SWATH-MS identification of CXCL7, LBP, TGFß1 and PDGFRß as novel biomarkers in human systemic mastocytosis.

Mastocytosis is a rare myeloproliferative disease, characterised by accumulation of neoplastic mast cells in one or several organs. It presents as cutaneous or systemic. Patients with advanced systemic mastocytosis have a median survival of 3.5 years. The aetiology of mastocytosis is poorly understood, patients present with a broad spectrum of varying clinical symptoms that lack specificity to point clearly to a definitive diagnosis. Discovery of novel blood borne biomarkers would provide a tractable method for rapid identification of mastocytosis and its sub-types. Moving towards this goal, we carried out a clinical biomarker study on blood from twenty individuals (systemic mastocytosis: n = 12, controls: n = 8), which were subjected to global proteome investigation using the novel technology SWATH-MS. This identified several putative biomarkers for systemic mastocytosis. Orthogonal validation of these putative biomarkers was achieved using ELISAs. Utilising this workflow, we identified and validated CXCL7, LBP, TGFß1 and PDGF receptor-ß as novel biomarkers for systemic mastocytosis. We demonstrate that CXCL7 correlates with neutrophil count offering a new insight into the increased prevalence of anaphylaxis in mastocytosis patients. Additionally, demonstrating the utility of SWATH-MS for the discovery of novel biomarkers in the systemic mastocytosis diagnostic sphere.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).

Dynamic covalent chemistry.

Dynamic covalent chemistry relates to chemical reactions carried out reversibly under conditions of equilibrium control. The reversible nature of the reactions introduces the prospects of "error checking" and "proof-reading" into synthetic processes where dynamic covalent chemistry operates. Since the formation of products occurs under thermodynamic control, product distributions depend only on the relative stabilities of the final products. In kinetically controlled reactions, however, it is the free energy differences between the transition states leading to the products that determines their relative proportions. Supramolecular chemistry has had a huge impact on synthesis at two levels: one is noncovalent synthesis, or strict self-assembly, and the other is supramolecular assistance to molecular synthesis, also referred to as self-assembly followed by covalent modification. Noncovalent synthesis has given us access to finite supermolecules and infinite supramolecular arrays. Supramolecular assistance to covalent synthesis has been exploited in the construction of more-complex systems, such as interlocked molecular compounds (for example, catenanes and rotaxanes) as well as container molecules (molecular capsules). The appealing prospect of also synthesizing these types of compounds with complex molecular architectures using reversible covalent bond forming chemistry has led to the development of dynamic covalent chemistry. Historically, dynamic covalent chemistry has played a central role in the development of conformational analysis by opening up the possibility to be able to equilibrate configurational isomers, sometimes with base (for example, esters) and sometimes with acid (for example, acetals). These stereochemical "balancing acts" revealed another major advantage that dynamic covalent chemistry offers the chemist, which is not so easily accessible in the kinetically controlled regime: the ability to re-adjust the product distribution of a reaction, even once the initial products have been formed, by changing the reaction's environment (for example, concentration, temperature, presence or absence of a template). This highly transparent, yet tremendously subtle, characteristic of dynamic covalent chemistry has led to key discoveries in polymer chemistry. In this review, some recent examples where dynamic covalent chemistry has been demonstrated are shown to emphasise the basic concepts of this area of science.

Simultaneous selection, amplification and isolation of a pseudo-peptide receptor by an immobilised N-methyl ammonium ion template.

Immobilised N-methyl ammonium ions have been used to simultaneously select, amplify and isolate a pseudo-peptide receptor from a dynamic library of hydrazones.

Identification and Isolation of a Receptor for N-Methyl Alkylammonium Salts: Molecular Amplification in a Pseudo-peptide Dynamic Combinatorial Library.

A cyclic pseudo-peptide receptor for acetylcholine has been amplified and isolated from a dynamic combinatorial library by virtue of templated stabilization under thermodynamic control (see scheme, TFA=trifluoroacetic acid). This is a demonstration of significant molecular amplification in dynamic systems to evolve a novel receptor.

Postablative risk of endometrial carcinoma in New Zealand white rabbits given high-dose estrogen.

OBJECTIVE: To follow a population at high risk for endometrial carcinoma after endometrial ablation, to determine if ablation alters the incidence or detection of endometrial pathology. STUDY DESIGN: The animal model included 33 New Zealand white rabbits. Of this cohort, 17 underwent surgical ablation of the endometrium via laparotomy, while 16 served as controls. Vaginal bleeding was assessed with monthly cotton swab examinations as well as daily observation of the subjects. All animals received unopposed estrogen for 18 months prior to necropsy. RESULTS: No animal in either arm of the study demonstrated vaginal bleeding. Two rabbits from the ablation group and three controls showed histologic evidence of atypical endometrial hyperplasia or adenocarcinoma (P > .20). One additional animal from each group had hyperplasia without atypia. CONCLUSION: This animal model suggests that endometrial ablation does not decrease the risk of endometrial carcinoma in patients at high risk of developing endometrial pathology. Detection of hyperplasia or carcinoma in such a population may prove difficult due to the absence of traditional signs of endometrial abnormalities.

Primary peritoneal carcinoma presenting on routine papanicolaou smear.

BACKGROUND: Primary peritoneal carcinoma is an uncommon disease, characterized by peritoneal carcinomatosis without other identifiable primary tumor. It typically presents resembling ovarian cancer, with abdominal pain and distention and in an advanced stage. We report a unique presentation of this disease. CASE: A 76-year-old woman had severe glandular dysplasia on a screening Papanicolaou smear. An ectocervical lesion was biopsied, revealing moderately differentiated adenocarcinoma. Cervical stenosis prevented sampling of the endocervix and endometrium. Colonoscopy and mammography did not reveal malignancy. Total abdominal hysterectomy with bilateral salpingo-oophrectomy was performed. Surgery revealed surface implants on the pelvic organs, with minimal involvement of the ovaries. Histologic examination revealed adenocarcinoma with papillary serous differentiation. Surgical and microscopic findings were consistent with a diagnosis of primary peritoneal carcinoma. CONCLUSION: Primary peritoneal carcinoma usually presents in a manner similar to that of ovarian cancer, but atypical presentations also occur. While a Papanicolaou smear suggestive of carcinoma usually represents a primary cervical malignancy, this case serves as a reminder that other metastatic malignancies should be considered.

Risk factors for antihypertensive medication refill failure by patients under Medicaid managed care.

Antihypertensive medication noncompliance is common and leads to substantial morbidity for patients and increased health care costs for managed-care organizations. A retrospective cohort study using pharmacy prescription profiles to estimate noncompliance was conducted to determine important risk factors for patient noncompliance with antihypertensive therapy for Medicaid enrollees participating in a managed-care plan. The pharmacy and claims data for 1395 patients with uncomplicated hypertension who were enrollees of Tennessee's Medicaid managed-care program were analyzed to determine the frequency of the enrollees' failure to obtain timely antihypertensive medication refills (hereafter referred to as refill failure) and to identify the predictors of refill failure. Overall, refill failure occurred in 33% of 7413 refill opportunities studied, whereas refill failure occurred in 32% of the cases in which medication was dosed once daily and in 35% of the cases in which medication was dosed more than once daily. For patients taking alpha-blockers, there was a significantly lower rate of refill failure (11.0%) than for patients taking angiotensin-converting enzyme inhibitors, direct vasodilators, and thiazide diuretics. Patients taking calcium channel blockers, had a significantly lower rate of refill failure (38.5%) than for patients taking thiazide diuretics (45.5%). Younger age, medication class, multiple-daily dosing regimen, and fewer provider visits were all found to be significant independent predictors of refill failure, whereas gender and regimen complexity were not significant predictors in this population. Health care systems planning pharmacy-based interventions to improve patient compliance with antihypertensive medication for patients in a Medicaid managed-care program can expect to encounter high levels of refill failure and may want to target enrollee subgroups by age, medication class, or dosing regimen for intensive intervention efforts.

Neurophysiological model of tinnitus: dependence of the minimal masking level on treatment outcome.

Validity of the neurophysiological model of tinnitus (Jastreboff, 1990), outlined in this paper, was tested on data from multicenter trial of tinnitus masking (Hazell et al., 1985). Minimal masking level, intensity match of tinnitus, and the threshold of hearing have been evaluated on a total of 382 patients before and after 6 months of treatment with maskers, hearing aids, or combination devices. The data has been divided into categories depending on treatment outcome and type of approach used. Results of analysis revealed that: i) the psychoacoustical description of tinnitus does not possess a predictive value for the outcome of the treatment; ii) minimal masking level changed significantly depending on the treatment outcome, decreasing on average by 5.3 dB in patients reporting improvement, and increasing by 4.9 dB in those whose tinnitus remained the same or worsened; iii) 73.9% of patients reporting improvement had their minimal masking level decreased as compared with 50.5% for patients not showing improvement, which is at the level of random change; iv) the type of device used has no significant impact on the treatment outcome and minimal masking level change; v) intensity match and threshold of hearing did not exhibit any significant changes which can be related to treatment outcome. These results are fully consistent with the neurophysiological interpretation of mechanisms involved in the phenomenon of tinnitus and its alleviation.

Contralateral suppression of transient evoked otoacoustic emissions: intra-individual variability in tinnitus and normal subjects.

Contralateral acoustic stimulation reduces the amplitude of the transient evoked otoacoustic emission (TEOAE) in humans. The mechanism is thought to be mediated, at least in part, through the medial olivocochlear efferent system innervating the outer hair cells. To assess its usefulness as a possible clinical test, TEOAE suppression was measured in each ear of 12 subjects over a 6-week period, and these data are shown in detail for four subjects representing extremes of variability in a tinnitus and a non-tinnitus group. Intra-subject test results (n = 18) exhibited a varying extent of suppression values and the variance of each session, consisting of three tests, was not statistically different from one session to another. There was no dependence on variables such as ear (right or left), session, day of testing or their interaction. There was a significant difference in the variability between the tinnitus and the normal group.

X-ray Damage to CF3CO2-Terminated Organic Monolayers on Si/Au: Principal Effect of Electrons.

The relative importance of x-rays alone and of x-ray-generated primary and secondary electrons in damaging organic materials was explored by use of self-assembled monolayers (SAMs) on multilayer thin-film supports. The substrates were prepared by the deposit of thin films of silicon (0, 50, 100, and 200 angstroms) on thick layers of gold (2000 angstroms). These systems were supported on chromium-primed silicon wafers. Trifluoroacetoxy-terminated SAMs were assembled on these substrates, and the samples were irradiated with common fluxes of monochromatic aluminum K(alpha) x-rays. The fluxes and energy distributions of the electrons generated by interactions of the x-rays with the various substrates, however, differed. The substrates that emitted a lower flux of electrons exhibited a slower loss of fluorine from the SAMs. This observation indicated that the electrons-and not the x-rays themselves-were largely responsible for the damage to the organic monolayer.

Ecological Risk Assessment at The Regional Scale: Ecological Archives A005-001.

Ecological risk assessments are used by policy makers and regulatory agencies for balancing and comparing ecological risks associated with environmental hazards. An approach for regional-scale ecological risk assessment is described and demonstrated by modeling environmental risks associated with elevated ozone in a forested region. The demonstration illustrates (1) how a regional-scale risk assessment might be done, (2) the importance of spatial characteristics in considering regional-scale risk, and (3) the necessity of considering terrestrial and aquatic linkages. Generic problems often encountered when doing regional assessments, the foremost of which is the frequent lack of region-specific information and spatial data, are also highlighted. In the demonstration, two levels of elevated ozone and five different at-risk regional features are considered (forest cover, forest edge, forest interior, landscape pattern, and lake water quality). The mechanism for impacts on these features is ozone-induced stress in coniferous trees, patches of which can then be killed by bark beetle attacks. A stochastic spatial model of land-cover change is developed to evaluate the risks or probabilities of significant changes in the selected ecological features as a consequence of these ozone-triggered beetle attacks. Risk to regional water quality of lakes is evaluated by linking the land-cover output from the spatial stochastic model to an empirical water-quality model that is sensitive to land-cover changes within a lake's watershed. The risk analysis shows that those environmental features that are sensitive to the location of coniferous forest (such as forest edge) are at risk of a significant change due to ozone-induced conifer mortality even though overall coniferous forest cover is only slightly affected. The analysis also suggests a high probability of changes in regional water quality of lakes as a consequence of location-specific forest-cover change.

Quasi-random hypergraphs.

We describe a large equivalence class of properties shared by most hypergraphs, including so-called random hypergraphs. As a result, it follows that many global properties of hypergraphs are actually consequences of simple local conditions.

Quasi-random graphs.

We introduce a large equivalence class of graph properties, all of which are shared by so-called random graphs. Unlike random graphs, however, it is often relatively easy to verify that a particular family of graphs possesses some property in this class.

The effect of luteal phase estrogen antagonism on endometrial development and luteal function in women.

Previous studies of the role of estrogen in primate luteolysis, designed to investigate the effects of estrogen antagonism or selective inhibition of luteal phase estrogen production on luteal function, have ignored the impact of such treatments on secretory endometrial development. We examined the effect of luteal phase estrogen antagonism on endometrial maturation and luteal function in six women. In each of two menstrual cycles in each woman, blood samples were obtained on alternate days from cycle days 3-9, daily until 1 day after the urinary LH surge (day 0), and again on alternate days until the onset of menses. In the second of each pair of cycles, clomiphene citrate (100 mg) was administered daily from 2 days after the LH surge until menses. Endometrial biopsy was performed 13 days after the LH surge in each cycle. Serum FSH, LH, estradiol, and progesterone (P) were measured by RIA. The endometrial histological date and concentration of cytosolic (C) and nuclear (N) estrogen (ER) and P (PR) receptors were determined. We found significant (P less than 0.05) increases in luteal phase serum FSH, LH, estradiol, and P levels in the clomiphene cycle compared to those in the control cycle. Endometrial histology was significantly (P less than 0.002) different during estrogen antagonism; a maturation delay of more than 2 days was found in all six women during the clomiphene cycle. Luteal phase duration was unchanged by clomiphene (P = 0.29). Endometrial ER-C [7.38 +/- 2.52 (+/- SEM) vs. 38.75 +/- 10.17 fmol/mg protein], ER-N (248 +/- 84 vs. 685 +/- 80 fmol/mg DNA), and PR-C (97 +/- 38 vs. 189 +/- 38 fmol/mg protein) were significantly lower (P less than 0.03) in the clomiphene cycle than in the control cycle, whereas PR-N was not different (P greater than 0.10). These data suggest that luteal phase estrogen 1) modulates endometrial PR and 2) plays an important role in secretory endometrial development.

Dissecting hematoma (aneurysm) of coronary arteries.

Isolated dissecting hematoma (aneurysm) of a coronary artery is a rare occurrence that often results in myocardial infarction and sudden death. A case of dissecting hematoma involving the left main, left anterior descending, and left circumflex coronary arteries is described in a patient who had received vigorous closed-chest cardiac resuscitation. This is believed to be the first reported case of coronary artery dissection caused by epicardial trauma from closed-chest cardiac resuscitation. This case demonstrates that dissecting hematoma of the coronary artery can be a complication of cardiac resuscitation.

Isometric embeddings of graphs.

We prove that any finite undirected graph can be canonically embedded isometrically into a maximum cartesian product of irreducible factors.

Conservative management of patients with premature rupture of fetal membranes.

The management of pregnant patients with premature rupture of membranes (PROM) prior to 32 weeks' gestation or at 32 to 34 weeks' gestation is controversial. In a retrospective analysis of 109 patients with PROM at or prior to 34 weeks' gestation, 53 (49%) were managed conservatively, and labor was eigher induced or occurred spontaneously within 24 hours in 56 (51%). Patients initially presenting with chorioamnionitis were excluded from this study, as were all patients with evidence of a fetal anomaly or a medical indication for delivery. The 53 patients managed conservatively had a mean pregnancy prolongation of 21 days (range, 2 to 105 days median, 7 days). The infants of patients managed conservatively had a lower incidence of respiratory distress syndrome (P less than .0025), mortality (P less than .05), and intracranial hemorrhage (P less than .03). Sixty-four percent of the conservatively managed group versus 45% of the induced/spontaneous labor group were found to be normal upon physical and neurologic examination when discharged from the hospital (P less than .035). The difference in incidence of neonatal sepsis between these 2 groups was not statistically significant (P = .42). Immediate induction of labor and/or delivery for patients with PROM at less than 32 weeks' gestation resulted in a significant increase in perinatal mortality and morbidity.

On irregularities of distribution of real sequences.

A natural measure of the amount of unavoidable clustering that must occur in any bounded infinite sequence of real numbers is studied. We determine the extreme value for this measure and exhibit sequences that achieve this value.