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An excerpt from the book "Cancer: A Medical and Spiritual Guide for Patients and Their Families," by William A. Fintel and Gerald R. McDermott is presented.

The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Herein, we describe the synthesis and the structure−activity relationships of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]imidazoles as novel TRPV1 antagonists. Compound 46ad was among the most potent analogues in this series. This compound was orally bioavailable in rats and was efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. Compound 46ad also reversed thermal hyperalgesia in a model of inflammatory pain, which was induced by complete Freund's adjuvant (CFA).

A prospective study was established to identify the incidence of vesicoureteral reflux in the siblings of patients with reflux. Of 78 patients with reflux 104 siblings were screened with an awake voiding cystogram and 34 (32 per cent) were found to have reflux. Of these 34 siblings 25 (73 per cent) had no abnormal voiding symptoms or history of urinary tract infection. The highest incidence of reflux was found in the siblings of those patients with radiographic evidence of renal scarring. Early detection and followup in this high risk group may be a vital tool in determining more about the natural history of vesicoureteral reflux and its relationship to renal damage.

Detrusor and/or urethral sphincter dysfunction is associated with increased failure or complication of ureteral reimplantation. A group of 400 children who underwent ureteral reimplantation was reviewed and the failure rate was determined. Those patients in the primary reflux category who failed were reviewed in detail for voiding dysfunction. Excluding technical error or ureteral dysfunction, the greatest risk for failure or complication of ureteral reimplantation seems to be related to detrusor and/or urethral sphincter dysfunction. Voluntary detrusor-sphincter discoordination seems particularly prevalent in this high risk group. The findings are discussed in relation to the over-all management of these patients.

• The pathogenetic roles of idiopathic renal hypercalciuria and absorptive hypercalciuria in children with urolithiasis have not yet been determined. Oral calcium loading studies were performed in 21 children with unexplained calcareous urolithiasis. Thirteen children, aged 20 months to 17 years, were found to have renal hypercalciuria after an overnight fast (urinary calcium-urinary creatinine [UCa/UCr] ratio in milligrams, >0.21). Four children were found to have absorptive hypercalciuria. In this group, fasting UCa/UCr values were normal (SEM, 0.12 ± 0.02); however, UCa/UCr values were elevated (SEM, 0.31 ± 0.01) after the oral calcium load. Serum parathyroid hormone values were normal in all children with hypercalciuria. Urinary calcium excretion was normal in four patients. These data indicate that hypercalciuria may frequently occur in children with urolithiasis and that detailed metabolic evaluation is warranted in children with kidney stone disease.(Am J Dis Child 1982;136:675-678)

The critical weight hypothesis in relation to menarche, which is known as the Frisch-Revelle model, has been examined. Since, in eight samples, girls reached menarche at weights spanning a 71.4-kg (157-lb) range, Frisch and Revelle's concept of a critical weight of 47 to 48 kg (104 to 106 lb) cannot be applied meaningfully to individuals. Neither can the suggestion of an invariant mean weight be accepted, because significant differences occur among the mean menarcheal weights for several samples of normal white girls. Finally, when stature is held constant, there is some evidence that girls who reach menarche at younger ages are heavier than those who begin menstruating at older ages. Apparent reductions in variability when the estimated amount of total body water is used instead of body weight may result from statistical artifacts associated with regression analysis.

The cycloaddition reaction of 2,4-dinitrophenylsulfinylpropadiene with several nitrones has been investigated. The initial 3+2-cycloadduct readily undergoes a subsequent 2,3-sigmatropic rearrangement.

A prospective study was begun more than 10 years ago to identify the incidence of vesicoureteral reflux in the siblings of patients with reflux. A total of 354 siblings of 275 index patients was screened with a voiding cystourethrogram for the presence of reflux. Of the siblings tested 119 (34%) were found to have reflux, including 75% who were asymptomatic. Reflux was present in a significant percentage of younger siblings. No correlation with index patient reflux grade, sex or established renal damage could be related to the likelihood of sibling reflux. A slightly higher rate of reflux was found in the female siblings of female index patients, which is a variation from the initial study. The incidence of renal damage was significantly reduced in the siblings with reflux compared to the index patients, which was also true in the youngest patients, who are believed to be the most susceptible to reflux-mediated renal damage. Sibling reflux screening can be justified due to a high percentage of siblings found to have reflux without symptoms and a significant decrease in renal damage compared to the index (less than 5 years old) is still advisable, although children. Additional information will be needed before the genetic transmission of reflux can be clarified.

A polyurethane foam (PUF) sponge was mounted in a cassette sampler and evaluated as a sorbent for the collection of hexamethylene diisocyanate (HDI) monomer and HDI-based oligomers. Recovery studies indicated 112 ± 34% average recovery of HDI monomer and 92 ± 9% and 97 ± 25% average recovery of HDI-based oligomers when using impregnated PUF sponges. The PUF sponge was also evaluated during actual spray-painting operations. In a series of side-by-side sampling events, an impinger filled with 1-(2-methoxyphenyl)piperazine (MOP) in toluene was compared directly with a cassette sampler containing a PUF sponge impregnated with MOP or 1-(9-anthracenylmethyl)piperazine (MAP) in dimethyl sulfoxide (DMSO). For the analysis of HDI-based oligomer, there is no significant difference (p < 0.05, n = 7) in the air concentration when sampling with either the PUF sponge cassette or the impinger. The results are significant because they indicate that a PUF sponge, which is more convenient than an impinger, may be used for the collection of HDI-based oligomer generated during spray-painting operations.

Compound LY335979 is a P-glycoprotein inhibitor currently entering phase I clinical trials for potential reversal of multidrug resistance to cancer chemotherapy. In early exploratory studies, LY335979 was found to be rapidly transformed in incubations with liver microsomes from rats, dogs, monkeys, and humans. Although the parent compound was completely metabolized, no prominent metabolite peaks were observed. One peak did appear early in the time course, but it did not increase over time. In another preliminary experiment, rats were treated iv with [3H]LY335979 (prepared for pharmacology studies), and urine and bile fractions were collected. Analysis of the urine by reverse-phase HPLC with UV and radioactivity detection revealed that almost all of the material eluted with the solvent front. More than half the radioactivity in bile was accounted for by two peaks eluting earlier than the parent compound (the rest eluted at the solvent front). With both bile and the incubations with microsomes, initial attempts to isolate metabolites were not successful. There was also evidence in both systems of products derived from cleavage of LY335979 (by both further metabolism and degradation). LC/NMR was thus used to analyze materials directly in their respective matrices. An N-oxide metabolite (LY389551) formed by oxidation of the quinoline nitrogen was identified in the microsomal incubations; in bile, three glucuronide metabolites were identified, all of which were conjugates of products formed by oxidation of the quinoline ring of LY335979. There have been few reports in the literature of LC/NMR analysis of bile, which is a more complex matrix than either urine or microsomal suspensions. However, the HPLC techniques developed in this work for the HPLC/UV and LC/MS analyses of LY335979 metabolites in the microsomal matrix and in bile proved readily adaptable for LC/NMR. Using a 500-MHz instrument, basic 1H NMR spectra could be obtained in 2-3 hr with approximately 100 ng of material in the LC/NMR microprobe. With approximately 1.5 microg of material injected onto the column, 1H-1H correlation spectroscopy spectra could be acquired overnight. Along with LC/MS data, the LC/NMR technique facilitated direct identification of a number of metabolites of LY335979 at a point at which their identification by traditional methods would not have been pursued.

In many ways, the management of urethral stricture disease in children parallels that in adults, but striking differences exist. The technical demands made because of the small size of the strictures and the delicacy of the tissues involved certainly provide more of a challenge. Newer instrumentation, improved techniques, and increased experience in children are helping us to meet these challenges. Visual urethrotomy should be considered the initial treatment of choice for anterior urethral strictures, and urethroplasty should be reserved for treatment failures. Attention to technical detail and proper patient preparation will ensure optimum results from urethroplasty. Posterior urethral strictures as a result of pelvic injury can be influenced by proper initial management but remain an open surgical disease of considerable challenge.

ObjectivesThis is a report of five cases of abnormal fetal genitalia detected by routine prenatal ultrasound.MethodsRetrospective review was conducted to identify all cases of abnormal fetal genitalia identified by routine obstetrical ultrasound at our institution in which postpartum follow-up was available.ResultsFive cases of prenatal sonographically diagnosed abnormal fetal genitalia were confirmed postnatally. The abnormalities include ambiguous genitalia, severe hypospadias with unilateral cryptorchidism, megalourethra, and concealed penis. In all cases, other anomalies were discovered during the prenatal ultrasound.ConclusionsPrenatal ultrasound may detect a variety of abnormalities of the fetal genitalia.

Experimental results for flexural wave propagation in elastic beams of circular cross sections resulting from very sharp impacts are presented. It is noted that a well-defined wave system precedes the main pulse. The experimental results are correlated with theoretical predictions from both the Pochhammer-Chree and Timoshenko theories.

A theoretical analysis of the turbulent operation of the visco seal is presented. The resulting turbulent sealing equation correlated well with test data. It is shown, that good sealing capability can be obtained over a wide range of geometrical variables. It was also found that for shaft diameters over 1 inch, curvature effects are small; and that within the accuracy of the test data, the sealing capability is independent of thread location, shaft or sleeve. Power loss for seals of length to diameter ratio greater than one can be conservatively estimated by treating the seal as a smooth shaft rotating in a close clearance sleeve and neglecting the grooves.

Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor (ER) in vitro assays. X-ray crystal structures of SERBA-1 in ER and help explain observed -selectivity of this ligand. SERBA-1 in vivo demonstrates involution of the ventral prostate in CD-1 mice (ER effect), while having no effect on gonadal hormone levels (ER effect) at 10× the efficacious dose, consistent with in vitro properties of this molecule.

Ketorolac has been used to provide effective postoperative analgesia in children and decreases hospitalization for pediatric patients undergoing ureteroneocystostomy. However, it can cause severe side effects, including increased bleeding and renal insufficiency, which can be devastating in a child. Little has been reported on the safety of ketorolac by evaluating creatinine, hematocrit and complications.

Ureteral calculi were found in 5 children who were receiving or had recently completed remission induction therapy for acute leukemia or lymphoma. All 5 patients had abdominal or back pain and 3 had gross hematuria. The diagnosis of urolithiasis was suggested by excretory urograms that showed obstructive uropathy (4 patients) and by computerized tomography scans that demonstrated ureterovesical obstruction (1 patient with acute renal failure and anuria). With a single exception the calculi were not associated with urinary tract infections. Chemical analyses in the 2 patients tested indicated that the stones were composed of calcium, in contrast to the uric acid and xanthine compositions of stones in earlier studies of patients with leukemia or lymphoma. Factors that might have predisposed our patients to calculi formation include corticosteroid therapy, immobilization owing to bed rest and urinary alkalization. Other possible contributing factors were urinary stasis (2 patients) and a familial tendency for renal calculi to develop (2). There was no evidence of idiopathic hypercalciuria in either patient tested. Prompt detection of urolithiasis in children undergoing induction chemotherapy for a malignant disease may avoid potentially serious consequences from urinary tract obstruction.

Diurnal incontinence secondary to dysfunctional voiding is a problem that is commonly encountered by the pediatric urologist. We have observed that reflux is more common in these children and hypothesized that urinary tract infection would influence the rate of reflux as well as the rate of significant urinary tract abnormalities, such as renal scarring. We prospectively evaluated 308 incontinent children with a voiding cystourethrogram and upper tract studies. Of these patients 162 (53%) had had previous culture proved urinary tract infection, while 146 (47%) had no history of infection. A total of 90 patients (29%) had an abnormal voiding cystourethrogram, which demonstrated reflux in all but 1. Among the patients with a history of urinary tract infection reflux was found in 34% compared to 23.3% in those with no history of urinary tract infection (p = 0.82). Five patients had significant cortical scarring, of whom 4 had grade III or greater reflux along with urinary tract infection. We conclude that urinary tract infection is not helpful in determining which patients with dysfunctional voiding will exhibit vesicoureteral reflux but it is important in detecting significant upper tract abnormalities, such as renal scarring. We discuss appropriate evaluation in children who present with incontinence secondary to dysfunctional voiding with or without urinary tract infections.