Bisindolylmaleimide Ligands Stabilize c-MYC G-Quadruplex DNA Structure and Downregulate Gene Expression.

G-Quadruplex (G4) structures play a pivotal role in diverse biological functions, including essential processes, such as telomere maintenance and gene regulation. G4 structures formed in functional regions of genomes are actively pursued toward therapeutics and are targeted by small-molecule ligands that alter their structure and/or stability. Herein, we report the synthesis of bisindolylmaleimide-based (BIM) ligands, which preferentially stabilize parallel G4 structures of c-MYC and c-KIT oncogenes over the telomeric h-RAS1 G4 and duplex DNAs. The preferential stabilization of parallel G4s with BIM ligands is further validated by the DNA polymerase stop assay, where stop products were only observed for templates containing the c-MYC G4 sequence. Nuclear magnetic resonance (NMR) titration studies indicate that the lead ligand BIM-Pr1 forms a 2:1 complex with c-MYC G4 DNA with a KD of 38 ± 5 µM. The BIM ligand stacks at the 5' and 3' quartets, with molecular modeling and dynamics studies supporting the proposed binding mode. The ligand is cytotoxic to HeLa cells and downregulates c-MYC gene expression. Collectively, the results present bisindolylmaleimide scaffolds as novel and powerful G4 targeting agents.

The emerging role of nebulization for maintenance treatment of chronic obstructive pulmonary disease at home.

Inhalation therapy is the cornerstone of chronic obstructive pulmonary disease (COPD) management. However, for many COPD patients who are managed at home, nebulization therapy offers an effective alternative treatment and fulfills the gap of catering to the specific population of patients who are unable to use handheld inhaler devices appropriately. The present review highlights key aspects, namely selection of the right beneficiaries for home nebulization, available drugs in nebulized formulations for the treatment of COPD, and the importance of care, cleaning, and maintenance, which are prerequisites for ensuring successful nebulization therapy.

Immediate effect of horse riding simulator on adductor spasticity in children with cerebral palsy: A randomized controlled trial.

BACKGROUND: Spastic cerebral palsy (CP) is the most common type of CP. Hip adductor spasticity leads to discomfort, stiffness, and difficulties in doing physical activities such as sitting, transfer, and walking. Management of hip adductor spasticity is still a challenge in the field of rehabilitation. Horse riding simulator (HRS) has been reported to have beneficial effects on spasticity, postural control, and motor function in children with spastic CP. OBJECTIVE: The aim of the study was to determine the immediate effect of HRS on adductor spasticity in children with CP. METHODS: Twenty-four children with CP were selected and were divided into two groups: experimental and control (12 children in each group). Experimental group was exposed to HRS and control group to the corner seat placement. Adductor tone and passive hip abduction range of motion were measured before and after the intervention. RESULTS: Post intervention scores in the group of HRS show significant reduction in adductor spasticity and improvement in hip abduction range of motion, whereas no difference have been reported in the control group. HRS has positive effects on reducing spasticity and improving range of motion in hip joint in spastic CP. CONCLUSION: It was concluded that immediate effect of HRS is successful in reducing the adductor spasticity and improving abduction range of motion in hip, which could be incorporated with regular physiotherapy intervention.

Synthesis of the Dynamical Properties of Feedback Loops in Bio-Pathways.

Feedback loops regulate various biological functions such as oscillations, bistability, and robustness. They play a significant role in developmental signalling and failure of feedback can lead to disease. Systematic analysis of feedback loops could be useful in understanding their properties and biological effects. We propose here a method to automatically analyze feedback loops in bio-pathways and synthesize temporal logic properties which describe their dynamics. Starting with an ordinary differential equations (ODEs) based model of a bio-pathway, for a chosen feedback loop present in the pathway, we use a convolutional neural network to classify the behaviours of the key components of the feedback according to templates specified in bounded linear temporal logic (BLTL). Once a template has been identified, we instantiate the symbolic variables appearing in the template and synthesize properties using a parameter estimation procedure based on sequential hypothesis testing. We have applied this framework to a number of bio-pathway models and validated that the synthesized properties faithfully describe the behaviours of the feedback loops.

Knowledge gaps persist and hinder progress in eliminating mumps.

Mumps, a common childhood disease in the pre-vaccine era that causes swelling of the parotid salivary glands, can lead to orchitis, viral meningitis, and sensorineural deafness. While the incidence of disease decreased dramatically after the vaccine was added to standard vaccination schedules, the disease has made a substantial resurgence in recent years. As a result, it becomes critical to examine the factors involved in recurring outbreaks. Although low and incomplete vaccination coverage may be a key reason, it does not fully explain the issue due to the high rate of occurrence in populations with high vaccination coverage rates. Multiple studies suggest that waning immunity and secondary vaccine failure play a large role, the effects of which were previously masked by subclinical boosting. Significant knowledge gaps persist around the exact role and mechanism of waning immunity and demonstrate the need for more research in this area, as well as a reevaluation of mumps vaccine policy.

Improving the lean muscle color of dark-cutting beef by aging, antioxidant-enhancement, and modified atmospheric packaging.

The objective was to evaluate the effects of wet-aging, rosemary-enhancement, and modified atmospheric packaging on the color of dark-cutting beef during simulated retail display. No-roll dark-cutting strip loins ( = 12; pH > 6.0) were selected from a commercial packing plant within 3 d postharvest. Using a balanced incomplete block design, dark-cutting loins were sectioned in half, and assigned to 1 of 3 aging periods: 7, 14, or 21 d. After respective aging, each aged section was divided into 3 equal parts, and randomly assigned to 1 of 3 enhancement treatments: nonenhanced dark-cutting, dark-cutter enhanced with 0.1% rosemary, and dark-cutter enhanced with 0.2% rosemary. Following enhancement, steaks were randomly assigned to 1 of 3 packaging treatments: high-oxygen modified atmospheric packaging (HiOx-MAP; 80% O and 20% CO), carbon monoxide modified atmospheric packaging (CO-MAP; 0.4% CO, 69.6% N, and 30% CO), and polyvinyl chloride overwrap (PVC; 20% O). Instrumental and visual color measurements were recorded during 5 d simulated retail display. Lipid oxidation was determined utilizing the thiobarbituric acid reactive substances (TBARS) method. There was a significant packaging × enhancement × display time interaction for values and chroma ( 0.001). On d 0 of display, dark-cutting steaks enhanced with 0.1% and 0.2% rosemary and packaged in HiOx-MAP had greater ( 0.001) values and chroma than other dark-cutting packaging/enhancement treatments. A significant packaging × enhancement × display time interaction resulted for values ( 0.001). Dark-cutting steaks enhanced with 0.2% rosemary and packaged in HiOx-MAP was lighter ( 0.001; greater values) than other dark-cutting treatments on d 5 of display. There were no differences ( 0.34) in discoloration scores on d 5 among different dark-cutting treatments when steaks were packaged in HiOx- and CO-MAP. There was an aging period × enhancement × packaging interaction ( < 0.0033) for lipid oxidation. On d 0 of display, there were no differences ( 0.54) in TBARS values between different aging periods and enhancement treatments. Dark-cutting steaks enhanced with 0.2% rosemary had lower ( 0.001) TBARS values than 0.1% rosemary on d 5 when aged for 21 d and in HiOx-MAP. The results suggest that rosemary enhancement with CO- or HiOx-MAP has the potential to improve the surface color of dark-cutting beef.

Communication-related allegations against physicians caring for premature infants.

OBJECTIVE: Maternal-fetal medicine physicians (MFMp) and neonatal-perinatal medicine physicians (NPMp) caring for premature infants and their families are exposed to significant risk for malpractice actions. Effective communication practices have been implicated to decrease litigious intentions but the extent of miscommunication as a cause of legal action is essentially unknown in this population. Analysis of communication-related allegations (CRAs) may help toward improving patient care and physician-patient relationships as well as decrease litigation risks. STUDY DESIGN: We retrospectively reviewed the Westlaw database, a primary online legal research resource used by United States lawyers and legal professionals, for malpractice cases against physicians involving premature infants. Inclusion criteria were: 22 to 36 weeks gestational age, cases related to peripartum events through infant discharge and follow-up, and legal records with detailed factual narratives. RESULTS: The search yielded 736 legal records, of which 167 met full inclusion criteria. A CRA was identified in 29% (49/167) of included cases. MFMp and/or NPMp were named in 104 and 54 cases, respectively. CRAs were identified in 26% (27/104) and 35% (19/54) of MFMp- and NPMp-named cases, respectively, with a majority involving physician-family for both specialties (81% and 74%, respectively). Physician-family CRAs for MFMp and NPMp most often regarded lack of informed consent (50% and 57%, respectively), lack of full disclosure (41% and 29%, respectively) and lack of anticipatory guidance (36% and 21%, respectively). CONCLUSIONS: This study of a major legal database identifies CRAs as significant causes of legal action against MFMp and NPMp involved in the care of high-risk women and infants delivered preterm. Physicians should be especially vigilant with obtaining genuine informed consent and maintaining open communication with families.

Proximal Tibia Bone Graft: An alternative Donor Source especially for Foot and Ankle Procedures.

Bone graft is essential in various orthopaedic procedures. Among the many donor sites for harvesting autologous bone graft, the iliac crest has been the most commonly used. However, for foot and ankle procedures the proximal tibia has gained popularity as an alternative donor site due to its anatomic proximity to the primary surgical site. In this article we evaluated the possible complications associated with harvesting proximal tibia bone graft. Our study showed the low incidence of morbidity in harvesting proximal tibia bone graft, thereby providing a good alternative donor for foot and ankle procedures.

Effects of aging on the fundamental color chemistry of dark-cutting beef.

The objective of the current study was to evaluate the effects of aging on myoglobin chemistry of dark-cutting beef. Ten USDA Choice (mean pH = 5.6; normal pH beef) and 10 no-roll dark cutter (mean pH = 6.4) strip loins were obtained from a commercial packing plant within 3 d of harvest. Loins were cut into 4 sections, vacuum packaged, randomly assigned to 0-, 21-, 42-, and 62-d aging at 2°C in the dark. Following aging, loin sections were cut into 2.5-cm-thick steaks and were used to determine bloom development, oxygen consumption (OC), metmyoglobin reducing activity (MRA), and lipid oxidation. Surface color readings were measured using a HunterLab Miniscan XE Plus spectrophotometer. A significant muscle type × aging time interaction resulted for OC ( < 0.001). Normal pH steaks declined more ( < 0.001) in OC during aging than dark-cutting beef. On d 0, dark-cutting beef had a greater OC ( < 0.001) than normal pH beef. There was a significant muscle type × oxygenation time × aging period interaction for L* values, deoxymyoglobin (DeoxyMb), and oxymyoglobin (OxyMb). When dark-cutting sections were aged for 62 d, both 0 and 60 min bloom development L* values were greater ( < 0.0001) than 0 min dark-cutting sections aged for 21 or 42 d. At all aging periods, normal pH beef had greater OxyMb content and lower DeoxyMb ( < 0.0001) during bloom development than dark-cutting beef. An aging period × muscle type interaction was significant for % overall reflectance ( = 0.0017) and absorbance ( = 0.0038). Dark cutting and normal pH beef loin sections aged for 62 d had greater reflectance ( < 0.0001) than 21 d. On d 0, dark-cutting beef had greater ( < 0.0001) MRA than normal pH beef. There were no significant ( = 0.14) differences in MRA between 42 and 62 d between dark-cutting and normal pH beef. Dark cutting steaks had lower thiobarbituric acid reactive substances values ( < 0.0001) than normal pH steaks. The results indicate that characterizing the myoglobin chemistry during aging will help to design strategies to improve appearance of high pH beef.

First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

The state of point-of-care ultrasonography use and training in neonatal-perinatal medicine and pediatric critical care medicine fellowship programs.

OBJECTIVE: The current state of point-of-care ultrasonography (POCUS) use and education in neonatal-perinatal medicine (NPM) and pediatric critical care medicine (PCCM) is unknown. Our aim was to quantify POCUS use, training and perceptions regarding education and barriers among the United States NPM and PCCM fellowship programs. STUDY DESIGN: A 14-question survey was emailed to the fellowship directors of all the United States NPM and PCCM fellowship programs. RESULTS: The response rate was 55% (52/95) and 59% (39/66) for NPM and PCCM programs, respectively. Over 90% of respondents in both groups believe that fellows and attendings should receive POCUS training. PCCM programs, compared with NPM, had greater access to POCUS machines (97% vs 63%, P<0.001), and more often used POCUS for diagnoses and management (76% vs 29%, P<0.001) and procedural guidance (95% vs 37%, P<0.001). The most common indications were cardiac/hemodynamics, pulmonary pathology and vascular access in both specialties. PCCM reported more training to fellows (90% vs 29%, P<0.001). Both group perceived lack of time to learn, lack of equipment/funds, liability concerns, lack of personnel to train physicians and cardiology/radiology resistance as significant barriers to POCUS implementation. CONCLUSIONS: Both NPM and PCCM fellowship programs believe in the benefits of POCUS and that their physicians should receive the necessary training. Compared with PCCM, NPM fellowships programs have less access to POCUS machines and less frequently use POCUS and train their fellows and attendings. There remain significant barriers to utilization of POCUS, especially in NPM.

Effects of extended aging and modified atmospheric packaging on beef top loin steak color.

The objective of this study was to evaluate the effects of extended aging and modified atmospheric packaging on beef LM color. Using a randomized complete block design, each beef longissimus lumborum muscle ( = 10; USDA Choice, 3 d postmortem) was equally divided into 3 sections and randomly assigned to 1 of 3 aging periods (21, 42, or 62 d at 2°C). After respective aging, each loin section was cut into four 2.5-cm-thick steaks and randomly assigned to 1 of 3 packaging types (PVC, HiOx-MAP [80% oxygen and 20% carbon dioxide], or CO-MAP [0.4% carbon monoxide, 69.6% nitrogen, and 30% carbon dioxide]). The steaks were displayed under continuous fluorescent lighting for 6 d, and surface color was determined daily using a HunterLab Miniscan XE Plus spectrophotometer and a visual panel. The fourth steak was used to characterize oxygen consumption (OC), lipid oxidation, and metmyoglobin reducing activity (MRA) on 21, 42, and 62 d (before display). On d 6 display, MRA, OC, and lipid oxidation also were measured. An increase in aging time decreased ( < 0.0001) muscle pH. Loin sections aged for 42 and 62 d had a lower ( < 0.0002) pH compared with loin sections aged for 21 d. An aging period × packaging × display time interaction ( < 0.0001) resulted for a* values (redness), chroma, and visual color (muscle color and surface discoloration). As aging time increased, HiOx-MAP had the most discoloration ( < 0.0001) compared with other packaging types on d 6. At all aging periods, steaks packaged in CO-MAP had greater ( < 0.0001) MRA on d 6 than PVC and HiOx-MAP, whereas steaks packaged in HiOx-MAP had the least MRA ( < 0.0001). There were no differences ( = 0.34) in thiobarbituric acid reactive substances values between steaks aged for 21 and 42 d when steaks were packaged in CO-MAP and displayed for 6 d. However, steaks packaged in HiOx-MAP and displayed 6 d had greater ( < 0.0001) lipid oxidation than CO-MAP. Steaks packaged in HiOx-MAP had a lower ( < 0.0001) OC compared with PVC and CO-MAP when aged for 42 and 62 d. There were no differences ( = 0.49) in OC between steaks packaged in PVC and HiOx-MAP when aged for 21 d and displayed 6 d. The results indicate that extended aging is detrimental to color stability when packaged in PVC and HiOx-MAP. However, steaks in CO-MAP had stable red color during display. Decreased color stability in PVC and HiOx-MAP could be associated, in part, with decreased MRA and OC.

Biophysical characterization of small molecule antiviral-loaded nanolipogels for HIV-1 chemoprophylaxis and topical mucosal application.

UNLABELLED: Nanocarriers are versatile vehicles for drug delivery, and emerging as platforms to formulate and deliver multiple classes of antiretroviral (ARV) drugs in a single system. Here we describe the fabrication of hydrogel-core and lipid-shell nanoparticles (nanolipogels) for the controlled loading and topical, vaginal delivery of maraviroc (MVC) and tenofovir disoproxil fumarate (TDF), two ARV drugs with different mechanisms of action that are used in the treatment of HIV. The nanolipogel platform was used to successfully formulate MVC and TDF, which produced ARV drug-loaded nanolipogels that were characterized for their physical properties and antiviral activity against HIV-1 BaL in cell culture. We also show that administration of these drug carriers topically to the vaginal mucosa in a murine model leads to antiviral activity against HIV-1 BaL in cervicovaginal lavages. Our results suggest that nanolipogel carriers are promising for the encapsulation and delivery of hydrophilic small molecule ARV drugs, and may expand the nanocarrier systems being investigated for HIV prevention or treatment. STATEMENT OF SIGNIFICANCE: Topical, mucosal intervention of HIV is a leading strategy in the efforts to curb the spread of viral infection. A significant research thrust in the field has been to characterize different dosage forms for formulation of physicochemically diverse antiretroviral drugs. Nanocarriers have been used to formulate and deliver small molecule and protein drugs for a range of applications, including ARV drugs for HIV treatment. The broad significance of our work includes evaluation of lipid-shell, hydrogel-core nanoparticles for formulation and topical, vaginal delivery of two water-soluble antiretroviral drugs. We have characterized these nanocarriers for their physical properties and their biological activity against HIV-1 infection in vitro, and demonstrated the ability to deliver drug-loaded nanocarriers in vivo.

Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas.

BACKGROUND: In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial. PATIENTS AND METHODS: Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity. RESULTS: PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001). CONCLUSION: Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response. CLINICALTRIALSGOV: NCT00844649.

CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer.

BACKGROUND: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. PATIENTS AND METHODS: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. RESULTS: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. CONCLUSION: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.

Assessment of hot flushes and vaginal dryness among obese women undergoing bariatric surgery.

OBJECTIVE: Menopausal symptoms are associated with a negative impact on the quality of life, leading women to seek medical treatment. Obesity has been linked to higher levels of menopausal symptoms such as hot flushes. This assessment will explore whether the prevalence and bother of hot flushes and vaginal dryness change from pre- to post-bariatric surgery among obese midlife women. METHODS: This study is a longitudinal analysis of data from 69 women (ages 35-72 years) undergoing bariatric surgery with reported reproductive histories and menopausal symptoms at preoperative and 6-month postoperative visits. Prevalence of and degree of bother of hot flushes and vaginal dryness at pre- and post-surgery were compared using McNemar's test and Wilcoxon signed-rank test. RESULTS: The reported degree of bother of symptoms associated with hot flushes decreased from pre- to post-surgery (p < 0.01). There was no significant change in the prevalence of hot flushes or vaginal dryness in the overall study sample. CONCLUSIONS: The degree of bother of symptoms associated with hot flushes among midlife women may decrease after bariatric surgery. These results highlight important secondary gains, including less bothersome menopausal symptoms, for women who choose bariatric surgery for weight loss.

Reverse electron transport effects on NADH formation and metmyoglobin reduction.

The objective was to determine if NADH generated via reverse electron flow in beef mitochondria can be used for electron transport-mediated reduction and metmyoglobin reductase pathways. Beef mitochondria were isolated from bovine hearts (n=5) and reacted with combinations of succinate, NAD, and mitochondrial inhibitors to measure oxygen consumption and NADH formation. Mitochondria and metmyoglobin were reacted with succinate, NAD, and mitochondrial inhibitors to measure electron transport-mediated metmyoglobin reduction and metmyoglobin reductase activity. Addition of succinate and NAD increased oxygen consumption, NADH formation, electron transport-mediated metmyoglobin reduction, and reductase activity (p<0.05). Addition of antimycin A prevented electron flow beyond complex III, therefore, decreasing oxygen consumption and electron transport-mediated metmyoglobin reduction. Addition of rotenone prevented reverse electron flow, increased oxygen consumption, increased electron transport-mediated metmyoglobin reduction, and decreased NADH formation. Succinate and NAD can generate NADH in bovine tissue postmortem via reverse electron flow and this NADH can be used by both electron transport-mediated and metmyoglobin reductase pathways.

Species-specific effects on non-enzymatic metmyoglobin reduction in vitro.

Our objectives were to determine the non-enzymatic metmyoglobin reduction properties of bovine, porcine, and equine myoglobins and to characterize the effects of pre-incubation of 4-hydroxy-2-nonenal (HNE) with myoglobins on non-enzymatic metmyoglobin reduction in vitro. Purified bovine, porcine, and equine metmyoglobins (0.05 mM) were reduced at pH 5.6 and 7.4 in the presence or absence of HNE. Rates of metmyoglobin reduction were monitored by spectrophotometry, and myoglobin adducts were characterized by high-resolution mass-spectrometry. Results showed that the species origins of individual myoglobins determined rates of non-enzymatic reduction (beef>equine>pork; P<0.05). Irrespective of species, pre-incubation of HNE myoglobin decreased non-enzymatic metmyoglobin reduction compared with control at both pH 5.6 and 7.4 (P<0.05). Mass spectrometric analysis revealed adducts of HNE with bovine, porcine, and equine myoglobins. The results indicate that the amino acid composition and the covalent binding of HNE with myoglobin can significantly decrease the ability of heme to accept electrons.

Validation of noninvasive hemoglobin measurement by pulse co-oximeter in newborn infants.

OBJECTIVE: To describe the accuracy of noninvasive hemoglobin (Hb) obtained with pulse co-oximeter (SpHb) compared with total Hb (tHb) from laboratory co-oximeter in neonates. STUDY DESIGN: Neonates with birth weight (BW) <3000 g admitted to LAC+USC Medical Center neonatal intensive care unit were included. SpHb was recorded using Masimo Radical-7 and compared with tHb. A total of three data sets were obtained for each patient. Regression analysis and Bland-Altman analysis were performed. RESULT: Sixty-one patients (mean±s.d., BW 1177±610 g and gestational age 28.7±3.9 weeks) were enrolled. The mean tHb value was 13.9±2.0 g dl(-1) and the mean SpHb was 14.0±2.0 g dl(-1). There was a moderately positive correlation between SpHb and tHb (r=0.66, P<0.001) with a bias and precision of -0.09±1.67 g dl(-1). Data from a subgroup of infants with gestational age ⩽32 weeks (52/61 patients) were analyzed, and the correlation coefficient was moderately positive (r=0.69, P<0.001) with a bias and precision of -0.23±1.60 g dl(-1). CONCLUSION: Our results suggest that noninvasive SpHb may be considered as an adjunct to invasive tHb measurements in newborn infants <3000 g especially in preterm infants ⩽32 weeks of gestation.