The statistical-thermodynamic basis for computation of binding affinities: a critical review.

Although the statistical thermodynamics of noncovalent binding has been considered in a number of theoretical papers, few methods of computing binding affinities are derived explicitly from this underlying theory. This has contributed to uncertainty and controversy in certain areas. This article therefore reviews and extends the connections of some important computational methods with the underlying statistical thermodynamics. A derivation of the standard free energy of binding forms the basis of this review. This derivation should be useful in formulating novel computational methods for predicting binding affinities. It also permits several important points to be established. For example, it is found that the double-annihilation method of computing binding energy does not yield the standard free energy of binding, but can be modified to yield this quantity. The derivation also makes it possible to define clearly the changes in translational, rotational, configurational, and solvent entropy upon binding. It is argued that molecular mass has a negligible effect upon the standard free energy of binding for biomolecular systems, and that the cratic entropy defined by Gurney is not a useful concept. In addition, the use of continuum models of the solvent in binding calculations is reviewed, and a formalism is presented for incorporating a limited number of solvent molecules explicitly.     

Transformation of lisianthus (Eustoma grandiflorum)

Transformed plants from three cultivars of Eustoma grandiflorum (lisianthus) were produced by cocultivating young leaf pieces with Agrobacterium tumefaciens strain A722 containing the binary vectors pKIWI110 and pLN26. Both vectors contain the selectable marker gene for neomycin phosphotransferase II. pKIWI110 also contains the reporter gene for β-d-glucuronidase, and pLN26, the chalcone synthase antisense gene. Southern DNA analysis revealed that all the kanamycin-resistant transformants tested contained copies of the transgenes integrated in their genome. The two plants transformed with pKIWI110 show β-d-glucuronidase expression in their mature leaves and selected transformants passed on the kanamycin-resistant phenotype to the F1 generation. Received: 8 January 1997 / Revision received: 12 May 1997 / Accepted: 3 June 1997     

Initiating Antiretroviral Therapy for HIV at a Patient’s First Clinic Visit: The RapIT Randomized Controlled Trial

BackgroundHigh rates of patient attrition from care between HIV testing and antiretroviral therapy (ART) initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit.ConclusionsOffering single-visit ART initiation to adult patients in South Africa increased uptake of ART by 36% and viral suppression by 26%. This intervention should be considered for adoption in the public sector in Africa.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01710397","term_id":"NCT01710397"}}NCT01710397, and South African National Clinical Trials Register DOH-27-0213-4177.     

Superomedial pedicle technique of reduction mammaplasty

A series of 148 patients who underwent reduction mammaplasty utilizing the superomedial pedicle technique is presented. Resections as large as 4100 gm per breast with nipple-areola transpositions up to 30 cm were done with reliable nipple-areola survival, including preservation of sensation. The superior pedicle technique of breast reduction is recognized by many as technically easier and capable of producing a longer-lasting aesthetic effect. Classically, however, it has been limited to smaller resections. By incorporating the medial quadrant in the superior pedicle, more aggressive reductions can be safely undertaken with the same excellent results. Details of the procedure, the anatomic basis for its success, and complications are discussed.     

Evidence for Des-Tyr1-D-Ala2-leucine5-enkephalinamide calcium agonist activity in vascular smooth muscle

Intravenous administration of the enkephalin analog Des-Tyr1-D-Ala2-Leu5-enkephalinamide (DTALE) to conscious dogs produces a pressor response that is not inhibited by naloxone. In an attempt to explain this observed pressor activity in vivo, the effect of DTALE on vascular smooth muscle was investigated in vitro. DTALE was found to contract rat thoracic aorta strips in a dose-dependent and naloxone-insensitive manner. Pretreatment with reserpine (5 mg/kg) or prazosin was without significant effect. However, a significant inhibition was obtained with cyproheptadine (p less than 0.001, n = 5), a 5-hydroxytryptamine (5-HT) receptor antagonist that also has calcium channel blocking activity. Treatment with ketanserin (0.1 microM), a selective 5-HT2-receptor antagonist, had no effect. Reduction of the extracellular calcium concentration from 1.6 to 1.2 mM or 0.8 mM significantly diminished DTALE activity (1.2 mM, p less than 0.025; 0.8 mM, p less than 0.01; n = 3). Pretreatment with the calcium channel antagonists verapamil (0.1 microM) and nitrendipine (0.05 microM) significantly inhibited DTALE activity (p less than 0.001 for both treatments). DTALE also exhibited increased potency in partially depolarized smooth muscle preparations. These results suggest that DTALE may produce vasoconstriction by inducing or facilitating calcium influx. This activity upon arterial vascular strips may provide explanation for the observed pressor response in chronically instrumented conscious dogs.     

Dermal cylindroma (turban tumor). Case report.

We present an unusual case of massive dermal cylindroma (turban tumor), occupying the entire scalpand forehead. It was treated by a total scalping procedure and skin grafting in two stages. Additional tumors of the face, neck, chest, shoulders, and back were excised and closed. The nose was treated by shoving and dermabrasion, similar to a rhinophyma. The lip was treated by dermabrasion. There has been no evidence of recurrence in the scalp which was treated by excision and grafting. There is now a papular quality of the skin over the nose and on the uppler lip, indicating that regrowth may occur. The etiology, pathology, and a review of the literature are presented.     

Tsundu: Becoming a Lama./Mystic Vision, Sacred Art: Tibetan Thangka Painting in Kathmandu Valley

Tsundu: Becoming. Lama. 1997. 19 minutes, color. video by Raju Mani Gurung. Mystic Vision, Sacred Art: Tibetan Thangka Painting in Kathmandu Valley. 1996. 28 minutes, color. video by Raju Mani Gurung and Anne Kaufman. For more information, contact Documentary Educational Resources, 101 Morse Street, Watertown, MA 02472.     

Estimation from Censored Medical Cost Data

This paper applies the inverse probability weighted least‐squares method to predict total medical cost in the presence of censored data. Since survival time and medical costs may be subject to right censoring and therefore are not always observable, the ordinary least‐squares approach cannot be used to assess the effects of explanatory variables. We demonstrate how inverse probability weighted least‐squares estimation provides consistent asymptotic normal coefficients with easily computable standard errors. In addition, to assess the effect of censoring on coefficients, we develop a test comparing ordinary least‐squares and inverse probability weighted least‐squares estimators. We demonstrate the methods developed by applying them to the estimation of cancer costs using Medicare claims data. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)