Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype.

BACKGROUND: We have previously found decreased CYP2C19 activity in Tanzanians tested with mephenytoin and omeprazole in relation to genotype when compared with white and Asian subjects. OBJECTIVE: We investigated the impact of CYP2C19 genotype and phenotype on chloroguanide (INN, proguanil) metabolism to its metabolites cycloguanil and 4-chlorophenylbiguanide. METHODS: A single oral chloroguanide dose was given to 25 healthy Tanzanian subjects with CYP2C19 genotypes (CYP2C19*1, CYP2C19*2, and CYP2C19*3). Homozygous wild-type and mutated genotype groups were chosen randomly, but the heterozygous genotype group was chosen with a range in phenotype. We used a novel HPLC method for drug determination. RESULTS: Pharmacokinetics of chloroguanide did not differ between groups. Maximum plasma concentration (Cmax) and area under the plasma concentration versus time [AUC(0-infinity)] for cycloguanil was significantly lower (t test P < .05) in the homozygously mutated group compared with the homozygously wild-type group. There were similar significant group differences of median urinary excretion. The chloroguanide/cycloguanil ratio closely correlated (r(s) = .87) with omeprazole metabolic ratio, confirming that Tanzanian subjects are generally slower CYP2C19 metabolizers. It also confirms that CYP2C19 genotype and phenotype predicts cycloguanil formation. In addition, a 3-hour plasma sample metabolic ratio also seems to be a proper time for omeprazole phenotyping in Tanzanian subjects. Because the plasma concentrations of cycloguanil and 4-chlorophenylbiguanide covary (r(s) = .89), it is now suggested that their formation be catalyzed by the same enzyme (ie, CYP2C19) through a common intermediate, the structure of which is also presented. CONCLUSIONS: As shown in an earlier study, also with a third substrate, Tanzanians have a lower capacity to form cycloguanil than white and Asian subjects. Individuals with two mutated alleles have lower metabolic capacity than individuals with two wild-type alleles or individuals in the heterozygous group, which may lead to chloroguanide therapeutic failure. This knowledge should be important when selecting appropriate patients and doses of chloroguanide in different populations.

Methadone, ciprofloxacin, and adverse drug reactions.

Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 years, caused profound sedation, confusion, and respiratory depression. We suggest that this was caused by ciprofloxacin inhibition of CYP1A2 and CYP3A4 activity, two of the cytochrome p450 isozymes involved in the metabolism of methadone.

Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype.

OBJECTIVE: To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil). METHODS: Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both. Sixty-two were phenotyped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined. The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP). RESULTS: Eight subjects were classified as mephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous for mutated alleles. The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR > 7, which is the antimode found previously in white subjects and Asian subjects. Of the 251 volunteers genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele. The allele frequencies of CYP2C19*1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 0.59; P < .01). CONCLUSION: Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population.

Contrast-enhanced radiography by differential absorption, using a laser-produced x-ray source.

RATIONALE AND OBJECTIVES: The authors evaluate the feasibility of differential imaging of contrast media, with division of individual pixel values obtained from digital images generated by characteristic radiation from a laser-produced plasma, bridging the K-absorption edge of the contrast agent. METHODS: Laser pulses from an ultrashort-pulse terawatt laser system were focused onto gadolinium and tantalum targets, creating a plasma from which characteristic radiation and Bremsstrahlung was emitted. The elements of the target were selected so the characteristic emission lines of one of the elements were below the K edge of the contrast agent and the emission lines of the other element above. A phantom with gadolinium and other elements in various concentrations was examined. One radiographic exposure was made using a gadolinium target source and a subsequent exposure using a tantalum source. Both images were recorded digitally and the transmission ratios calculated by division of the individual pixel values. RESULTS: When viewed separately, the two images of the test phantom appeared similar. In the differential image, only the gadolinium solutions were bright, reflecting a difference in attenuation between the two exposures. CONCLUSIONS: Element-specific radiographs can be obtained by differential imaging. When fully explored, the technique may allow for contrast-enhanced radiography with increased sensitivity and decreased contrast dose.

Spatial resolution requirements in digital radiography of scaphoid fractures. An ROC analysis.

PURPOSE: To investigate the spatial resolution requirements in digital radiography of scaphoid fractures. MATERIAL AND METHODS: Included in the study were 60 scaphoid radiographs with and 60 without fractures of the scaphoid bone. The film-screen images were digitized using pixel sizes of 115, 170, and 340 microns along with 170 microns with a 10:1 wavelet compression. The digital images were displayed on a 1280 x 1024 x 8 bits monitor, and 5 observers evaluated the images in 5 randomized sessions. The results for each pixel size were then compared to the film-screen images by ROC analysis. RESULTS: The mean area under the ROC curves was larger for the film-screen images than for the digital images at all resolutions. However, this difference was not significant when the areas under the ROC curves for the film-screen images were compared to the digital images of 115, 170, and 170 microns with 10:1 compression. There was a significant difference for the 340-microns pixel size in favour of the film-screen images. The mean ROC curves for the digital images were very similar for the 115 and 170 microns pixel sizes, although slightly better for 115 microns. At 170 microns, the compression seemed to have a relatively small negative effect on the diagnostic performance; the deterioration was greater when the pixel size was increased to 340 microns. There was no obvious correlation between diagnostic performance and the experience of the observers in using work-stations. CONCLUSIONS: The pixel size of 170 microns is adequate for the detection of subtle fractures, even after wavelet compression by a ratio of 10:1.

Radiation dose reduction in computed skeletal radiography. Effect on image quality.

PURPOSE: To evaluate the effect of radiation dose reduction on image ++quality in computed musculoskeletal radiography and determine optimal exposure range. MATERIAL AND METHODS: In 11 corpses, 1 hand and 1 hip were examined with film-screen radiography, and a series of computed radiographs was obtained using exactly the same technique except for the exposure, which was 100, 50, 25, 12.5, 6.25, and 1.56% of the mAs numbers used for the film-screen images. The computed hip radiographs were processed in 2 different ways, one simulating the film-screen images and one using contrast enhancement. Four radiologists reviewed the images regarding the following parameters: cortical bone, trabecular bone, joint space, and soft tissue, giving each a diagnostic quality rating on a scale from 1 to 5. The median and mean values were found for the pooled results. RESULTS: For the hands, the computed radiographs were ranked inferior to the film-screen images for all parameters except soft tissue, where the computed radiographs scored higher. The computed images with 50 and 25% exposure were ranked equal to the 100% ones. The quality rating slowly declined with lower exposures. For the hips, the 100 and 50% computed radiographs were generally similar to or slightly better than the film-screen images. The decline was somewhat faster than for the hands. The contrast-enhanced hip images scored less than the nonenhanced images at any given exposure for all parameters except soft tissue, where the contrast-enhanced images scored better at all exposures. The difference between nonenhanced and enhanced images became less at the lower exposures. CONCLUSION: Lowering the exposure in computed musculoskeletal radioagrphy below the level of film-screen radiography is feasible, especially in the peripheral skeleton. Contrast enhancement seems to be valuable only in the evaluation of soft-tissue structures.

Hip configuration and function in bladder exstrophy treated without pelvic osteotomy.

Nine children with congenital bladder exstrophy treated without pelvic osteotomy were analyzed clinically and radiologically at a mean age of 13 years (range 9-16 years). The acetabular and femoral version angles were measured by computed tomography (CT) imaging. Two of the children had a slight waddling gait, but none of them had any pain and they could participate in sports without problems. They had a normal range of hip movements and a normal foot progression angle. The acetabulum was retroverted by an average of 5 degrees, but was balanced by an increased anteversion of the femur which on the average was 10 degrees-20 degrees higher than normal. The femoral head in all hips was spherical, and no hip showed dysplasia. In bladder exstrophy, retroversion of the acetabulum was balanced by an increased anteversion of the femur, resulting in a normal range of hip movements and a normal gait in later childhood.

Flare phenomenon in osteosarcoma after complete remission.

A patient undergoing cytostatic therapy for osteosarcoma of the right humerus had bone scans at 2-mo intervals. A skeletal focus of increased radiotracer accumulation occurred and subsequently was confirmed by CT and MRI. A necrotic metastasis was found during biopsy. There were no remaining viable tumor cells. This finding confirms the presence of the flare phenomenon in skeletal metastases in primary malignant bone tumors and that radionuclide imaging may fail to detect intramedullary foci of viable metastases in these tumors.

The diagnosis of anastomotic leak after gastroesophagostomy with biliary scintigraphy.

Tc-99m HIDA scintigraphy in a patient with septic complications after partial resection of the esophagus and gastroesophagostomy demonstrated a free bile leak through the anastomosis to the thoracic drains. Concomitant attempts to verify this with dye ingestion (methylene blue) and x-ray examinations were negative.

Computed vs. film-screen magnification radiography of fingers in hyperparathyroidism. An ROC analysis.

One hundred randomly selected patients with suspected or known hyperparathyroidism were examined in a prospective study of the 2nd and 3rd fingers with film-screen and digital luminescence radiographs using magnification technique. The digital images were displayed on a work-station and printed as hard-copies. Two radiologists evaluated the film-screen images regarding subperiosteal and intracortical resorption and their results were defined as "gold standard" regarding the absence or presence of these changes. Four radiologists evaluated these changes in the 3 image forms and an ROC analysis was performed. Comparing the areas under the ROC curves no significant difference was found between the film-screen images and the 2 digital display forms. These results suggest that currently available digital systems provide adequate diagnostic accuracy for evaluation of subtle skeletal changes.

Film-screen vs. digital radiography in rheumatoid arthritis of the hand. An ROC analysis.

In a prospective investigation the diagnostic accuracy of film-screen and digital radiography in rheumatoid arthritis of hands was compared. Seventy hands of 36 patients with established rheumatoid arthritis were included in the study. Each of 11 joints in every hand was evaluated regarding the following radiologic parameters: soft tissue swelling, joint space narrowing, erosions and periarticular osteopenia. The digital images were obtained with storage phosphor image plates and evaluated in 2 forms; as digital hard-copy on film and on a monitor of an interactive workstation. The digital images had a resolution of either 3.33 or 5.0 lp/mm. ROC curves were constructed and comparing the area under the curves no significant difference was found between the 3 different imaging forms in either resolution group for soft tissue swelling, joint space narrowing and erosions. The film-screen image evaluation of periarticular osteopenia was significantly better than the digital hard-copy one in the 3.33 lp/mm resolution group, but no significant difference was found in the 5.0 lp/mm group. These results support the view that currently available digital systems are capable of adequate diagnostic performance.

Posterolateral lumbar fusion. Outcome of 71 consecutive operations after 4 (2-7) years.

We report the outcome of 71 consecutive posterolateral lumbar fusions without spinal instrumentation. The indication for the operation was spondylolysis-olisthesis, degenerative disc disease/facet joint arthrosis, or pain after prior laminectomy. Concerning pain relief, 29/43 patients with spondylolysis-olisthesis were classified as good. The corresponding figures in the group with degenerative disc disease and/or facet joint arthrosis were 8/16 patients and in the group with pain post-laminectomy, 6/12 patients. No surgical complications were noted. In the total material 54 patients had a solid fusion, as defined by radiographic osseous trabecular bridging at all intended levels. One-level fusions tended to heal solidly in a higher frequency than two-level fusions. For the spondylolysis-olisthesis group, healed fusion correlated with a good clinical result. Such a correlation could not be verified for the other diagnostic groups. We conclude that non-instrumented posterolateral lumbar fusion is a valid method for treating low-grade spondylolysis-olisthesis, especially when the aim is to fuse a single level. Improved patient selection methods are required in fusion for degenerative disc disease and pain after laminectomy.

Bovine bone grafting in occipito-cervical fusion for atlanto-axial instability in rheumatoid arthritis.

Bovine bone chips (Surgibone) were used in occipito-cervical fusion in nine patients with atlanto-axial instability due to rheumatoid arthritis. The patients were examined with CT 12-15 months after surgery. Graft resorbtion was observed in one patient. The other 8 patients showed preserved grafts, in most cases the grafts appeared to be in contact with the underlying bone. One patient was revised, and at the grafted site a bony bridge was found. In conclusion, the use of bovine chips in posterior occipito-cervical fusion will not lead to predictable bone union. However, there seem to be exceptions to that rule.

Generation of x rays for medical imaging by high-power lasers: preliminary results.

PURPOSE: To evaluate the use of x-ray imaging performed with a high-power laser system in biologic and medical studies. MATERIALS AND METHODS: A compact terawatt laser system based on chirped pulse amplification in titanium-doped sapphire was used. X rays were generated by irradiating a high-atomic-number target (tantalum). RESULTS: When photons with an energy below 10 keV were removed with use of 3 mm of aluminum, the half-value layer in aluminum for the remaining x rays was approximately 10 mm. The x-ray source allowed performance of biologic magnification radiography. Star-pattern tests indicated an equivalent focal spot size of less than 60 microns. Exposures of a single pulse could be obtained. The duration of a single x-ray pulse was estimated to be of the order of picoseconds. CONCLUSION: With use of subpicosecond laser pulses, x-ray generation can occur with a smaller equivalent focal spot size than with conventional x-ray sources.

Technetium-99m-nanocolloid scintigraphy in orthopedic infections: a comparison with indium-111-labeled leukocytes.

Twenty-three patients with clinically suspected acute or chronic osteomyelitis and 21 patients with suspected joint prosthetic infection underwent scintigraphy using both 99mTc-nanocolloid and 111In-labeled leukocytes. The scintigrams of the two tracers were blindly interpreted by three independent observers. Their evaluations showed high correspondence. Patients were classified as having no infection, probable infection or proven infection according to specific criteria which included results of bacteriological cultures and histopathological examinations. For proven and probable infection taken together, the sensitivity with 99mTc-nanocolloid was 94%, the specificity 84% and the accuracy 87%, compared with 75%, 90% and 85% with 111In-labeled leukocytes. We conclude that 99mTc-nanocolloid scintigraphy is at least equivalent with 111In-leucocyte scintigraphy, and its additional advantages are shorter examination time, less complexity and better radiation dosimetry.

Replacement of the os trapezium by polyurethane implants.

Twenty-five patients with arthrosis of the first carpometacarpal joint had the os trapezium replaced by a polyurethane implant (Tecoflex), and the results were evaluated after three years (range 28-47 months). There were three failures in which the implants had been removed because of dislocation with pain. The clinical results in the remaining 22 cases in terms of relief of pain and thumb function were comparable with previous series of silicone implants. Radiographic examination showed no signs of bone resorption or other unfavourable tissue reactions around the implants, but subluxation of the implants was seen in half of the cases. Implant subluxation might be caused by poor design of the implant or the limited amount of fibrous foreign-body reaction around the polyurethane material that resulted in less firm encapsulation than occurred around silicone implants.

Necrosis observed on CT enhancement is of prognostic value in soft tissue sarcoma.

Fifty-one patients with deep-seated soft tissue sarcoma of the extremities and trunk wall were examined with contrast-enhanced CT for presence of nonenhanced tumor areas (CT necrosis). After a median follow-up time of 3 years, 19 of the 41 patients with CT necrosis had developed metastases, compared to none of the 10 patients who had tumors without CT necrosis. Tumors with CT necrosis were larger than tumors without, but in tumors of similar size, absence of CT necrosis was a favorable prognostic sign.

The usefulness of nocturnal resting splints in the treatment of ulnar deviation of the rheumatoid hand.

Seven patients with definite RA and bilateral ulnar deviation of Fearnley grade I were included in a study of the usefulness of nocturnal resting splints. Each patient used the splint on average 17 months on one hand, randomly chosen, with the free hand as control. Joint mobility, grip strength, pain and radiographic findings were recorded at start and finish of the study. Splint treatment influenced grip strength positively, and most patients stated pain relief during the night. However, all but one patient showed progression of ulnar deviation in both hands, and there was no significant difference in progression between treated and nontreated hands. This study thus supported the use of resting splints at night for pain relief but not for prevention of ulnar deviation.

Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma.

From 1980 through 1986, 119 patients with soft tissue sarcomas of the extremities were referred to our tumor center either before surgery (n = 78) or immediately after incisional biopsy or marginal excision (n = 41). The tumors were classified according to anatomic location at admittance as subcutaneous (n = 40), intramuscular (n = 30), and extramuscular tumors (n = 49). Open biopsy was omitted in 75 of the 78 patients referred before surgery; the preoperative diagnosis was based on physical and radiographic findings and fine-needle aspiration cytology. The surgical intention for subcutaneous tumor was to obtain a wide margin, which required a cuff of fat tissue around the tumor and inclusion of the deep fascia beneath the tumor. A wide margin for an intramuscular tumor implied no open biopsy and an unbroken muscle fascia or thick muscle cuff around the tumor (primary myectomy). The 70 patients with subcutaneous and intramuscular tumors were all treated by local surgery. A wide margin was obtained in 56 patients who were not given radiotherapy. During a median follow-up of 5 years (range, 3.5 to 10 years), four of these 56 patients--47 of whom had high-grade malignant tumors--had a local recurrence. We conclude that routine combination of limb-sparing surgery with adjuvant radiotherapy is not necessary in patients with soft tissue sarcoma. Two thirds of soft tissue sarcomas of the extremities are primarily subcutaneous or intramuscular tumors, the majority of which can be treated by local surgery without local adjuvant therapy with a local recurrence rate of less than 10%, irrespective of malignancy grade.