Factors Affecting the In Vivo Lactone Stability and Systemic Clearance of the Lipophilic Camptothecin Analogue AR-67

Purpose  

The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3^rd generation camptothecin analogue.     

Native valve right sided infective endocarditis

Right-sided infective endocarditis (RSIE) accounts for 5–10% of all cases of infective endocarditis (IE), and is predominantly encountered in the injecting drug user (IDU) population, where HIV and HCV coinfections often coexist. Staphylococcus aureus is the most common pathogen. The pathogenesis of RSIE is still not well understood. RSIE usually presents as a persistent fever with respiratory symptoms whilst signs of systemic embolisation as seen in left-sided IE are notably absent. The prompt diagnosis of RSIE thus requires a high index of suspicion. Transthoracic echocardiography (TTE) can detect the majority of RSIE, whilst transoesophageal echocardiography (TOE) can increase sensitivity. Virulence of the causative organism and vegetation size are the major determinants of prognosis. Most cases of RSIE resolve with appropriate antibiotic administration.     

Preliminary noise reduction efforts in a medical intensive care unit

Noise is a significant contributor to sleep disruption in the intensive care unit (ICU) that may result in increased patient morbidity such as delirium and prolonged length of stay in ICU. We conducted a pre-post intervention study in a 24-bed tertiary care academic medical ICU to reduce the mean noise levels. Baseline dosimeter recordings of ICU noise levels demonstrated a mean noise level of 54.2 A-weighted decibels (dBA) and peak noise levels of 109.9 dBA, well above the Environmental Protection Agency’s recommended levels. There were 1735 episodes of “defects” (maximum noise levels > 60 dBA). Following implementation of multipronged interventions, although the mean noise levels did not change significantly between pre- and post-intervention (54.2 vs 53.8 dBA; p = 0.96), there was a significant reduction in the number of “defects” post-intervention (1735 vs 1289, p ≤ 0.000), and the providers felt that the patients were sleeping longer in the ICU post-intervention.     

Double appendixes: A rare case report

Anomalies of the appendix are rare, and one of the rarest is the double appendixes. Most anomalies of the appendix are observed in adults and are discovered incidentally during surgery that does not primarily involve the appendix. It is usually missed, often with life‐threatening consequences.     

Impact of surgeon experience and buttress material on postoperative complications after laparoscopic sleeve gastrectomy

Background

Sleeve gastrectomy is gaining popularity whether as a primary, staged or revisional operation. The aim of this study is to evaluate the perioperative safety and the learning curve for laparoscopic sleeve gastrectomy (LSG).

Methods

We performed a retrospective review of the prospectively collected data for all patients who underwent LSG for the treatment of morbid obesity at our institution from January 2003 to December 2008.

Results

Data from 230 consecutive patients [male 47%, female 53%; mean age 44.0?±?10.0?years, mean preoperative body mass index (BMI) 56.7?±?11.5?kg/m²], who were operated upon by three surgeons with different degrees of bariatric experience, were analyzed. There was no 30-day mortality, but there were two cases of late mortality (0.87%). Early complications were noted in 23 cases (10.0%), including 10 cases of leak (4.3%) and 10 cases of hemorrhage (4.3%). In 17 cases (7.4%) reoperations were performed. The rates of overall and major complications did not differ among surgeons or between early and late period of experience for the three surgeons; this trend held true individually and in subgroups. Overall, over the course of the learning curve, a significant decrease in operative time was noted. The only factor that was independently associated with complications was use of buttress material; the likelihood of complications was found to be 72% lower in patients in whom buttress material was used.

Conclusions

LSG constitutes a potentially safe anti-obesity procedure with acceptable morbidity. Experience at the beginning can be discouraging, even for surgeons with advanced laparoscopic skills. LSG can be performed safely, with proper mentoring and in appropriate settings, even by less experienced bariatric surgeons. The use of staple-line reinforcement was associated with improved perioperative outcomes, and it should be considered in an attempt to decrease leaks.     

Nondetectable Prostate Carcinoma (pT0) after Radical Prostatectomy: A Narrative Review

(1) Background: Following radical prostatectomy (RP), the absence of a demonstrable tumor on the specimen of a previously histologically proven malignancy is known as the pT0 stage. The aim of our present study is to perform a narrative review of current literature in order to determine the frequency and oncological outcomes in patients with pT0 disease. (2) Methods: A narrative review of all available literature was performed. (3) Results: The incidence of pT0 ranges between 0.07% and 1.3%. Predictors of the pT0 stage are only a single biopsy core with low-grade cancer, a cancer length not exceeding 2 mm and a high prostate volume. Biochemical recurrence ranges between 0 and 11%. (4) Conclusions: The absence of malignancy in the RP specimen despite a previous positive biopsy is a rare and unpredictable finding. Although the prognosis is considered to be excellent in most of the cases, a continued close follow-up is warranted.     

Effect of Thalidomide on the Expression of TNF-α m-RNA and Synthesis of TNF-α in Cells from Leprosy Patients with Reversal Reaction

Hypersensitivity reactions called reversal reaction (RR) and erythema nodosum leprosum (ENL) occur in leprosy. They are characterized by an increase in tumor necrosis factor-alpha (TNF-α). Thalidomide is an effective treatment for ENL but not RR. Its effectiveness in ENL is attributed to inhibition of TNF-α, and this does not explain its failure to treat RR. We assessed thalidomide's effect on TNF-α in RR. Mononuclear cells from RR and non-RR patients and healthy individuals were treated with thalidomide and M.leprae (AFB), a cytosol fraction of M. leprae or Dharmendra lepromin. Thalidomide suppressed TNF-α, but when some RR patients' cells were stimulated with AFB, it enhanced TNF-α.     

Mitochondrial ribonuclease P structure provides insight into the evolution of catalytic strategies for precursor-tRNA 5′ processing

Ribonuclease P (RNase P) catalyzes the maturation of the 5′ end of tRNA precursors. Typically these enzymes are ribonucleoproteins with a conserved RNA component responsible for catalysis. However, protein-only RNase P (PRORP) enzymes process precursor tRNAs in human mitochondria and in all tRNA-using compartments of Arabidopsis thaliana. PRORP enzymes are nuclear encoded and conserved among many eukaryotes, having evolved recently as yeast mitochondrial genomes encode an RNase P RNA. Here we report the crystal structure of PRORP1 from A. thaliana at 1.75 Å resolution, revealing a prototypical metallonuclease domain tethered to a pentatricopeptide repeat (PPR) domain by a structural zinc-binding domain. The metallonuclease domain is a unique high-resolution structure of a Nedd4-BP1, YacP Nucleases (NYN) domain that is a member of the PIN domain-like fold superfamily, including the FLAP nuclease family. The structural similarity between PRORP1 and the FLAP nuclease family suggests that they evolved from a common ancestor. Biochemical data reveal that conserved aspartate residues in PRORP1 are important for catalytic activity and metal binding and that the PPR domain also enhances activity, likely through an interaction with pre-tRNA. These results provide a foundation for understanding tRNA maturation in organelles. Furthermore, these studies allow for a molecular-level comparison of the catalytic strategies used by the only known naturally evolved protein and RNA-based catalysts that perform the same biological function, pre-tRNA maturation, thereby providing insight into the differences between the prebiotic RNA world and the present protein-dominated world.