Ceftolozane/Tazobactam Pharmacokinetics in a Critically Ill Adult Receiving Continuous Renal Replacement Therapy

Limited data are available on ceftolozane/tazobactam dosing in patients receiving continuous renal replacement therapy (CRRT). Thus we performed a pharmacokinetic analysis of intravenous ceftolozane/tazobactam in a critically ill patient receiving CRRT at our medical center. A 47‐year‐old critically ill man with multidrug‐resistant Pseudomonas aeruginosa pneumonia, bacteremia, and osteomyelitis was receiving ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) every 8 hours while receiving continuous venovenous hemodiafiltration (CVVHDF). After the fifth dose of ceftolozane/tazobactam, plasma samples were obtained at 1‐, 2‐, 4‐, 6‐, and 8‐hour time points. Two additional post‐hemodialysis filter plasma samples were obtained to assess CVVHDF clearance. The maximum and minimum plasma concentrations for ceftolozane were 163.9 μg/ml and 79.4 μg/ml, respectively. The area under the plasma concentration–time curve from 0–8 hours (AUC_0–8) was 689 μg hour/ml; the plasma half‐life was 13.3 hours. The ceftolozane CVVHDF clearance and total clearance were 2.4 L/hour and 2.9 L/hour, respectively. Compared with a patient with normal renal function, this patient receiving CVVHDF had decreased ceftolozane clearance. A ceftolozane/tazobactam dosage of 1.5 g every 8 hours should adequately achieve a desired drug concentration above the minimum inhibitory concentration of 8 μg/ml for the treatment of pneumonia. Additional pharmacokinetic data are needed to confirm our results and for alternative forms of CRRT.     

A rapid, economical, and simple method for concentration of Schistosoma mansoni ova in feces

An easy, rapid, and economical method for concentration of Schistosoma mansoni ova in feces is described. The basic procedure involves 20 minutes of gravity sedimentation of a fecal suspension sieved through gauze and suspended in a 5% (volume/volume) solution of glycerol in tap water with Ig/L benzoic acid. There is excellent recovery of S. mansoni ova. It can be applied under field conditions and can be implemented by any laboratory with routine facilities. It also allows detection of other ova, larva, and to some extent, cysts.     

Relationship between Albuminuria and Total Proteinuria in Systemic Lupus Erythematosus Nephritis: Diagnostic and Therapeutic Implications

Background and objectives: Albuminuria is regarded a sensitive measure of progression of glomerular disease. This study was undertaken in patients who had systemic lupus erythematosus glomerulonephritis (n = 57) and were followed in the Ohio SLE Study to determine whether measuring albuminuria offered clinical advantages over that of total proteinuria.Design, setting, participants, & measurements: Twenty-four-hour urine collections (n = 127) were obtained at baseline and annually for measurement of microalbumin, total protein, and creatinine.Results: There was a strong linear relationship between microalbumin-creatinine and protein-creatinine ratios over the entire range of protein-creatinine ratios; however, in the protein-creatinine ratio range 0.0 to 0.3, as the protein-creatinine ratio increased, the microalbumin-protein ratio increased much more than the protein-creatinine ratio. Also, the greater the protein-creatinine ratio, the greater was the evidence for nonselective proteinuria (protein-creatinine ratio − microalbumin-creatinine ratio).Conclusions: For the diagnosis of proteinuria renal flare, measuring albuminuria offers no advantage over measuring total proteinuria because changes in protein-creatinine and microalbumin-creatinine ratios are highly correlated over the designated ranges for systemic lupus erythematosus glomerulonephritis proteinuric flares. In those with normal-range proteinuria, subsequent changes in microalbumin-protein ratio might be a better forecaster of renal flare than changes in protein-creatinine or microalbumin-creatinine ratio. High protein-creatinine ratios are associated with evidence of nonselective proteinuria, which may increase the nephrotoxicity of proteinuria. Thus, using high-threshold criteria for systemic lupus erythematosus flare (allowing greater proteinuria increase before flare is declared) may expose the kidney to greater nephrotoxicity than using the low-threshold criteria for systemic lupus erythematosus flare.Glomerular injury usually induces an increase in glomerular permeability to macromolecules, resulting in increased urinary excretion of plasma proteins. Under conditions of severe glomerular injury, albumin (molecular weight approximately 69 kD) is the most abundant protein excreted in the urine, generally accounting for much more than 50% of the urinary proteins (1). Thus, albuminuria is the hallmark of glomerular proteinuria; however, under conditions of mild glomerular injury, albumin usually comprises much less than 50% of urinary proteins (1). The low rate of albuminuria compared with that of total proteinuria (albumin + nonalbumin proteinuria) in mild glomerular injury is thought to be the result, at least in part, of the greater capacity of the renal tubules to absorb filtered albumin compared with that of larger proteins such as IgG (molecular weight approximately 150 kD) (2–4). Hereafter, “total proteinuria” is referred to as proteinuria.The prime example of using albuminuria to monitor progression of early glomerular injury is in diabetic glomerulosclerosis, where increases in albuminuria are indicative of progression of diabetic glomerulosclerosis, even when the proteinuria rate is within the normal range (e.g., <200 mg/24 h) (5–8). For measurement of low-level changes in albuminuria, immunoassays have been developed to detect urine albumin in concentrations <1 mg/dl. These are referred to as “microalbumin” assays (1). Normal 24-h urine albumin excretion by these assays is <30 mg albumin/g creatinine (8). Albuminuria rates of 30 to 300 mg/g creatinine are referred to as “microalbuminuria.” Albuminuria rates beyond that range are referred to as “macroalbuminuria” (8). When the macroalbuminuria range is reached in diabetic nephropathy, albumin becomes the dominant urinary protein and proteinuria parallels albuminuria. At that point, the advantage of measuring albuminuria over proteinuria is generally lost (7).It is well established that in chronic kidney disease (CKD), albuminuria and proteinuria are highly correlated (7–9), particularly when 24-h proteinuria exceeds 500 mg (7); however, in systemic lupus erythematosus glomerulonephritis (SLE GN), the relationship between proteinuria and albuminuria has not been rigorously examined (10–12). It is plausible that albuminuria–proteinuria relationships are different in SLE GN compared with that of other forms of CKD. Mechanisms that could account for such differences include the following: (1) The microalbuminuria assay does not detect intact albumin that has been modified in vivo. The latter process is particularly common in patients with diabetes and CKD (13). The extent to which albumin is modified in SLE is unknown. (2) Albumin that undergoes glomerular filtration in CKD is extensively absorbed by the renal tubules. The fraction of albumin that is not absorbed undergoes extensive degradation, apparently by proximal tubular lysosomes, with excretion in urine as low molecular weight peptides <10 kD. These peptides are not measured by the immunoassay for microalbuminuria or by the usual clinical measures of proteinuria such as pyrogallol red or Coomassie blue (4,13,14). In experimental models of GN, renal tubular degradation of albumin does not occur (13,14). Thus, intact albumin could be overrepresented in SLE GN urine compared with that of CKD urine. (3) There is evidence from experimental models that some conditions of moderate albuminuria may be entirely the result of failure of renal tubular retrieval of albumin that normally is filtered by the normal glomerulus (15,16). Renal tubular albumin retrieval could differ between SLE and other CKD conditions. (4) Hypoalbuminuria independent of urine protein loss commonly occurs in SLE. The apparent mechanism is inflammation-induced albumin catabolism (17). This mechanism could influence albuminuria–proteinuria relationship in SLE GN compared with that of other causes of CKD in which inflammation is not a prominent feature. This study explores the relationship between albuminuria and proteinuria in patients with SLE GN across a wide range of proteinuria, including threshold ranges that commonly are used for identifying SLE proteinuric flares.     

Autograft containment in posterolateral spine fusion.

BACKGROUND CONTEXT: Pseudoarthrosis rates in lumbar intertransverse fusion remain high. Compression and displacement of the developing fusion mass by the paraspinal musculature may be a contributory factor. Biocontainment devices have been clinically used in the skull and mandible to guide bone regeneration. The role of a mechanical device in containing graft material in the developing posterolateral lumbar spine fusion is unclear. PURPOSE: To determine the benefits of using a bioabsorbable graft-containment device for lumbar intertransverse fusion, and to evaluate the biocompatibility of this implant by histological analysis of the host tissue reaction. STUDY DESIGN: A rabbit intertransverse spine fusion model was used to evaluate a bioabsorbable graft-containment implant. Study and control groups were compared with regard to the rate, volume, and quality of fusion, as well as host tissue reaction to the graft and implant. METHODS: Fourteen adult male New Zealand White rabbits underwent bilateral posterolateral intertransverse spine arthrodesis at L3-L4. The control group (n=7) received autograft alone, and the study group received autografts placed in open meshed hemicylinders fashioned from LactoSorb sheets (LactoSorb; Biomet Orthopedics Inc., Warsaw, IN). Spines were harvested at 6 weeks and imaged. Radiographs and computed tomography (CT) images were used to calculate the rate, area, and volume of fusion mass. Sections were fixed and stained with hematoxylin-eosin and Mallory trichrome for histological analysis of fusion and host tissue response. The Mann-Whitney nonparametric statistical test was used for the radiographic and CT qualitative assessments. The CT volume quantitation was analyzed using the Student t test. A p value of <.05 was used to assign statistical significance. RESULTS: The fusion rates on radiographs and CT imaging did not show a significant difference (p>.05) between the biocontainment and control groups. The volume of fusion revealed a significant increase with biocontainment (mean+/-standard error; total left+right fusion sides=2.88+/-0.30 cc) compared with controls (2.12+/-0.15 cc) (p<.05). Histology revealed no difference in the maturity or the quality of the fusion mass between the two groups. Inflammatory response around the developing fusion mass and muscle necrosis were slightly increased in the study group. The LactoSorb biocontainment material led to variable inflammatory reaction, with some areas showing little or no response and other showing an inflammatory response with fibrous connective tissue, lymphocyte infiltration, and focal foreign body giant cell reaction. CONCLUSIONS: The incidence of fusion was similar with or without a containment device for onlay bone graft. A significant increase in the volume of the fusion suggests that a biocontainment device does play a role in protecting the developing fusion mass from the mechanical effects of the paraspinal musculature. The clinical use of this device cannot be justified at this time, and further studies will determine whether this increase in fusion volume will translate into a better incidence and volume of fusion in primate and human models.     

Immunohistochemical comparison of gastrointestinal stromal tumor and solitary fibrous tumor

CONTEXT: The differential diagnosis of gastrointestinal stromal tumors (GIST) and solitary fibrous tumors (SFT) may be a diagnostic challenging because of overlapping clinicopathologic features. Many studies have shown consistent immunoreactivity for CD117 (c-Kit) in GIST. However, only a few studies have evaluated CD117 expression in SFT, and these studies have used an antibody from Santa Cruz Biotechnology. In non-GIST lesions, reactivity with this antibody has been shown to differ from that with a CD117 antibody from Dako Corporation. The immunoreactivity of SFT with the Dako CD117 antibody has not been reported. Conversely, CD99 is a marker for SFT, and its expression in GIST has not been evaluated. OBJECTIVE: To study the immunohistochemical profiles of GIST and SFT to evaluate their diagnostic overlap. DESIGN: We studied the immunoreactivity of 27 unequivocal GIST and 19 unequivocal extra-abdominal SFT for CD117, CD34, CD99, alpha-smooth muscle actin, vimentin, CD31, S100 protein, and muscle-specific actin. All antibodies, including CD117, were from Dako Corporation. RESULTS: We found positive immunoreactivity for CD117 in 100% of GIST and none of SFT; for CD34 in 89% of GIST, and 100% of SFT; for CD99 in 89% of GIST and 100% of SFT; for alpha-smooth muscle actin in 48% of GIST and 31% of SFT; for vimentin in 89% of GIST and 90% of SFT; and for muscle-specific actin in 22% of GIST and none of SFT. None of the GIST or SFT showed immunoreactivity for CD31 and S100 protein. CONCLUSIONS: The major difference between GIST and SFT was strong CD117 immunoexpression in all GIST and an absence of this expression in all SFT. With the exception of muscle-specific actin, the prevalence of immunoreactivity for the markers studied did not differ substantially between these 2 tumors. We conclude that GIST and SFT show distinctly divergent immunoprofiles with respect to CD117 and muscle-specific actin.     

Statistical Pitfalls in Medical Research

In conducting and reporting of medical research, there are some common pitfalls in using statistical methodology which may result in invalid inferences being made. This paper is aimed to highlight to inexperienced statisticians or non-statistician some of the common statistical pitfalls encountered when using statistics to interpret data in medical research. We also comment on good practices to avoid these pitfalls.     

Evaluation of crystals in formalin-fixed, paraffin-embedded tissue sections for the differential diagnosis of pseudogout, gout, and tumoral calcinosis.

Hematoxylin-eosin (H&E)-stained sections may not allow proper evaluation of birefringence properties of the crystals in the lesions of pseudogout, gout, and tumoral calcinosis. This study was undertaken to verify the application of a special stain that could facilitate the evaluation of the birefringence properties of these crystals for definitive diagnosis. We evaluated previously described nonaqueous alcoholic eosin staining (NAES) method based on the principle of using alcoholic eosin without hematoxylin and any other aqueous reagents for staining of formalin-fixed, paraffin-embedded tissue sections. Two observers, in a blinded fashion, evaluated the sections stained with routine H&E and NEAS method without the knowledge about clinical diagnosis. All pseudogout (nine sections from seven cases) and gout (eight sections from five cases) lesions demonstrated birefringence in the sections stained with NAES method. H&E-stained sections showing the respective diagnostic histomorphology failed to demonstrate the birefringent crystals by polarizing microscopy in all the eight sections from gout and in seven of nine sections from pseudogout. Only two H&E-stained sections showed scant calcium pyrophosphate dihydrate (CPPD) crystals in pseudogout. None of the three sections from two cases of tumoral calcinosis showed birefringence with either stain. We conclude that CPPD in pseudogout and monosodium urate in gout may not polarize in the routine H&E-stained sections. However, polarizing microscopy of sections stained with NAES method allowed demonstration of CPPD crystals with positive birefringence in pseudogout, MSU crystals with negative birefringence in gout, and calcium hydroxyapatite crystals without birefringence in tumoral calcinosis. Section stained with NAES method is a significantly useful adjunct to the routine H&E stain for proper evaluation of the crystals under polarizing microscope in these lesions.