Why address posterior tibial plateau fractures?

Management of posterior tibial plateau fractures has gained much interest over the past few years. Fracture morphology, trauma mechanism, and soft-tissue injury have been identified as the key factors determining the treatment strategy and outcome. We provide a rationale for the operative management of posterior tibial plateau fractures by discussing the interplay between fracture morphology, trauma mechanism, and soft-tissue injury. The trauma mechanism has proven to be an important tool, not only to understand fracture morphology, but also to assess concomitant soft-tissue (i.e. ligamentous) injury. Subsequently, soft-tissue injury might play a role in future classification and diagnostic work-up of tibial plateau fractures, particularly in fractures with posterior involvement. Plate osteosynthesis using a posterior approach is safe and should be considered routinely in coronal fractures of the posterior tibial plateau, as illustrated.

Nursing home placement is related to dementia progression: experience from a clinical trial. Alzheimer's Disease Cooperative Study.

OBJECTIVES: To examine the relationship between nursing home placement (NHP) and measures of change in other well-established clinical disease assessments in a longitudinal study of patients with probable AD. BACKGROUND: NHP is a common, major milestone in the natural history of AD. NHP is a readily identified event that can be accurately dated. NHP can be used in survival analyses, which are an efficient means of determining efficacy in clinical trials. NHP usually occurs in the setting of severe AD, but in cross-sectional studies, the strength of the association with disease severity has been controversial. DESIGN/METHODS: We used data from 341 AD patients who were enrolled in a recently published clinical trial of selegiline and tocopherol. At entry, all were rated as Clinical Dementia Rating (CDR) stage 2, were community-dwelling, and had an identified caregiver. Patients were followed at 3-month intervals for 2 years. We examined the relationship between four measures of dementia severity and a measure of behavioral dysfunction and NHP. The measures included changes in CDR status, changes in activities of daily living performance, changes from baseline to last measurement in dependence level, changes from baseline to last measurement on the Blessed Dementia Rating Scale (BDRS) score, and changes from baseline to last measurement on the total score and subscales of the Behavior Rating Scale for Dementia (BRSD). Statistical models were used to assess the strength of the associations. RESULTS: At the end of the 2-year period, 33% of patients had been institutionalized. The NHP patients did not differ at baseline from the not-NHP patients in gender, age, caregiver status, duration of illness, CDR sum of boxes, BDRS, or dependence level. The NHP patients had a lower baseline Mini-Mental State Examination score and a slightly worse BRSD total score. Patients reaching CDR3 were eight times more likely to be institutionalized than those who remained at CDR2. The change scores on all four dementia severity measures were strongly associated with NHP; the change score on the BRSD and its subscales were not. On the other hand, adverse events that included a behavioral disturbance, especially agitation, were associated with NHP. CONCLUSION: These data show that NHP closely reflects dementia progression in the context of a clinical trial. Coupled with the high face validity of NHP as a milestone of severe dementia, NHP is a valid primary outcome measure for AD clinical trials.

A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study.

BACKGROUND: Laboratory and epidemiologic studies suggest that anti-inflammatory/immunosuppressive therapy may be useful in the treatment of AD. In preliminary studies, a regimen of low to moderate dose prednisone was found to suppress peripheral inflammatory markers without adverse effects in subjects with AD. METHODS: We conducted a randomized, placebo-controlled multicenter trial to determine whether prednisone treatment slowed the rate of cognitive decline in AD. The active treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks tapered to a maintenance dose of 10 mg daily for 1 year, followed by gradual withdrawal during an additional 16 weeks. The primary outcome measure was the 1-year change in the cognitive subscale of the AD Assessment Scale. RESULTS: A total of 138 subjects were randomized to the drug and placebo groups. There was no difference in cognitive decline between the prednisone and placebo treatment groups in the primary intent-to-treat analysis, or in a secondary analysis considering completers only. Subjects treated with prednisone showed behavioral decline compared with those in the placebo group. CONCLUSION: A low-dose regimen of prednisone is not useful in the treatment of AD.

Temperature dependence of glucocorticoid binding in sensitive and refractory murine leukaemia cells.

The validity of in vitro assays in predicting the susceptibility of leukaemic cells to glucocorticoid-mediated lysis was evaluated in a panel of six murine leukaemia cell lines. In this panel susceptibility to glucocorticoids ranged from highly sensitive to fully resistant. The panel was screened for specific 3H-dexamethasone binding in whole cells and for activation of cytosolic receptors in cell lysates. Specific binding of 3H-dexamethasone was strongly affected by the incubation temperature. In all cell lines, rapid and reversible changes were observed in the stability of agonist-receptor association with a transition temperature of 28 degrees C. Below this temperature, intracellular receptors were found to be in a stable-binding, high-affinity configuration, masking differences in receptor status among the various cell lines. When assayed at 37 degrees C, refractory and fully resistant cells revealed nonsaturating, low-affinity binding of steroid. Saturating, high-affinity binding was, however, restored in these cells by the drug meta-iodobenzylguanidine with concomitant sensitization to dexamethasone-induced lysis. Contrary to observations with intact cells, heat-induced agonist-receptor dissociation in cytosols caused irreversible loss of (re)binding capacity. Activation of cytosolic receptors only recognized fully resistant cell lines as being deficient in the transformation of liganded receptors into a DNA-binding configuration. The assay, however, could not discriminate between three cell lines with highest but varying degrees of sensitivity because of maximal activation. The results indicate that non-physiological temperature and cell disruption strongly and differentially affect steroid binding and receptor activation, respectively. The observations may account for the poor correlation between conventional predictive assays and steroid responsiveness in clinical leukaemia.

Steroid-induced elevation of glucose in Alzheimer's disease: relationship to gender, apolipoprotein E genotype and cognition.

Glucose and insulin may play an important role in the pathophysiology and symptomatology of Alzheimers disease (AD), and prior studies suggest interactions among glucose, insulin, gender and apolipoprotein E genotype. We analyzed the relationship between steroid-induced glucose elevation and gender, presence of the apolipoprotein E epsilon 4 (APOE-4) allele and cognition using data from a multicenter trial of prednisone therapy in AD. The low-dose prednisone regimen (initial dose: 20 mg/day, maintenance dose: 10 mg/day) caused a moderate increase in random blood glucose (mean post-baseline glucose 115 mg/dl). There was a significant interaction between rise in glucose, gender and presence of the APOE-4 allele. There was no important relationship between glucose and cognitive function at baseline or with prednisone treatment. Meta-analysis including data from three other AD trials showed a small influence of random blood glucose on cognitive scores. These results support a relationship between gender, apolipoprotein E genotype and glucose metabolism, but do not indicate that mild changes in glucose have an important impact on cognitive function.

Agonist-free transformation of the glucocorticoid receptor in human B-lymphoma cells.

Nuclear translocation of activated glucocorticoid receptors (GRs) is a necessary step in the signal transduction by these GC hormones. Although in vitro activation of GRs can occur in the absence of a functional ligand, it is generally assumed that binding of a cognate hormone is required for activation of the intracellular GR. By indirect immunocytochemistry and Western-blot analysis, it was found that, in spontaneously aggregated human lymphoma DoHH2 cells, hormone-free GRs are located in the nucleus. Disruption of the aggregates redistributed GRs to a predominantly cytosolic location. Upon spontaneous re-aggregation the GR again became localized to the nucleus. Intracellular cross-linking of the heteromeric receptor complex was applied to investigate the protein composition of cytoplasmic and nuclear receptors. Untransformed, cytosolic GRs could be demonstrated by [3H]dexamethasone binding capacity and hsp90 co-immunoprecipitation, whereas absence of these characteristics suggested an activated conformation of the nuclear GRs. These observations suggest that cell-cell interactions are capable of transforming GRs in the absence of a ligand.

High levels of non-activated receptors in glucocorticoid-sensitive S49wt mouse lymphoma cells incubated with dexamethasone.

Upon agonist binding the heteromeric glucocorticoid receptor complex undergoes a conformational change (receptor activation). This event involves the dissociation of a dimer of 90 kDa heat shock proteins. Whereas receptor activation in cytosolic assays is both rapid and irreversible, less is known about the receptor activation and translocation in intact cells during challenge with an agonist. In this paper we report on the receptor status of glucocorticoid-sensitive murine S49 lymphoma cells during dexamethasone exposure. By three different assays, ligand (re)binding, nuclear translocation and hsp90 co-immunoprecipitation, it was found that the majority of the glucocorticoid receptor protein was in a non-activated conformation. Furthermore, prolonged exposure to dexamethasone did not result in increased levels of activated receptors. By assessing receptor activation in situ we found that physiological temperature was less effective in dissociating hsp90 compared to room temperature. These findings indicate that the physiological temperature negatively controls receptor activation, probably due to a thermolabile interaction between the hormone and its cognate receptor.

Safety and efficacy of atovaquone and proguanil hydrochloride for the prophylaxis of Plasmodium falciparum malaria in South Africa.

The objective of this study was to determine the safety and efficacy of atovaquone and proguanil hydrochloride combination therapy for the prophylaxis of Plasmodium falciparum malaria in at-risk nonimmune subjects in South Africa. This open-label trial was conducted at research sites in South Africa during the main malaria transmission season, February through July. The study volunteers were temporarily living in, or traveling to, a malaria-endemic area. They received I tablet of 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for up to 10 weeks. Subjects were monitored using sequential clinical and laboratory assessments. Thick blood smears were stained and evaluated by a central laboratory. An immunochromatographic test for P. falciparum was also used for on-site patient management. Prophylactic success was summarized using a 95% confidence interval for the proportion of subjects who did not develop parasitemia or who withdrew due to a treatment-related adverse event. A total of 175 subjects (15% women) were enrolled in the trial. The mean duration of drug exposure was 8.9 weeks. The combination of atovaquone and proguanil hydrochloride was well tolerated. The most frequently reported adverse events considered possibly related to study treatment were headache (7%), abdominal pain (2%), increased cough (2%), and skin disorder (2%). No serious adverse events were reported, and no treatment-emergent effects were noted for any laboratory variables. One subject who was noncompliant with therapy developed parasitemia, and 3 subjects withdrew due to a treatment-related adverse event (2 subjects with headache and 1 with nausea and dizziness). The prophylaxis success rate was 97%. In this study, atovaquone and proguanil hydrochloride combination therapy had an excellent safety and efficacy profile for prophylaxis of P. falciparum malaria in nonimmune subjects.

Chemical characterization and comparative cellular effects of meta-iodobenzyl guanidine and benzyl guanidine.

meta-Iodobenzyl guanidine (MIBG) combines the structural properties of the neuron-blocking agents bretylium and guanethidine and is being used increasingly for various clinical applications. Different samples of MIBG were assayed for possible contamination with benzyl guanidine (BG). Fast-atom-bombardment mass spectrometry (FAB-MS) analysis showed a prominent but variable m/z 150 signal, corresponding to a protonated BG. The MS/MS fragmentation pattern of these [M + H]+ ions was similar to that obtained from FAB-MS-generated, protonated BG, confirming the proposed molecule and associated structures. RP-HPLC analysis of both guanidines, however, excluded the possibility of contamination of MIBG with BG. It was therefore concluded that the BG signal was an artifact of the FAB-MS procedure. In addition, the importance of the meta-substituted iodine for the biological activity of MIBG was investigated. Three different biochemical and cell-biological properties of MIBG were compared with those of its precursor MIBA and BG. The assays used were: inhibition of the catecholamine "Uptake I" system in SK-N-SH neuroblastoma and PC-12 pheochromocytoma cells, inhibition of mitochondrial respiration, and general cytotoxicity in L1210 leukemia cells. Of the drugs tested, MIBG was the most efficient in Uptake I inhibition and was more toxic in survival assays, but as compared with BG it was almost equipotent in inhibiting mitochondrial respiration. These findings contribute to a further elucidation of the mechanism by which MIBG exerts its various actions.

Bcl-2 expression and glucocorticoid-induced apoptosis of leukemic and lymphoma cells.

The lytic response of lymphoid cells to glucocorticoid hormones (GC) is prototypical of the induction of apoptosis: a special form of cellular demise for the removal of unwanted or redundant cells. Initiation and execution of a death programme are therefore major checkpoints in GC-sensitivity. Although Bcl-2 protein can prevent or delay apoptosis of lymphoma and leukemia cells, exposed to multiple cytotoxic agents, its antagonism of GC-induced apoptosis appears most critical in conferring resistance to corticosteroids. Moreover, Bcl-2 may modulate GC-signalling to apoptosis through its association with fundamental cellular processes such as energy state, Ca2+ homeostasis and transmembrane transport. However, this signalling pathway can also be interrupted by Bcl-2- independent mechanisms. This review discusses the various cellular and oncogenetic factors that control GC sensitivity of leukemia/lymphoma cells and proposes a hypothesis of how GC may induce a death programme, sensitive to blockade by Bcl-2.

Theophylline analysis at the chest clinic--comparison of a portable versus conventional system.

The running cost and clinical application of a new, portable, direct-injection, high-performance, liquid chromatograph for the measurement of theophylline was compared with conventional laboratory-based analysis by studying the two methods in two parallel chest clinics. Thirty-six patients were managed with the portable method and 33 by the conventional system. They were already receiving theophylline preparations for treatment of their asthma or chronic airflow limitation. Over the 12-week period of study, the percentage of patients with levels in the therapeutic range rose from 33% to approximately 87% in both clinics, but this change was achieved in only 6 weeks using the portable system. Patients whose theophylline levels were increased into the therapeutic range had improved symptom scores as measured by visual analogue scales but we were unable to demonstrate any significant change in spirometry. The cost of the portable system compared favourably with laboratory analysis, and had the additional benefit of quicker detection of non-compliance and facility for discussion with the patients at the time of consultation.

Rapid measurement of anticonvulsant drug concentrations in the out-patient clinic, using HPLC with direct injection of plasma.

A manual column-switching technique is described for the measurement of phenytoin, phenobarbitone, carbamazepine, and carbamazepine 10,11-epoxide. The analytical system is designed to be portable for use at the out-patient clinic and comprises an isocratic pump, UV detector and injection valve, together with a preparation column. Diluted plasma or serum is injected, without pre-extraction, onto a preparation column which replaces the sample loop on the injection valve. After washing unwanted material to waste, the preparation column is switched in-line with the analytical column, where separation of analytes occurs. The precision, accuracy and carryover of this extra-laboratory system are comparable with those obtained with laboratory-based immunoassay systems. Operation of the system allows the reporting of results within 5 min of sample injection and requires no specialist skills. The technique should be of particular interest to district general hospital laboratories where workload does not justify the cost of an automated HPLC system as the total capital cost is comparable to that of a portable glucose analyser. In contrast to immunoassay systems consumable costs are minimal. The equipment is easy to transport and may be used in the out-patient department to provide an analytical service similar to that provided for the determination of prothrombin time at the anticoagulant clinic.

Practical assessment of the NBT-PABA pancreatic function test using high performance liquid chromatography determination of p-aminobenzoic acid in urine.

A practical method for determining p-aminobenzoic acid in urine by high-performance liquid chromatography has been assessed. The technique is quick, requires no extraction steps and has good precision. Using this method, healthy individuals had a p-aminobenzoic acid excretion index of 94% +/- 18 (mean +/- 1 SD). Patients with proven, severe chronic exocrine pancreatic dysfunction had index values of less than 5-25%. Unlike chemical methods available, there were no interferences in any of the urines tested, nor did 12 compounds tested interfere with the analysis.

Serum total bile acid levels in patients receiving rifampicin and isoniazid.

Serum bile acid levels in 61 patients receiving daily doses of rifampicin and isoniazid for the treatment of tuberculosis have been investigated. Bile acids were measured using 3 alpha-hydroxysteroid dehydrogenase in a continuous-flow system. Abnormally elevated levels were found in 44 patients (72%) during the period of study up to 80 days after onset of treatment. The results showed a mean of 24.9 mumol/l and a positively skewed distribution. Whilst marginally raised levels of bilirubin were seen in some samples (mean 8.2 mumol/l), these did not reflect the marked changes observed in bile acids. Patients receiving rifampicin and isoniazid may therefore have markedly elevated levels of total serum bile acids, while other tests used to assess liver function can remain normal.

Drugs as probes of organ function: evaluation of the hepatobiliary axis using oral rifampicin and novel high performance liquid chromatography.

Investigation of the uptake and metabolism of drugs by organs such as the liver may allow assessment of specific aspects of organ function. Rifampicin, when orally administered, is transported into the hepatocyte from portal blood and thence passes, with its deacetylated metabolite, into the systemic circulation and into bile. This paper reports an investigation of the pharmacokinetics of a sub-therapeutic oral dose of rifampicin in healthy subjects, in patients with cirrhosis and in subjects with Gilbert's syndrome. The areas under the plasma concentration curves (AUC) in patients with cirrhosis were significantly greater than in healthy subjects. Subjects with Gilbert's syndrome had decreased AUCs compared with healthy subjects and were clearly distinguished from patients with cirrhosis. Rifampicin concentration in serum was measured by HPLC using a novel direct injection technique.

Atovaquone and proguanil hydrochloride for prophylaxis of malaria.

BACKGROUND: The spread of drug-resistant malaria and appreciation of side effects associated with existing antimalarial drugs emphasize the need for new drugs to prevent malaria. The combination of atovaquone and proguanil hydrochloride was previously shown to be safe and highly effective for treatment of malaria, including multi-drug-resistant Plasmodium falciparum. METHODS: We reviewed results of clinical trials that evaluated either a fixed-dose combination of atovaquone and proguanil hydrochloride for malaria prophylaxis or atovaquone alone for causal prophylactic activity against P. falciparum. RESULTS: In three placebo-controlled trials, 331 subjects received 250 mg atovaquone and 100 mg proguanil hydrochloride (or an equivalent dose based on body weight in children) once daily for 10 to 12 weeks. The overall efficacy for preventing parasitemia was 98%. Among 175 nonimmune volunteers taking the same dose of atovaquone/proguanil once daily for 10 weeks while temporarily residing in a malaria-endemic area, malaria developed in one patient who was noncompliant with therapy. Results of volunteer challenge studies indicate that both atovaquone and proguanil have causal prophylactic activity directed against the liver stages of P. falciparum. Adverse events occurred with similar or lower frequencies in subjects treated with atovaquone/proguanil compared to placebo. Less than 1% of patients discontinued from these studies due to a treatment-related adverse event. CONCLUSION: A fixed-dose combination of atovaquone and proguanil hydrocloride is a promising new alternative for malaria prophylaxis.

Antimicrobial activity of electrolyzed saline solutions.

Electrolysis of solutions containing certain electrolytes, through the use of novel electrodes, produces significant levels of ozone, oxygen, and chlorine at the anode. The process works at ordinary temperatures, and with dilute solutions. These solutions, after electrolysis, can be much more effective, by a factor of several hundred, against microorganisms than solutions containing comparable hypochlorite solutions.

A novel reconstructive technique for pylorus-preserving pancreaticoduodenectomy: avoidance of early postoperative gastric stasis.

In 30 patients a reconstructive technique was used after pylorus-preserving pancreaticoduodenectomy in which the anastomoses were constructed in the sequence: duodenojejunal, hepaticojejunal (8-10 cm distal) and finally duct-to-mucosa pancreaticojejunal to a separate Roux loop. Indications for surgery included periampullary tumours, (n = 13), carcinoma of the head of the pancreas (n = 10) and chronic pancreatitis (n = 4). No patient required prolonged (> 7 days) nasogastric intubation for primary gastroparesis in the early postoperative period. Postoperative morbidity (17% overall) delayed recovery and return of gastrointestinal function in one patient with a minor biliary leak (closed with 5 days' somatostatin treatment). Other morbidity included gastrointestinal haemorrhage (n = 1), wound infection (n = 2) and respiratory infection (n = 2). There were no pancreatic leaks. One patient died from a subhepatic abscess (mortality 3%). Retrospective investigations, at 3-18 months postoperatively, included endoscopy (normal in 20 patients, none taking anti-ulcer therapy), gastric emptying studies in the first 10 patients (no delay) and bentiromide test in 12 patients considered to have normal pancreatic remnants (all patients > 24% PABA excretion index). All patients who underwent resection for tumour returned to their preoperative weight.

Monitoring faecal contamination of the Thames estuary using a semiautomated early warning system.

The Colifast Early Warning System, based on measuring beta-galactosidase activity (2 h method), was evaluated for monitoring the level of faecal contamination in the upper tidal Thames. Two trials were performed, one following heavy rain in November 2000, the next during a dry and sunny period in July 2001. In general the beta-galactosidase activity and the two coliform reference methods (recovery following membrane filtration with membrane lauryl sulphate broth (MLSB) and Colilert Quantitray) were comparable. However, in several samples in July the beta-galactosidase activity seemed to overestimate the number of culturable coliforms, suggesting that the rapid enzymatic method detected beta-galactosidase produced by other bacterial sources, such as Aeromonas spp. or Vibrio spp., or nonculturable coliforms. The later could be attributed to sunlight-induced injury. Nevertheless, the rapid method based on beta-galactosidase activity gave an estimate of the level of culturable coliforms, which did not differ from both coliform reference methods by more than one log. Monitoring of beta-galactosidase activity in river water samples using the Colifast Analyser may therefore be useful as an early warning indicator of faecal contamination.

Early warning of faecal contamination of water: a dual mode, automated system for high- (< 1 hour) and low-levels (6-11 hours).

There is a recognised need for methods that permit rapid estimation of the sanitary quality of water e.g. during raw water monitoring and emergencies involving water treatment failure or main breaks in a distribution network. In this study, two models for predicting the level of faecal contamination of water were studied. The first format, based on measurement of beta-galactosidase activity by the automated Colifast analyser, detected faecal contamination of high levels, corresponding to > 15 thermotolerant coliforms (FC)/5 mL, in 1-3 h, in a format that allowed for semi-quantification of results. By setting up a cut-off level, the system could be used as an operational tool identifying random increases in faecal contamination during routine raw water monitoring. A second Presence-Absence format was dependent upon the growth of low levels of FC with subsequent detection in the Colifast analyser. 95% of water samples containing 1-15 FC/sample volume showed positive detection after 11 h.