A modified perineal approach for the management of strangulated rectal prolapse: A case report.

INTRODUCTION: Conditions associated with increased intraabdominal pressure may lead to rectal prolapse. Like any pathological herniation, rectal prolapse can strangulate if incarcerated. When a patient presents with signs and symptoms of strangulation, emergent surgical intervention is warranted. This report strives to strengthen existing evidence for the use of an Altemeier-type perineal approach as a viable choice for the management of strangulated rectal prolapse in healthy individuals. PRESENTATION OF CASE: A healthy 70-year-old female presents with worsening rectal pain and an irreducible strangulated rectal prolapse. She is brought to the operating suite for an emergent exploration under anesthesia followed by an Altemeier-type procedure without diverting colostomy. The postoperative course is uneventful, and the patient is discharged on postoperative day three. Upon follow up, the patient reports having normal bowel function, and there is no evidence of recurrence. DISCUSSION: Rectal prolapse is traditionally managed through either a perineal or transabdominal approach depending on the patient's clinical disposition. Incarcerated prolapse is a precursor to strangulation, and recent case reports have demonstrated the efficacy of the Altemeier procedure (perineal rectosigmoidectomy) to treat strangulated prolapse. Our initial exploration under anesthesia revealed a small section of ischemic rectal mucosa that was proximal to the rectosigmoid junction. As a result, we decided to remain within perineal parameters and perform the resection in an Altemeier-type fashion based on the boundary of ischemia. CONCLUSION: An Altemeier approach was a reasonable option for emergent surgical management of strangulated rectal prolapse in an otherwise relatively healthy individual. This case has been reported in line with the SCARE criteria (Agha et al. [1]).

Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines.

8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2-15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

A new "keyhole" approach for multilevel anterior lumbar interbody fusion: the perinavel approach-technical note and literature review.

PURPOSE: The purpose of this study is to evaluate the feasibility and the safety of a new skin incision for minimally invasive anterior lumbar interbody fusion (ALIF): the perinavel incision. METHODS: Demographic and clinical data from patients who underwent ALIF with the perinavel incision were collected. Indications to surgery, preoperative symptoms, radiological data, number of treated levels, intraoperative and early postoperative complications and wound-related problems were analysed. RESULT: Ninety-seven patients underwent ALIF with this new skin incision. One hundred fifty-seven levels were treated (mean 1.7 level per patient) being L4-L5 the most frequently treated. Intraoperative complications were represented only by the venous injury with a rate of 3.09% (3 cases). Postoperative complications were all linked to skin incision issues: a case of wound dehiscence and a case of superficial infection. No case of skin necrosis occurs at 3-month follow-up. CONCLUSIONS: In this paper, the perinavel skin incision was demonstrated to be as safe as traditional approaches for ALIF. Furthermore, with this incision it is possible to perform multilevel (L3-S1) ALIF, which means a good option in minimally invasive surgery as well as revision surgery. These slides can be retrieved under Electronic Supplementary Material.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents.

A series of ruthenium coordination complexes containing hydroxyquinoline ligands were synthesized that exhibited radically improved potencies up to 86-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100-fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis but appear to be mediated by cell-cycle independent mechanisms. The ruthenium complexes do not inhibit the proteasome at concentrations relevant for cell death, and contrary to previous reports, clioquinol and other hydroxyquinoline compounds do not act as direct proteasome inhibitors to induce cell death.

A new type of DNA "light-switch": a dual photochemical sensor and metalating agent for duplex and G-quadruplex DNA.

Ru(bpy)2dppz, a well studied "light-switch" metal complex, transforms into a photochemical "light-switch" and DNA damaging agent by incorporating structural strain. This distorted compound is photoreactive and ejects a ligand upon binding duplex and G-quadruplex DNA, producing a reactive metal center that metalates the DNA.

Light-activated ruthenium complexes photobind DNA and are cytotoxic in the photodynamic therapy window.

Incorporation of biquinoline ligands into Ru(II) polypyridyl complexes produces light-activated systems that eject a ligand and photobind DNA after irradiation with visible and near-IR light. Structural analysis shows that distortion facilitates the photochemistry, and gel shift and cytotoxicity studies prove the compounds act as anti-cancer photodynamic therapy (PDT) agents in the tissue penetrant region.

Strained ruthenium complexes are potent light-activated anticancer agents.

Strained ruthenium (Ru) complexes have been synthesized and characterized as novel agents for photodynamic therapy (PDT). The complexes are inert until triggered by visible light, which induces ligand loss and covalent modification of DNA. An increase in cytotoxicity of 2 orders of magnitude is observed with light activation in cancer cells, and the compounds display potencies superior to cisplatin against 3D tumor spheroids. The use of intramolecular strain may be applied as a general paradigm to develop light-activated ruthenium complexes for PDT applications.

Porous Silicon-Based Quantum Dot Broad Spectrum Radiation Detector.

Silicon is a convenient and inexpensive platform for radiation detection, but has low stopping power for x-rays and gamma-rays with high energy (e.g., 100 keV, as used in computed tomography and digital radiography, or 1 MeV, as desired for detection of nuclear materials). We have effectively increased the stopping power of silicon detectors by producing a layer of porous or micro-machined silicon, and infusing this layer with semiconductor quantum dots made of electron-dense materials. Results of prototype detectors show sensitivity to infrared, visible light, and x-rays, with dark current of less than 1 nA/mm2.

Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.

Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signaling molecules. Nuclear magnetic resonance (NMR)-based metabolomic studies of human tumors have identified a marked increase in the intracellular concentration of phosphocholine relative to normal tissues. We postulated that the observed intracellular pooling of phosphocholine may be required to sustain the production of the pleiotropic lipid second messenger, phosphatidic acid. Phosphatidic acid is generated from the cleavage of phosphatidylcholine by phospholipase D2 and is a key activator of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival signaling pathways. In this study we show that the steady-state concentration of phosphocholine is increased by the ectopic expression of oncogenic H-Ras(V12) in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feed-forward amplification of cancer survival signaling pathways.

Primary culture of lobster (Homarus americanus) olfactory sensory neurons.

Lobster olfactory sensory neurons have contributed to a number of advances in our understanding of olfactory physiology. To facilitate further study of their function, we have developed conditions allowing primary culture of the olfactory sensory neurons in a defined medium. The most common cells in the culture were round cell bodies with diameters of 10-15 micro m that often extended fine processes, features resembling olfactory sensory neurons. We discovered that acetylcholinesterase acted as a growth factor for these cells, improving their survival in culture. We also confirmed previous evidence from spiny lobsters that poly-D-lysine was a superior substrate for olfactory cells of this size and morphology. We then identified olfactory sensory neurons in the culture in two ways. Almost half the cells tested responded to application of a complex odorant with an inward current. An even more rigorous test was made possible by the development of an antiserum to OET-07, an ionotropic glutamate receptor homolog specifically expressed by Homarus americanus olfactory sensory neurons. It labeled a majority of the round cells in the culture, unequivocally identifying them as olfactory sensory neurons.

Development and rupture of a de novo basilar artery aneurysm after surgical removal of a cerebellar arteriovenous malformation.

BACKGROUND: The de novo development of an aneurysm in an previously normal artery is an uncommon event. We describe a patient who developed a de novo bleeding aneurysm of the basilar artery in the three weeks following the surgical removal of a large cerebellar AVM. METHOD-FINDINGS: A 48-year-old man suddenly developed transient headache, vertigo and disturbance of balance. Neuroradiological examinations showed the presence of a large AVM of the right cerebellar hemisphere. The AVM was removed successfully; following the operation there were repeated bleeding episodes at the operating site, requiring surgical evacuation. Three weeks after the AVM removal he suffered from a massive subarachnoid haemorrhage due to the rupture of an aneurysm developed de novo in the basilar artery. INTERPRETATION: This is the first reported case, to our knowledge, of a de novo aneurysm developed in an artery hemodynamically related to a surgically removed AVM. This complication was probably due to the postoperative hemodynamic changes in the vessels afferent to the AVM, associated with arterial wall dysplasia.

Soft metal preferences of 1,3-benzenediamidoethanethiol.

Recent studies indicate that the sodium salt of 1,3-benzenediamidoethanethiol (BDET) is both economical and effective in precipitating mercury and other heavy metals from water. Because wastewaters and contaminated natural waters may contain a variety of heavy metals, it is important to determine how different heavy metals may interact with BDET, and whether free metals may displace those that are bound. To explore this possibility, Cd-, Cu-, Pb-, Mn-, Hg- and Zn-BDET were leached separately under a nitrogen purge for up to 240 h in pH 3 aqueous solutions containing 0.100 mmol of all five heavy metals. The leaching studies indicate that dissolved Hg has a strong tendency to displace Cd, Cu, Mn, Pb, and Zn from the BDET structure.

Chemical precipitation of heavy metals from acid mine drainage.

The 1,3-benzenediamidoethanethiol dianion (BDET, known commercially as MetX) has been developed to selectively and irreversibly bind soft heavy metals from aqueous solution. In the present study BDET was found to remove > 90% of several toxic or problematic metals from AMD samples taken from an abandoned mine in Pikeville, Kentucky. The concentrations of metals such as iron, may be reduced at pH 4.5 from 194 ppm to below 0.009 ppm. The formation of stoichiomietric BDET-metal precipitates in this process was confirmed using X-ray powder diffraction (XRD), proton nuclear magnetic resonance (1H NMR), and infrared spectroscopy (IR).

Advanced mercury removal from gold leachate solutions prior to gold and silver extraction: a field study from an active gold mine in Peru.

Mercury contamination in the Gold-Cyanide Process (GCP) is a serious health and environmental problem. Following the heap leaching of gold and silver ores with NaCN solutions, portions of the mercury-cyano complexes often adhere to the activated carbon (AC) used to extract the gold. During the electrowinning and retorting steps, mercury can be (and often is) emitted to the air as a vapor. This poses a severe health hazard to plant workers and the local environment. Additional concerns relate to the safety of workers when handling the mercury-laden AC. Currently, mercury treatment from the heap leach solution is nonexistent. This is due to the fact that chelating ligands which can effectively work under the adverse pH conditions (as present in the heap leachate solutions) do not exist. In an effort to economically and effectively treat the leachate solution prior to passing over the AC, a dipotassium salt of 1,3-benzenediamidoethanethiol (BDET2-) has been developed to irreversibly bind and precipitate the mercury. The ligand has proven to be highly effective by selectively reducing mercury levels from average initial concentrations of 34.5 ppm (parts per million) to 0.014 ppm within 10 min and to 0.008 ppm within 15 min. X-ray powder diffraction (XRD), proton nuclear magnetic resonance (1H NMR), Raman, and infrared (IR) spectroscopy demonstrate the formation of a mercury-ligand compound, which remains insoluble over pH ranges of 0.0-14.0. Leachate samples from an active gold mine in Peru have been analyzed using cold vapor atomic fluorescence (CVAF) and inductively coupled plasma optical emission spectroscopy (ICP-OES) for metal concentrations before and after treatment with the BDET2- ligand.

Muscarinic receptors in cell lines from ovarian carcinoma: negative correlation with survival of patients.

OBJECTIVES: Tumor cells are similar in many respects to embryonic cells, indicating that embryonic genes are reactivated during malignant growth. In previous studies, we observed muscarinic acetylcholine receptors, which are expressed in embryonic cells during morphogenesis and are also found in human melanomas and melanoma cell lines. We determined the presence of muscarinic receptors in a collection of ovarian tumor cell lines for which clinical data were available. METHODS: Muscarinic receptor status of 39 cell lines derived from 34 patients was determined by Western blotting. RESULTS: Twenty-three cell lines were receptor positive, and 16, receptor negative. Kaplan-Meier analysis of receptor status of the tumor cell lines and survival time of patients from which the cell lines were established showed that expression of muscarinic receptors was associated with a reduced probability (P = 0.025) of survival: This is within the range of other established prognostic factors reported in the literature. CONCLUSIONS: A large percentage of ovarian tumor cell lines express muscarinic receptors. Muscarinic receptor expression is an embryonic trait and is correlated with reduced survival of patients. The results from this study provide further evidence of the involvement of muscarinic receptors in the progression of malignant carcinomas.

Polarized targeting of peripheral membrane proteins in neurons.

Differential targeting of neuronal proteins to axons and dendrites is essential for directional information flow within the brain, however, little is known about this protein-sorting process. Here, we investigate polarized targeting of lipid-anchored peripheral membrane proteins, postsynaptic density-95 (PSD-95) and growth-associated protein-43 (GAP-43). Whereas the N-terminal palmitoylated motif of PSD-95 is necessary but not sufficient for sorting to dendrites, the palmitoylation motif of GAP-43 is sufficient for axonal targeting and can redirect a PSD-95 chimera to axons. Systematic mutagenesis of the GAP-43 and PSD-95 palmitoylation motifs indicates that the spacing of the palmitoylated cysteines and the presence of nearby basic amino acids determine polarized targeting by these two motifs. Similarly, the axonal protein paralemmin contains a C-terminal palmitoylated domain, which resembles that of GAP-43 and also mediates axonal targeting. These axonally targeted palmitoylation motifs also mediate targeting to detergent-insoluble glycolipid-enriched complexes in heterologous cells, suggesting a possible role for specialized lipid domains in axonal sorting of peripheral membrane proteins.

Genetic and structural determinants of virus neutralizing antibodies.

Neutralizing antibodies (Abs) are the principal protective mechanism against disease caused by reinfection with viruses. Ab-mediated neutralization of viruses is a complex process comprising multiple mechanisms. Every structural aspect of Abs is potentially capable of modulating the level of neutralizing activity or the mechanisms of neutralization. The focus of our laboratory is to understand the genetic and structural basis of Ab-mediated neutralization of human viral pathogens. We demonstrated the unexpected finding that virus antigen-binding fragments of Abs (Fabs) mediate potent virus neutralizing effects in vivo. This work has led to a broad investigation of the importance of the genetics, chemistry, and structure of the combining site to the neutralizing activity of antiviral Abs. Ongoing work in our laboratory reveals that effect or functions specified by the Ab isotype such as polymer formation, interactions with complement, interactions with Fc receptors, and the ability to transcytose mucosal epithelia, also modulate the mechanism and level of neutralizing effects mediated by antiviral Abs.

Anti-Yo antibody-positive cerebellar degeneration associated with endometrial carcinoma: case report and review of the literature.

Paraneoplastic cerebellar degeneration (PCD) is a rare, severely debilitating disease, often with a rapid onset and progression, which predate the diagnosis of malignancy. Despite characteristic features, diagnosis is commonly difficult and successful therapy, which relies on early instigation of treatment, is rare. Here we present a patient in whom anti-Yo antibody-positive PCD was associated with endometrial carcinoma and an extensive review of the literature outlining the clinical features, pathogenesis and treatment of PCD.