Follow up on uncemented total knee arthroplasty.

Follow up data on 42 uncemented total knee arthroplasty patients were examined at an average follow-up period of 5 to 7 years. The prosthetic components were examined clinically using the modified Hospital for Special Surgery knee rating system and radiographically using fluoroscopically guided radiographs. When compared to the preliminary report, the knee rating score dropped from an average of 94 to 78, with most of the poor results due to patellar failure requiring revision. As in our preliminary study, complications centered on the metal-backed patellar component. Revision of the patellar component was required in 19 of 42 knees (45%). Three of 42 (7%) tibial components required revision, and 2 of 42 (5%) femoral components were revised. Interface lucencies were examined and changes were documented. Other complications included osteolysis in 4 of 42 (10%), bent patellar component in 3 of 42 (7%), and loose titanium mesh (5%).

Developmental time courses in the brain and kidney of two enzymes that oxidize gamma-hydroxybutyrate.

The postnatal developmental profiles of two enzymes that oxidize gamma-hydroxybutyrate (GHB) were examined during the period when the brain concentration of GHB was changing from the higher fetal level (7 microM) to the lower adult level (2 microM). At 20 days of age, the maximal oxidative capacity (Vmax) of GBH dehydrogenase (GHB-D) in the brain reached a rate that was approximately 50% greater than either adult or 18-day fetal values. The Vmax for GBH-oxoacid transhydrogenase (GHB-T) in the brain was negligible at 18 days of gestation but increased 40-fold by 20 days and 100-fold by 70 days after birth. In contrast to the brain, the GHB concentration in the kidney remained at approximately 65% of the adult level from birth to 15 days of age and then rose to adult levels. The activities of both GHB-D and GHB-T were 20% of their adult values in the newborn kidney, and both enzymes increased to near adult activities by 20 days. It appears that GHB-D is the predominant catabolic enzyme for GHB in the fetal and neonatal brain, whereas in the kidney both enzymes participate from the earliest time examined.

Evidence for cooperativity between neurons and astroglia in the regulation of CO2 fixation in vitro.

Increases in the extracellular potassium concentration which correspond to the increased potassium concentration seen with both normal and abnormal neuronal stimulation produce marked increases in the rate of CO2 fixation in astroglial cells in primary culture. This increase in CO2 fixation is seen only in astroglial cells; the low rate of CO2 fixation seen in the neurons did not respond to the increased potassium concentration. Cultures of astroglia and mixed astroglia-neurons were labeled with NaH[14C]O3 for 20 h to obtain material for preliminary identification of the labeled products of CO2 fixation in the extracellular and intracellular compartments. While both cultures had similar intracellular levels of labeled products (mainly amino acids), astroglial cultures released 4-fold more labeled products into the extracellular fluid. While labeled glutamine is a prominent product of astroglia, the bulk of the released labeled products are nonamino acids. These are presumably the products available to be recycled back to surrounding neurons (which cannot fix CO2) to replenish intermediates of the TCA cycle lost due to release of the neurotransmitters glutamate, aspartate and GABA.

Carbon dioxide fixation in neuronal and astroglial cells in culture.

The concentration of potassium in the extracellular fluid has been found to stimulate the rate of CO2 fixation by astroglial cells grown in primary culture. Raising the concentration of extracellular potassium increased both the initial rate of formation of the 14C-labeled products of 14CO2 fixation and the final steady-state level of these products within the cells. In contrast, neither veratridine nor L-glutamate affected the rate of CO2 fixation in astroglial cells. The very low rate of CO2 fixation found in primarily neuronal cultures was unaffected by increased extracellular potassium as was CO2 fixation in fibroblasts. When cultured alone, astroglial cells release a large fraction of the 14C-labeled products of CO2 fixation into the surrounding medium. Mixed cultures of astroglia and neurons also fix CO2 but, in contrast to astroglia cultured alone, release only a small fraction of the 14C-labeled products into the culture medium.

An overview of gamma-hydroxybutyrate catabolism: the role of the cytosolic NADP(+)-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway.

Two enzymes have been found which catalyze the initial step in the catabolism of GHB. The oxidation of GHB to SSA, catalyzed by both of these enzymes, is coupled to the reduction of an oxoacid. In the case of the mitochondrial transhydrogenase, the coupling is obligatory. Although coupling is not obligatory for the GHB dehydrogenase, the stimulation provided by the coupled reaction, and the nature of the kinetics of the uncoupled reaction, may not only allow the reaction to proceed, but may provide a means of regulating the rate of the reaction under in vivo conditions. Since the oxidation of GHB to SSA is the rate limiting step in the overall catabolic pathway (the rate of conversion of GHB to SSA proceeds at approximately one one thousandth of the rate at which SSA is oxidized to succinate by SSA dehydrogenase (30)), factors which regulate the rate of either or both of these enzymes will, in turn, influence tissue levels of endogenous GHB as well as the duration and magnitude of the physiological effect of a dose of GHB.

Pyretic action of low doses of gamma-hydroxybutyrate in rats.

gamma-Hydroxybutyrate (GHB) has been found to have a biphasic effect on body temperature with increased body temperature after low doses (5-10 mg/kg) and decreased body temperature after high doses (300-500 mg/kg). Brain levels of GHB between 30 and 60 min post-injection of GHB were not altered by the low doses (5-10 mg/kg), although a dose of 200 mg/kg produced a large increase in the brain concentration.

Vascular complication of knee arthroplasty under tourniquet. A case report.

An 80-year-old white male was treated with a right total knee arthroplasty after three years of incapacitating knee pain that did not respond to conservative therapy. A pneumatic tourniquet was placed around the right proximal thigh prior to surgery. Before applying the dressing, assessment of the right foot revealed an adequate vascular status. On the first postoperative morning, the popliteal and pedal pulses were absent. An arteriogram identified complete occlusion of the distal superficial femoral artery and popliteal artery down to and including the trifurcation. After a right femoral artery embolectomy, the pulses returned and the patient suffered no residual deficit from the arterial occlusion. The patient had a prior history of prostatic carcinoma and was taking diethylstilbestrol; these factors, along with age-associated atherosclerotic disease and the tourniquet application, created a favorable environment for such a rare complication. Factors that may compromise vascularity when using the pneumatic tourniquet must be given due consideration.

Preliminary results of Miller-Galante uncemented total knee arthroplasty.

From July 1984 through February 1986, a total of 46 knees were placed in 42 patients. The average age of all patients was 58 years (range, 32 to 68). Osteoarthritis was the diagnosis in 38 knees, traumatic arthritis in 5, and rheumatoid arthritis in 3. During follow up, averaging 3.6 years (range, 2.0 to 4.5), the total knee score based on a modified Hospital for Special Surgery knee rating scale improved from a preoperative average of 59 to 93 postoperatively. Radiographically, partial radiolucencies (less than 1 mm) were present in at least one view in 72% of the knees in which the interface was well visualized. No radiolucencies were progressive. Complications occurred mainly in the patellar components, as 17% of metal-backed uncemented patellae required revision to cemented non-metal backed components. There were no deep infections. The authors remain cautiously optimistic while awaiting long-term follow up.

Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitochondria.

A transhydrogenase that catalyzes the oxoacid-dependent oxidation of specific hydroxyacids has been found in rat kidney, liver, and brain. The hydroxyacids that have been found to be substrates for this enzyme are gamma-hydroxybutyrate, D-alpha-hydroxyglutarate, and L-beta-hydroxybutyrate. The oxoacids that are the best substrates for this enzyme are alpha-ketoglutarate and succinic semialdehyde; alpha-ketoadipate and oxalacetate are also substrates. This enzyme is located in the mitochondrial fraction of the cell and is not dependent on added NAD+ or NADP+.

Oxidation of gamma-hydroxybutyrate to succinic semialdehyde by a mitochondrial pyridine nucleotide-independent enzyme.

An antibody that inhibits over 95% of the cytosolic NADP+-dependent gamma-hydroxybutyrate (GHB) dehydrogenase activity of either rat brain or kidney was found to inhibit only approximately 50% of the conversion of [1-14C]GHB to 14CO2 by rat kidney homogenate. A similar result was obtained with sodium valproate, a potent inhibitor of GHB dehydrogenase. The mitochondrial fraction from rat brain and kidney was found to catalyze the conversion of [1-14C]GHB to 14CO2. The dialyzed mitochondrial fraction also catalyzed the oxidation of GHB to succinic semialdehyde (SSA) in a reaction that did not require added NAD+ or NADP+ and which was not inhibited by sodium valproate. The enzyme from the mitochondrial fraction which converts GHB to SSA appears to be distinct from the NADP+-dependent cytosolic oxidoreductase which catalyzes this reaction.

Long-term results of valgus tibial osteotomy.

Valgus tibial osteotomy is a well-recognized procedure for medial compartment arthritis of the knee. The femorotibial angle must be adequately realigned; most unsatisfactory outcomes result from undercorrection. This study of 27 patients (38 knees) with a valgus tibial osteotomy for unicompartmental arthritis of the knee emphasizes the importance of correct alignment. Alignment outside the acceptable range did accelerate deterioration in these patients, followed for an average of 53 months. In 25 of the 38 knees (66%) results were good to excellent. An alignment of 6 degrees or more of valgus produced an excellent to good result in 21 of 23 knees (91%). Alignment of less than 6 degrees of valgus yielded excellent to good results in 4 of 15 knees (27%). Although at the end of one year, 31 of the 38 knees were rated as excellent to good, these knees progressively deteriorated. The knees in 6 degrees or more of valgus seldom deteriorated while those in less than 6 degrees of valgus deteriorated more frequently. A valgus tibial osteotomy is an excellent procedure provided the tibiofemoral angle is realigned to 6 degrees or more of valgus.

Evidence for the participation of a cytosolic NADP+-dependent oxidoreductase in the catabolism of gamma-hydroxybutyrate in vivo.

The concentration of gamma-hydroxybutyrate (GHB) in brain, kidney, and muscle as well as the clearance of [1-14C]GHB in plasma have been found to be altered by the administration of a number of metabolic intermediates and drugs that inhibit the NADP+-dependent oxidoreductase, "GHB dehydrogenase," an enzyme that catalyzes the oxidation of GHB to succinic semialdehyde. Administration of valproate, salicylate, and phenylacetate, all inhibitors of GHB dehydrogenase, significantly increased the concentration of GHB in brain; salicylate increased GHB concentration in kidney, and alpha-ketoisocaproate increased GHB levels in kidney and muscle. The half-life of [1-14C]GHB in plasma was decreased by D-glucuronate, a compound that stimulates the oxidation of GHB by this enzyme and was increased by a competitive substrate of the enzyme, L-gulonate. The results of these experiments suggest a role for GHB dehydrogenase in the regulation of tissue levels of endogenous GHB.

Osteonecrosis of bone associated with combination chemotherapy without corticosteroids.

Osteonecrosis (aseptic or avascular necrosis of bone) is an entity with many causes that can occur at a variety of sites. It is a known complication of corticosteroid therapy, either alone or combined with other drugs in the treatment of malignancy. Osteonecrosis associated with chemotherapy that does not include corticosteroids is rare; three such cases have been reported in the English literature. One received cyclophosphamide alone, another vinblastine and bleomycin, while the third received cyclophosphamide, methotrexate, and 5-fluorouracil. The authors report a 40-year-old woman who had a left radical mastectomy in 1978 and a right radical mastectomy in 1980 for infiltrating ductal adenocarcinoma of the breasts. She received melphalan following the first surgery and a combination of doxorubicin, cyclophosphamide, and 5-fluorouracil after the second operation. In 1984 she noted pain in both knees that slowly increased in severity. A bone scan revealed increased periarticular activity in the medial and lateral femoral condyles of both knees compatible with bilateral osteonecrosis. There was no evidence of metastatic carcinoma on the bone scan. The patient was treated surgically with drilling and autologous bone grafting. A bone biopsy at the time of surgery revealed osteonecrosis but no metastatic adenocarcinoma.

2-Deoxyglucose incorporation into rat brain glycogen during measurement of local cerebral glucose utilization by the 2-deoxyglucose method.

The incorporation of 14C into glycogen in rat brain has been measured under the same conditions that exist during the measurement of local cerebral glucose utilization by the autoradiographic 2-[14C]deoxyglucose method. The results demonstrate that approximately 2% of the total 14C in brain 45 min after the pulse of 2-[14C]deoxyglucose is contained in the glycogen portion, and, in fact, incorporated into alpha-1-4 and alpha-1-6 deoxyglucosyl linkages. When the brain is removed by dissection, as is routinely done in the course of the procedure of the 2-[14C]deoxyglucose method to preserve the structure of the brain for autoradiography, the portion of total brain 14C contained in glycogen falls to less than 1%, presumably because of postmortem glycogenolysis which restores much of the label to deoxyglucose-phosphates. In any case, the incorporation of the 14C into glycogen is of no consequence to the validity of the autoradiographic deoxyglucose method, not because of its small magnitude, but because 2-[14C]deoxyglucose is incorporated into glycogen via [14C]deoxyglucose-6-phosphate, and the label in glycogen represents, therefore, an additional "trapped" product of deoxyglucose phosphorylation by hexokinase. With the autoradiographic 2-[14C]deoxyglucose method, in which only total 14C concentration in the brain tissue is measured by quantitative autoradiography, it is essential that all the labeled products derived directly or indirectly from [14C]deoxyglucose phosphorylation by hexokinase be retained in the tissue; their chemical identity is of no significance.

Regulation and properties of an NADP+ oxidoreductase which functions as a gamma-hydroxybutyrate dehydrogenase.

A number of naturally occurring biological intermediates have been found to inhibit competitively the activity of a highly purified NADP+-dependent oxidoreductase which catalyzes the simultaneous oxidation of gamma-hydroxybutyrate to succinic semialdehyde, and the reduction of D-glucuronate to L-gulonate. Of the inhibitors studied, those with the lowest Ki are the alpha-keto analogues of the branched chain or aromatic amino acids. The Vmax and Km for this enzyme are affected by pH; consequently, changes in substrate concentration can markedly alter the pH optimum. The enzyme has been found to be inhibited by reducing agents such as dithiothreitol and mercaptoethanol, protected against this inhibition by oxidizing agents such as oxidized glutathione or H2O2, and finally, protected against heat inactivation by the presence of either NADP+ or NADPH.

Kinetics of coupled gamma-hydroxybutyrate oxidation and D-glucuronate reduction by an NADP+-dependent oxidoreductase.

A highly purified NADP+-dependent oxidoreductase from hamster liver (1) has been found to catalyze a reaction in which the oxidation of gamma-hydroxybutyrate is coupled to the reduction of D-glucuronate. In the coupled reaction, NADP+ is required in catalytic rather than stoichiometric amounts. When the coupled reaction is carried out under limiting conditions for the oxidation of gamma-hydroxybutyrate (i.e. a very low concentration of NADP+ and an inhibitory concentration of NADPH) the rate of gamma-hydroxybutyrate oxidation is determined by the concentration of D-glucuronate and can be stimulated at least 8-fold by D-glucuronate. The kinetics of the oxidation of gamma-hydroxybutyrate have been studied in both the uncoupled and the coupled reaction. In the coupled reaction the reduction of D-glucuronate drives the oxidation of gamma-hydroxybutyrate; the Km for NADP+ is markedly lower than the Km determined in the uncoupled reaction (1.4 X 10(-6) M as compared to 2 X 10(-5) M), and the inhibition by NADPH can be completely overcome. The kinetics of the uncoupled reaction suggest that, unlike many other dehydrogenases, the oxidation of gamma-hydroxybutyrate catalyzed by this enzyme proceeds by a Rapid Equilibrium Random Bi Bi mechanism.