Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue.

The mechanism of action (MoA) of a clickable fatty acid analogue 8-(2-cyclobuten-1-yl)octanoic acid (DA-CB) has been investigated for the first time. Proteomics, metabolomics, and lipidomics were combined with a network analysis to investigate the MoA of DA-CB against Mycobacterium smegmatis (Msm). The metabolomics results showed that DA-CB has a general MoA related to that of ethionamide (ETH), a mycolic acid inhibitor that targets enoyl-ACP reductase (InhA), but DA-CB likely inhibits a step downstream from InhA. Our combined multi-omics approach showed that DA-CB appears to disrupt the pathway leading to the biosynthesis of mycolic acids, an essential mycobacterial fatty acid for both Msm and Mycobacterium tuberculosis (Mtb). DA-CB decreased keto-meromycolic acid biosynthesis. This intermediate is essential in the formation of mature mycolic acid, which is a key component of the mycobacterial cell wall in a process that is catalyzed by the essential polyketide synthase Pks13 and the associated ligase FadD32. The multi-omics analysis revealed further collateral alterations in bacterial metabolism, including the overproduction of shorter carbon chain hydroxy fatty acids and branched chain fatty acids, alterations in pyrimidine metabolism, and a predominate downregulation of proteins involved in fatty acid biosynthesis. Overall, the results with DA-CB suggest the exploration of this and related compounds as a new class of tuberculosis (TB) therapeutics. Furthermore, the clickable nature of DA-CB may be leveraged to trace the cellular fate of the modified fatty acid or any derived metabolite or biosynthetic intermediate.

Fight and build: solidarity economy as ontological politics.

This essay explores the potential of solidarity economy (SE) as theory, practice, and movement, to engender an ontological politics to create and sustain other worlds that can resolve the existential crises of ecological destruction and historic inequalities. We argue that such a politics is necessary to go beyond the world as it is and exceed the dictates of a dominant modernity-capitalism, white supremacy, patriarchy-that positions itself as the only singular reality-or One World World (Law J (2011) What's Wrong with a One World World. Heterogeneities. http://www.heterogeneities.net/publications/Law2011WhatsWrongWithAOneWorldWorld.pdf). What is needed are alternatives to development in contrast to alternative developments. Over the past decade, the SE movement in Massachusetts has advanced a fight and build approach, which has reframed economy as a matter of concern, as something that communities can, and already do, shape themselves-and that powerfully disrupts the reality of a singular capitalist economy. At the same time, the heterogeneous elements of SE are caught up in and assembling political projects with multiple orientations: modernist, social justice, and ontological (Escobar, Pluriversal politics: the real and the possible, Duke University Press, Durham, 2020). SE movement can remain stuck in a modernist politics of growing and scaling businesses and jobs. Even though a social justice approach attends to power and is more amenable to a relational view of reality where things only exist in interconnection, it too can remain mired in One World World liberal politics of redistribution and market 'solutions'. How SE movement might actualize an ontological politics is a matter of care, an attunement to how relational worlds are coming into being and maintained. As an ontological politics, SE is not about economy qua economy at all, but about creating and sustaining worlds, pluriversal realities where we can be in solidarity with other people, beings, and planetary life systems.

Evaluation of the use of non-formulary oncology medications restricted to outpatient use in hospitalized patients after implementation of a criteria-for-use algorithm.

OBJECTIVE: To decrease the number of orders and total hospital spend for inpatient use of antineoplastic drugs of interest, while evaluating each case for urgent or emergent need for administration. METHODOLOGY: This study is a multicenter, retrospective, cost-evaluation, cohort study performed in five Ascension Seton hospitals in the Austin, Texas area between 1 January 2013 and 31 December 2018. Patients were identified via a dispense analysis report for the antineoplastic drugs of interest. RESULTS: An overall reduction of 56% was seen in orders processed with a 62% decrease in annual hospital spending after implementation of the criteria-for-use algorithm. When results were evaluated without including rituximab orders, a reduction of 17% was seen in orders processed with a 21% decrease in annual hospital spending. DISCUSSION AND CONCLUSION: The decreases in our primary outcomes were primarily driven by a reduction in the use of one drug, rituximab. Overall, implementation of a criteria-for-use algorithm was effective in reducing both overall number of orders and hospital spending for restricted antineoplastic agents.

Stereotactic Vertebroplasty for Spinal Metastases with Multilevel Bilateral Pedicle Fractures: A Technical Note.

Vertebral compression fractures (VCFs) represent a significant cause of disability and primarily result from either underlying vertebral body neoplasms or osteoporosis. Vertebroplasty (VP) is a procedure commonly utilized to repair pathologic VCFs in order to manage pain and reinstate vertebral body height. However, there is a paucity of literature on how to manage painful multilevel VCFs with concomitant bilateral pedicle fractures. We describe a patient with a primary prostatic carcinoma and VCFs of the third and fourth lumbar vertebrae (L3 and L4, respectively) with concomitant bilateral pedicle fractures secondary to metastatic disease. Due to the degree of damage to the L3 and L4 vertebral bodies and pedicles, a VP performed via a percutaneous approach was deemed to be too high risk. VP for L3 and L4 was instead performed by utilizing stereotactic spine navigation and an intraoperative O-arm (Medtronic Corporation, Minneapolis, Minnesota). Our result indicates a potential role for stereotactic spine navigation in vertebroplasty for complex pathologic VCFs.

Reductive Cleavage of Organic Peroxides by Iron Salts and Thiols.

Despite the low bond strength of the oxygen-oxygen bond, organic peroxides are often surprisingly resistant to cleavage by nucleophiles and reductants. As a result, achieving decomposition under mild conditions can be challenging. Herein, we explore the reactivity of a selection of peroxides toward thiolates, phenyl selenide, Fe(II) salts, and iron thiolates. Peroxides activated by conjugation, strain, or stereoelectronics are rapidly cleaved at room temperature by thiolate anions, phenylselenide, or Fe(II) salts. Under the same conditions, unhindered dialkyl peroxides are only marginally reactive; hindered peroxides, including triacetone triperoxide and diacetone diperoxide (DADP), are inert. In contrast, all but the most hindered of peroxides are rapidly (<1 min at concentrations down to ∼40 mM) cleaved by mixtures of thiols and iron salts. Our observations suggest the possible intermediacy of strongly reducing complexes that are readily regenerated in the presence of stoichiometric thiolate or hydride. In the case of DADP, an easily prepared explosive of significant societal concern, catalytic amounts of iron and thiol are capable of promoting rapid and complete disproportionation. The availability of inexpensive and readily available catalysts for the mild reductive degradation of all but the most hindered of peroxides could have significant applications for controlled remediation of explosives or unwanted radical initiators.

Reliability of three methods of computer-aided thermal pattern analysis.

BACKGROUND: The objective of this study was to assess three methods of computer-aided thermal pattern analysis for a) examiner reliability, b) inter-method differences, and c) determine which method yields the highest percent-similarity between paired test-retest scans. METHODS: Three examiners compared two sets of thermal scans from the same 30 subjects using three different methods of scan alignment. The results were evaluated by the Intraclass Correlation Coefficient and the Wilcoxon signed-rank test, at the 5% level of significance. RESULTS: Intra and inter-examiner ICC scores for all methods were acceptable (> 0.75). There were no statistically significant differences (at the Bonferroni-corrected level of significance of 0.0004%) in percent similarity of the scans between the three methods CONCLUSIONS: The results contribute evidence to the reliability of TPC program software. Manually aligning the readings plays an important role in obtaining precise TPC percent-similarities.

Thermal patterns and health perceptions.

INTRODUCTION: Thermal pattern analysis is thought to be an indicator of health. However, the validity of this concept has not been established. To further investigate the relationship between thermal pattern analysis and health perceptions, thermal scans were assessed in conjunction with results from the SF-12 health survey. METHODS: Sixty-eight chiropractic students were recruited to receive two paraspinal thermal scans, 5 minutes apart, on three visits that were 1 week apart. Each scan produces three graphs or channels; one for each of left and right sides of the spine and a delta or difference between left and right. The scans were imported into a thermal pattern calculator (TPC) providing a percent similarity between the two. The TPC percent were compared with to their corresponding SF-12 scores. RESULTS: There were no significant findings in the left or delta channel. For the right channel, there was a decrease in mental health perception in participants having a TPC percent of 70.8 or higher (32.3% of all visits). CONCLUSION: Participants in this study who had right channel TPC percent of 70.8 or higher were associated with lower mental health perception scores. The study is considered a preliminary inquiry only due to the small sample size.

Postinfectious gastroparesis related to autonomic failure: a case report.

BACKGROUND AND AIM: Severe dysautonomia may be secondary to viral infections, resulting in impaired autoimmune, cardiovascular, urinary and digestive dysfunction. Herein, we present a case of a 31-year-old white female patient who had severe gastroparesis related to autonomic failure following an episode of acute gastroenteritis. This seems to be the first report providing thorough assessment of the enteric and autonomic nervous system by analysis of full-thickness small intestinal biopsies, cardiovagal testing and autopsy. HOSPITAL COURSE: This patient affected by a severe gastroparesis was treated with antiemetics, prokinetics, analgesics and gastric electrical stimulation to control symptoms. Nutritional support was made using jejunal feeding tube and, in the final stage of disease, with total parenteral nutrition. Autonomic studies revealed minimal heart rate variability and a disordered Valsalva manoeuvre although the enteric nervous system and the smooth muscle layer showed a normal appearance. Hospital courses were complicated by episodes of bacteraemia and fungemia. Serum antiphospholipid antibodies were noted but despite anticoagulation, she developed a pulmonary embolism and shortly thereafter the patient died. Autopsy revealed acute haemorrhagic Candida pneumonia with left main pulmonary artery thrombus. Sympathetic chain analysis revealed decreased myelinated axons with vacuolar degeneration and patchy inflammation consistent with Guillain-Barre syndrome. The evaluation of the enteric nervous system in the stomach and small bowel revealed no evidence of enteric neuropathy or myopathy. CONCLUSION: A Guillain-Barre-like disease with gastroparesis following acute gastroenteritis is supported by physiological and autonomic studies with histological findings.

Comparison of implantation and pregnancy rates in African American and white women in an assisted reproductive technology practice.

OBJECTIVE: To compare IVF outcomes between infertile African American and white women. DESIGN: Retrospective cohort study. SETTING: Hospital-based IVF practice. PATIENT(S): Women undergoing IVF procedures between November 1996 and June 2000. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rates. RESULT(S): There were 24 African American and 273 white women < or =40 years of age who underwent 25 and 333 IVF cycles, respectively. African American women were more likely to have had tubal factor as a primary diagnosis, to have had a child, and to have undergone fewer previous assisted reproductive technology (ART) cycles as compared to white women. No differences between the two groups for clinical variables were noted with the exception of body mass index (BMI [kg/m(2)], 27.1 in African Americans vs. 24.8 in whites). Implantation rates were higher in African American than in white women (35% vs. 23%, respectively). Pregnancy rates were 71% in African Americans and 48% in whites. After adjustment for tubal factor, BMI, and parity, the odds ratio for pregnancy in African American women versus white women increased from 2.6 to 3.3. CONCLUSION(S): This is the first study to demonstrate a significantly higher clinical pregnancy rate in African American women as compared to white women undergoing ART. These data strongly contradict a recent study comparing the same two groups of women undergoing ART. We urge other ART centers to report their data pertaining to race.

Seminal plasma and IVF potential. Biochemical constituents of seminal plasma of males from in vitro fertilization couples.

PURPOSE: Many components of seminal plasma play a role in sperm motility by serving as energy sources. Human seminal plasma contains over 30 proteins, including forward motility proteins, antifertility proteins, and coagulation/liquefaction proteins. This study was designed to determine any correlation between motility or fertilization rates and concentrations of fructose, lactic acid, citric acid, carnitine, and protein in human seminal plasma. METHODS: Fertilization rates were determined by in vitro methods. Fructose, lactic acid, citric acid, and carnitine concentrations were ascertained using high performance liquid chromatography. Protein concentration was determined by Bradford assay. RESULTS: Protein concentrations were significantly different as a function of sperm motility levels. Other constituents of human seminal plasma showed an overall correlation, though not significant. No constituent exhibited significant differences as a function of fertility levels. CONCLUSIONS: Protein concentration was significantly lower for samples with high motility. No significant differences between fertility levels and constituents measured were found.

Purposeful assessment techniques (PAT) applied to an OSCE-based measurement of competencies in a pediatric dentistry curriculum.

Careful measurements of knowledge, attitude, and psychomotor and communication skills are necessary components of testing in a competency-based approach to education in dentistry. In an effort to address these requirements, Baylor College of Dentistry (BCD), Dallas, Texas, has applied Purposeful Assessment Techniques (PAT) to the Objective Structured Clinical Examination (OSCE) currently in use. PAT are those techniques that allow one to work toward development of linear measurement scales that are "person-free" and "item-free." Person-free measurement means that useful data are produced regardless of the group being measured and item-free measurement means that it does not matter which mix of items is completed over the course of an assessment. The Rasch probabilistic model and a guiding definition of Objective Measurement were used in an effort to implement PAT for the BCD OSCE. A Rasch analysis of a BCD-administered OSCE produced an item map that demonstrated the range of difficulty of items by student performance. This item map can be used to determine which items can be repeated on subsequent tests to allow for linear measurement of students' progression through the curriculum. The movement toward PAT described in this paper demonstrates how careful and evolving measurement in dental education can be of great benefit to faculty, staff, students, and the public.

Using videotaped specimens to test quality control in a computer-assisted semen analysis system.

OBJECTIVE: To determine the feasibility of using semen samples previously recorded on videotape for intralaboratory and interlaboratory quality control of computer-assisted semen analysis (CASA) systems. DESIGN: Blinded, controlled study. SETTING: Pooled semen specimens from two normal human volunteers in an academic research environment. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Semen parameters from a videotape analyzed internally and by four external laboratories. RESULT(S): Preliminary experiments designed to examine intralaboratory variation by repeated analysis of semen samples recorded on videotape revealed some significant differences for every variable examined. When these data were analyzed by using the larger biologic error caused by subsampling, no significant differences were found for any of the variables examined. When either a standard set or the specific laboratories' sets of parameters were used to analyze the same videotaped semen specimen, no statistically significant differences were detected for sperm concentration for motility among the five laboratories after the biological error caused by subsampling was applied to results. CONCLUSION(S): These data strongly suggest that videotaped semen specimens can serve as quality control for intralaboratory and interlaboratory testing of CASA equipment as long as the biologic error caused by subsampling is used to compare results.

Cardiovascular and metabolic responses during 30 minutes of treadmill exercise shortly after consuming a small, high-carbohydrate meal.

Fourteen male endurance runners (VO2peak = 64.8 +/- 8.7 ml x kg(-1) x min(-1)) participated in this study to determine the cardiovascular and metabolic responses during 30 minutes of treadmill running at a moderate intensity soon after consuming a small, high-carbohydrate meal (CHO-M). In randomized order on separate days, subjects either consumed the CHO-M (2088 kJ; 77% carbohydrate) 15 minutes prior to running or they fasted (FAST). Data were collected for 5 minutes beginning at 5, 15, and 25 minutes of the 30-minute run. Heart rate (HR) was determined, a metabolic measurement cart was used to determine VO2 and respiratory exchange ratio (RER), and the CO2 rebreathing procedure (Collier plateau method) was used to determine cardiac output (Q). Statistical analyses indicated that the CHO-M did not affect HR, stroke volume, Q, VO2, or RER compared to FAST. However, all grouped CHO-M and FAST variables, except VO2, changed significantly across the 30-minute exercise session. These data suggest that a small, high-carbohydrate meal does not alter cardiovascular and metabolic function during moderate-intensity exercise in endurance-trained subjects.

Control of air quality in an assisted reproductive technology laboratory.

OBJECTIVE: To investigate the effect of improved air quality on IVF and subsequent embryo development. DESIGN: Retrospective cohort study. SETTING: Hospital-based IVF facility composed of an anteroom, a cleanroom, and an adjacent operating room. PATIENT(S): Two-hundred seventy-five couples requesting IVF between 1993 and 1997. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Particle counts (sizes 0.3, 0.5, 1.0, and 5.0 microm); IVF rates; and embryo quality (stage and grade). RESULT(S): Clinical pregnancy rates decreased from 35% in 1993 to 16% in 1994 (numerous construction odors were detected during 1994) and increased steadily after the cleanroom was built (rates for 1995-1997 were 20%, 32%, and 59%, respectively). Fertilization rates decreased between 1993 (74%) and 1994 (60%) and then steadily increased after cleanroom installation (62% in 1995, 71% in 1996, and 69% in 1997). The proportion of embryos past the four-cell stage decreased from 66% in 1993 to 61% in 1994 but then increased steadily in the years after the cleanroom was built (78%, 77%, and 83% in 1995, 1996, and 1997, respectively). During the same 5-year period, there were no differences in embryo quality or number of embryos transferred. CONCLUSION(S): Construction of a Class 100 cleanroom improved air quality and IVF rate and increased the number of embryos past the four-cell stage available for transfer.

Live birth of a bear cub following nonsurgical embryo collection.

In the near future, 6 of 8 bear species will face extinction mainly because of loss of their natural habitat. This loss of habitat will ultimately require some of these bears to be maintained in zoos and wildlife preserves in the hope of conserving genetic diversity. If the giant panda is representative of other bear species, reproductive performance will be inhibited in such an environment. In this study, we used the nonendangered American black bear (Ursus americanus) as the model for developing appropriate embryo transfer procedures. The donor bear mated numerous times between late May and early June. In late July we anesthetized her and used a series of telescoping sheaths to gain access to the uterus Then we passed a catheter through the largest sheath, inflated the balloon, and, using a 20-mL syringe, repeatedly infused into and then aspirated from the uterus PBS + BSA. We emptied the syringe into Petri dishes and observed 2 embryos. We rinsed the embryos, placed them in human tubal fluid + HSA + HEPES and then held them at 35 degrees C for 5 h. The recipient mated during mid-June; in late July we anesthetized her and, with the aid of laparoscopy, transferred an embryo into the cranial portion of the uterine horn ipsilateral to the ovary containing a CL. The recipient delivered 2 cubs in January. Necropsy results indicated that the neonates lived for 6 to 8 wk before succumbing to flooding in the den. The DNA from hair samples belonging to the neonates indicated that the male cub belonged to the donor, the female cub to the recipient. The delayed implantation mechanism in bears probably allowed for the successful development of the embryo in the presence of a substantial asynchrony between the donor and the recipient (13 d). We conclude that embryo transfer is possible in the American black bear and can lead to the birth of live cubs.

Serum progesterone, oestradiol, luteinizing hormone and prolactin profiles in the female black bear (Ursus americanus).

Identifying steroid and pituitary hormone profiles in the female black bear (Ursus americanus) throughout pregnancy may provide a greater understanding of the reproductive cycle and indicate which hormones are required for implantation. Our objective was to assess endocrine activity in black bears oestrus onset, at oestrus, during pregnancy and after parturition. Serum samples were obtained from 12 captive, 16 uncollared and five radiocollared free-ranging female black bears from March through the end of December and assayed for serum progesterone, oestradiol, luteinizing hormone (LH) and prolactin (PRL). In captive bears, progesterone concentrations were low at days 0-10 after oestrus and increased significantly days 25-35 and 45-52 after oestrus. Oestradiol concentrations were high at oestrus (day 0) and days 4-10 after oestrus and then decreased days 25-35 and 45-52 after oestrus. LH concentrations were not significantly different throughout the sampling period. Changes in PRL concentrations pattern were similar to those of oestradiol, with elevated levels at oestrus and days 4-10 after oestrus, followed by a significant decrease 45-52 days after oestrus. In non-collared free-ranging bears, progesterone concentrations increased gradually after mating with a further significant increase in November-December. Oestradiol concentrations were highest in March (before mating) and in June (during mating) followed by a significant decrease in July (early delay period) and November-December (peri-implantation period). LH concentrations were low until November-December and then increased significantly. PRL concentrations were low in March (before mating), increased significantly during the mating season in June, decreased slightly in July, and were low in November-December (peri-implantation period). In radiocollared free-ranging bears, serum progesterone concentrations were elevated in pregnant bears in December and extremely low in lactating and non-lactating bears in March. Oestradiol levels were slightly higher in pregnant bears in December than in non-lactating or lactating bears in March. PRL concentrations were considerably higher in lactating bears in March than in pregnant bears in December. Our results suggest that: (1) serum progesterone concentrations are low, but detectable during the early delay implantation period and greatly elevated during the peri-implantation period; (2) serum oestradiol concentrations are elevated at oestrus and decline during the delay period; (3) LH may be involved in luteal activation; and (4) the decline of serum PRL concentrations during short days may be necessary for implantation to occur.

Colorectal cancer--chemoprevention.

Colorectal cancer is the second leading cause of death from cancer in The United States. During the last fifteen years, emphasis has been placed on identification of high risk patients and families and outline of appropriate surveillance regimens for normal and high risk patients for colorectal cancer. Parallel to this effort, abundant clinical data has been accumulated that chemoprevention of colorectal cancer with nonsteroidals and aspirin may be possible. Interruption of prostaglandin metabolism appears to be one of the mechanisms of action but not the only therapeutic arm. Currently, sulindac, aspirin, calcium and selenium supplementation are attractive recommendations to at risk patients awaiting results of clinical trials. Other agents in development add excitement to the concept of colorectal cancer chemoprevention.