In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin.

In a previous study we demonstrated that indomethacin potentiated the hydro-osmotic action of vasopressin in vivo. It was hypothesized that this action of indomethacin was due to its ability to suppress renal medullary prostaglandin synthesis, since in vitro studies have suggested that prostaglandins interfere with the ability of vasopressin to stimulate production of its intracellular mediator, cyclic AMP. In the present study this hypothesis was tested in vivo. Anesthetized rats undergoing a water diuresis were studied. In a control group, bolus injections of 200 muU of vasopressin caused a rise in urinary osmolality (Uosm) from 124 +/- 6 to 253 +/- 20 mosmol/kg H2O (P less than 0.005). In a group treated with 2 mg/kg of indomethacin the same dose of vasopressin caused a significantly greater (P less than 0.001) rise in Uosm from 124 +/- 7 to 428 +/- 19 mosmol/kg H2O. Medullary tissue cyclic AMP rose from 9.4 +/- 0.9 to 13.4 +/- 1.7 (P less than 0.05) pmol/mg tissue protein after vasopressin administration in animals receiving no indomethacin, while in indomethacin-treated animals there was a significantly greater rise (P less than 0.001) in medullary cyclic AMP from 10.4 +/- 0.9 to 21.6 +/- 2.1 pmol/mg tissue protein in response to the vasopressin injections. In neither control animals nor indomethacin-treated animals were there significant changes in renal hemodynamics, as measured by clearance techniques. Indomethacin, when given alone, had no effect on Uosm or medullary tissue cyclic AMP. Indomethacin did, however, reduce medullary prostaglandin E content from 84.7 +/- 15.0 to 15.6 +/- 4.3 pg/mg tissue. This study has shown that indomethacin, in a dose which suppresses medullary prostaglandin content, potentiates the ability of vasopressin to increase the tissue content of its intracellular mediator, cyclic AMP. Indomethacin caused no demonstrable inhibition of cyclic AMP phosphodiesterase. Therefore, it seems likely that indomethacin enhanced the ability of vasopressin to increase medullary cyclic AMP levels by causing an increased production rather than decreased destruction of the nucleotide. We conclude that this action of indomethacin contributes to its ability to potentiate the hydro-osmotic action of vasopressin in vivo. A corollary to this conclusion is that endogenous medullary prostaglandin E's may be significant physiological modulators of the renal response to vasopressin.

Charcoal sorbent-induced hypolipidemia in uremia and diabetes.

Rats with hyperlipidemia associated with streptozotocin-induced diabetes or azotemia after subtotal nephrectomy were administered a diet containing 5% activated charcoal. Significant lowering of nonfasting serum cholesterol and triglyceride levels resulted. Charcoal-feeding also altered the abnormal high density lipoprotein electrophoresis pattern of diabetic rats toward normal.

Normal and abnormal morphology of the corpus callosum.

We studied the normal and abnormal morphology of the corpus callosum in 450 midline sagittal magnetic resonance scans. Clinical information was required to differentiate acquired and congenital defects. Four forms of congenital anomalies were observed: focal attenuations, cysts, partial agenesis, and complete agenesis. Acquired changes resulted from hydrocephalus, white matter diseases, vascular accidents, tumor, and trauma.

Aluminum intoxication in a child: treatment with intraperitoneal desferrioxamine.

We report the successful chelation of aluminum and the clinical resolution of severe aluminum intoxication in an infant receiving chronic peritoneal dialysis through the use of intraperitoneal desferrioxamine. Following the introduction of desferrioxamine, urine and dialysate fluid aluminum levels exceeded those noted without the chelating agent, thus demonstrating enhanced removal of aluminum. As a result of therapy, plasma and bone aluminum levels decreased markedly, and previously noted histomorphometric abnormalities on bone biopsy resolved. Clinically, the aluminum-associated osteomalacia and microcytic hypochromic anemia completely reversed. Moderate developmental delay has also improved slightly but persists. Our experience suggests that intraperitoneal chelation therapy with desferrioxamine may be helpful to reverse aluminum intoxication in children with chronic renal failure. However, limited exposure to aluminum should remain a primary goal.

Serum antibody response to pneumococcal vaccine in children with nephrotic syndrome.

Children with nephrotic syndrome are susceptible to serious pneumococcal disease and may be immunodeficient on the basis of abnormal humoral immune responses to natural antigens or immunoglobulin loss during relapse. As part of an ongoing study to evaluate pneumococcal anticapsular antibody concentration and immunologic competence, 27 steroid-responsive and six steroid-resistant patients with nephrotic syndrome, and 12 age-matched control subjects, were vaccinated with polyvalent pneumococcal vaccine. Antibody responders were defined as patients with at least a twofold increase in antibody after vaccination as well as an antibody concentration greater than 200 ng of anticapsular antibody nitrogen per milliliter (ngN/ml) after vaccination. Pneumococcal antibody concentrations before and after vaccination were significantly depressed in steroid-resistant patients when compared with control subjects (P less than .002) and with the steroid-responsive nephrotic syndrome group (P less then .001). Steroid-responsive nephrotic children who were not receiving corticosteroid therapy at the time of vaccination had significantly higher antibody concentrations to five pneumococcal types before vaccination and to seven types after vaccination compared with control subjects (P less than .05). Fewer steroid-responsive patients receiving corticosteroids achieved antibody concentrations greater than or equal to 200 ngN/ml against type 19F compared with patients not receiving steroids or with control subjects (P less than .05). These results suggest that pneumococcal vaccine is immunogenic in children with steroid-responsive nephrotic syndrome and may protect these patients from disease due to pneumococcal types contained in the vaccine.

Evaluation of a protocol for lactate dehydrogenase (LD) isoenzymes.

Two divergent laboratory approaches to the measurement of lactate dehydrogenase (LD) isoenzymes (LDIs) were evaluated. Abnormal values for total creatine kinase (CK), CK-MB, total LD, and LDIs were greater than 250 U/L, greater than or equal to 5% total CK, greater than 180 U/L, and LD1/LD2 ratio greater than 1.0, respectively. The first approach, measuring LDI on all requests regardless of total LD activity, showed the following results: 161 LDI specimens, 63 CK-MB + (LD1 greater than LD2, 6; LD1/LD2 normal, 57); 98 CK-MB - (LD1 greater than LD2, 5, LD1/LD2 normal, 93). Medical chart review of the 98 CK-MB negative specimens, representing 44 patients, showed that in seven patients with acute myocardial infarction (MI), none would have been missed clinically even if LDIs had not been done, and in only one case did LDIs play a confirmatory role in a patient who persistently had CK-MB-negative results but who had a strong clinical suspicion of MI. None of the 42 patient specimens with normal total LD activity had an LD1 greater than LD2. The second approach, measuring LDIs only if requested, only if total CK was abnormal, only if results for CK-MB were negative, and only if total LD was abnormal, showed the following results: 71 LDI specimens were not done (46 with normal total LD, 25 CK-MB + specimens). Medical chart review of the 71 LDIs not determined, representing 38 patients, showed that none of the 14 patients with the final diagnosis of MI would have been clinically missed, even if LDI had not been done, and in only one instance did LDIs confirm the clinical suspicion of MI in a patient with previously negative results for CK-MB. The LDI protocol represented by the second approach has been shown to be an effective means of identifying those occasional patients who require this confirmatory test, in whom the CK-MB results are negative but in whom there is a strong clinical suspicion of MI.

Efficacy of using total bilirubin values as a guide for screening direct bilirubin requests.

Two divergent laboratory approaches to the determination of direct bilirubin were assessed. The first approach, assaying direct bilirubin (DB) on all total bilirubin (TB) requests regardless of TB values, resulted in a true negative rate (normal TB level less than 1.0 mg/dL [less than 17 mumol/L], and DB level, less than 0.4 mg/dL [less than 6.8 mumol/L]) of 98.7% (984/997 specimens) and a low false negative (normal TB level, abnormal DB level) rate of 1.3% (13 of 997). The second approach, assaying DB on physician request and only if the TB level was greater than or equal to 1.0 mg/dL (1.7 mumol/L), resulted in a true negative rate (normal TB level, no liver disease) of 87.7% (150%) of 171 patients) and a relatively low false negative rate (normal TB level, liver disease) of 12.3% (21 of 171) patients. Medical chart review revealed that, with either approach, none of the patients with false negative results with hepatobiliary disease would have been missed clinically, even if the DB assay had not been done. It is possible to screen DB requests using a TB of 1.0 mg/dL (17 mumol/L) as a means to determine whether DB should be assayed.

Hypomagnesemia in acute and chronic care patient populations.

The frequency and prevalence of hypomagnesemia (less than 0.72 mmol/L) in two divisions of a consolidated medical center with two distinct patient populations, acute and chronic, was studied. In the acute care patient population, the frequency and prevalence of hypomagnesemia was 41.4% (222 of 536 determinations) and 26.1% (92 of 353 patients) compared to a frequency of 12.5% (50 of 399 determinations) and prevalence of 3.5% (9 of 258 patients) in the chronic care population. Although the two divisions have similar numbers of hospital discharges, the acute care facility handles acute medical and all surgical cases, whereas the chronic care facility handles primarily psychiatric cases. In the acute care facility, the most common diagnoses associated with hypomagnesemia were coronary artery disease, malignancy, coronary artery bypass surgery, chronic obstructive pulmonary disease and alcoholism, whereas in the chronic care facility, alcoholism, liver disease, and carcinoma were the most frequent diagnoses associated with hypomagnesemia. The frequency and prevalence of hypomagnesemia in a patient population depends on the type of patient population studied and is significantly greater in the acute care compared to the chronic care patient population.

Assessment of a critical limit protocol for point-of-care glucose testing.

A critical limit protocol requiring that all point of care glucose meter readings > 22.2 mmol/L (400 mg/dL) and < 2.2 mmol/L (40 mg/dL) be immediately confirmed by the laboratory was assessed. A total of 193 (2%) of 9,523 glucose meter determinations (63 patients) were > 22.2 or < 2.2 mmol/L. One hundred twenty-two (63%) of critically high and low glucose readings were followed up, and 71 (37%) results were not. Seventy-seven percent (55 of 71) of results without follow up were in patients with multiple glucose meter/central lab comparisons, suggesting that users may have thought it unnecessary to confirm such results. Split sample quality control specimens showed good correlation (r = 0.927) between glucose meter and central lab results, whereas correlation for follow-up glucose results was poorer (r = 0.793), perhaps reflecting time delay in obtaining a lab sample. For follow-up results, only 18% of high/low critical limit glucose meter readings were confirmed by drawing a lab specimen within 10 minutes. Fifty-eight percent were in 17 patients with multiple previous glucose meter readings, suggesting that users may have though it less urgent to confirm a sequence of such results. Eleven follow-up results (9%) showed a > 50% discordance between glucose meter/central lab with three (27%) glucose meter errors, emphasizing the need to confirm critically high/low glucose meter results to avoid potential errors. The critical limit protocol now requires that only the initial critically high/low glucose meter reading be confirmed by the lab and that these patients now be followed with lab values until glucose levels are between 5.6-16.7 mmol/L (100-300 mg/dL) before the glucose meter can again be used.

Evaluation of dipstick urine studies using a scoring system based on test performance characteristics.

A weighted scoring system based on the selection of four measures of the performance characteristics of a laboratory test--sensitivity, specificity, and false positive and false negative rates--was devised to provide a rationale basis for ranking and evaluating dipstick urine screening tests as a criterion for elimination of routine urine microscopic examination. Equal weight was assigned to each performance characteristic, and an arbitrarily chosen scoring scale of 100 was selected for simplicity. When a summation procedure was applied to urine studies available in the medical literature, three categories of author acceptability were found: accept: score greater than 80; conditional accept: score 70-80; reject: score less than 70. Studies incorporating leukocyte esterase (LE) were found to have the highest scores and the highest author acceptability, whereas studies lacking LE had the lowest scores and lowest author acceptability. This easy-to-use, weighted scoring system is proposed as a guide for deciding whether dipstick screening tests are acceptable as a way of eliminating routine microscopic examination.

Dipstick testing of urine--can it replace urine microscopy?

One thousand consecutive urine specimens were studied to assess the sensitivity of a commercially available dipstick (Chemstrip 8, Boehringer Mannheim Corp., Indianapolis, IN) to predict the presence or absence of microscopic abnormalities. The Chemstrip 8 had a sensitivity of 78%, specificity of 54%, and a false negative rate of 38%. An additional 1,000 consecutive urine specimens were then studied using the Chemstrip 9, a reagent dipstick that includes the leukocyte esterase (LE) test. The Chemstrip 9 had a sensitivity of 82%, specificity of 42%, and a false negative rate of 36%. Chi-squared analysis revealed that the two dipsticks were not significantly different (chi 2 = 0.17, P greater than 0.5). Clinical review of patients with false negative results showed that approximately one-third to one-half of these patients had either spinal cord injury or genitourinary problems. Maximal potential savings in workload of approximately 10% were found if microscopic examinations were to be performed only on urine specimens with abnormal dipsticks. Our data suggest that in our patient population, we should not eliminate microscopic urine examination based on abnormal dipstick findings.

The clinical usefulness of an algorithm for the interpretation of biochemical profiles with hypercalcemia.

A logical, systematic approach to the interpretation of diagnostic biochemical profiles in patients with hypercalcemia has been attempted through the use of algorithms (decision trees). A tentative algorithm (ALG-I) and an expanded and modified version (ALG-II) were compared for effectiveness in tests of 80 patients with hypercalcemia at Charity Hospital in New Orleans. The overwhelming majority (69%) of these patients had malignant disease. Comparative performance indicated that the modified algorithm (ALG-II) assigned the correct diagnostic categories in 66% of cases, compared with 53% for ALG-I, but the clinical performance of ALG-I improved (agreement rate of 60%) when it was assumed that patients with malignancy could have coexisting hyperparathyroidism or pseudohyperparathyroidism. The clinical trial indicated that both algorithms were fairly comparable and that their primary use would be as teaching aids for medical students and residents to suggest various diagnostic possibilities for hypercalcemia in patients.

Clinical assessment of the electrophoretic separation of alkaline phosphatase isoenzymes.

Over a five-month period, using data from patients in whom alkaline phosphatase (ALP) isoenzyme studies were requested routinely, we compared actual clinical diagnoses with the predicted diagnoses based on the results of electrophoretic separation of ALP isoenzymes on cellulose acetate before and after heat treatment and on elevated enzymatic activity of gamma glutamyl transferase (GGT) and alanine aminotransferase (ALT) activity. ALP isoenzymes were interpreted on a qualitative basis (presence or absence of liver, bone, or other isoenzyme) by individual clinical pathologists. Overall, the consistency of agreement in 61 patients was 66% for GGT, 51% for ALP isoenzymes, and 21% for ALT. In 44 patients with definite diagnoses, the sensitivity and specificity, respectively, of each laboratory test for patients with liver disease were 88 +/- 5.7% and 64 +/- 14.5% (ALP isoenzymes); 88 +/- 5.7% and 91 +/- 8.6% (GGT); and 6 +/- 4.1% and 91 +/- 8.6% (ALT). In patients with bone disease, the sensitivity and specificity of ALP isoenzymes was 75 +/- 10.8% and 86 +/- 6.6%, respectively. The results indicate that isoenzymes as currently performed need to be improved through standardization of the interpretation of ALP isoenzyme patterns to establish uniformity of comments.

Antibiotic susceptibility of Burkholderia pseudomallei from tropical northern Australia and implications for therapy of melioidosis.

From a prospective melioidosis study commencing in 1989 at Royal Darwin Hospital, 170 initial isolates of Burkholderia pseudomallei were available for susceptibility testing. Of these 163 (96%) were susceptible to meropenem/imipenem, ceftazidime, trimethoprim-sulphamethoxazole (SMX/TMP) and doxycycline. Seven (4%) showed primary resistance; three had low-level resistance to SMX/TMP, one to ceftriaxone and amoxycillin/clavulanate (AMOX/CA) and three to doxycycline. Of 167 patients who survived their initial presentation, seven (4%) had culture positive infections which persisted for greater than 3 months after start of therapy. All ultimately cleared carriage of B. pseudomallei though three required changing to SMX/TMP after development of doxycycline resistance. Nineteen (11%) of the initial survivors clinically relapsed and 17 of these had repeat isolates available for testing. Four of these had acquired resistance: one to doxycycline, one to AMOX/CA and ceftazidime, one to SMX/TMP and one to both SMX/TMP and doxycycline. Molecular typing using randomly amplified polymorphic DNA and pulsed-field gel electrophoresis showed all but one relapse isolate to be the same as the original strain. These data are similar to published data from Thailand. As melioidosis has a high mortality (21% in this series) these results emphasize the need for prolonged eradication therapy and regular clinical and microbiological monitoring so that the emergence of resistance can be detected early and appropriate treatment modifications made.

Medical Positron Imaging with a Dense Drift Space MultiWire Proportional Chamber.

A multiplanar positron camera is proposed, made of six MWPC modules, arranged to form the lateral surface of a hexagonal prism. Each 50 x 50 cm(2) module has a single MWPC sandwiched by two 2-cm thick lead glass tube converters. The experimental results for a 15 x 15 cm(2) test module are reported. For 511 keV gamma-rays incident almost perpendicular onto a 1.0-cm thick converter, a detection efficiency of 4.3%, a time resolution of 130 ns (FWHM) and a spatial resolution of 2.8 mm (FWHM) have been measured with a standard Argon-Methane (70-30) mixture at 1.2 atm. The chamber may also be operated in high resolution mode: 1.2-mm (FWHM) spatial resolution has been measured at a 50% lower efficiency. The use of fast delay lines (specific delay 8 ns/cm) for the position read-out ensures a high rate capability. The expected performance of the six-module MWPC camera is discussed and compared with that of a BGO crystal ring camera. The MWPC solution seems very attractive not only for its low cost and simplicity of construction, but also for its fully three-dimensional imaging capability.

CSF bacterial antigen detection tests offer no advantage over Gram's stain in the diagnosis of bacterial meningitis.

While bacterial antigen detection (BAD) tests have been used on cerebrospinal fluid (CSF) with success in the diagnosis of bacterial infection in developing countries, their value in the developed world has been recently questioned. In Darwin, Northern Territory (NT), there are good diagnostic resources but high rates of infectious disease, so it was unclear which findings were applicable to our own population. This study aimed to determine the utility of the BAD tests in detection of bacterial meningitis from CSF in patients studied at Darwin, using a retrospective review of hospital case records and microbiology laboratory reports, over a 19 month period, and utilising a clinical component in the case definition of bacterial meningitis. The sensitivity of the BAD test in the diagnosis of acute bacterial meningitis was 28.6%, with a specificity of 98.7% and a positive predictive value of 85.7%. The cost per positive test was computed at $240. No cases of bacterial meningitis which were positive on the BAD test were missed on Gram's stain of CSF. We conclude that in our setting BAD tests alone are not sensitive enough to confidently diagnose bacterial meningitis. BAD tests are more costly and offer no advantage in speed of diagnosis or in antibiotic pre-treated patients, compared to routine Gram's stain.

Surveillance of antibiotic resistance in invasive isolates of Neisseria meningitidis in Australia 1994-1999.

A total of 1434 strains of Neisseria meningitidis isolated from cases of invasive meningococcal disease (IMD) in Australia between 1994 and 1999 were examined by standard methods for susceptibility to antibiotics used for treatment and prophylaxis. The proportion of isolates fully susceptible to penicillin decreased from 45% in 1994 to 26% in 1999 (P<0.001). All the other isolates were less sensitive to penicillin except for two meningococci with a penicillin MIC of 1 mg/l. The geometric mean penicillin MIC increased from 0.045 to 0.065 mg/l from 1994 to 1999. There was no significant difference in the geometric mean penicillin MICs of serogroup B and serogroup C meningococci. Penicillin susceptibility was significantly associated with a poorer outcome. Isolates from survivors of IMD had a higher geometric mean penicillin MIC (0.06 mg/l) than those from fatal cases (0.048 mg/l) (P< 0.001). This suggests that factors other than the decrease in susceptibility to penicillin observed were more relevant to outcome in IMD. All isolates were fully susceptible to ceftriaxone. Rifampicin resistance was infrequent (eight isolates in 6 years) and sporadic. A single isolate had decreased quinolone susceptibility. Despite the significant shift in susceptibility to penicillin recorded, this group of antibiotics remains a suitable treatment for IMD in Australia.

Magnetic resonance and CT imaging correlated with clinical status in SSPE.

Five patients afflicted with subacute sclerosing panencephalitis were studied with computed tomography and magnetic resonance imaging. Computed tomography documented changes of nonspecific cerebral atrophy and low attenuation in the subcortical white matter. Magnetic resonance imaging revealed bilateral, symmetric, and diffuse abnormal increased signal in the white matter of the cerebral hemispheres with normal posterior fossa structures in 4 of 5 patients. Magnetic resonance imaging was superior to computed tomography in demonstrating the total extent of abnormality and may be the imaging modality of choice for this childhood disease.

Use of C-terminal parathyroid assays in a large metropolitan hospital.

The use of C-terminal parathyroid (C-PTH) assays, performed at a commercial laboratory, was evaluated for one year at Charity Hospital, New Orleans. Of 72 patients, the most frequent diagnosis was primary hyperparathyroidism (1 degree HPT) (n = 17, 24 percent), followed by malignancy (n = 15, 21 percent), chronic renal disease (n = 10, 14 percent), and thiazide diuretics (n = 5, 7 percent). In the 1 degree HPT group, all were hypercalcemic (mean serum calcium, 11.6 ml per dL) and had elevated C-PTH. Patients with malignancy had higher mean serum calcium levels than patients with 1 degree HPT. Three patients with malignancy had elevated C-PTH; two had suspected coexisting 1 degree HPT and neoplasm; and one had suspected pseudohyperparathyroidism. Patients with chronic renal disease undergoing dialysis treatment had the highest C-PTH recorded (all had elevated C-PTH) but only 50 percent were hypocalcemic. Three of the five patients on thiazide diuretics had increased C-PTH, indicating that the withdrawal of this drug may unmask underlying hyperparathyroidism. Appropriate reasons for ordering C-PTH include evaluation of hypercalcemia (n = 32, 44 percent) or hypocalcemia (n = 12, 17 percent); indicated clinical reasons not included in the hyper- or hypocalcemic groups, including chronic renal disease in patients undergoing dialysis or transplant (n = 5, 7 percent); in suspected 1 degree HPT, (n = 5, 7 percent); and in patients with renal stones (n = 2, 3 percent) or on thiazide diuretics (n = 2, 3 percent). Based on laboratory and clinical criteria, C-PTH assay was appropriately used in 81 percent of the patients surveyed (58/72).

How effective are screening tests for microalbuminuria in random urine specimens?

The effectiveness of four urine screening tests-microalbumin (MAlb), total protein (TProt), total protein/creatinine ratio (TProt/Cr R), and dipstick (DPalb) test for albumin-were evaluated for the detection of MAlb in random urine specimens. The following criteria were used to assess the effectiveness of each urine screening test: 100% specificity (no false positive results); cost effectiveness; rapidity and ease of performing the screening test; and increased laboratory efficiency. A "gold standard" for presence of MAlb in random urine samples was defined as a microalbumin/creatinine ratio (MAlb/Cr R) of > or = 30 mg/g. The least costly urine screening test was the DPalb, which, if assigned a value of 1.0, allowed a cost ranking order for the screening tests-DPalb (1.0) < urine TProt (1.03) < urine TProt/Cr R (2.1) < urine MAlb (7.0). Two hundred urine samples from diabetic inpatients and outpatients were tested. Only two screening tests--MAlb and DPalb--achieved 100% specificity without increasing laboratory costs (small net savings), whereas the other two screening tests--TProt and TProt/Cr R-only achieved 100% specificity with increased laboratory costs. Theoretical prevalence rate analysis showed that urine MAlb screening would be effective at all prevalence rates for overt nephropathy. TProt and DPalb urine screening testing would be most effective in populations with prevalence rates of > or = 15% for overt nephropathy. The TProt/Cr R ratio would only be effective in populations with prevalence rates of > or = 30%. Of the four urine screening tests, only DPalb would significantly streamline the process of measuring urine MAlb. The dipstick test is inexpensive, easy and rapid to perform, does not delay measuring the ratio, since there is no wait for the screening test result, and can be used by referring laboratories to screen urine specimens before they are submitted to a central laboratory, thereby reducing laboratory workload.