Neighborhood behavior: a useful concept for validation of "molecular diversity" descriptors.

When searching for new leads, testing molecules that are too "similar" is wasteful, but when investigating a lead, testing molecules that are "similar" to the lead is efficient. Two questions then arise. Which are the molecular descriptors that should be "similar"? How much "similarity" is enough? These questions are answered by demonstrating that, if a molecular descriptor is to be a valid and useful measure of "similarity" in drug discovery, a plot of differences in its values vs differences in biological activities for a set of related molecules will exhibit a characteristic trapezoidal distribution enhancement, revealing a "neighborhood behavior" for the descriptor. Applying this finding to 20 datasets allows 11 molecular diversity descriptors to be ranked by their validity for compound library design. In order of increasing frequency of usefulness, these are random numbers = log P = MR = strain energy < connectivity indices < 2D fingerprints (whole molecule) = atom pairs = autocorrelation indices < steric CoMFA fields = 2D fingerprints (side chain only) = H-bonding CoMFA fields.

Bioisosterism as a molecular diversity descriptor: steric fields of single "topomeric" conformers.

The comparative molecular field analysis steric field of a single "topomeric" conformer is introduced as a molecular diversity descriptor particularly useful for combinatorial chemistry involving variations around a fixed "core". Using this new descriptor, 736 commercially available thiols are divided into 231 bioisosteric clusters, whose compositions agree at least as well with medicinal chemical experience and intuition as do clusters derived from Tanimoto differences between 2D fragment occurrences. However, in practice topomeric steric fields complement 2D fingerprints, being the two most frequently useful descriptors yet found for neighborhood-based design of combinatorial libraries.

Successful repair of an unusual hernia associated with traumatic pubic diastasis.

A 70-year-old man had an unusual type of supravesical small bowel hernia associated with herniation of the bladder through a traumatic diastasis of the pubic symphysis. The diastasis was closed with prosthetic mesh through a preperitoneal approach. In patients in whom a scrotal hernia develops after a previous pelvic fracture, especially those with evidence of a pubic diastasis, an unusual type of hernia should be suspected. A preperitoneal surgical approach best reveals the anatomy and allows appropriate repair. The best procedure for prevention of such hernias is primary reduction of any substantial pubic diastasis, but operative intervention is not indicated in all patients.

Percutaneous removal of kidney stones. Preliminary report.

We have performed percutaneous extractions of renal pelvic stones in 15 patients with the use of the Wolf percutaneous universal nephroscope. At one session, with the patient under general anesthesia, a percutaneous tract is dilated to 24 F, and the stone is immediately removed. Fifteen stones have been removed successfully by ultrasonic lithotripsy, basket retrieval, use of a forceps, or a combination of these techniques. Average operating time has been 1 hour and the mean hospitalization time 4 days. The advantages of this technique are that a skin incision of only 1 to 2 cm is required to remove the stone, hospital days are fewer than with open procedures, and postoperative morbidity is minimal. In selected situations, this method represents a significant advance over standard open surgical procedures for removal of renal pelvic stones.

Safety of same-day sequential extracorporeal shock wave lithotripsy and dissolution of gallstones by methyl tert-butyl ether in dogs.

Passage of stone fragments after extracorporeal shock wave lithotripsy (ESWL) of gallstones has resulted in biliary colic, duct obstruction, and pancreatitis in some patients. Rapid dissolution of these fragments with methyl tert-butyl ether (MTBE) may prevent such side effects and achieve complete clearance of gallstones within hours rather than several months to a year or longer. This study examines the safety of same-day ESWL fragmentation and MTBE dissolution of surgically implanted human gallstones in 15 dogs. The animals were randomly assigned to one of four treatment groups to assess MTBE absorption from the gallbladder and to observe hematology and chemistry profiles after 0, 400, and 1,200 shock waves from a lithotriptor followed by MTBE dissolution therapy. They were sacrificed either immediately after treatment (12 dogs) or 2 weeks later (3 dogs). The results demonstrated that although ESWL causes moderate trauma to the gallbladder, this did not result in increased MTBE absorption or histologic evidence of mucosal disruption. Blood profiles demonstrated an increase in only the level of aspartate aminotransferase. The three dogs that were sacrificed 2 weeks after the combined treatment had no residual evidence of gallbladder injury or remaining stone material. In all animals, severe injury occurred where shock waves passed through lung or air-filled colon. This study suggests that same-day sequential fragmentation of gallstones by ESWL followed by dissolution of stone fragments with use of MTBE may be associated with only mild to moderate and reversible gallbladder trauma and can rapidly achieve clearance of gallstones.

Transurethral microwave thermotherapy for prostatism: early Mayo Foundation experience.

As part of a multicenter investigative trial, transurethral microwave thermotherapy of the prostate was used in 60 men with symptomatic benign prostatic hypertrophy. A single office treatment on the Prostatron, a device that provides concurrent microwave heating of the prostate and conductive cooling of the urethra, was well tolerated and caused no major adverse events. Symptomatic improvement, especially the decrease in nocturia and urgency, was dramatic, and urinary flow was improved at 6 weeks. Continued follow-up suggests that further improvement will be achieved and that transurethral microwave thermotherapy has a role in the treatment of benign prostatic hypertrophy.

A prospective randomized comparison of epidural infusion of fentanyl and intravenous administration of morphine by patient-controlled analgesia after radical retropubic prostatectomy.

In a prospective, randomized study, continuous infusion of epidural fentanyl citrate (group E) was compared with patient-controlled intravenously administered morphine sulfate (group P) for analgesia in 66 men after radical retropubic prostatectomy. Although both methods provided satisfactory analgesia, the mean comfort level scores were lower (that is, greater comfort) in group E than in group P at all observation times. The difference in mean resting comfort level scores between groups E and P was statistically significant (P < or = 0.05) at 9 of the 11 observation times. In addition, significant differences in comfort level scores were noted at 8 of the 11 observation times during deep breathing, 5 of 11 during coughing, and 3 of 9 during ambulation. Maximal and minimal comfort level scores recorded by each patient during the course of the study were significantly lower (that is, less pain) in group E than in group P for all four categories of activity. The percentage of patients who reported no pain was significantly higher in group E than in group P at 9 of 11 observation times during resting and 5 of 11 observation times during deep breathing. No significant differences were noted in side effect profiles or duration of hospital stay. In summary, when two effective methods of analgesia used after radical retropubic prostatectomy were compared prospectively, patients who received epidural infusion of fentanyl were more comfortable than those with patient-controlled intravenous administration of morphine, as evidenced by lower mean, maximal, and minimal comfort level scores and a greater proportion of patients with complete relief of pain.

Leiomyosarcoma of urinary bladder.

A retrospective analysis of 5 cases of primary leiomyosarcoma of the bladder seen during 1958 through 1978 revealed that segmental resection is curative in selected cases but that more extensive extirpation may be warranted, depending on the stage of the disease. Radiation therapy had no effect on regional disease. Early diagnosis and aggressive surgical therapy are important.

Perioperative complications of pelvic lymphadenectomy and radical retropubic prostatectomy for Stages C and D1 prostate cancer.

The complications experienced by 205 consecutive patients who underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for surgical Stages C and D1 prostate cancer were analyzed. One hundred five patients had pathologic Stage C disease, and 100 patients had pathologic Stage D1 disease. Seven patients had thromboembolic complications. Wound or pelvic hematomas developed in 6 patients. Only two lymphoceles were detected. Rectal injuries occurred in 6 patients, of whom 4 required colostomies. The overall incidence of perioperative complications was 17 per cent. There was one postoperative death.

Primary radiologic realignment of membranous urethral disruptions.

A forty-two-year-old man with a traumatic, membranous urethral disruption underwent initial suprapubic catheter urinary diversion followed by a primary realignment twenty-one days after injury. Realignment was accomplished radiologically using an anterograde guide wire engaged by a retrograde stone basket and subsequent Foley catheter placement over the wire. The patient has remained totally continent, having partial erections, two years after injury, with no further intervention.

Bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for Stage C adenocarcinoma of prostate.

A series of 105 patients with surgical Stage C adenocarcinoma of the prostate underwent pelvic lymphadenectomy and radical retropubic prostatectomy and were followed up from one and one-half to fifteen years; 33 (31%) of the 105 had clinical Stage C disease. Of the 105 patients, 92 were at risk for greater than or equal to two years, 42 for greater than or equal to five years, and 12 for greater than or equal to ten years. Survival and disease progression were related to tumor grade (Mayo grades 1 through 4) and tumor bulk (less than 3, 3 to 10, greater than 10 cm3) but not to seminal vesicle involvement. Twenty-seven patients received adjuvant treatment (orchiectomy, DES, radiation, or combinations of these); it was administered to patients with higher tumor grades, larger tumor bulk, and/or residual cancer. Overall actuarial survival at five and ten years was 85 per cent and 72 per cent, respectively; five-year nonprogression rate was 64 per cent. Local recurrence was noted in only 8 patients (7.6%). Radical surgical treatment for nonbulky Stage C disease of the prostate is associated with favorable survival results and good local control. Adjuvant treatment may favorably affect disease outcome. Clinical seminal vesicle involvement with negative urethrocystoscopy should not necessarily deter the surgeon from planning radical prostatectomy. Prospective adjuvant treatment protocols need to be developed to identify the value of adjuvant hormone and/or radiation therapy.

Testicular adnexal fibrous pseudotumors.

Fibrous pseudotumors of the testicular adnexae presenting clinically as a testicular malignancy are uncommon. Although fibrous pseudotumors are benign, they are usually diagnosed after radical orchiectomy. Radical orchiectomy occasionally may be avoided if this benign process is considered in the differential diagnosis of testicular neoplasms.

Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma.

OBJECTIVES: This report focuses on the long-term follow-up of patients with endoscopically treated upper tract transitional cell carcinoma (TCC) to determine the effectiveness of endoscopic therapy. METHODS: From May 1983 to April 1994, 44 patients with TCC of the upper urinary tract underwent conservative endourologic treatment with either electrocautery fulguration or neodymium:yttrium-aluminum-garnet laser at our institution. The mean follow-up period was 5 years (range, 3 months to 11 years). RESULTS: Renal pelvic tumor sizes ranged from 0.4 to 4.0 cm (mean, 1.5) and ureteral tumors from 0.2 to 1.0 cm (mean, 0.5). The majority of tumors were of pathologic grade 3 or less, and all were Stage T2 or less. Seventeen of 44 patients (38.6%) had local tumor recurrence (mean time to recurrence, 12.8 months; range 1.5 to 64). Mean recurrence time was 7.3 months for renal pelvic tumors and 17.8 months for ureteral tumors. Nineteen of 44 patients (43.2%) developed bladder tumors. The overall 5-year disease-free rate was 57%. No recurrent tumor was shown to have increased in grade, and one recurrent tumor was proved to have progressed in stage. Six patients (14%) ultimately required a nephroureterectomy for recurrence. There were no major complications as a result of endoscopic therapy. Six patients (14%) died of the effects of metastatic TCC, 5 of whom had known muscle invasive bladder TCC. CONCLUSIONS: Endourologic techniques and the conservative treatment of upper urinary tract TCC is an evolving field and can be safely and effectively used as a first-line treatment for upper tract TCC in selected patients.

Bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for adenocarcinoma of prostate with regional lymph node involvement.

Ninety-nine patients with adenocarcinoma of the prostate and regional lymph node involvement underwent pelvic lymphadenectomy. Therapeutic results were analyzed in 70 patients who subsequently underwent radical retropubic prostatectomy with or without concomitant therapy (usually hormonal) and in 29 patients who received radiation or hormonal treatment only but without prostatectomy. Follow-up ranged from one to fourteen and one-half years. The over-all projected survival rates (Kaplan-Meier) at five and ten years (88 per cent and 71 per cent, respectively) in the prostatectomy series were comparable to those of an age-matched control group. Concomitant bilateral orchiectomy provided a high projected (76 per cent at ten years) nonprogression rate. Over-all survival rates in the nonprostatectomy series were poor. Only the number of nodes involved was associated with survival and time to disease progression. Patient age, tumor bulk, seminal vesicle involvement, and tumor grade (Mayo and Gleason scores) had no definite relationship to survival. Pelvic lymphadenectomy and radical retropubic prostatectomy for prostatic adenocarcinoma may be therapeutic in some patients with limited (less than or equal to two positive nodes) nodal disease.

Percutaneous ultrasonic lithotripsy.

Percutaneous ultrasonic lithotripsy, endoscopically guided calculus fragmentation and removal through a percutaneous track, is the most widely used technique in the United States for removal of symptomatic upper urinary tract calculi. This article reviews the establishment of percutaneous renal access, track dilatation, and stone removal methods that constitute this technique.

Visualizing substructural fingerprints.

Substructural fingerprints have proven very useful for chemical library and diversity analysis, but their high dimensionality makes them poorly suited to principal components analysis and to standard nonlinear mapping methods. By using a combination of optimizable K-dissimilarity selection (OptiSim) and a modified stress function that suppresses effects of distances that fall beyond a characteristic horizon, it is possible to relax principal components analysis coordinates into more consistently meaningful projections from fingerprint space into two dimensions. The nonlinear maps so obtained are useful for characterizing combinatorial libraries, for comparing sublibraries, and for exploring the distribution of biological properties across structural space.

Mobile atheroma of the aortic arch and the risk of carotid artery disease.

BACKGROUND: Mobile atheromas of the aortic arch are associated with otherwise unexplained strokes and transient ischemic attacks (TIA). They are associated with increased perioperative strokes in patients undergoing coronary artery bypass surgery. Peripheral embolization is an additional risk. Transesophageal echocardiography (TEE) accurately identifies mobile atheroma. Anticoagulant therapy may have therapeutic considerations in the management of this condition. However, the risk of significant carotid artery disease associated with mobile atheromas is unknown. METHODS: Between March 1994 and July 1998, 40 patients with mobile atheromas by TEE and evidence of embolization were studied. All patients were captured prospectively in a vascular registry and were retrospectively reviewed. Carotid artery disease was evaluated using carotid duplex imaging in an accredited vascular laboratory. All patients with significant carotid disease, 70% or greater stenosis, underwent arteriography. Patients with significant carotid artery stenosis then underwent carotid endarterectomy. All patients with mobile atheromas were maintained on anticoagulation. RESULTS: Forty patients with mobile atheromas of the aortic arch were diagnosed with TEE. All 40 patients had evidence of embolization. Patient age ranged from 57 to 73 years (mean 68.4). There were 22 men and 18 women. Twenty of 40 (50%) patients presented with symptoms of TIA. Eleven of 40 (28%) patients presented with diffuse atheroembolization (lower extremity embolization and renal insufficiency). Six of 40 (15%) patients presented with a completed stroke. Three of 20 (7%) patients presented with acute extremity ischemia secondary to a peripheral embolus. Twenty-three of 40 (58%) of patients had significant carotid artery stenosis, 70% or greater stenosis. These 23 patients underwent both arteriography and carotid endarterectomy without complication. All patients were treated with anticoagulation and have remained anticoagulated. Clinical follow-up between 2 to 48 months (mean 18) has demonstrated no further evidence of systemic embolization in these 40 patients. Repeat TEE was performed in 6 of 40 patients. These follow-up studies no longer visualized mobile atheromas. CONCLUSIONS: Mobile atheromas are recognized sources for embolization. Routine carotid duplex imaging should be performed in patients found to have mobile atheromas of the aortic arch. Carotid endarterectomy appears to be safe in patients who have combined carotid artery stenosis and mobile atheromas. Anticoagulation may have therapeutic considerations in the management of this condition.

Transurethral microwave thermotherapy v sham treatment: double-blind randomized study.

Transurethral microwave thermotherapy (TUMT) is a single-session, 1-hour office-based treatment for benign prostatic hyperplasia. A randomized, double-blind study has been conducted at our institutions involving 115 patients who, after satisfying the entry criteria, were randomized in a 2:1 fashion to receive TUMT or a sham treatment. Three months' unblinding revealed both statistically and clinically significant improvement in the efficacy measures for the real treatment compared with the sham. The mean Madsen Symptom Score decreased 55% and the mean peak flow rate increased 58% in the TUMT-treated patients v 28% and 27% in the sham-treated patients (P < 0.001). Also, the TUMT-treated patients improved in mean AUA Symptom Score by 43% v 26% for sham-treated patients (P < 0.01). Reclassification of patients after therapy showed a greater shift to the mild category of AUA Symptom Score: 37% for TUMT patients v 6.5% for sham-treated patients. In addition, prostate-specific antigen elevation to >4 times baseline was noted 1 week after TUMT v no statistically significant change for sham-treated patients. This double-blind study demonstrates that thermotherapy's efficacy is not placebo related and that the mechanism of action is related to thermal ablation of transition zone adenoma.

Prediction of stone composition from plain radiographs: a prospective study.

BACKGROUND AND OBJECTIVES: Stone composition, as reflected in radiographic appearance, is important to help choose between SWL and percutaneous/endoscopic procedures. Predicting a stone's composition accurately from a plain radiograph would be a useful tool in clinical decision-making. However, the ability of physicians to predict composition has not been adequately assessed. A prospective study was designed to quantify the accuracy of a panel of physicians who routinely deal with stones in classifying stone composition solely from radiographs. MATERIALS AND METHODS: A panel of six members was created to review 100 plain-film radiographs from patients with renal stones of known composition. The panel consisted of two urologists, two radiologists, and two nephrologists, all of whom have expertise in stone disease. If the composition guessed was at least 40% of the total stone composition, the response was deemed correct. RESULTS: Overall, there was an average 39% correct response score among the six panelists. When the stones were divided by size, 35% were <1 cm, and 65% were larger. The accuracy of chemical composition determination did not improve with greater stone size, nor was there a difference in accuracy for pure and mixed stones. The most frequently misclassified stone was calcium phosphate, with only 14% being correctly diagnosed. CONCLUSIONS: With a random sampling of plain radiographs, a panel of physicians specializing in stone disease correctly diagnosed the composition of renal calculi less than half of the time without being given clinical information.

Combined carotid endarterectomy with transluminal angioplasty and primary stenting of the supra-aortic vessels.

BACKGROUND: Carotid endarterectomy (CEA) is the standard of care for patients with high-grade carotid artery stenosis who are acceptable surgical candidates. Focal occlusive lesions of the origin of aortic arch vessels can be effectively and safely treated with balloon angioplasty and primary stenting. The purpose of this study was to retrospectively review results of carotid endarterectomy for high-grade carotid bifurcation stenosis combined with intraoperative retrograde transluminal angioplasty and primary stenting of a hemodynamically significant stenosis at the origin of a proximal ipsilateral aortic arch vessel. METHODS: Between October 1994 and August 1998, 592 patients underwent CEA. Six patients were found to have hemodynamically significant tandem lesions affecting one of the aortic arch vessels and the ipsilateral ICA for an overall incidence of 1%. Age ranged from 63 to 78 years (mean 74.7). Four of 6 (67%) patients had asymptomatic lesions, and 2 of 6 (33%) had symptoms of cerebral ischemia. Five patients had tandem lesions affecting the proximal left common carotid artery and the left ICA. One patient had a tandem lesion affecting the innominate artery and the right ICA. Carotid duplex imaging and arch and cerebral arteriography was performed in all six patients. Arteriography confirmed high-grade stenoses in both the ICA and ipsilateral proximal aortic arch vessel. The range of stenoses in the ICA was 70 to 95% (mean 80.8%) measured arteriographically. The range of stenoses at the origin of the aortic arch vessels was 75-90% (mean 79.2%). All six patients underwent combined retrograde transluminal balloon angioplasty and primary stenting of the ipsilateral CCA or innominate artery with temporary occlusion of the ICA for cerebral protection. The endovascular procedure was then followed with standard surgical endarterectomy using an inline shunt. RESULTS: All six procedures were successfully completed. There were no periprocedural strokes or other morbidities. Follow-up ranged from 6 to 43 months (mean 23.6) and showed no evidence of recurrent stenosis by carotid duplex imaging. No TIAs or strokes related to the surgically corrected lesions were noted during the follow-up period. One patient suffered a right hemispheric stroke secondary to a high-grade right carotid stenosis which occurred two months after her procedure surgically correcting tandem lesions on the opposite side. CONCLUSIONS: Carotid endarterectomy with balloon angioplasty and primary stenting of an ipsilateral hemodynamically significant aortic arch trunk vessel stenosis can be safely and successfully accomplished and avoids the need for an intra/extrathoracic bypass procedure.