Chemoselective Oxidation of Thiols with Oxoammonium Cations.

The oxidation of various aryl and aliphatic thiols with the commercially available and environmentally benign reagent Bobbitt's salt (1) has been investigated. The reaction affords the corresponding disulfide products in good to excellent yields (71-99%) and can be accomplished in water, methanol, or acetonitrile solvent. Moreover, the process is highly chemoselective, tolerating traditionally oxidation-labile groups such as free amines and alcohols. Combined experimental and computational studies reveal that the oxidation takes place via a polar two-electron process with concomitant and unexpected deoxygenation of the oxoammonium cation through homolysis of the weak N-O bond, differing from prototypical radical-based thiol couplings. This unusual consumption of the oxidant has significant implications for the development of new nitroxide-based radical traps for probing S-centered radicals, the advancement of new electrochemical or catalytic processes involving nitroxide/oxoammonium salt redox couples, and applications to biological systems.

Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients.

A reduction in 5-hydroxyindoleacetic acid in cerebrospinal fluid was found in depressed and manic patients both while they were symptomatic and also after treatment. The concentration of homovanillic acid was initially reduced and then tended to increase after treatment.

Estimation of the impact of genital warts on health-related quality of life.

OBJECTIVES: One of the two new human papillomavirus (HPV) vaccines protects against HPV types 6 and 11, which cause over 95% of genital warts, in addition to protecting against HPV types 16 and 18. In anticipation of HPV vaccine implementation, the impact of genital warts on health-related quality of life (HRQoL) was measured to assess the potential benefits of the quadrivalent over the bivalent vaccine. METHODS: Genitourinary medicine clinic patients aged 18 years and older with a current diagnosis of genital warts were eligible; 81 consented and were interviewed by a member of the research team. A generic HRQoL questionnaire, the EQ-5D (comprising EQ-5D index and EQ visual analogue scale (VAS) scores) and a disease-specific HRQoL instrument, the CECA10, were administered. Previously established UK population norms were used as a control group for EQ-5D comparisons. RESULTS: Cases (with genital warts) had lower EQ VAS and EQ-5D index scores than controls. After adjusting for age a mean difference between cases and controls 30 years of age and under (n = 70) of 13.9 points (95% CI 9.9 to 17.6, p<0.001) for the EQ VAS and 0.039 points (95% CI 0.005 to 0.068, p = 0.02) on the EQ-5D index (also adjusted for sex) was observed. The difference between cases and controls for the EQ VAS was especially notable in young women. CONCLUSIONS: Genital warts are associated with a significant detriment to HRQoL. The potential added benefit of preventing most cases of genital warts by HPV vaccination should be considered in decisions about which HPV vaccine to implement in the United Kingdom.

Novel Strategies to Improve Resident Selection by Improving Cultural Fit: AOA Critical Issues.

Residency selection is a perennial multifactorial process that differs considerably from the recruitment processes that other professional occupations enjoy. The 2016 meeting of the American Orthopaedic Association's Council of Orthopaedic Residency Directors highlighted a series of symposia that sought to present a novel manner of resident selection. Specifically, the presenters for each symposium were asked to do the following: present some general recruitment best practices in industries outside of medicine, present how branding of a program may translate into a better interview season, investigate evidence that the applicant pool to orthopaedic surgery may have changed and that residency program brands may have to reflect this, and assess our current evaluation techniques for talent identification and resident selection with respect to a specific department's appearance or brand. The meeting concluded with an understanding of the level to which programs can successfully create or adopt a brand and how this may go a long way in focusing the entire match process and allow emphasis to be placed on applicants who possess desired traits. The goal for this meeting was that attendees would leave with tangible practices and techniques that could be adopted at their home institutions.

The erythrocyte lithium-plasma lithium ratio in patients with primary affective disorder.

Increasing attention has been given to the significance of intra-cellular concentrations of the lithium ion in patients treated with this drug. The erythrocyte has been the most common cell investigated because of its accessibility and certain similarities between the ion transport mechanisms of this cell and the neuron. Intraerythrocyte lithium is expressed as the ratio of lithium in the cell to the plasma lithium concentration (lithium ratio). The lithium ratio has been reported to be related to a number of clinical variables, including treatment response, clinical state, side-effects, toxicity, diagnosis, and electrophysiological effects. We have investigated the lithium ratio in a large series of patients with a primary affective disorder and in a smaller control group. We found a significantly higher mean lithium ratio in the bipolar diagnostic group than in the unipolar and control groups. There was a trend, not statistically significant, in the unipolar and bipolar groups for females to have higher lithium ratios than males. While not diagnostic, the lithium ratio appears to be another biological variable where bipolar patients, as a group, differ from normals and others with an affective disorder.

Extinction of prolactin gene expression in somatic cell hybrids is correlated with the repression of the pituitary-specific trans-activator GHF-1/Pit-1.

The tissue-specific expression of the PRL and GH genes is dependent on the presence of a pituitary-specific trans-activator, GHF-1/Pit-1. Previous studies indicate that somatic cell hybridization of rat pituitary GH3 cells with LB82 mouse fibroblasts frequently results in the extinction of GH and PRL expression. The extinction of the GH gene occurs at the transcriptional level, and is accompanied by repression of GHF-1/Pit-1 synthesis. To elucidate the mechanism of PRL extinction we further characterized these same somatic cell hybrid lines as well as the parental GH3 and LB82 cells. The pattern of PRL extinction and reexpression paralleled that of GH in the three hybrid lines that were examined. Two of these lines extinguished both GH and PRL synthesis, while a third displayed reexpression of both genes, apparently due to the loss of mouse chromosomal material. These studies revealed that the extinction of PRL expression in these hybrid lines occurs at the level of mRNA accumulation and is strongly correlated with the loss of GHF-1/Pit-1 mRNA and protein synthesis. These data suggest that in pituitary x fibroblast hybrids repression of the trans-activator GHF-1/Pit-1 is a primary mechanism for the extinction of PRL and GH gene expression.

Cerebral evoked potential changes produced by treatment with lithium carbonate.

To confirm and extend previous findings concerning evoked potential (EP) changes produced by lithium carbonate (Li), 12 depressive patients were studied while on placebo and on therapeutic doses of Li. Four kinds of EPs were recorded from 14 leads: somatosensory (SEP) to left (LSEP) and right (RSEP) median nerve stimuli; visual (VEP) to a checkerboard flash; auditory (AEP) to binaural click. Plasma and erythrocyte (RBC) Li levels and Hamilton Depression ratings were obtained. Li produced a number of amplitude changes in EPs of all sensory modalities, while there were few latency changes; in general, amplitudes of positive components were increased, while negative component amplitudes were reduced. The spatial distributions of EP peaks were mainly unaltered by Li. The amount of EP amplitude change with Li tended to be correlated with plasma and RBC Li levels. No convincing correlations were found between alterations in EPs and depression ratings. The nature of the EP changes with Li was generally not concordant with normalization of the deviant EP characteristics found in depressives. The findings indicate that Li produces more widespread CNS changes than suggested by previous reports; it appears that these tend to be related to Li levels, but not to the therapeutic effects of Li.

Prediction of the lithium ratio in man by means of an in vitro test.

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium-sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+-loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.

Lithium and the kidney: a review.

The effects of lithium on renal water and electrolyte transport have generally been considered to be reversible following the cessation of lithium treatment. However, several recent reports have suggested that lithium-induced nephrogenic diabetes insipidus may persist for months or even years after lithium is discontinued. In addition, a number of reports have described the development of renal insufficiency (in association with interstitial nephritis) in some patients who have been chronically treated with lithium. The authors briefly review the effects of lithium on renal tubular transport and critically examine the reports of lithium-induced renal disease.

Erythrocyte concentrations of the lithium ion: clinical correlates and mechanisms of action.

When lithium carbonate is administered to individuals, there is considerable intersubject variation in the extent of accumulation of Li+ by erythrocytes. The primary reason for this is differences in the activity of a Li+-Na+ counterflow system, which, under clinical conditions, removes Li+ from the cell. It appears that some bipolar patients accumulate more Li+ in their red cells than either unipolar depressives or normal controls. The precise clinical characteristics of the bipolar patients who accumulate relatively large amounts of erythrocyte Li+ need to be clarified in future research. Finally, the measurement of red cell concentrations of Li+, in addition to the usual plasma measurement, can be used as an indicator of patient compliance.

Protein-protein interactions: lessons learned.

Protein-Protein (P-P) interactions play a pivotal role in determining cellular structure and in all cellular processes. The nature of P-P interactions is complex, and despite the large amount of research that has occurred in the field, is still poorly understood. Abnormal P-P interactions are particularly important because of their association with a variety of diseases, including cancer. This review examines P-P interactions with particular emphasis on the discovery of new anti-tumor drugs, including underlying physical forces that determine affinity and specificity and discusses classical and newer strategies used to discover inhibitors of P-P interactions, providing a number of recent cancer-related case studies and commentary.

Estrogen response element binding induces alterations in estrogen receptor-alpha conformation as revealed by susceptibility to partial proteolysis.

Genes whose expression is highly induced by estradiol (E(2)) contain multiple estrogen response elements (EREs) in their promoters. Previously we reported that estrogen receptor-alpha (ERalpha) binds cooperatively to and E(2) synergistically activates reporter gene expression from three or four tandem copies of a consensus ERE (EREc38). Here we evaluated how ERalpha binding to one, two, three or four tandem copies of EREc38 affects ERalpha conformation as detected by altered ERalpha trypsin digestion patterns in Western blots. E(2)- or 4hydroxytamoxifen (4-OHT)-occupied ERalpha bound to the pS2 ERE or to a single copy of EREc38 showed enhanced susceptibility to trypsin digestion compared to E(2)- or 4-OHT-ERalpha incubated with DNA lacking an ERE. ERalpha binding to multiple tandem copies of EREc38 further increased sensitivity to trypsin digestion. These results correlate with synergistic transcription and cooperativity of ERalpha binding to multiple tandem copies of EREc38. These observations suggest that EREc38 binding alters the overall conformation of ERalpha and that multiple tandem copies of EREc38 enhance these conformational changes. We hypothesize that ERE-induced alterations in ERalpha conformation modulate interaction with coregulatory proteins, resulting in synergistic transcriptional activation.

Prediction of dosage of lithium carbonate: use of a standard predictive method.

The nomogram developed by Cooper and associates used to predict the dose of Lithium Carbonate (Li+) which is needed to attain therapeutic Li+ concentrations has, in general, proven to be accurate and clinically useful. However, there may be some patients in whom the pharmacokinetic disposition of Li+ varies sufficiently so that accurate dosage predictions cannot be made; a report of one such patient is given.

Plasma and erythrocyte electrolytes in affective disorders.

Plasma and erythrocyte sodium (Na+), total and free (ultrafiltrable) plasma magnesium (Mg2+) as well as erythrocyte magnesium were measured in patients with affective disorders and in healthy control subjects. Depressed and manic patients had higher total plasma Mg2+ than did hospitalized healthy control subjects, but concentrations of ultrafiltrable Mg2+ did not differ. Although erythrocyte Mg2+ was significantly elevated in the depressed subjects in comparison with that found in the non-hospitalized healthy controls, this difference was not seen between the depressives and the hospitalized healthy controls. Depressed, manic or healthy control subjects did not differ with respect to either plasma or erythrocyte.

Comparison of craniofacial morphology in monozygotic twins with their siblings.

Lateral cephalometric radiographs from 33 families of monozygotic twins and their siblings were digitized. Eight skeletal parameters were measured: FA to SN, SNA, SNB, ANB, angle of convexity, mandibular plane to SN angle, Y axis and pogonion to NB distance. Monozygotic twin pairs and their siblings showed a normal distribution pattern for all the skeletal parameters, except the pogonion to NB distance measurement. There was found to be a statistically significant correlation between age and facial angle and ANB. A familial aggregation effect was found for SNA, ANB and angle of convexity. Some genetic influence was found for FA, mandibular plane angle and Y axis, while the Pg to NB distance showed neither genetic influence, nor a familial aggregation.

Comparison of dentofacial morphology in monozygotic twin pairs with their siblings using LISREL.

Lateral cephalometric radiographs from 33 families of monozygotic twins and their siblings were digitized. Seven dentofacial parameters were measured: 1 to SN, 1 to NA, 1 to NA(mm), 1 to 1, 1 to Mandibular Plane Angle, 1 to NB(mm) and 1 to APg(mm). Data from monozygotic twin pairs and siblings were analyzed using LISREL to determine variance components of heredity, common environment and random environment. Five of the parameters measured showed heredity as the primary factor of variance, while two, 1 to NB(mm) and 1 to APg(mm) showed a common environment as having the greatest effect.