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The surface [C/N] ratios of evolved giants are strongly affected by the first dredge-up (FDU) of nuclear-processed material from stellar cores. C and N also have distinct nucleosynthetic origins and serve as diagnostics of mixing and mass-loss. We use subgiants to find strong trends in the birth [C/N] with [Fe/H], which differ between the low-α and high-α populations. We demonstrate that these birth trends have a strong impact on the surface abundances after the FDU. This effect is neglected in current stellar models, which use solar-scaled C and N. We map out the FDU as a function of evolutionary state, mass, and composition using a large and precisely measured asteroseismic data set in first-ascent red giant branch (RGB) and core He-burning, or red clump (RC), stars. We describe the domains where [C/N] is a useful mass diagnostic and find that the RC complements the RGB and extends the range of validity to higher mass. We find evidence for extra mixing on the RGB below [Fe/H] = −0.4, matching literature results, for high-α giants, but there is no clear evidence of mixing in the low-α giants. The predicted signal of mass-loss is weak and difficult to detect in our sample. We discuss implications for stellar physics and stellar population applications. [ABSTRACT FROM AUTHOR]

Physical organic chemistry might be regarded as officially recognized as a distinct discipline through the publication of L. P. Hammett's book of that title, although substantial earlier work can be traced back to the turn of the 20th century. Many of the instrumental tools that helped the discipline develop in so many different ways began to appear in the late thirties and during World War II and were soon built to be increasingly operated in the "hands-on" mode. This development became very popular in academia, where instruments are not operated for you by an expert, but even if you are an undergraduate, you can more or less be the expert yourself and take many varieties of data on instruments usually available on a 24 h basis. It has been my privilege and joy to begin research in chemistry just as these waves of change began to grow and to savor the great contribution that the new methods, such as measurement of 14C, UV-vis, IR, NMR, and hands-on use of computers, made in facilitating our research programs at MIT and later at Caltech. Among those programs, which will be discussed, were 14C tracing of carbocation rearrangements and benzyne formation, electrical effects of substituents, Grignard reagents, synthesis of small-ring compounds, (2 + 2) cycloaddition reactions of halogenated ethylenes, assisting in development of 19F, 13C, and 15N NMR for conformational analysis, other structural, kinetic, and tracer studies, as well as helping through textbooks to bring Hückel MO theory and the elements of NMR to familiarity for organic chemists. From the very beginning of my research career, I have been the beneficiary of personal mentoring which has been very crucial to my success in research and is an important theme in what follows. [ABSTRACT FROM AUTHOR]

Abstract: Evidence for an analgesic interaction between delta-9-tetrahydrocannabinol (Δ9-THC) and morphine was sought using an experimental pain model applied to normal volunteers. The study incorporated a double blinded, four treatment, four period, four sequence, crossover design. Subjects received Δ9-THC 5 mg orally or placebo and 90 min later morphine 0.02 mg/kg intravenously or placebo. Fifteen minutes later subjects rated the pain associated with the application of thermal stimuli to skin using two visual analog scales, one for the sensory and one for the affective aspects of pain. Among sensory responses, neither morphine nor Δ9-THC had a significant effect at the doses used, and there was no significant interaction between the two. Among affective responses, although neither morphine nor Δ9-THC had a significant effect, there was a positive analgesic interaction between the two (p =0.012), indicating that the combination had a synergistic affective analgesic effect. The surprisingly limited reported experimental experience in humans does not support a role for Δ9-THC as an analgesic or as an adjunct to cannabinoid analgesia, except for our finding of synergy limited to the affective component of pain. Comparison of our results with those of others suggests that extrapolation from experimental pain models to the clinic is not likely to be a straight-forward process. Future studies of Δ9-THC or other cannabinoids in combination with opiates should focus upon clinical rather than experimental pain. [Copyright &y& Elsevier]

Virtually all recent textbooks for elementary organic chemistry courses now offer substantial components of physical organic chemistry, an emerging discipline first known by that name in 1940. It may come as a surprise to learn of an elementary textbook using many physical principles was published in 1935 by Howard J. Lucas of the California Institute of Technology. A comparison will be made of the subject matter of the Lucas book with two highly respected texts of about the same period, written by Paul Karrer and Louis and Mary Fieser. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Arachidonic acid (AA) stimulation of adhesion of human metastatic breast carcinoma cells to collagen type IV depends on the protein kinase C (PKC) pathway(s) and is associated with the translocation of PKCµ from the cytoplasm to the membrane. In the present study, we have further explored the role of PKCµ in AA-stimulated adhesion. PKCµ activation site serines 738/742 and autophosphorylation site serine 910 are rapidly phosphorylated, and in vitro PKCµ kinase activity is enhanced in response to AA treatment. Inhibition of PKCµ activation blocks AA-stimulated adhesion. A phosphorylated, truncated species of PKCµ was detected in AA-treated cells. This 77-kDa protein contains the kinase domain but lacks a significant portion of the regulatory domains. Inhibition of calpain protease activity blocks generation of the truncated protein, promotes accumulation of the activated, full-length protein in the membrane, and blocks the AA-mediated increase in adhesion, p38 MAPK activity is also required for AA-stimulated adhesion. Activation of PKCµ and p38 are independent events. However, inhibition of p38 activity reduces calpain-mediated proteolysis of PKCµ and in vivo calpain activity, suggesting a role for p38 in regulation of calpain activity and a point for cross-talk between the PKC and MAPK pathways. These results support the hypothesis that AA stimulates activation of PKCµ, which is cleaved by calpain at the cell membrane. The resulting truncated kinase, as well as the full-length kinase, may be required for increased cell adhesion to collagen type IV. Additionally, these studies present the first evidence for calpain cleavage of a non-structural protein leading to the promotion of tumor cell adhesion. [ABSTRACT FROM AUTHOR]

Examines the equilibrium constants and kinetics for reactions of alpha-phenyl-substituted cyclopropylcarbinyl radicals. Use of laser-flash photolysis in determining Arrhenius functions for cyclizations; Temperature range for the kinetics of the cyclizations; Calculation of ring-opening reactions from temperature-dependent functions.

Presents information pertaining to the use of the ab initio molecular orbital calculations at the MP2/6-311+G**//HF/6-31G* and MP2/6-311+G**//HF/6-31+G* levels, in ascertaining the optimized structures and relative energies regarding the conformers associated with succinic acid and its monoanion in the gas phase. Information on the lowest energy structure for the monoanion; Computing of the diacid and monoanion; Indication of results.

Provides information on a study examining thiourea derivatives as carrier groups in Pt(II) antitumor compounds in search for alternative ligand systems. Methodology used to conduct the study; Results of the study; Discussion on the results.

The first results of the effects of solvents on the directly bonded 1J(13C,H) NMR coupling constant in methane are reported. This information was sought to answer the question of whether the gas phase values for this NMR coupling should be used as anchor points in correlations of organic and inorganic molecular properties with NMR parameters obtained in solution. Reported are accurate values of methane's 1H solvents chemical shifts along with the first data on methane's 13C–1H isotope solvent shifts. Three methane NMR parameters, 1J(13C,H) , 1H chemical shift and 13C–1H isotope shift, have been measured in a set of solvents and D 2 O at ambient pressure and 21 °C. Although the magnitude of the chemical shifts changes are significant, changes of the other two parameters are small. These results bear on the selection of reference molecules for correlations between molecular structure and NMR. After considering the properties of the various solvents, where known, no significant correlations could be found. The values of the 13C–1H isotope shift reported here agree with current theory. [ABSTRACT FROM AUTHOR]

The appearance of the authoritative and comprehensive book, High-Resolution Nuclear Resonance Spectroscopy, by John A. Pople, William G. Schneider, and Harold J. Bernstein in 1959 came at just the right time for chemists and other scientists to develop a clear vision of the wide breadth of applications of this critical emerging field and, in addition, to have the opportunity to learn the underlying basic theory in substantial detail. [ABSTRACT FROM AUTHOR]

Purpose A novel strategy for management of acute pain associated with sickle cell disease (SCD), referred to as the oral tier approach, is described. Summary SCD is an inherited blood disorder characterized by episodic acute pain known as vaso-occlusive crisis (VOC), which is the most common reason for emergency department visits and hospital admissions in patients with SCD; these patients are often treated with parenteral opioids on admission and then transitioned to oral opioids prior to discharge. In this report, experience with use of the oral tier approach in 3 patients with SCD hospitalized for management of VOC is reported. As per usual practice, acute pain was initially managed with parenteral opioids via patient-controlled analgesia (PCA). Once pain control was established, an oral tier was added. The oral tier consisted of 3 orders. The first order was for an oral opioid, to be administered every 3 hours on a scheduled basis; however, the patient could refuse 1 or more of these scheduled doses. Two additional orders specified that the patients could receive additional oral opioids in incremental doses for moderate (grade 4–7) or severe (grade 8–10) pain if appropriate. To facilitate transition to an oral regimen with which the patients might be discharged, they were encouraged to use oral opioids in preference to parenteral opioids. Opioid usage and average daily pain scores for the 3 patients are reported. Conclusion Healthcare providers can use the oral tier approach to facilitate rapid inpatient conversion from i.v. PCA to oral opioids while providing adequate pain control in patients with SCD who develop VOC. [ABSTRACT FROM AUTHOR]

Editorial. Comments on the variety of methods, concerns and clinical issues related to cost-effectiveness analyses of treatment strategies for prostate cancer. Potential bias to the analyses of pharmaceutical agents; Different perceptions towards the optimal form of therapy for lowering testosterone levels; Factors that contribute to patients' preference.

Chronic red blood cell transfusions reduce acute care utilization for sickle cell disease (SCD) pain. However, little is known about whether chronic transfusions treat or prevent the development of non-crisis pain. We investigated patient-report of pain in adults with SCD receiving chronic exchange transfusions (CET) compared to adults not on CET with similar disease characteristics. Eleven participants receiving chronic exchange transfusion (CET) for at least one year were compared to 33 participants not receiving CET. Participants completed validated patient-reported outcomes regarding pain impact and quality of life at regularly scheduled visits or before CET. One year of health care utilization and opioid prescriptions were examined. After 1:1 propensity matching was performed for age, genotype, WBC and neutrophil counts, patients on CET had lower Pain Impact scores (-5.1, p = 0.03) and higher Neuropathic (7.4, p < 0.001) and Nociceptive Pain Quality (3.7, p < 0.001) scores, all indicating worse pain. However, CET was associated with a reduction in annual all cause admissions (-3.1, p < 0.001), length of stay (-2.1 days, p < 0.001) and ED visits (-2.7, p < 0.001). CET was not associated with differences in opioids dispensed. After adjusting for disease characteristics, CET was associated with worse pain impact and neuropathic and nociceptive pain quality, lower health care utilization and with similar levels of opioids dispensed. This data suggest that CET may reduce hospitalizations for acute pain but may not adequately treat nociceptive or neuropathic pain in SCD. [ABSTRACT FROM AUTHOR]

The conformational populations of cis-1,3-cyclopentanedicarboxylic acid (1) and its mono- and dianion were established in DMSO solution by comparing the vicinal proton--proton coupling constants (³JHH) obtained in solution to their theoretical counterparts. Geometries used for ³JHH theoretical estimation (using Karplus-type equations) were obtained from optimized structures at the B3LYP/6-31G(2d,2p) level. The diacid (1) adopted many conformations, whereas the ionized species (1A mono- and 1B dianion) assumed single conformations. A downfield chemical shift of 19.45 ppm (ΔδH = 7.43 ppm) observed at -60 °C was indicative of intramolecular hydrogen bonding in 1A, which was later corroborated by determining the ratio of the first (K1) to the second (K2) ionization constants. K1/K2 in DMSO (1.3 x 107) was significantly larger than the value in water (2 x 10). In addition, K1/KE = 200 (where KE is the acidity constant of the monomethylester of 1) was greater than the intramolecular hydrogen bonding threshold value of 2. The calculated intramolecular hydrogen bond strength of 1A was ~3.1 kcal mol-1, which is ~2.7 kcal mol-1 more stable than the values for cis-1,3-cyclohexanedicarboxylic acid (2A). Thus, the relative energies of intramolecular hydrogen bonding in the monoanions 1A and 2A suggests that 1,3-diaxial conformers are more favored for cyclopentane than for cyclohexane rings. [ABSTRACT FROM AUTHOR]

Octopus cyanea is taken as an unregulated, recreationally fished species from the intertidal reefs of Ningaloo, Western Australia. Yet despite its exploitation and importance in many artisanal fisheries throughout the world, little is known about its life history, ecology and vulnerability. We used stylet increment analysis to age a wild O. cyanea population for the first time and gonad histology to examine their reproductive characteristics. O. cyanea conforms to many cephalopod life history generalisations having rapid, non- asymptotic growth, a short life-span and high levels of mortality. Males were found to mature at much younger ages and sizes than females with reproductive activity concentrated in the spring and summer months. The female dominated sex- ratios in association with female brooding behaviours also suggest that larger conspicuous females may be more prone to capture and suggests that this intertidal octopus population has the potential to be negatively impacted in an unregulated fishery. Size at age and maturity comparisons between our temperate bordering population and lower latitude Tanzanian and Hawaiian populations indicated stark differences in growth rates that correlate with water temperatures. The variability in life history traits between global populations suggests that management of O. cyanea populations should be tailored to each unique set of life history characteristics and that stylet increment analysis may provide the integrity needed to accurately assess this. [ABSTRACT FROM AUTHOR]

The rotational freedom of the carbon-carbon single bonds of 1,2-disubstituted ethanes affords the possibility of these compounds existing as a rapidly interconverting mixture of conformers in solution. The conformational preferences of one such compound, 3-(trimethylsilyl)propionic acid, and its anion were studied in water, dimethyl sulfoxide, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, tetrahydrofuran, and toluene with ¹H NMR spectroscopy. The conformational preferences were determined from the vicinal proton-proton coupling constants between the hydrogen nuclei of the CH2CH2 group with the aid of the Altona equations to derive the equilibrium anti and gauche percentages of rotamers from the averaged NMR-time scale couplings. Conformational analyses of 4,4-dimethylpentanoic acid and its anion as well as 2-(trimethylsilyl)ethanesulfonate anion were also conducted to compare the relative structural influences on the conformational preferences of silicon and carbon. [ABSTRACT FROM AUTHOR]

Abstract: During hematogenous cancer metastasis, tumor cells separate from a primary mass, enter the bloodstream, disperse throughout the body, migrate across vessel walls, and generate distant colonies. The later steps of metastasis superficially resemble leukocyte extravasation, a process initiated by selectin-mediated cell tethering to the blood vessel wall followed by integrin-mediated arrest and transendothelial migration. Some cancer cells express P-selectin ligands and attach to immobilized P-selectin, suggesting that these cells can arrest in blood vessels using sequential selectin- and integrin-mediated adhesion, as do leukocytes. We hypothesize that selectin binding may regulate subsequent integrin-mediated steps in metastasis. Using a model system of cultured Colo 320 human colon adenocarcinoma cells incubated with soluble P-selectin-IgG chimeric protein, we have found that P-selectin can stimulate activation of the α5β1 integrin resulting in a specific increase of adhesion and spreading of these cells on fibronectin substrates. P-selectin binding also induced activation of p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase (PI3-K). PI3-K inhibitors blocked P-selectin-mediated integrin activation, cell attachment, and cell spreading. Inhibition of p38 MAPK activation blocked cell spreading, but not cell attachment. P-selectin binding also resulted in formation of a signaling complex containing PI3-K and p38 MAPK. These results suggest that P-selectin binding to tumor cells can activate α5β1 integrin via PI3-K and p38 MAPK signaling pathways leading to increased cell adhesion. We propose that P-selectin ligands are important tumor cell signaling molecules that modulate integrin-mediated cell adhesion in the metastatic process. [Copyright &y& Elsevier]

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation. [ABSTRACT FROM AUTHOR]

• Cannabinoid profiles by mass spectrometry identify dronabinol vs cannabis users. • This mass spectrometry-based method measures 11 cannabinoids in urine. • Urine cannabinoids were evaluated in control, cannabis and dronabinol users. • Cannabigerol and cannabidiol had the greatest sensitivity in detecting cannabis use. Dronabinol is used to treat a variety of conditions, including loss of appetite in people with AIDS and severe nausea and vomiting caused by cancer chemotherapy. Its therapeutic potential for pain management is now being explored in specific populations. Monitoring dronabinol compliance is challenging because its active ingredient, Δ-9-tetrahydrocannabinol (THC), is also present in cannabis. We developed a rapid LC-MS/MS assay with minimal specimen preparation to quantitate 11 cannabinoids in urine. Using this assay coupled with urine samples from normal controls, cannabis, and dronabinol users, we show the ability to differentiate cannabis from dronabinol use. Residual clinical urine samples from 55 cannabinoid positive subjects and 31 negative controls, as well as prospective samples from 5 patients receiving dronabinol therapy were obtained for analysis. In the dronabinol group, only the THC metabolites 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH) and 11-hydroxy-Δ-9-tetrahydrocannabinol (THC-OH) were detected. Minor cannabinoids were detected in 91% of cannabis group samples and their detection was more frequent in samples with increased THC metabolite concentrations. Of minor cannabinoids evaluated, cannabigerol (CBG) and cannabidiol (CBD) had the greatest sensitivity in detecting cannabis use. This method has a high sensitivity for the detection of cannabis use with implications for evaluating dronabinol compliance. [ABSTRACT FROM AUTHOR]

In 2011 Yale New Haven Hospital, in response to high utilization of acute care services and widespread patient and health care personnel dissatisfaction, set out to improve its care of adults living with sickle cell disease. Re-organization components included recruitment of additional personnel; re-locating inpatients to a single nursing unit; reducing the number of involved providers; personalized care plans for pain management; setting limits upon access to parenteral opioids; and an emphasis upon clinic visits focused upon home management of pain as well as specialty and primary care. Outcomes included dramatic reductions in inpatient days (79%), emergency department visits (63%), and hospitalizations (53%); an increase in outpatient visits (31%); and a decrease in costs (49%). Providers and nurses viewed the re-organization and outcomes positively. Most patients reported improvements in pain control and life style; many patients thought the re-organization process was unfair. Their primary complaint was a lack of shared decision-making. We attribute the contrast in these perspectives to the inherent difficulties of managing recurrent acute and chronic pain with opioids, especially within the context of the imbalance in wellness, power, and privilege between persons living with sickle cell disease, predominantly persons of color and poor socio-economic status, and health care organizations and their personnel. [ABSTRACT FROM AUTHOR]

Background: Despite the clinical significance of red blood cell (RBC) alloantibodies, there are currently no laboratory tests available to predict which patients may be at risk of antibody formation after transfusion exposure. Given their phagocytic and inflammatory functions, we hypothesized that differences in circulating monocytes may play a role in alloimmunization.Study Design and Methods: Forty-two adults with sickle cell disease (SCD) were recruited, with data extracted from the electronic medical record and peripheral blood analyzed by flow cytometry for total monocytes, monocyte subsets (CD14 high/CD16 low+ classical monocytes, CD14 high/CD16 high+ intermediate monocytes, and CD14 intermediate/CD16 high+ non-classical/inflammatory monocytes), and FcγR1 (CD64) expression. Thirteen "non-responder" patients (non-alloimmunized patients with documented RBC transfusion at the study institution) were compared to 20 alloimmunized "responder" patients, who had a total of 44 RBC alloantibodies identified.Results: There were no significant differences in the percentages of total monocytes, monocyte subsets, or measured cytokines between non-responders and responders. However, non-responders had higher CD64 expression on classical monocytes (MFI mean 3424 ± standard deviation 1141) compared to responders (MFI mean 2285 ± 1501), p = 0.029, and on intermediate monocytes (MFI mean 3720 ± 1191) compared to responders (MFI mean 2497 ± 1640), p = 0.033.Conclusions: Monocytes and the inflammatory milieu increasingly are being appreciated to play a role in some complications of SCD. The differences in FcγR1 expression on monocyte subsets noted between responders and non-responders, which cannot be directly explained by the serum cytokines evaluated, warrant further investigation. [ABSTRACT FROM AUTHOR]

The DNA methyltransferase, Dnmt3a, is dynamically regulated throughout mammalian B cell development and upon activation by antigenic stimulation. Dnmt3a inactivation in hematopoietic stem cells has been shown to drive B cell-related malignancies, including chronic lymphocytic leukemia, and associates with specific DNA methylation patterns in transformed cells. However, while it is clear that inactivation of Dnmt3a in hematopoietic stem cells has profound functional effects, the consequences of Dnmt3a inactivation in cells of the B lineage are unclear. To assess whether loss of Dnmt3a at the earliest stages of B cell development lead to DNA methylation defects that might impair function, we selectively inactivated Dnmt3a early in mouse B cell development and then utilized whole genome bisulfite sequencing to generate base-resolution profiles of Dnmt3a+/+ and Dnmt3a2/2 naïve splenic B cells. Overall, we find that global methylation patterns are largely consistent between Dnmt3a+/+ and Dnmt3a2/2 naïve B cells, indicating a minimal functional effect of DNMT3A in mature B cells. However, loss of Dnmt3a induced 449 focal DNA methylation changes, dominated by loss-of-methylation events. Regions found to be hypomethylated in Dnmt3a2/2 naïve splenic B cells were enriched in gene bodies of transcripts expressed in B cells, a fraction of which are implicated in B cell-related disease. Overall, the results from this study suggest that factors other than Dnmt3a are the major drivers for methylome maintenance in B cell development. [ABSTRACT FROM AUTHOR]

A phase 1 study was conducted to determine the dose-limiting toxicities and maximum-tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory CLL/SLL or B- or T-cell lymphoma. Eighteen treated patients were evaluable for response. The MTD was 1.3 mg/m2bortezomib and 10 mg/m2romidepsin; median treatment duration was 3 cycles at this dose. The dose-limiting toxicities were grade 3 fatigue, vomiting, and chills. Two patients had partial responses, one lasting >2 years, 8 had stable disease, and 8 had progressive disease. The median duration of stable disease was 3.5 cycles. Correlative studies examining expression of NF-кB, XIAP, Bcl-xL, and Bim yielded variable results. The safety profile was consistent with that reported for single-agent bortezomib and romidepsin. This regimen has modest activity in heavily pretreated patients with relapsed/refractory CLL or B- or T-cell lymphoma. NCT00963274. [ABSTRACT FROM AUTHOR]

DE-71, a commercial mixture of polybrominated diphenyl ethers widely used in flame retardants, is a pervasive environmental contaminant due to its continuing release from waste material and its long half-life in humans. Although the genotoxic potential of DE-71 appears to be low based on bacterial mutagenicity, it remains a public health concern due to its reported involvement in tumor development. Molecular mechanisms by which DE-71 influences tumor incidence or progression remain understudied. We used liver carcinoma tissue from mice exposed to DE-71 to test the hypothesis that epigenetic alterations consistent with tumor development, specifically DNA methylation, result from long-term DE-71 exposure. We profiled DNA methylation status using the methylated-CpG island recovery assay coupled with microarray analysis of hepatocellular carcinoma DNA from animals exposed to DE-71. DE-71 exposure had little impact on global DNA methylation. However, we detected gene body–specific hypomethylation within the Tbx3 locus, a transcription factor important in liver tumorigenesis and in embryonic and cancer stem cell proliferation. This nonpromoter hypomethylation was accompanied by upregulation of Tbx3 mRNA and protein and by alterations in downstream cell cycle–associated marker expression. Thus, exposure to DE-71 may facilitate tumor development by inducing epigenetic programs that favor expansion of progenitor cell populations. [ABSTRACT FROM AUTHOR]

Background. Patients with SCD now usually live well into adulthood. Whereas transitions into adulthood are now often studied, little is published about aging beyond the transition period. We therefore studied age-associated SCD differences in utilization, pain, and psychosocial variables. Methods. Subjects were 232 adults in the Pain in Sickle Cell Epidemiology Study (PiSCES). Data included demographics, comorbidity, and psychosocial measures. SCD-related pain and health care utilization were recorded in diaries. We compared 3 age groups: 16–25 (transition), 26–36 (younger adults), and 37–64 (older adults) years. Results. Compared to the 2 adult groups, the transition group reported fewer physical challenges via comorbidities, somatic complaints, and pain frequency, though pain intensity did not differ on crisis or noncrisis pain days. The transition group utilized opioids less often, made fewer ambulatory visits, and had better quality of life, but these differences disappeared after adjusting for pain and comorbidities. However, the transition group reported more use of behavioral coping strategies. Conclusion. We found fewer biological challenges, visits, and better quality of life, in transition-aged versus older adults with SCD, but more behavioral coping. Further study is required to determine whether age-appropriate health care, behavioral, or other interventions could improve age-specific life challenges of patients with SCD. [ABSTRACT FROM AUTHOR]

Importance: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain.Objective: To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks.Design, Setting, Participants: Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014.Interventions: Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years.Main Outcomes and Measures: The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels).Results: Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks.Conclusions and Relevance: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option.Trial Registration: clinicaltrials.gov Identifier: NCT00869206. [ABSTRACT FROM AUTHOR]

Thefraction of gaucheconformers of N,N-dimethylsuccinamic acid (1)andits Li+, Na+, K+, Mg2+, Ca2+, and N(Bu)4+salts were estimatedin DMSO and D2O solution by comparing the experimentalvicinal proton–proton couplings determined by 1HNMR spectroscopy with those calculated using the Haasnoot, de Leeuw,and Altona (HLA) equation. In DMSO, the gauchepreferenceswere found to increase with decreasing Ahrens ionic radius of themetal counterion. The same trend was not seen in D2O, wherethe gauchefraction for all of the metallic saltswere estimated to be approximately statistical or less. This highlightsthe importance of metal chelation on the conformation of organic moleculesin polar aprotic media, which has implications for protein folding. [ABSTRACT FROM AUTHOR]

Substituent effects in N-H...O hydrogen bonds were estimated by comparing the acidities of two series of model compounds: N-benzoylanthranilic acids (A) and 4-ben-zoylamidobenzoic acids (B). Intramolecular N--H...O hydrogen bonds were found to be present in the A series of compounds, while B acids were used as control models. The respective pKa values for A and B acids were determined experimentally in DMSO solution using proton NMR spectroscopy. With X = H, the pK, for A and B acids were observed to be 7.6 and 11.6, respectively, a difference of 4.0 units (ΔpKa). However, with X = p-NO2 the ΔpKa, value between A and B acids increased to 4.7 units: the pKa values for A and B acids were determined as 6.7 and 11.4, respectively. The ΔpKa values between A and B acids as a function of the X substiruents were studied in 10 other examples. The effects of X substituents in A acids could be predicted on the basis of the observed linear Hammett correlations, and the sensitivity of each substituent effect was found to be comparable to those observed for the ionization of substituted benzoic acids (p = 1.04 for A acids, and p = 1.00 for benzoic adds) [ABSTRACT FROM AUTHOR]

Arachidonic acid stimulates cell adhesion by activating α2β1 integrins in a process that depends on protein kinases, including p38 mitogen activated protein kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules that contribute to the spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. Arachidonic acid-treated cells showed increased attachment and spreading on collagen type IV, as measured by electric cell-substrate impedance sensing. Fatty acid-treated cells displayed short cortical actin filaments associated with an increased number of β1 integrin-containing pseudopodia, whereas untreated cells displayed elongated stress fibers and fewer clusters of β1 integrins. Confocal microscopy of arachidonic acid-treated cells showed that vinculin and phospho-p38 both appeared enriched in pseudopodia and at the tips of actin filaments, and fluorescence ratio imaging indicated the increase was specific for the phospho-(active) form of p38. Immunoprecipitates of phospho-p38 from extracts of arachidonic acid-treated cells contained vinculin, and GST-vinculin fusion proteins carrying the central region of vinculin bound phospho-p38, whereas fusion proteins expressing the terminal portions of vinculin did not. These data suggest that phospho-p38 associates with particular domains on critical focal adhesion proteins that are involved in tumor cell adhesion and spreading, and that this association can be regulated by factors in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Arachidonic acid stimulates cell adhesion by activating α2β1 integrins in a process that depends on protein kinases, including p38 mitogen activated protein kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules that contribute to the spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. Arachidonic acid-treated cells showed increased attachment and spreading on collagen type IV, as measured by electric cell-substrate impedance sensing. Fatty acid-treated cells displayed short cortical actin filaments associated with an increased number of β1 integrin-containing pseudopodia, whereas untreated cells displayed elongated stress fibers and fewer clusters of β1 integrins. Confocal microscopy of arachidonic acid-treated cells showed that vinculin and phospho-p38 both appeared enriched in pseudopodia and at the tips of actin filaments, and fluorescence ratio imaging indicated the increase was specific for the phospho-(active) form of p38. Immunoprecipitates of phospho-p38 from extracts of arachidonic acid-treated cells contained vinculin, and GST-vinculin fusion proteins carrying the central region of vinculin bound phospho-p38, whereas fusion proteins expressing the terminal portions of vinculin did not. These data suggest that phospho-p38 associates with particular domains on critical focal adhesion proteins that are involved in tumor cell adhesion and spreading, and that this association can be regulated by factors in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

A predominantly trans-1,2-disubstituted ethane system - N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide - is of particular interest for conformational analysis, because it contains both an organic and a highly polar substituent, making it soluble and thus applicable to study in a large variety of solvents. The fraction of the trans conformer of this molecule in a wide range of protic and aprotic solvents was determined by the nuclear magnetic resonance proton couplings to be approximately 90%, in contrast to the previously assumed 100%. The consistently strong preference of the trans conformation should establish N,N,N-trimethyl-(3,3-dimethylbutyl)ammonium iodide as a possibly useful ' trans-standard' in conformational analysis, much more so than 1,2-ditert-butylethane, which has a poor solubility in many solvents. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The conformational preferences of N,N-dimethylsuccinamic acid and its Li+salt were estimated by comparing the respective experimental NMR vicinal proton–proton coupling constants to semiempirical coupling constants for each staggered conformer as derived by the Haasnoot–De Leeuw–Altona method. The strong gauchepreferences for the Li+salts clearly depended more on the solvents’ hydrogen-bond donating strength (α) than on their hydrogen-bond accepting (β) counterpart, where α and β are the corresponding Kamlet–Taft parameters. [ABSTRACT FROM AUTHOR]

The populations of diaxial (aa) and diequatorial (ee) conformers of trans-1,2- and cis-1,3-cyclohexanedicarboxylic acids (CDCAs; 1 and 2, respectively) and their salts were determined in water and dimethyl sulfoxide (DMSO) solutions from vicinal proton-proton NMR J couplings (3JHH). Optimized geometries and free energies for these compounds were obtained at the M06-2X/cc-pVTZ(-f)++ level. Although carboxylic acid groups in cyclohexane rings are generally believed to be far more stable (2 kcal/mol) in equatorial than axial positions, this investigation demonstrated that an aa conformation (normally assumed to be completely insignificant for these compounds) can be favored depending on the medium and ionization state: strong ee preferences (>90%) were observed in water and DMSO for both diacids and their salts, except for the dianion of 1 in DMSO, which was found to be substantially aa (57%). The possibility of intramolecular hydrogen bonding (H-bonding) was also investigated; the ratios of the ionization constants (K1/K2) indicated an absence of intramolecular H-bonding because K1/K2 104 (a standard criterion for non-H-bonding in dicarboxylic acids) for both 1 and 2 in water and also for 2 in DMSO. For 1, K1/K2 increased drastically in DMSO (K1/K2 = 4 × 106), where 3JHH and the ratio K1/KE = 10, KE being the acidity constant of the monomethyl ester of 1, indicated the formation of an intramolecular H-bond for the monoanion in this solvent. An explanation for the observation of compact dianions in solution in terms of the generalized Born equation is also provided. [ABSTRACT FROM AUTHOR]

Abstract: Arachidonic acid (AA) stimulates cell adhesion through a p38 mitogen activated protein kinase-mediated RhoA signaling pathway. Here we report that a proteomic screen following AA-treatment identified nucleolin, a multifunctional nucleolar protein, in a complex with the GTPase, RhoA, that also included the Rho kinase, ROCK. AA-stimulated cell adhesion was inhibited by expression of nucleolin-targeted shRNA and formation of the multiprotein complex was blocked by expression of dominant-negative RhoA. AA-treatment also induced ROCK-dependent serine phosphorylation of nucleolin and translocation of nucleolin from the nucleus to the cytoplasm, where it appeared to co-localize with RhoA. These data suggest the existence of a new signaling pathway through which the location and post-translational state of nucleolin are modulated. Structured summary: Nucleolin physically interacts with RHOA by anti bait coimmunoprecipitation (View Interaction 1, 2) Nucleolin and RHOA colocalize by fluorescence microscopy (View interaction) ROCK physically interacts with RHOA by pull down (View interaction) ROCK physically interacts with HSP 90-beta , HSP70 , Nucleolin , Nebulin and RHOA by pull down (View interaction) Nucleolin physically interacts with ROCK2 by anti bait coimmunoprecipitation (View interaction) ROCK physically interacts with Nucleolin and RHOA by pull down (View interaction) [Copyright &y& Elsevier]

Arachidonic acid, a dietary cis-polyunsaturated fatty acid, stimulates adhesion and migration of human cancer cells on the extracellular matrix by activation of intracellular signaling pathways. Polyubiquitin chains bearing linkages through different lysine residues convey distinct structural and functional information that is important for signal transduction. We investigated whether ubiquitination was required for arachidonic acid-induced cellular adhesion and migration of MDA-MB-435 cells on collagen type IV. An E1 (ubiquitin-activating enzyme) inhibitor, PYR-431, completely abrogated arachidonic acid-stimulated adhesion. Additionally, expression of a lysine null mutant ubiquitin prevented activation of cellular adhesion. Cells expressing ubiquitin in which lysine 63 (K63) was mutated to arginine (K63R) were unable to adhere to collagen upon exposure to arachidonic acid. When K63 was the only lysine present, the cells retained the ability to adhere, indicating that K63-linked ubiquitin is both necessary and sufficient. Moreover, K63-linked ubiquitin was required for the induction of cell migration by arachidonic acid. The ubiquitin mutants and PYR-431 did not prevent arachidonic acid-induced phosphorylation of TGF-β activated kinase-1 (TAK1) and p38 MAPK, suggesting K63-linked ubiquitination occurs downstream of MAPK. These novel findings are the first to demonstrate a role for K63-linked ubiquitination in promoting cell adhesion and migration. L'acide arachidonique, un acide gras cis-polyinsaturé de la diète, stimule d'adhésion et la migration des cellules cancéreuses d'origine humaine sur la matrice extracellulaire en activant des voies de signalisation intracellulaire. Les chaines de poly-ubiquitine liées via différents résidus lysine transmettent des informations structurales et fonctionnelles distinctes importantes pour la transduction de signaux. Nous avons examiné si l'induction par l'acide arachidonique de l'adhésion et de la migration des cellules MDA-MB-435 au collagène de type IV nécessitait l'ubiquitination. Un inhibiteur de l'enzyme d'activation de l'ubiquitine E1, le PYR-431, a complètement aboli l'adhésion stimulée par l'acide arachidonique. De plus, l'expression d'une ubiquitine mutante dépourvue de résidus lysine empêchait l'activation de l'adhésion cellulaire. Les cellules exprimant une ubiquitine dans laquelle la lysine 63 (K63) était mutée en arginine (K63R) ne pouvaient adhérer au collagène à la suite d'une exposition à l'acide arachidonique. Lorsque la K63 était la seule lysine présente, les cellules conservaient leur capacité d'adhésion, indiquant que seule l'ubiquitine liée par la K63 est nécessaire et suffisante. De plus, l'ubiquitine liée par la K63 était requise à l'induction de la migration cellulaire par l'acide arachidonique. L'ubiquitine mutée et le PYR-431 n'empêchaient pas la phosphorylation induite par l'acide arachidonique des kinases TAK1 (TGF-β activated kinase 1) et p38 MAPK, suggérant que l'ubiquitination via la K63 se produit en aval de MAPK. Ces résultats originaux sont les premiers à démontrer le rôle de l'ubiquitination via la K63 dans la promotion de l'adhésion et de la migration cellulaires. [ABSTRACT FROM AUTHOR]

Abstract: Treatment options for sickle cell disease (SCD) pain could be tailored to pain locations. But few epidemiologic descriptions of SCD pain location exist; these are based on few subjects over short time periods. We examined whether SCD pain locations vary by disease genotype, gender, age, frequency of pain, depression, pain crisis or healthcare utilization. We enrolled 308 adults with SCD in 2002–2004. Subjects kept daily pain diaries for up to 6months, including a body chart. Mixed model and generalized estimating equations were employed for analyses. Two hundred and sixty subjects completed at least one body chart. An average of 3.3/16 sites (25%) were painful. The number of pain sites varied by age, depression, frequent pain days, crisis and unplanned hospital/ED utilization. Lower back, knee/shin and hip, hurt on average more than a third of pain days, while jaw and pelvis hurt on fewer than 10% of days. Odds of a crisis were increased substantially when pain was in the arm, shoulder, upper back, sternum, clavicle, chest or pelvis (OR>1.5) while the odds of unplanned utilization were substantially increased for the sternum, clavicle and chest (OR>2.0). Pain in SCD varies considerably both within and between subjects, although it occurs most commonly in the lower back and lower extremities. The number and location of pain sites vary significantly by age, frequent pain, crisis and utilization. Identification and understanding of combinations of pain location and intensity may help to understand the etiology of SCD and improve SCD management. [Copyright &y& Elsevier]

Rho GTPases are critical components of cellular signal transduction pathways. Both hyperactivity and overexpression of these proteins have been observed in human cancers and have been implicated as important factors in metastasis. We previously showed that dietary n-6 fatty acids increase cancer cell adhesion to extracellular matrix proteins, such as type IV collagen. Here we report that in MDA-MB-435 human melanoma cells, arachidonic acid activates RhoA, and inhibition of RhoA signaling with either C3 exoenzyme or dominant negative Rho blocked arachidonic acid-induced cell adhesion. Inhibition of the Rho kinase (ROCK) with either small molecule inhibitors or ROCK Il-specific small interfering RNA (siRNA) blocked the fatty acid-induced adhesion. However, unlike other systems, inhibition of ROCK did not block the activation of p38 mitogenactivated protein kinase (MAPK); instead, Rho activation depended on p38 MAPK activity and the presence of heat shock protein 27 (HSP27), which is phosphorylated downstream of p38 after arachidonic acid treatment. HSP27 associated with p115-RhoGEF in fatty acid-treated cells, and this association was blocked when p38 was inhibited. Furthermore, siRNA knockdown of HSP27 blocked the fatty acid-stimulated Rho activity. Expression of dominant negative p115-RhoGEF or p115-RhoGEF-specific siRNA inhibited both RhoA activation and adhesion on type IV collagen, whereas a constitutively active p115-RhoGEF restored the arachidonic acid stimulation in cells in which the p38 MAPK had been inhibited. These data suggest that n-6 dietary fatty acids stimulate a set of interactions that regulates cell adhesion through RhoA and ROCK II via a p38 MAPK-dependent association of HSP27 and p115-RhoGEF. [ABSTRACT FROM AUTHOR]

Pulmonary epithelial injury is central to the pathogenesis of many lung diseases, such as asthma, pulmonary fibrosis, and the acute respiratory distress syndrome. Regulated epithelial repair is crucial for lung homeostasis and prevents scar formation and inflammation that accompany dysregulated healing. The extracellular matrix (ECM) plays an important role in epithelial repair after injury. Vitronectin is a major ECM component that promotes epithelial repair. However, the factors that modify cell-vitronectin interactions after injury and help promote epithelial repair are not well studied. Inter-α-trypsin inhibitor (Ia1) is an abundant serum protein. lal heavy chains contain von Willebrand A domains that can bind the arginine-glycine-aspartate domain of vitronectin. We therefore hypothesized that la1 can bind vitronectin and promote vitronectin-induced epithelial repair after injury. We show that lal binds vitronectin at the arginine-glycine-aspartate site, thereby promoting epithelial adhesion and migration in vitro. Furthermore, we show that Ia1 deficient mice have a dysregulated response to epithelial injury in vivo, consisting of decreased proliferation and epithelial metaplasia. We conclude that Ia1 interacts not only with hyaluronan, as previously reported, but also other ECM components like vitronectin and is an important regulator of cellular repair after injury. [ABSTRACT FROM AUTHOR]

The conformational equilibrium of 3-(dimethylazinoyl)propanoic acid (DMAPA, azinoyl = N+(O-) has a weak pH-dependence in D2O, with a slight preference for trans in alkaline solutions. The acid ionization constants of the protonated amine oxide and carboxylic functional groups as determined by NMR spectroscopy were 7.9 × 10-4and 6.3 × 10-6, respectively. The corresponding value of K1/K2 of 1.3 × 102 is not deemed large enough to provide experimental NMR evidence for a significant degree of intramolecular hydrogen bonding in D2O. Conformational preferences of DMAPA are mostly close to statistical (gauche/trans = 2/1) in other protic solvents, e.g., alcohols. However, the un-ionized form of DMAPA appears to be strongly intramolecularly hydrogen-bonded and gauche in aprotic solvents. [ABSTRACT FROM AUTHOR]

Conformational preferences of glutaric, 3-hydroxyglutaric and 3-methylglutaric acid, and their mono- and dianions have been investigated with the aid of NMR spectroscopy. In contrast to succinic acid, glutaric acid displays essentially statistical conformational equilibria in polar and non-polar solutions of high and low hydrogen-bonding ability with no clear evidence for intramolecular hydrogen-bonding interactions. The acid ionization constant ratios, K1/K2, in D2O and DMSO of glutaric, 3-hydroxyglutaric, and 3-methylglutaric acids also indicate that intramolecular interactions are much less important than, or indeed insignificant, for shorter-chain acids. FTIR studies on 3-methylglutaric acid indicate some preference for either association with solvent or dimerization, depending on the solvent, rather than intramolecular hydrogen bonding. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Researchers of sickle cell disease have traditionally used health care utilization as a proxy for pain and underlying vaso-occlusion. However, utilization may not completely reflect the amount of self-reported pain or acute, painful episodes (crises). Objective: To examine the prevalence of self-reported pain and the relationship among pain, crises, and utilization in adults with sickle cell disease. Design: Prospective cohort study. Setting: Academic and community practices in Virginia. Patients: 232 patients age 16 years or older with sickle cell disease. Measurements: Patients completed a daily diary for up to 6 months, recording their maximum pain (on a scale of 0 to 9); whether they were in a crisis (crisis day); and whether they used hospital, emergency, or unscheduled ambulatory care for pain on the previous day (utilization day). Summary measures included both simple proportions and adjusted probabilities (for repeated measures within patients) of pain days, crisis days, and utilization days, as well as mean pain intensity. Results: Pain (with or without crisis or utilization of care) was reported on 54.5% of 31 017 analyzed patient-days (adjusted probability, 56%). Crises without utilization were reported on 12.7% of days and utilization on only 3.5% (unadjusted). In total, 29.3% of patients reported pain in greater than 95% of diary days, whereas only 14.2% reported pain in 5% or fewer diary days (adjusted). The frequency of home opiate use varied and independently predicted pain, crises, and utilization. Mean pain intensity on crisis days, noncrisis pain days, and total pain days increased as the percentage of pain days increased (P < 0.001). Intensity was significantly higher on utilization days (P < 0.001). However, utilization was not an independent predictor of crisis, after controlling for pain intensity. Limitations: The study was done in a single state. Patients did not always send in their diaries. Conclusion: Pain in adults with sickle cell disease is the rule rather than the exception and is far more prevalent and severe than previous large-scale studies have portrayed. It is mostly managed at home; therefore, its prevalence is probably underestimated by health care providers, resulting in misclassification, distorted communication, and undertreatment. [ABSTRACT FROM AUTHOR]

The reaction of 2,4-dichloro-1,1-difluoro-3-phenyl-2-cyclobutene 1 with excess phenyllithium and subsequent transformations of the products have been reinvestigated. The phenyllithium reaction appears to proceed through the intermediacy of a fluorotriphenylcyclobutadiene 2 to produce a well-characterized dimeric trans-hexaphenyldifluorotricyclooctadiene 3a. Subsequent transformations of 3a gave a pen- taphenyldihydrodifluoropentalene 4, which on acid hydrolysis formed a pentaphenyldihydropentalenone 5. When 3a was photolyzed in benzene, after purification, it afforded 6, an isomer of 5, probably by way of 7, an isomer of 4. Thermolysis of 3a also provided, in low yield, a substance believed to be a pentaphenylfluorophenanthrene 8. Along with isolation of 3a, and probably arising from a different isomer of the 3 family, was a pentaphenyifluorophenanthrene 9, which was suspected of being an isomer of 8. Single-crystal X-ray studies were used to derive structures for 4, 5, 6, and 9. Formation of the unusual and intriguing transformation products has at least been rationalized. [ABSTRACT FROM AUTHOR]

Understanding the factors that determine molecular shape enables scientists to begin to understand and tailor molecular properties and reactivity. Many biomolecules and bioactive compounds contain aliphatic heterocyclic rings whose conformations play a major role in their biological activity. The interplay of a number of factors, both steric and electronic, is examined for 5-hydroxyhexahydropyrimidine (1) and related compounds with use of spectroscopy and molecular modeling. [ABSTRACT FROM AUTHOR]