Prospective Comparative Study of Variable Dosage and Variable Frequency Regimens for Administration of Gentamicin

In patients with impaired renal function, careful adjustment of gentamicin dosage is required to achieve therapeutic yet nontoxic concentrations. Two regimens that differ in pharmacodynamic characteristics have been recommended for this purpose: prolonging the intervals between administration of equal doses (variable frequency regimen [VFR]) or administering a loading dose followed at the usual intervals by reduced maintenance doses (variable dosage regimen [VDR]). These regimens were compared in a prospective, randomized study of 20 seriously ill hospitalized patients, 10 on VFR and 10 on VDR. Wide variability in peak serum levels of gentamicin was observed both between patients and in individual patients after separate injections of the same dosage. As predicted by the design of these regimens, the trough serum levels of gentamicin correlated significantly with the serum creatinine concentrations in patients on the VDR but not in patients on the VFR. A gentamicin trough level of ≥4 μg/ml was the only variable among those tested that correlated significantly with development or progression of renal insufficiency during treatment with gentamicin, but such trough levels were observed frequently on both regimens. Whereas this study does not permit a direct comparison of the therapeutic efficacy of VDR and VFR, no difference in the risk of nephrotoxicity with these regimens was observed.     

Dexmedetomidine overdose in the perioperative setting

OBJECTIVE: To report 3 cases of accidental dexmedetomidine overdose in the perioperative setting and review the pathophysiology of alpha2-agonist overdose. case summaries: Three patients accidentally received overdoses of dexmedetomidine, one intraoperatively (192 microg over 20 min) and 2 postoperatively (4 and 2 rather than 0.4 and 0.2 microg/kg/h; 0.5 microg/kg/min rather than 0.5 microg/kg/h). Hemodynamic parameters remained stable for all 3 patients. The most notable sign was oversedation diagnosed either clinically or using a bispectral index monitor; Naranjo criteria suggest possible or probable association of the reactions with dexmedetomidine. In all 3 cases, oversedation resolved within one hour of drug discontinuation. There were no other sequelae, and the remainder of each patient's hospital course was unremarkable. DISCUSSION: As of this writing, dexmedetomidine dosing in excess of the label recommendation has been reported, but accidental dexmedetomidine overdose in clinical practice has not been described. Excessive levels of sedation were the only significant finding in all 3 patients. Dexmedetomidine's short redistribution half-life of 6 minutes should lead to rapid resolution of oversedation induced by overdoses if the overall duration of infusion is short (< or =8 h). While the patients reported here were hemodynamically stable, dexmedetomidine may engender significant hemodynamic changes either because of sympatholysis at normal doses or vasoconstriction at higher than recommended doses. The absence of a significant hypertensive response to high dexmedetomidine concentrations suggests that dexmedetomidine-induced hypertension may be multifactorial, not simply related to plasma drug concentrations. CONCLUSIONS: Practitioners presented with dexmedetomidine overdose should be prepared to manage oversedation. While hemodynamic alterations may be seen with dexmedetomidine use, hypertension from high dexmedetomidine plasma concentrations is not a consistent response. Practitioners using dexmedetomidine should carefully note that dosing for this agent is described by the manufacturer in microg/kg/h, not microg/kg/min.     

STUDIES ON TUBERCLE BACILLUS-HISTIOCYTE RELATIONSHIP : V. PASSIVE TRANSFER OF CELLULAR RESISTANCE

Studies of passive transfer of cellular resistance, as manifested by refractoriness to necrotization with virulent tubercle bacilli, have shown that immune histiocytes or immune lymphocytes were effective transferring agents; immune polymorphonuclear leucocytes and immune serum as well as comparable cells from normal animals lacked this capacity. Comparisons of immune histiocytes and immune lymphocytes showed that the former cells were more efficient; this was indicated by (a) the smaller numbers of immune histiocytes needed for passive transfer, (b) the longer duration of cellular resistance in recipients given histiocytes than in those given lymphocytes, (c) the greater capacity of histiocytes to effect serial passive transfer, and (d) the ability of histiocytic but not lymphocytic lysates to transfer cellular resistance. Experiments to establish the mechanism of passive transfer of cellular resistance showed that there was no active induction of resistance in recipients through transfer of bacillary antigens contained in immune histiocytes; in fact, the results of serial passive transfers with immune histiocytes suggested an active replication of the "cell resistance factor."     

Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts

G protein-coupled receptors (GPCRs) play a key role in regulating bone remodeling. Whether GPCRs exert anabolic or catabolic osseous effects may be determined by the rate of receptor desensitization in osteoblasts. Receptor desensitization is largely mediated by direct phosphorylation of GPCR proteins by a family of enzymes termed GPCR kinases (GRKs). We have selectively manipulated GRK activity in osteoblasts in vitro and in vivo by overexpressing a GRK inhibitor. We found that expression of a GRK inhibitor enhanced parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor-stimulated cAMP generation and inhibited agonist-induced phosphorylation of this receptor in cell culture systems, consistent with attenuation of receptor desensitization. To determine the effect of GRK inhibition on bone formation in vivo, we targeted the expression of a GRK inhibitor to mature osteoblasts using the mouse osteocalcin gene 2 (OG2) promoter. Transgenic mice demonstrated enhanced bone remodeling as well as enhanced urinary excretion of the osteoclastic activity marker dexoypyridinoline. Both osteoprotegrin and OPG ligand mRNA levels were altered in calvaria of transgenic mice in a pattern that would promote osteoclast activation. The predominant effect of the transgene, however, was anabolic, as evidenced by an increase in bone density and trabecular bone volume in the transgenic mice compared with nontransgenic littermate controls.     

Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling

Mice deficient in the adaptor Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) exhibit a bleeding disorder and lack T cells. Linker for activation of T cells (LAT)-deficient mice exhibit a similar T cell phenotype, but show no signs of hemorrhage. Both SLP-76 and LAT are important for optimal platelet activation downstream of the collagen receptor, GPVI. In addition, SLP-76 is involved in signaling mediated by integrin alphaIIbbeta3. Because SLP-76 and LAT function coordinately in T cell signal transduction, yet their roles appear to differ in hemostasis, we investigated in detail the functional consequences of SLP-76 and LAT deficiencies in platelets. Previously we have shown that LAT(-/-) platelets exhibit defective responses to the GPVI-specific agonist, collagen-related peptide (CRP). Consistent with this, we find that surface expression of P-selectin in response to high concentrations of GPVI ligands is reduced in both LAT- and SLP-76-deficient platelets. However, platelets from LAT(-/-) mice, but not SLP-76(-/-) mice, aggregate normally in response to high concentrations of collagen and convulxin. Additionally, unlike SLP-76, LAT is not tyrosine phosphorylated after fibrinogen binding to integrin alphaIIbbeta3, and collagen-stimulated platelets deficient in LAT spread normally on fibrinogen-coated surfaces. Together, these findings indicate that while LAT and SLP-76 are equally required for signaling via the T cell antigen receptor (TCR) and pre-TCR, platelet activation downstream of GPVI and alphaIIbbeta3 shows a much greater dependency on SLP-76 than LAT.     

Dramatic increase in the utilization of multiparametric magnetic resonance imaging for detection and management of prostate cancer

Purpose

Multiparametric MRI (mpMRI) of the prostate is an evolving technology that provides functional information of the prostate that helps distinguish benign from malignant lesions. We hypothesized that mpMRI is rapidly adopted in the US to fill the unmet need for a non-invasive, accurate screening tool. The aim of this study is to assess the increasing utilization of mpMRI for the diagnosis and management of prostate cancer.

Methods

We conducted a retrospective review of an institutional clinical data repository of four million patients. Clinical information from all men undergoing mpMRI from October 2013 to December 2015 was collected in a prospectively designed database. Individual chart reviews were performed for each patient.

Results

1521 mpMRI of the prostate were performed with an increase in the use of 486% over 26 months. The most common indication for mpMRI was abnormal screening (64%) and 47% of these men went on to prostate biopsy, either by cognitive mapping (65%) or MRI–US fusion targeting (35%). 261 men elected to defer prostate needle biopsy after informative decision-making with their urologist. 12.7% of mpMRI were performed for active surveillance, 7.5% for clinical staging, and 3.2% by radiation oncologists planning radiotherapy. 7% of mpMRI were performed to evaluate the pelvis for biochemical recurrence, a third of which identified a region of suspicion for targeted.

Conclusion

Prostate mpMRI is increasingly performed for both the diagnosis and management of prostate cancer. As clinical utilization increases along with the diffusion of technology and radiologic expertise, MpMRI has the potential to influence clinical decision-making and fulfill the need for a non-invasive, accurate tool for the diagnosis and management of prostate cancer.

     

Resistance of Pseudomonas aeruginosa to gentamicin and related aminoglycoside antibiotics

This study was undertaken to investigate biochemical, genetic, and epidemiological aspects of resistance to aminoglycoside antibiotics among 650 consecutive isolates of Pseudomonas aeruginosa from Parkland Memorial Hospital, Dallas, Tex. In 364 strains, minimal inhibitory concentrations were 25 mug/ml or greater for gentamicin (G), tobramycin (T) or kanamycin (K). Four patterns of resistance were noted: (A) G, T, K (four strains), (B) G, K (23 strains), (C) T, K (one strain), and (D) K (336 strains). Gentamicin acetyltransferase (GAT) activities were associated with resistance to gentamicin in strains of groups A and B, whereas kanamycin phosphotransferase activity was found in strains of group D. The GAT from group B strains acetylates both gentamicin and tobramycin. Resistance to gentamicin and susceptibility to tobramycin may reflect the fact that the K(m)'s for tobramycin (25 to 44 mug/ml) of GAT activities in these group B strains are much greater than the K(m)'s for gentamicin (1.9 to 2.7 mug/ml) and exceed the minimal inhibitory concentrations for tobramycin (1.25 to 7.5 mug/ml). GAT from strains of group A was associated with resistance to G, T, and K. Gentamicin acetyltransferases can be distinguished by their specificities for aminoglycoside substrates. The substrate specificity of GAT from group B strains is similar to that reported for GAT(I), but the specificity of GAT from group A strains differs from those described for GAT(I) and GAT(II). Conjugal transfer of gentamicin or tobramycin resistance from our strains of P. aeruginosa to various potential recipient strains was not observed. Pyocin typing showed that many, but not all, of the strains resistant to gentamicin were similar, and retrospective epidemiological investigation revealed that these strains were isolated almost exclusively from patients in the adult and pediatric burn intensive care units and geographically continguous areas of the hospital.     

Effects of bilateral swing-away grab bars on the biomechanics of stand-to-sit and sit-to-stand toilet transfers

Purpose: Kinetic characteristics of transfers to and from a toilet performed using bilateral grab bars are not fully quantified to inform grab bar design and configuration. The purpose of this study was to (1) determine effects of bilateral swing-away grab bars on peaks of ankle, knee and hip joint moments during grab bar assisted stand-to-sit and sit-to-stand transfers; and (2) determine effects of three different heights and widths of swing-away grab bars on the same kinetic characteristics.

Methods: Healthy subjects (N?=?11, age 25–58?years) performed stand-to-sit and sit-to-stand transfers with and without grab bars. In transfers with grab bars, 9 grab bar configurations were tested by varying their height from the floor (0.787?m, 0.813?m, 0.838?m; 31″–33″) and width, the distance of each grab bar from the toilet’s centerline (0.330?m, 0.356?m, 0.381?m; 13″–15″). Motion capture, force plate and inverse dynamics analysis were used to determine lower limb joint moments.

Results: The use of bilateral grab bars generally reduced the peak magnitude of extension moments at lower limb joints during stand-to-sit and sit-to-stand transfers (p?Conclusion: The obtained results suggest that the studied ranges of grab bar configurations reduce moment demands on the leg joints and thus decrease difficulty and required lower limb muscle effort to perform the transfers.

• Implications for Rehabilitation

• Maximizing the benefits of assistive technology in the built environment requires a careful assessment of their spatial and configurational dimensions, especially in respect to the needs and abilities of the intended users.

• Examining the kinetic characteristics of transfers to and from a toilet using the swing-away grab bars is useful for informing grab bar design and configuration recommendations for assisted living and skilled nursing facilities.

• Our findings suggest that the swing-away grab bars located at certain ranges are a reasonable alternative to the grab bars mandated by the current Americans with Disabilities Act (ADA) Accessibility Guidelines.

• Future research investigating the effects of grab bars on transfer performance should consider additional factors, such as a wider range of abilities and transfer methods of the users.