Pruned receptor surface models and pharmacophores for three-dimensional database searching

A pharmacophore represents the 3D arrangement of chemical features that are shared by molecules exhibiting activity at a protein receptor. Pharmacophores are routinely used in 3D database searching for identifying potential lead compounds. The lack of shape constraints causes the query to identify compounds that could not fit into the active site. In the absence of structural information, a receptor surface model (RSM) can be used to represent the active site. The RSM consists of a surface that envelops a set of known actives after these have been aligned using their common features. When used for database searching, a RSM is overconstraining as it restricts access to regions that could be occupied by ligands, such as the solvent-protein interface or unexplored pockets. We describe a protocol for developing pruned RSMs using information gleaned from 3D quantitative structure-activity relationship (QSAR) models. We examined the performance of queries that consist of pharmacophores used alone or with pruned or unpruned RSMs by performing searches on six databases containing known actives distributed among inactives. The pruned RSMs yield an average selectivity 1.8 times greater than that for pharmacophore queries, compared to 1.6 times for unpruned RSMs. However, the pruned RSMs retrieve on average 73% of the actives identified using the pharmacophores, compared to 40% for the unpruned RSMs. As such, pruned RSMs represent a useful compromise between the high sensitivity of pharmacophores and the high selectivity of unpruned RSMs.     

Melanoma-inhibiting activity assay predicts survival in patients receiving a therapeutic cancer vaccine after complete resection of american joint committee on cancer stage III melanoma

Background More than half of melanoma patients rendered disease free by lymph node dissection will experience disease recurrence. We hypothesized that serum levels of melanoma-inhibiting activity (MIA) protein might be useful to stratify risk and identify subclinical recurrence in patients undergoing adjuvant immunotherapy. We examined MIA levels in the serum of stage III patients treated after surgery with a therapeutic cancer vaccine. Methods Three cohorts of 25 patients were randomly selected from our melanoma database on the basis of time to death (group 1, <1 year; group 2, 1–5 years; group 3, >5 years). Prospectively collected serum samples were assayed in a blinded fashion for MIA by enzyme-linked immunosorbent assay. Results MIA was increased at any time in 19 (76%) of 25, 4 (16%) of 25, and 1 (4%) of 25 patients in groups 1, 2, and 3, respectively. The median survival was 11 months for the 25 patients with increased MIA and >75 months for the 50 patients with normal MIA. MIA increased above normal a median of 1 month (mean, 75 days) before clinical recurrence. All patients with increased MIA after 2 months of treatment subsequently died of melanoma. One patient in whom initially increased levels decreased to normal within 2 months is disease free. Conclusions Serum MIA levels provide important prognostic information early in the course of stage III melanoma and often detect melanoma recurrences before clinical evidence of disease.     

Surgical masks: operative field contamination following visor-to-visor contact

BACKGROUND: Clashing of surgical visor masks frequently occurs when two surgeons bend over an operative field simultaneously; however, it is unknown whether this results in contamination. The purpose of the present study was to determine the potential for operative field contamination following surgical visor-mask clashes. The nature of bacterial contamination was also assessed. METHODS: Thirty sham operative procedures were performed under normal operating conditions for a specified time period. The number of surgical visor mask clashes during each procedure was determined by randomization (0, 1, 2, 3, 4 or 6 clashes). All procedures were performed over a standard blood agar plate array. The degree of bacterial contamination was assessed by counting c.f.u. that developed after 24 h of incubation. Bacterial types were also determined. RESULTS: Surgical visor mask clashes resulted in increased contamination of the operative field; however, this was found to be independent of the number of clashes. 95% of pathogens were coagulase negative Staphylococcus species. Other bacteria included Micrococcus species, Bacillus species, Corynebacterium species, various Gram negative bacilli and Staphylococcus aureus (< 1%). CONCLUSION: Surgical visor mask clashes increase the risk of bacterial contamination of the operative field.     

Herbert Moran Memorial Lecture. World War I: the genesis of craniomaxillofacial surgery?

Herbert Moran enlisted in the Royal Army Medical Corps early in World War I. His autobiography captures the impact of contemporary experience of wartime gunshot wounds, seen in vast numbers and with little understanding of the requirements of wartime surgery. Wounds of the face and brain were numerous, especially in trench fighting. In France, Germany, Britain and elsewhere, surgeons and dentists collaborated to repair mutilated faces and special centres were set up to facilitate this. The innovative New Zealand surgeon Harold Gillies developed his famous reconstructive techniques in the Queen's Hospital at Sidcup, with the help of dental surgeons, anaesthetists and medical artists. The treatment of brain wounds was controversial. Many surgeons, especially on the German side, advocated minimal primary operative surgery and delayed closure. Others advocated early exploration and immediate closure; among the first to do so was the Austro-Hungarian otologist Robert Bárány. In 1918, the pioneer American neurosurgeon Harvey Cushing published well-documented proof of the desirability of definitive operative management done as soon as possible. Few World War I surgeons developed their knowledge of plastic surgery, neurosurgery and oral surgery in post-war practice. An exception was Henry Newland, who went on to pioneer the development of these specialties in Australasia. After World War II, the French plastic surgeon Paul Tessier created the multidisciplinary subspecialty of craniomaxillofacial surgery, with the help of his neurosurgical colleague Gérard Guiot, and applied this approach to the correction of facial deformities. It has become evident that the new subspecialty requires appropriate training programs.     

Clinical nerve conduction and needle electromyography studies

The electrodiagnostic study, consisting of nerve conduction studies and needle electromyography, is a useful adjunct to the clinical examination of the peripheral nervous system. The three types of nerve conduction study are motor, sensory, and mixed, of which motor is the least sensitive. Electromyography records the intrinsic electrical activity of muscle fibers, thus providing the physiologic status of muscle function. To interpret the electrodiagnostic study results, the clinician must understand the anatomic and physiologic basis of the studies. Peripheral nerve entrapment initially results in focal demyelination; thus, nerve conduction velocity slows across the site. However, with radiculopathy and nerve root compression, the nerve conduction study may be normal. Both nerve trauma and polyneuropathy show marked differences in their effect on the results of electrodiagnostic studies.     

The total percentage of biopsy cores with cancer improves the prediction of pathological stage after radical prostatectomy

OBJECTIVE: To examine whether the simple variable 'percentage of cancer-positive biopsy cores' is a significant predictor of true pathological stage after radical prostatectomy and can be used to improve pathological stage prediction by simple means. PATIENTS AND METHODS: In all, 375 patients had a radical prostatectomy for localized prostate cancer in two UK centres; 260 had complete preoperative staging information. Logistic regression was used and predicted probability graphs constructed to assess predictors of pathological stage. RESULTS: In this study, only PSA (P = 0.004) and percentage cancer-positive biopsy cores (P < 0.001) were significant predictors of pathological stage. The final model was an acceptable classifier for pathological stage (area under the receiver operating characteristic curve 0.76, specificity 85%, sensitivity 47%). A patient with a PSA of 10 ng/mL and one of six cores positive for cancer would have a predicted probability of extraprostatic disease of 20%, whereas the same patient with all six biopsy cores positive would have a predicted probability of extraprostatic disease of 80%. CONCLUSIONS: The percentage of cancer-positive biopsy cores significantly predicts the disease stage after radical prostatectomy. This variable is easy to obtain by the clinician and avoids the need to estimate the percentage of biopsy tissue infiltrated by cancer. This readily available information can easily be computed and may help to counsel patients about realistic expectations of organ-confined disease in relation to surgery as a treatment option.