Quantification of Heteroaggregation between Citrate-Stabilized Gold Nanoparticles and Hematite Colloids.

Collisions with and attachment to natural colloids (heteroaggregation) is likely to influence significantly the fate, transport, and toxicity of engineered nanoparticles (ENPs). This study investigated heteroaggregation between hematite (α-Fe2O3) colloids and citrate-capped gold nanoparticles (Cit-AuNPs) using a novel approach involving time-resolved dynamic light scattering and parallel experiments designed to quantify nanoparticle attachment and heteroaggregate surface charge. Experiments were performed in low ionic strength synthetic water at environmentally relevant pH in the presence and absence of Suwannee River Natural Organic Matter (SRNOM). In the absence of SRNOM at pH values where Cit-AuNPs and hematite are oppositely charged, attachment efficiencies are high and Cit-AuNPs are capable of destabilizing hematite following an "electrostatic patch" mechanism. Furthermore, maximum observed surface coverages were far below those predicted by geometry alone, a fact predicted by the random sequential adsorption (RSA) model that has significant implications for the estimation of heteroaggregate attachment efficiencies. At pH values where both particles are negative or in the presence of small amounts of SRNOM, attachment was minimal. Calculated attachment efficiencies using the measured surface coverages corroborate these findings. The calculation of attachment efficiencies and the identification of mechanisms governing heteroaggregation represents an important step toward predicting the transport, fate, and toxicity of ENPs in the environment.

Clinical, electrophysiologic and serologic evidence of cancer associated retinopathy preceding a diagnosis of breast cancer.

We report the case of a woman in her 50s who presented headaches, blurred vision, diplopia and loss of peripheral vision. She was treated for normal tension glaucoma based on optic nerve cupping prior to the development of diplopia. Records demonstrated visual field constriction over 4 months despite well-controlled intraocular pressures. Examination revealed decreased visual acuity and visual field constriction. The multifocal electroretinogram was abnormal. After a thorough review of her medical and family history, a concern for cancer-associated retinopathy developed. Blood samples were positive for antiretinal antibodies against 23 kDA and 46 kDA proteins. Cancer screening was recommended as the aetiology for retinopathy was unknown and revealed a left breast lump. Following lumpectomy with adjuvant chemoradiation, her visual acuity normalised and visual field defects completely resolved. This case serves to provide an example that distant systemic symptoms may be a manifestation of the underlying malignancy and the importance of clinical suspicion with prompt evaluation.

Identification of biaryl sulfone derivatives as antagonists of the histamine H3 receptor: discovery of (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916).

The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.

Melatonin Does Not Improve Sleep Quality in a Randomized Placebo-controlled Trial After Primary Total Joint Arthroplasty.

INTRODUCTION: Sleep disturbance is a common concern among patients who have undergone total joint arthroplasty (TJA). Poor sleep during the postoperative period affect quality of life directly and may influence pain recovery after TJA. The purpose of this prospective study was to investigate whether the daily use of exogenous melatonin for 6 weeks after TJA can mitigate the effects of TJA on sleep. METHODS: A cohort of 118 patients undergoing primary total hip arthroplasty or total knee arthroplasty from 2018 to 2020 were randomized to melatonin (6 mg) or placebo for 42 days after surgery. Inclusion criterion was patients undergoing unilateral primary TJA. Patients who underwent bilateral TJA and revision TJA, with a history of sleep disturbance, and on opioid medication or sleep aids preoperatively were excluded. Sleep quality was assessed at baseline and at 2 and 6 weeks postoperatively using the validated self-administered questionnaire, Pittsburgh Sleep Quality Index (PSQI). Continuous and categorical variables were analyzed using Student t-test and chi-square analysis, respectively. Multivariate linear regression analysis was also conducted. RESULTS: Patients in both groups exhibited higher PSQI scores, representing lower sleep quality, at both 2 and 6 weeks postoperatively compared with that at baseline. Overall, global PSQI scores were 6.8, 9.8, and 8.8 at baseline, week 2, and week 6, respectively. No significant differences were noted between melatonin and placebo groups at baseline (6.8 versus 6.8, P = 0.988), week 2 (10.2 versus 9.3, P = 0.309), or week 6 (8.8 versus 8.7, P = 0.928). In multivariable regression, the only significant predictors of increased PSQI scores were an elevated baseline PSQI score (at both time points), a decreased length of stay (at week 2 only), and patients undergoing total hip arthroplasty versus total knee arthroplasty (at week 6 only). CONCLUSION: Patients undergoing TJA had poor sleep quality both preoperatively and postoperatively. The use of exogenous melatonin did not demonstrate any notable effect on sleep quality.

Single-incision laparoscopic reversal of Hartmann procedure via the colostomy site only: first report.

BACKGROUND: Transumbilical single-incision laparoscopic surgery (SILS) provides an alternative to traditional multiport laparoscopic surgery. The technique may also avoid some of the difficulties surrounding laparoscopic Hartmann reversal. This case represents the first SILS Hartmann reversal via the colostomy site. METHODS: SILS Hartmann reversal was performed in a 56-year-old man with a history of resection for perforated diverticulitis. The procedure was performed via a single port placed into the former colostomy site. A combination of flexible and straight instruments was used. RESULTS: The procedure was completed successfully with an operative time of 104 minutes. Recovery was uneventful, and the patient was discharged on postoperative day 5, with no complaints at follow-up. CONCLUSION: SILS Hartmann procedure reversal via the colostomy site is safe. The approach avoids additional incisions and allows avoidance of dense adhesions to the previous midline incision--a new benefit of SILS, apart from cosmesis.

Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.

The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.

Hospital and long-term outcome after percutaneous endoscopic gastrostomy.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) has become the preferred method of providing long-term enteral nutrition. While hospitalized patients frequently have PEG inserted to facilitate enteral nutrition, little is known about these patients. The objective of the study was to determine hospital and long-term survival in patients who receive PEG while hospitalized for medical or surgical reasons. METHODS: Records of all patients aged 18 years and older who underwent PEG between January 1, 1999 and December 31, 2004 at a university-affiliated community-based tertiary care center were examined. RESULTS: 80 (11%) of 714 patients died during the index hospitalization. Older age, being married, mechanical ventilation, and dialysis were statistically significant predictors of hospital death (P < 0.05). There were nine complications and no deaths directly attributable to PEG. Overall survival was poor with 5.6% of patients dying within seven days of the procedure. Mortalities at 30, 60, and 365 days were 22%, 31% and 48%, respectively. Of the 80 patients who died prior to discharge, 40 (50%) died within one week of PEG placement. Fourteen (35%) of these 40 patients had treatment withdrawn. Kaplan-Meier median survival was 412 +/- 73 (mean +/- standard error) days. By Cox proportional hazard modeling, older age, cancer, heart disease, non-white race, and dialysis were significant predictors of post-PEG death (P < 0.05). CONCLUSIONS: Outcome after PEG is dependent on demographic factors and patient comorbidities. Given the very low initial complication rates, it may be advisable to delay PEG placement until just prior to discharge in order to prevent unnecessary procedures on those patients who are not likely to survive.

Congenic strains confirm aerobic running capacity quantitative trait loci on rat chromosome 16 and identify possible intermediate phenotypes.

We previously identified two inbred rat strains divergent for treadmill aerobic running capacity (ARC), the low-performing Copenhagen (COP) and the high-performing DA rats, and used an F(2)(COPxDA) population to identify ARC quantitative trait loci (QTLs) on rat chromosome 16 (RNO16) and the proximal portion of rat chromosome 3 (RNO3). Two congenic rat strains were bred to further investigate these ARC QTLs by introgressing RNO16 and the proximal portion of RNO3 from DA rats into the genetic background of COP rats and were named COP.DA(chr 16) and COP.DA(chr 3), respectively. COP.DA(chr 16) rats had significantly greater ARC compared with COP rats (696.7 +/- 38.2 m vs. 571.9 +/- 27.5 m, P = 0.03). COP.DA(chr 3) rats had increased, although not significant, ARC compared with COP rats (643.6 +/- 40.9 m vs. 571.9 +/- 27.5 m). COP.DA(chr 16) rats had significantly greater subcutaneous abdominal fat, as well as decreased fasting triglyceride levels, compared with COP rats (P < 0.05), indicating that genes responsible for strain differences in fat metabolism are also located on RNO16. While this colocalization of QTLs may be coincidental, it is also possible that these differences in energy balance may be associated with the superior running performance of COP.DA(chr 16) consomic rats.

Expressed sequence tags from phytophthora sojae reveal genes specific to development and infection.

Six unique expressed sequence tag (EST) libraries were generated from four developmental stages of Phytophthora sojae P6497. RNA was extracted from mycelia, swimming zoospores, germinating cysts, and soybean (Glycine max (L.) Merr.) cv. Harosoy tissues heavily infected with P. sojae. Three libraries were created from mycelia growing on defined medium, complex medium, and nutrient-limited medium. The 26,943 high-quality sequences obtained clustered into 7,863 unigenes composed of 2,845 contigs and 5,018 singletons. The total number of P. sojae unigenes matching sequences in the genome assembly was 7,412 (94%). Of these unigenes, 7,088 (90%) matched gene models predicted from the P. sojae sequence assembly, but only 2,047 (26%) matched P. ramorum gene models. Analysis of EST frequency from different growth conditions and morphological stages revealed genes that were specific to or highly represented in particular growth conditions and life stages. Additionally, our results indicate that, during infection, the pathogen derives most of its carbon and energy via glycolysis of sugars in the plant. Sequences identified with putative roles in pathogenesis included avirulence homologs possessing the RxLR motif, elicitins, and hydrolytic enzymes. This large collection of P. sojae ESTs will serve as a valuable public genomic resource.

Design and evaluation of novel biphenyl sulfonamide derivatives with potent histamine H(3) receptor inverse agonist activity.

Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.

Using a dense PTFE membrane without primary closure to achieve bone and tissue regeneration.

The most common types of barrier membranes used for bone or tissue regeneration are made of expanded-polytetrafluoroethylene (e-PTFE) or resorbable materials, such as collagen. Both the e-PTFE and resorbable membranes require primary soft tissue coverage. This article explores the use of a dense-polytetrafluoroethylene (d-PTFE) membrane, which does not require primary soft tissue coverage. The advantages of d-PTFE in contrast to the other more commonly used types of barrier membranes and the clinical significance of these advantages for implant surgical and restorative treatment are discussed.

Agonist lead identification for the high affinity niacin receptor GPR109a.

A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.

The potential use of selective 5-HT2C agonists in treating obesity.

Activation of central 5-HT2C receptors as a strategy for appetite suppression and weight control is supported by animal pharmacology and human clinical studies. Considerable evidence comes from the weight-loss effects of fenfluramine, a non-selective 5-HT2C agonist. Advances in molecular pharmacology have led to an understanding of the effects of 5-HT2C receptor activation on food intake and satiety, in addition to providing insight into the causes of cardiac valvular insufficiency and pulmonary hypertension associated with the use of fenfluramine. However, clinically validated animal models of drug-induced disease and knowledge of the molecular mechanisms of these safety issues is lacking. For this reason, the development of selective 5-HT2C agonists for the treatment of obesity has remained a challenge.