Radiographic evaluation of ventral instability in lumbar spondylolisthesis: do we need extension radiographs in routine exams?

Purpose

To determine the usefulness of acquiring extension radiographs for the evaluation of the degree of spondylolisthesis.

Methods

Routine radiographs of the lumbar spine were retrospectively evaluated in 87 patients (mean-age 63, range 32–86) by two independent radiologists. All patients received radiographs in standing neutral, flexion and extension position. Vertebral body depth, sagittal translational displacement and lordosis angle were measured and slip percentage (SP) was calculated on standing neutral, flexion and extension radiographs. Statistical analysis was performed with a two-sided t test. Inter- and intraobserver reliability was assessed using the kappa-coefficient.

Results

There was no statistically significant SP-difference between neutral standing and extension images. Ventral instability was diagnosed in 25–34 % (cut-off >8 % SP-difference) for neutral versus flexion comparison. The detection rate of flexion–extension radiographs representing the extremes of motion was lower with 15–22 %. Inter- and intraobserver reliability was good to excellent.

Conclusion

Slip percentage in routine standing extension radiography ultimately does not differ from that obtained in a static neutral standing view. Extension radiography may therefore be omitted in a routine work-up of ventral instability in lumbar spondylolisthesis.     

SILS Sigmoidectomy Versus Multiport Laparoscopic Sigmoidectomy for Diverticulitis

Background and Objectives:

In this single-institution study, we aimed to compare the safety, feasibility, and outcomes of single-incision laparoscopic sigmoidectomy (SILSS) with multiport laparoscopic sigmoidectomy (MLS) for recurrent diverticulitis.

Methods:

Between October 2011 and February 2013, 60 sigmoidectomies were performed by the same surgeon. Forty patients had a MLS and 20 patients had a SILSS. Outcomes were compared.

Results:

Patient characteristics were similar. There was no difference in morbidity, mortality or readmission rates. The mean operative time was longer in the SILSS group (P = .0012). In a larger proportion of patients from the SILSS group, 2 linear staplers were needed for transection at the rectum (P = .006). The total cost of disposable items was higher in the SILSS group (P < .0001). No additional ports were placed in the SILSS group. Return to bowel function or return to oral intake was faster in the SILSS group (P = .0446 and P = .0137, respectively). Maximum pain scores on postoperative days 1 and 2 were significantly less for the SILSS group (P = .0014 and P = .047, respectively). Hospital stay was borderline statistically shorter in the SILSS group (P = .0053). SILSS was also associated with better cosmesis (P < .0011).

Conclusion:

SILSS is feasible and safe and is associated with earlier recovery of bowel function, a significant reduction in postoperative pain, and better cosmesis.     

Sensory irritation as a basis for setting occupational exposure limits

There is a need of guidance on how local irritancy data should be incorporated into risk assessment procedures, particularly with respect to the derivation of occupational exposure limits (OELs). Therefore, a board of experts from German committees in charge of the derivation of OELs discussed the major challenges of this particular end point for regulatory toxicology. As a result, this overview deals with the question of integrating results of local toxicity at the eyes and the upper respiratory tract (URT). Part 1 describes the morphology and physiology of the relevant target sites, i.e., the outer eye, nasal cavity, and larynx/pharynx in humans. Special emphasis is placed on sensory innervation, species differences between humans and rodents, and possible effects of obnoxious odor in humans. Based on this physiological basis, Part 2 describes a conceptual model for the causation of adverse health effects at these targets that is composed of two pathways. The first, “sensory irritation” pathway is initiated by the interaction of local irritants with receptors of the nervous system (e.g., trigeminal nerve endings) and a downstream cascade of reflexes and defense mechanisms (e.g., eyeblinks, coughing). While the first stages of this pathway are thought to be completely reversible, high or prolonged exposure can lead to neurogenic inflammation and subsequently tissue damage. The second, “tissue irritation” pathway starts with the interaction of the local irritant with the epithelial cell layers of the eyes and the URT. Adaptive changes are the first response on that pathway followed by inflammation and irreversible damages. Regardless of these initial steps, at high concentrations and prolonged exposures, the two pathways converge to the adverse effect of morphologically and biochemically ascertainable changes. Experimental exposure studies with human volunteers provide the empirical basis for effects along the sensory irritation pathway and thus, “sensory NOAEC_human” can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an “irritative NOAEC_animal.” Usually the data for both pathways is not available and extrapolation across species is necessary. Part 3 comprises an empirical approach for the derivation of a default factor for interspecies differences. Therefore, from those substances under discussion in German scientific and regulatory bodies, 19 substances were identified known to be human irritants with available human and animal data. The evaluation started with three substances: ethyl acrylate, formaldehyde, and methyl methacrylate. For these substances, appropriate chronic animal and a controlled human exposure studies were available. The comparison of the sensory NOAEC_human with the irritative NOAEC_animal (chronic) resulted in an interspecies extrapolation factor (iEF) of 3 for extrapolating animal data concerning local sensory irritating effects. The adequacy of this iEF was confirmed by its application to additional substances with lower data density (acetaldehyde, ammonia, n-butyl acetate, hydrogen sulfide, and 2-ethylhexanol). Thus, extrapolating from animal studies, an iEF of 3 should be applied for local sensory irritants without reliable human data, unless individual data argue for a substance-specific approach.     

Exposure?response modelling for empagliflozin,a sodium glucose cotransporter 2 (SGLT2) inhibitor,in patients with type 2 diabetes

Aims

To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure−response (E−R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM).

Methods

Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1–100 mg once daily, duration ≤12 weeks) were used to develop E−R models for efficacy (glycosylated haemoglobin [HbA_1c], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E−R.

Results

The efficacy model predicted maximal decreases in FPG and HbA_1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl⁻¹) and 10–25 mg every day empagliflozin targeted 80–90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation.

Conclusions

E−R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.     

Implementation of a dynamic intestinal gut-on-a-chip barrier model for transport studies of lipophilic dioxin congeners

Novel microfluidic technologies allow the manufacture of in vitro organ-on-a-chip systems that hold great promise to adequately recapitulate the biophysical and functional complexity of organs found in vivo. In this study, a gut-on-a-chip model was developed aiming to study the potential cellular association and transport of food contaminants. Intestinal epithelial cells (Caco-2) were cultured on a porous polyester membrane that was tightly clamped between two glass slides to form two separate flow chambers. Glass syringes, polytetrafluoroethylene tubing and glass microfluidic chips were selected to minimize surface adsorption of the studied compounds (i.e. highly lipophilic dioxins), during the transport studies. Confocal microscopy studies revealed that, upon culturing under constant flow for 7 days, Caco-2 cells formed complete and polarized monolayers as observed after culturing for 21 days under static conditions in Transwells. We exposed Caco-2 monolayers in the chip and Transwell to a mixture of 17 dioxin congeners (7 polychlorinated dibenzo-p-dioxins and 10 polychlorinated dibenzofurans) for 24 h. Gas chromatography-high resolution mass spectrometry was used to assess the cellular association and transport of individual dioxin congeners across the Caco-2 cell monolayers. After 24 h, the amount of transported dioxin mixture was similar in both the dynamic gut-on-a-chip model and the static Transwell model. The transport of individual congeners corresponded with their number of chlorine atoms and substitution patterns as revealed by quantitative structure–property relationship modelling. These results show that the gut-on-a-chip model can be used, as well as the traditional static Transwell system, to study the cellular association and transport of lipophilic compounds like dioxins.

Novel microfluidic technologies allow the manufacture of in vitro organ-on-a-chip systems that hold great promise to adequately recapitulate the biophysical and functional complexity of organs found in vivo.