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A dilatometer cell that can detect sub angstrom changes in the length of solid specimens in the temperature range 5 K

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells., Competing Interests: Declaration of interests C.M.C. is a shareholder and consultant to Halda Therapeutics, which supports research in his laboratory., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed., Experimental Design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI)., Results: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib., Conclusions: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called R egulated I nduced P roximity Ta rgeting C himeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein., Competing Interests: Conflicts of Interest C.M.C. is a shareholder and consultant to Halda Therapeutics, which supports research in his laboratory.

In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.

BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.

Objectives: Bilateral pulmonary artery banding with or without ductal stenting has been performed as a resuscitative intervention for patients considered at too high risk for conventional single ventricle palliation. The purpose of the present study was to determine the outcomes using this strategy., Methods: We performed a retrospective review of 24 patients with single ventricle anatomy who were younger than 3 months who had undergone bilateral pulmonary artery banding and ductal stenting or maintenance of prostaglandin E(1) from January 2007 to October 2011 at our institution. The echocardiographic, angiographic, operative, and clinical data were reviewed. Follow-up data were available for 100% of the patients., Results: All 24 patients (13 male patients) underwent bilateral pulmonary artery banding at a median age of 8 days (range, 2-44 days). Their gestational age was 38 weeks (range, 27-41 weeks), and their weight was 3.01 kg (range, 1.5-4.4 kg). The cardiac diagnoses included hypoplastic left heart syndrome/variant hypoplastic left heart syndrome in 18, unbalanced atrioventricular canal in 4, and tricuspid atresia in 2. In the hypoplastic left heart syndrome group, 9 (50%) had an intact or a highly restrictive atrial septum requiring open (n = 1) or transcatheter (n = 8) atrial septostomy with or without atrial stent placement (n = 4). Ductal stenting was performed in 14 patients, and 10 patients were continued with prostaglandin E(1). Fifteen patients (62.5%) survived to undergo a Norwood procedure (n = 7), comprehensive stage 2 (n = 1), or primary cardiac transplantation (n = 7). Of the 9 who died, support was withdrawn in 5 because of a contraindication to transplantation, 1 because of sepsis and/or multiorgan system failure, and 1 for whom palliative care was desired. Two died awaiting transplantation. All 7 patients who underwent a conventional Norwood operation survived to discharge, and 6 of the 7 (85.7%) underwent bidirectional Glenn shunt placement. Of the 7 patients who underwent transplantation, 6 (85.7%) were alive at a median follow-up of 33.6 months., Conclusions: Bilateral pulmonary artery banding with or without ductal stenting is an effective method of resuscitation for high-risk neonates and infants with a single ventricle, allowing for reasonable survival to conventional first-stage palliation or primary transplantation., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Purpose: The optimal management of lower pole renal calculi is controversial. We compared shock wave lithotripsy (SWL) and ureteroscopy (URS) for the treatment of patients with small lower pole stones in a prospective, randomized, multicenter trial., Materials and Methods: A total of 78 patients with 1 cm or less isolated lower pole stones were randomized to SWL or URS. The primary outcome measure was stone-free rate on noncontrast computerized tomography at 3 months. Secondary outcome parameters were length of stay, complication rates, need for secondary procedures and patient derived quality of life measures., Results: A total of 67 patients randomized to SWL (32) or URS (35) completed treatment. The 2 groups were comparable with respect to age, sex, body mass index, side treated and stone surface area. Operative time was significantly shorter for SWL than URS (66 vs 90 minutes). At 3 months of followup 26 and 32 patients who underwent SWL and URS had radiographic followup that demonstrated a stone-free rate of 35% and 50%, respectively (p not significant). Intraoperative complications occurred in 1 SWL case (unable to target stone) and in 7 URS cases (failed access in 5 and perforation in 2), while postoperative complications occurred in 7 SWL and 7 URS cases. Patient derived quality of life measures favored SWL., Conclusions: This study failed to demonstrate a statistically significant difference in stone-free rates between SWL and URS for the treatment of small lower pole renal calculi. However, SWL was associated with greater patient acceptance and shorter convalescence.

Background: Erectile dysfunction (ED) may be one manifestation of a generalized vascular disorder characterized by endothelial dysfunction. Statin drugs may improve endothelial function, even before altering the lipid profile., Objective: We sought to determine whether the addition of a statin with sildenafil would improve ED in men who initially responded poorly to sildenafil., Methods: Men with moderate-to-severe ED despite an adequate sildenafil trial were enrolled in this randomized, double-blind, placebo-controlled pilot study. ED was defined using a validated self-administered questionnaire as a score of

Purpose: The optimal management of lower pole renal calculi is controversial. We compared shock wave lithotripsy (SWL) and ureteroscopy (URS) for the treatment of patients with small lower pole stones in a prospective, randomized, multicenter trial., Materials and Methods: A total of 78 patients with 1 cm or less isolated lower pole stones were randomized to SWL or URS. The primary outcome measure was stone-free rate on noncontrast computerized tomography at 3 months. Secondary outcome parameters were length of stay, complication rates, need for secondary procedures and patient derived quality of life measures., Results: A total of 67 patients randomized to SWL (32) or URS (35) completed treatment. The 2 groups were comparable with respect to age, sex, body mass index, side treated and stone surface area. Operative time was significantly shorter for SWL than URS (66 vs 90 minutes). At 3 months of followup 26 and 32 patients who underwent SWL and URS had radiographic followup that demonstrated a stone-free rate of 35% and 50%, respectively (p not significant). Intraoperative complications occurred in 1 SWL case (unable to target stone) and in 7 URS cases (failed access in 5 and perforation in 2), while postoperative complications occurred in 7 SWL and 7 URS cases. Patient derived quality of life measures favored SWL., Conclusions: This study failed to demonstrate a statistically significant difference in stone-free rates between SWL and URS for the treatment of small lower pole renal calculi. However, SWL was associated with greater patient acceptance and shorter convalescence.

PDGF-B is of central importance in mesangioproliferative diseases. PDGF-D, a new PDGF isoform, like PDGF-B, signals through the PDGF betabeta-receptor. The present study first determined that PDGF-D is mitogenic for rat mesangial cells and is not inhibited by a PDGF-B antagonist. Low levels of PDGF-D mRNA were detected in normal rat glomeruli. After induction of mesangioproliferative nephritis in rats by anti-Thy 1.1 mAb, glomerular PDGF-D mRNA and protein expression increased significantly from days 4 to 9 in comparison with nonnephritic rats. Peak expression of PDGF-D mRNA occurred 2 d later than peak PDGF-B mRNA expression. In addition, PDGF-D serum levels increased significantly in the nephritic animals on day 7. For investigating the functional role of PDGF-D, neutralizing fully human mAb were generated using the XenoMouse technology. Rats with anti-Thy 1.1-induced nephritis were treated on days 3 and 5 with different amounts of a fully human PDGF-DD-specific neutralizing mAb (CR002), equal amounts of irrelevant control mAb, or PBS by intraperitoneal injection. Specific antagonism of PDGF-D led to a dose-dependent (up to 67%) reduction of glomerular cell proliferation. As judged by double immunostaining for 5-bromo-2'-deoxyuridine and alpha-smooth muscle actin, glomerular mesangial cell proliferation was reduced by up to 57%. Reduction of glomerular cell proliferation in the rats that received CR002 was not associated with reduced glomerular expression of PDGF-B mRNA. PDGF-D antagonism also led to reduced glomerular infiltration of monocytes/macrophages (day 5) and reduced accumulation of fibronectin (day 8). In contrast, no effect was noted in normal rats that received an injection of CR002. These data show that PDGF-D is overexpressed in mesangioproliferative states and can act as an auto-, para-, or even endocrine glomerular cell mitogen, indicating that antagonism of PDGF-D may represent a novel therapeutic approach to mesangioproliferative glomerulonephritides.

Issues and Purpose: To examine healthcare providers' attitudes toward parent participation in the care of their hospitalized child., Design and Methods: In this descriptive, comparative study, 504 pediatric healthcare providers were surveyed to measure attitudes toward parent participation., Results: Results from 256 respondents indicated support for parent participation, but there was substantially less support for parental activities usually carried out by healthcare providers and those involving complex patient care tasks., Practice Implications: Although pediatric healthcare providers support parent participation, they tend to draw the line on what they believe are suitable parent activities. Newly developed pain standards and cardiopulmonary resuscitation guidelines incorporating parent participation have important implications for expanding the boundaries of parental involvement.

Platelet-derived growth factor (PDGF) has been directly implicated in developmental and physiological processes, as well as in human cancer and other proliferative disorders. We have recently isolated and characterized a novel protease-activated member of the PDGF family, PDGF D. PDGF D has been shown to be proliferative for cells of mesenchymal origin, signaling through PDGF receptors. Comprehensive and systematic PDGF D transcript analysis revealed expression in many cell lines derived from ovarian, renal, and lung cancers, as well as from astrocytomas and medulloblastomas. beta PDGF receptor profiling further suggested autocrine signaling in several brain tumor cell lines. PDGF D transforming ability and tumor formation in SCID mice was further demonstrated. Exploiting a sensitive PDGF D sandwich ELISA using fully human monoclonal antibodies, PDGF D was detected at elevated levels in the sera of ovarian, renal, lung, and brain cancer patients. Immunohistochemical analysis confirmed PDGF D localization to ovarian and lung tumor tissues. Together, these data demonstrate that PDGF D plays a role in certain human cancers.

The existence of intracellular rickettsiae requires entry, survival, and replication in the eukaryotic host cells and exit to initiate new infection. While endothelial cells are the preferred target cells for most pathogenic rickettsiae, infection of monocytes/macrophages may also contribute to the establishment of rickettsial infection and resulting pathogenesis. We initiated studies to characterize macrophage-Rickettsia akari and -Rickettsia typhi interactions and to determine how rickettsiae survive within phagocytic cells. Flow cytometry, microscopic analysis, and LDH release demonstrated that R. akari and R. typhi caused negligible cytotoxicity in mouse peritoneal macrophages as well as in macrophage-like cell line, P388D1. Host cells responded to rickettsial infection with increased secretion of proinflammatory cytokines such as interleukin-1beta (IL-1beta) and IL-6. Furthermore, macrophage infection with R. akari and R. typhi resulted in differential synthesis and expression of IL-beta and IL-6, which may correlate with the existence of biological differences among these two closely related bacteria. In contrast, levels of gamma interferon (IFN-gamma), IL-10, and IL-12 in supernatants of infected P388D1 cells and mouse peritoneal macrophages did not change significantly during the course of infection and remained below the enzyme-linked immunosorbent assay cytokine detection limits. In addition, differential expression of cytokines was observed between R. akari- and R. typhi-infected macrophages, which may correlate with the biological differences among these closely related bacteria.

Purpose: The efficacy of shock wave lithotripsy and percutaneous stone removal for the treatment of symptomatic lower pole renal calculi was determined., Materials and Methods: A prospective randomized, multicenter clinical trial was performed comparing shock wave lithotripsy and percutaneous stone removal for symptomatic lower pole only renal calculi 30 mm. or less., Results: Of 128 patients enrolled in the study 60 with a mean stone size of 14.43 mm. were randomized to percutaneous stone removal (58 treated, 2 awaiting treatment) and 68 with a mean stone size of 14.03 mm. were randomized to shock wave lithotripsy (64 treated, 4 awaiting treatment). Followup at 3 months was available for 88% of treated patients. The 3-month postoperative stone-free rates overall were 95% for percutaneous removal versus 37% lithotripsy (p <0.001). Shock wave lithotripsy results varied inversely with stone burden while percutaneous stone-free rates were independent of stone burden. Stone clearance from the lower pole following shock wave lithotripsy was particularly problematic for calculi greater than 10 mm. in diameter with only 7 of 33 (21%) patients becoming stone-free. Re-treatment was necessary in 10 (16%) lithotripsy and 5 (9%) percutaneous cases. There were 9 treatment failures in the lithotripsy group and none in the percutaneous group. Ancillary treatment was necessary in 13% of lithotripsy and 2% percutaneous cases. Morbidity was low overall and did not differ significantly between the groups (percutaneous stone removal 22%, shock wave lithotripsy 11%, p =0.087). In the shock wave lithotripsy group there was no difference in lower pole anatomical measurements between kidneys in which complete stone clearance did or did not occur., Conclusions: Stone clearance from the lower pole following shock wave lithotripsy is poor, especially for stones greater than 10 mm. in diameter. Calculi greater than 10 mm. in diameter are better managed initially with percutaneous removal due to its high degree of efficacy and acceptably low morbidity.

Objectives: To define the potential role of cryosurgical ablation of the prostate (CSAP) as a treatment option for patients with localized prostate carcinoma (PCA), we performed a retrospective outcomes analysis of a large database of patients undergoing CSAP constructed from five institutions and compared this with matching outcomes from contemporary reports of patient outcomes after radiotherapy., Methods: A total of 975 patients who underwent CSAP as primary therapy from January 1993 to January 1998 with sufficient outcomes data available were identified. Patients were stratified into three groups on the basis of their clinical features. Biochemical-free survival (BFS), post-CSAP biopsy results, and post-CSAP morbidities were calculated and recorded., Results: The median follow-up for all patients was 24 months. The percentages of patients in the low, medium, and high-risk groups were 25%, 34%, and 41%, respectively. For prostate-specific antigen thresholds of less than 0.5 and less than 1.0 ng/mL, the 5-year actuarial BFS ranged from 36% to 61% and 45% to 76%, respectively, depending on the risk category. Overall, the positive biopsy rate was 18%. Morbidities included impotence in 93%, incontinence in 7.5%, rectourethral fistula in 0.5%, and transurethral resection of the prostate in 13% of patients (10% approved warming catheters versus 40% nonapproved)., Conclusions: For each risk group, the 5-year BFS and positive biopsy rate after CSAP was comparable to matching outcomes reported after radiotherapy. Morbidities also seemed comparable, with impotence rates higher and rectal injury rates lower after CSAP than after radiotherapy. These data indicate that CSAP can be performed with low morbidity and can produce cancer-related results comparable to those reported for patients undergoing radiotherapy.

Purpose: We present the experience of the North American UroLume Multicenter Study Group with removal of the UroLume endoprosthesis., Materials and Methods: A total of 160 neurologically impaired patients were enrolled in the North American UroLume Multicenter Study Group for detrusor external sphincter dyssynergia application. Analysis was performed in 2 groups of patients in which the device was removed during insertion and after implantation, respectively., Results: Device retrieval was required during insertion in 21 patients (13%) mainly due to misplacement or migration in 17. Extraction was done with minimal complications and in all but 2 cases subsequent UroLume implantation was successful. Of 158 men with the device in place 31 (19.6%) required removal. In 34 procedures 44 devices were removed, mainly due to migration. Time from implantation to removal ranged from 4 days to 66 months (mean 22 months). The UroLume was removed en bloc in 20 cases and in parts or wire by wire in 19. The majority of patients had no or minimal complications after extraction. Only 2 patients had serious temporary complications, including bleeding and urethral injury, with no lasting consequences. No malignancy developed as a result of UroLume insertion., Conclusions: While there is a potential for urethral injury and bleeding, UroLume endoprosthesis removal is largely a simple procedure with minimal complications and consequences.

Because it is more commonly discovered as a result of an incidental finding on radiologic studies, renal cell carcinoma is being diagnosed at earlier stages. Patients still, however, present occasionally with locally advanced disease. Such a case is presented in a patient who required a partial colectomy at the time of radical nephrectomy to remove all of his disease. Also reviewed is the current state of treatment options available for renal cell carcinoma, including chemotherapy, radiation therapy, immunotherapy, and surgery. Despite advances in some of these areas, the mainstay of treatment for locally advanced renal cell carcinoma remains surgery.

Purpose: The American Urological Association convened the Ureteral Stones Clinical Guidelines Panel to analyze the literature regarding available methods for treating ureteral calculi and to make practice policy recommendations based on the treatment outcomes data., Materials and Methods: The panel searched the MEDLINE data base for all articles related to ureteral calculi published from 1966 to January 1996. Outcomes data were extracted from articles accepted after panel review. The data were then meta-analyzed to produce outcome estimates for alternative treatments of ureteral calculi., Results: The data indicate that up to 98% of stones less than 0.5 cm. in diameter, especially in the distal ureter, will pass spontaneously. Shock wave lithotripsy is recommended as first line treatment for most patients with stones 1 cm. or less in the proximal ureter. Shock wave lithotripsy and ureteroscopy are acceptable treatment choices for stones 1 cm. or less in the distal ureter., Conclusions: Most ureteral stones will pass spontaneously. Those that do not can be removed by either shock wave lithotripsy or ureteroscopy. Traditional blind basket extraction, without fluoroscopic control and guide wires, is not recommended. Open surgery is appropriate as a salvage procedure or in certain unusual circumstances.

Objective: Subtypologies of schizophrenia based on cross-sectional criteria, such as the nomenclature of the DSMs, have not been successful in identifying valid diagnostic subgroups among patients with schizophrenia. A subtypology that uses criteria to classify individuals on the basis of longitudinal deficits in self-care may identify a more valid subgroup of schizophrenic patients., Method: This study describes the clinical characteristics of a group of schizophrenic patients identified on the basis of a longitudinal criterion: at least 5 years of continuous and complete dependence on others for obtaining and maintaining the basic necessities of life, including food, clothing, and shelter., Results: Sixty-one "Kraepelinian" schizophrenic inpatients, when compared to 80 non-Kraepelinian schizophrenic inpatients who were similar in years of illness, age, and education, demonstrated more severe negative symptoms and more severe formal thought disorder; yet the severity of their delusions, hallucinations, and bizarre behavior did not differ significantly. None of the Kraepelinian patients and eight non-Kraepelinian patients met DSM-III-R criteria for schizoaffective disorder., Conclusions: Data from this replication study suggest that Kraepelinian schizophrenic patients, identified on the basis of a longitudinal course characterized by severe dysfunctions in self-care, may represent an alternative, and possibly more valid, method of subtyping schizophrenia.

A gold-tip laser sleeve for a bare laser fiber has been used for Nd:YAG laser irradiation of the prostate in both the canine model and a pilot clinical series. In the animal model, irradiation was undertaken using the Ablaser catheter through an open suprapubic cystotomy, and the procedure was monitored by video endoscopy via a perineal urethrostomy. Intraprostatic heating profiles were determined using real-time interstitial thermometry. As long as no carbonization occurred, irradiation with higher wattage resulted in higher intraprostatic temperatures. The "popcorn effect" caused a superficial temperature reduction but did not alter the ability of thermal conduction to heat deeper in the prostate. A small series of patients has been treated, with good results.

Ungated lithotripsy has raised the specter of possible cardiac arrhythmias. We reviewed ungated outpatient lithotripsy performed on 82 patients to evaluate the incidence of arrhythmias encountered and time saved. All patients were chosen in a random nonselected, prospective fashion. All treatments were performed on a mobile Medstone 1050 STS lithotriptor. The incidence of arrhythmias was 21%. All but 2 arryhthmias were benign and all reversed with gating. No arrhythmias occurred during treatment of right ureteral stones. In the left ureter only 1 patient had benign premature ventricular contractions during treatment. Arrhythmias occurred at 20 to 24 kv. in 20% of patients with right renal stones and 31% with left renal stones. All arrhythmias resolved with gating. No arrhythmias were encountered at an energy level of less than 20 kv. There was no evidence of electrocardiographic changes up to 1 hour after treatment. Pharmacological manipulation to maintain a heart rate of 100 may allow a treatment time of approximately 24 minutes. With ungating the rate may reach 120, allowing for a treatment time of approximately 20 minutes. In this series average ungated lithotripsy time was 36 minutes. In comparison, the average treatment time in 20 patients undergoing gated lithotripsy was 38.7 minutes. It is not clear from this study whether persistent ungated lithotripsy would have precipitated any life threatening arrhythmias since our practice has been to terminate the procedure and re-gate the shocks at the first sign of any persistent change in cardiac rhythm. Our data indicate that ungated lithotripsy with the Medstone device is safe when simple monitoring rules are followed.

The American Urological Association Nephrolithiasis Clinical Guidelines Panel recommendations for managing struvite staghorn calculi are based on a comprehensive review of the treatment literature and meta-analysis of outcome data from the 110 pertinent articles containing viable, unduplicated data. The panel concluded that the 3 most significant outcome probabilities are those of being stone-free, undergoing secondary unplanned procedures and having associated complications. Panel guideline recommendations for most standard patients are that neither shock wave lithotripsy monotherapy nor open surgery should be a first-line treatment choice but that a combination of percutaneous stone removal and shock wave lithotripsy should be used.

The theoretical role of sigma receptors in psychosis has led to the development of selective sigma receptor ligands as potential antipsychotic agents. BMY 14802 has its most potent binding at the sigma binding site, with some degree of serotonin subtype 1A and negligible dopamine receptor binding. It is atypical of standard neuroleptics in that it does not induce catalepsy in rats. It has been shown to have efficacy in animal models of psychosis. It was hypothesized that the drug would have antipsychotic effects in humans without producing the extrapyramidal side effects typical of standard neuroleptics. We report here the results of an uncontrolled, multicenter safety and efficacy study of patients with acute exacerbations of schizophrenia treated with BMY 14802. After 1 week of single-blind placebo treatment, 28 patients were treated with BMY 14802 (up to 3000 mg/day) for up to 4 weeks. There was no significant improvement in psychiatric symptoms, as measured by the total Brief Psychiatric Rating Scale scores or Clinical Global Improvement. There were no changes in involuntary movements, as measured by the Abnormal Involuntary Movement Scale, or in extrapyramidal symptoms as measured by the Simpson-Angus Scale.

A total of 130 patients with symptomatic lower third ureteral calculi underwent 136 treatments by 43 accredited urologists. These treatments were performed at a fixed lithotripsy site and 16 mobile sites using the Medstone lithotriptor from December 1990 through January 1992. The average stone size was 8.16 x 5.14 mm. A total of 126 patients underwent a single treatment and 4 underwent multiple treatment sessions. Of the 126 patients undergoing monotherapy 10 (8%) were lost to followup, while 101 of the remaining 116 evaluable patients (87%) were stone-free with a single treatment. The 15 patients in this subgroup who were considered failures and the 4 patients who underwent multiple treatments had overall larger stone sizes. The preoperative stent placement rate was only 32%. The treatments were well tolerated by the patients. Our report confirms a high efficacy rate with the second generation bathless lithotriptor for management of lower third ureteral calculi. The importance of a stable and qualified technical team cannot be overemphasized.

A wide variety of uropathologic circumstances may necessitate intervention. All urologic interventions depend on two simple rules for success. The first is visualization (via direct-vision endoscopy or videovision endoscopy, usually in combination with external imaging via fluroscopy), as failure to visualize the area of pathology properly may compromise or doom the procedure. The second is adequate access to the urinary tract via the endoscope, which is ensured by wire, catheter, or other appropriate access device. Failure of proper access dooms interventional urologic, uroradiologic, and endourologic procedures to failure.

At many centers circumstances have dictated that extracorporeal shock wave lithotripsy (ESWL*) be performed on an outpatient (that is same-day surgery or 1-day stay) basis. At our center, Louisiana Lithotripter, Inc., which is a privately owned ESWL unit located at Tulane University Hospital, we have had the opportunity to treat patients in the inpatient and outpatient setting since inception. Since our first ESWL treatment on December 18, 1985 we have treated more than 2,500 patients. Additionally, our unit was named an American Urological Association Training Center in October 1986, resulting in more than 200 urologist, nurse and technician trainee visits. The first 1,779 cases through December 31, 1988 have been thoroughly reviewed. The rate of outpatient ESWL has increased from 22% of the first 100 cases to more than 90% of the last 100. The cumulative over-all rate reached 70%. Currently, more than 95% of our cases are planned as same-day procedures. Safe and effective outpatient ESWL is able to be performed with first generation technology, paving the way for appropriate clinical application to newer technological modalities.

The Magnetip* double J type ureteral stent has been used in a wide variety of clinical urological settings. We reviewed the use of the stent in 50 patients. In 45 patients stents were placed in conjunction with extracorporeal shock wave lithotripsy, stone manipulation, obstruction due to pregnancy or malignancy, pyeloplasty and ureteroneocystostomy. In 83 per cent of the attempts the stent was placed successfully. Retrieval with the Magnetriever* was accomplished in 86 per cent of the cases (100 per cent in female and 76 per cent in male patients). Details of stent use are described.

In 1979 a survey of selected chicken eviscerating plants was conducted to determine the levels of coliforms, Escherichia coli, and Salmonellae sp. on eviscerated chickens under current manufacturing practices. A comparison was made of the data from this survey and one conducted in 1969. The 1979 survey found that the chickens did not have a statistically significant reduced incidence of salmonella compared to chickens analyzed in 1969. Also, much of the bacterial contamination on a carcass at the end of the evisceration line was transient and was readily removed by the final spray washer. The addition of chlorine to chiller water did not appear to have an unusually beneficial effect on the microbiological quality of the chickens. In 1969, in the nine plants studied, the incidence of salmonella on chickens at the exit of the chillers was 20.5%. In 1979, in the nine plants studied, the incidence of salmonella on chickens at the exit of the chillers was 11.6%. In 1979 there was about a 45% reduction in the incidence of salmonella in eviscerated chickens in the nine plants studied compared to the incidence of salmonella in eviscerated chickens in 1969.

The authors found that growth hormone (GH) response to edrophonium was no different in 12 Alzheimer's disease patients than in eight healthy elderly subjects. Previously reported differences could be due to differences in gender or baseline GH concentrations between patients and control subjects.

At the time of manufacture, 76% of 74 sets of raw beef patties collected in 42 federally inspected establishments had aerobic plate counts of 1,000,000 or fewer/g; 84% contained 100 or fewer coliforms/g; 92% contained 100 or fewer Escherichia coli/g; and 85% contained 100 or fewer staphylococcus aureus/g (geometric means of 10 patties/set). Salmonellae were isolated from only three (0.4%) of 735 beef patties.

One hundred ninety-seven cases of priapism have been recorded in the medical files of Charity Hospital Louisiana in New Orleans from 1938-1982. One hundred seventy-two adults and 25 children were registered in this series. Ninety-three per cent of the patients with priapism were black, and 86 patients of this group underwent 93 surgical procedures. The cases of 34 patients treated between July 1, 1981, and December 31, 1982, were thoroughly reviewed. Sixteen patients had a previous history of priapism. Average delay between onset of symptoms and presentation to the hospital for treatment was thirty hours. Sickle cell screens were obtained in 28 patients and were positive in 17. Twenty-nine patients were initially treated conservatively, with 17 priapisms eventually resolving, but the remaining 12 patients required surgical intervention. Overall, 50 per cent of the 34 patients had surgery. All of the surgical cases resolved satisfactorily with the Winter procedure. Complications with this procedure were uncommon, but postoperative bandaging was the chief cause of morbidity. Follow-up for at least six months revealed comparable sexual potency (80-83%) in either conservatively or surgically managed patients.

Glomus tumor is an infrequent skin lesion and a rare lesion on the male genitalia. This is the second reported case of this lesion on the penis.

Radiology is increasingly being used as a means of postmortem identification. We have devised a shadow positioning technique by which a postmortem radiograph of a skeletal part can exactly duplicate an antemortem radiograph, thus, faciliating identification by comparison of the antemortem and postmortem radiographs. The antemortem radiograph can be of any skeletal part and taken in any position.