurgical analysis indicated subsurface voids or inclusions, or both, immediately under the region that had been etched. This finding is consistent with thermal changes to the microstructure of the alloy that probably caused a focal reduction in the material strength. A high proportion (seven) of the ten stems had a poor cement mantle. Also, of the seven small stems that were used, six had been implanted in patients who weighed more than eighty kilograms, so there was relative undersizing of the prostheses. Early debonding of the proximal end of a Precoat femoral prosthesis from the cement mantle may occur as a result of a thin cement mantle, leading to loosening and possibly to early fatigue fracture of the stem if the distal portion of the stem remains solidly fixed in the distal portion of the cement column. On the basis of our experience, we recommend that patients who have radiographic evidence of a debonded Precoat femoral component should be informed of the risk of fatigue fracture of the stem and be followed closely even though there may be no symptoms of loosening of the femoral component.

Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase.

This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these compounds, 1k and 1l, have high levels of oral bioavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compounds demonstrate that peptidyl trifluoromethyl ketone inhibitors can achieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of diseases in which elastase is implicated.

Loosening and osteolysis of cemented joint arthroplasties. A biologic spectrum.

The purpose of this study was to characterize the cell types (using immunohistochemistry) and cytokine expression (using in situ hybridization) of tissues surrounding well fixed and loose cemented prostheses undergoing revision. Clinical and radiographic data were gathered prospectively for a series of cemented total joint replacements undergoing revision. Three groups were identified: (1) loose implants with osteolysis (10 specimens), (2) loose implants without osteolysis (11 specimens), and (3) well fixed implants (7 specimens). At surgery, a specimen was harvested from the bone cement interface. Immunohistochemical staining was performed using monoclonal antibodies to identify macrophages and lymphocyte subgroups. Human antisense probes were selected to identify the mRNA for specific cytokines using in situ hybridization. The percentage of positively staining cells was determined for each antibody or probe using a grid counting technique. Tissues from loose cemented prostheses with osteolysis contained significantly greater numbers of macrophages and T lymphocytes compared with tissues from loose and well fixed cemented prostheses without osteolysis. The number of interleukin-1 and interleukin-6 positive cells was highest in specimens with osteolysis and lowest in specimens from well fixed prostheses. These cytokines modulate the growth and differentiation of cells in the immune system and the monocyte and macrophage system and mediate the remodeling of bone and mesenchymal tissues. Specific cell populations and cytokine profiles appear to be involved in periprosthetic osteolysis; this information may be useful in planning strategies for prevention and treatment.

Intermittent pneumatic compression prophylaxis for proximal deep venous thrombosis after total hip replacement.

The efficacy of intermittent pneumatic compression in the prevention of proximal deep venous thrombosis was determined in a consecutive series of patients who had primary or revision total hip replacement. Two hundred and eighty-nine patients (242 primary and eighty revision hip replacements) who were at least forty years old were managed intraoperatively and postoperatively with intermittent pneumatic compression with use of thigh-high sequential compression sleeves and thigh-high elastic compression stockings as the only form of prophylaxis. Venous ultrasonography of the ipsilateral lower extremity was performed, at an average of five days postoperatively, to determine the presence of a thrombus in the femoral and popliteal veins. The prevalence of proximal deep venous thrombosis was 6 per cent (twenty of 322 procedures), and no patient had a clinically detected pulmonary embolism. The prevalence of a proximal thrombus was 4 per cent (ten of 233 procedures) when a regional anesthetic had been used and 11 per cent (ten of eighty-nine procedures) when a general anesthetic had been used; this difference was significant (p = 0.02). The prevalence of a proximal thrombus was 3 per cent (eight of 245 procedures) for patients who were less than seventy-five years old and 16 per cent (twelve of seventy-seven procedures) for patients who were seventy-five years old or more (p < 0.0001). No patient had a major bleeding complication. Twenty-nine other patients who had an additional risk factor for thrombosis, such as a history of deep venous thrombosis, were managed with intermittent pneumatic compression and low-dose warfarin. The prevalence of proximal deep venous thrombosis in this group of patients was 19 per cent (six of thirty-one procedures). Intraoperative and postoperative intermittent pneumatic compression, combined with the use of a regional anesthetic, was found to be highly effective in the prevention of proximal deep venous thrombosis after total hip replacement. Despite the limitations inherent in comparisons among series, it is noteworthy that the prevalence of proximal thrombosis in our series was similar to the reported prevalences in several large series of patients who had a total hip replacement and were managed with either low-dose warfarin or low-molecular-weight heparin. However, there was no risk of major postoperative bleeding in the current study.

Acetabular revision using a bone-ingrowth total hip component in patients who have acetabular bone stock deficiency.

The clinical and radiologic results of acetabular revision using a porous titanium-mesh metal-backed acetabular component fixed to the pelvis with screws were studied in 30 consecutive patients (32 hips) who had moderate or severe acetabular bone loss. All of the acetabula were classified as type III or IV according to the American Association of Orthopaedic Surgeons' acetabular grading system. Particulate autologous or allogenic bone-graft was used in 75% of the reconstructions. The mean follow-up period was 69 months (range, 46-109 months). Three acetabular components (9%) were rerevised for aseptic loosening at an average of 64 months, including one patient who had a primary diagnosis of radiation necrosis of the ilium. The average Harris hip score for the remaining 29 hips rose from 46 to 81. The radiologic failure rate was 3% (1 of 29 unrevised hips) for a total failure rate of 12%. No pelvic osteolysis was seen with this implant. Revision of acetabula that have moderate or severe bone deficiency by a bone-ingrowth acetabular component fixed with screws and bone-graft appears to be successful in restoring bone stock and providing a stable, pain-free reconstruction.

Porous pad separation and loosening of Harris-Galante femoral hip components.

Failure of the bond between the metal beads and the solid substrate of porous-coated chrome-cobalt femoral components, or so-called "bead shedding," has been reported previously and may indicate motion of the component within the femur or mechanical loosening of the prosthesis. Failure of the bond between a sintered titanium fibermesh pad and a titanium alloy femoral stem has not been documented in the literature to date. The separation of fibermesh pads from three Harris-Galante femoral prostheses (Zimmer, Warsaw, IN) is reported.

Primary total hip replacement with insertion of an acetabular component without cement and a femoral component with cement. Follow-up study at an average of six years.

We performed a retrospective study of a consecutive series of patients who had had a primary total hip replacement with so-called hybrid fixation of the components (an acetabular component inserted without cement and a femoral component inserted with cement) between September 1985 and June 1989. Clinical data were available for 114 patients (125 hips), of whom 110 (121 hips) also had radiographic data. The minimum duration of follow-up was fifty-six months or until revision, and the average duration was seventy-two months. The average Harris hip score improved from 47 points preoperatively to 91 points postoperatively (for the 109 patients who did not have subsequent revision of the femoral component). Only three patients who did not have a revision had more than slight pain in the hip. Four hips (3 percent) were revised for aseptic loosening of the femoral component at an average of fifty-five months; two of these four had a fracture of the femoral component. One patient had resection arthroplasty for late infection. One patient had disassembly of an acetabular polyethylene liner, and another had dissociation of a modular femoral head; both patients had a reoperation. Radiographically, two femoral components were definitely loose, as determined by subsidence of the component in one patient and a fracture of the cement in the other. Ten hips (8 percent) had endosteal lysis of the femur. Over-all, 5 percent (six) of 121 femoral components were either revised for loosening or had definite radiographic evidence of loosening, but no acetabular component was loose. The clinical results in the 104 patients (115 hips) for whom clinical and radiographic data were available were excellent at the time of intermediate follow-up. Since few hips had progressive radiolucent lines about the acetabular of femoral component, we are optimistic that the long-term results will also be satisfactory.

Increasing incidence of femoral osteolysis in association with uncemented Harris-Galante total hip arthroplasty. A follow-up report.

Sixty-nine consecutive uncemented total hip arthroplasties were performed in 59 patients using the Harris-Galante prosthesis (Zimmer, Warsaw, IN). The patients were reviewed an average of 44 and 71 months after surgery. Patients in whom femoral osteolysis was identified at the time of the first review were again evaluated at the second review to determine if the size of the osteolytic lesion had increased over time. At the initial review an average of 44 months postsurgery, the overall incidence of femoral osteolysis was 22%. At the second review, the incidence of femoral osteolysis had increased from 22 to 52%. Two thirds of the lytic lesions diagnosed at the time of the first review had increased in size. This study demonstrated that the incidence of femoral osteolysis in cementless hip arthroplasties increases with time and that the majority of existing lesions enlarge over time. Once lesions are identified, more frequent follow-up evaluations are recommended. Revision surgery may be required for progressive femoral osteolysis, despite the absence of significant clinical symptoms.