Optimised paediatric CT dose at a tertiary children's hospital in Japan: a 4-y single-centre analysis.

Since diagnostic reference levels (DRLs) for children are not currently established in Japan, the authors determined local DRLs for the full range of paediatric CT examinations in a single tertiary care children's hospital. A retrospective review of 4801 CT performance records for paediatric patients (<15 y old) who had undergone CT examinations from 2008 to 2011 was conducted. The most frequent examinations were of the head (52 %), followed by cardiac (15 %), temporal bone (9 %), abdomen (7 %), chest (6 %) and others (11 %). Approximately one-third of children received two or more CT scans. The authors' investigation showed that mean CTDIvol and DLP for head, chest and abdomen increased as a function of age. Benchmarking of the results showed that CTDIvol, DLP and effective dose for chest and abdomen examinations in this hospital were below average, whereas those for the head tended to be at or slightly above average of established DRL values from five countries. The results suggest that CT examinations as performed in a tertiary children's hospital in Japan are well optimised.

Lack of high-dose radiation mediated prostate cancer promotion and low-dose radiation adaptive response in the TRAMP mouse model.

Cancer of the prostate is a highly prevalent disease with a heterogeneous aetiology and prognosis. Current understanding of the biological mechanisms underlying the responses of prostate tissue to ionizing radiation exposure, including cancer induction, is surprisingly limited for both high- and low-dose exposures. As population exposure to radiation increases, largely through medical imaging, a better understanding of the response of the prostate to radiation exposure is required. Low-dose radiation-induced adaptive responses for increased cancer latency and decreased cancer frequency have been demonstrated in mouse models, largely for hematological cancers. This study examines the effects of high- and low-dose whole-body radiation exposure on prostate cancer development using an autochthonous mouse model of prostate cancer: TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP). TRAMP mice were exposed to single acute high (2 Gy), low (50 mGy) and repeated low (5 × 50 mGy) doses of X rays to evaluate both the potential prostate cancer promoting effects of high-dose radiation and low-dose adaptive response phenomena in this prostate cancer model. Prostate weights and histopathology were examined to evaluate gross changes in cancer development and, in mice exposed to a single 2 Gy dose, time to palpable tumor was examined. Proliferation (Ki-67), apoptosis, DNA damage (γ-H2AX) and transgene expression (large T-antigen) were examined within TRAMP prostate sections. Neither high- nor low-dose radiation-induced effects on prostate cancer progression were observed for any of the endpoints studied. Lack of observable effects of high- or low-dose radiation exposure suggests that modulation of tumorigenesis in the TRAMP model is largely resistant to such exposures. However, further study is required to better assess the effects of radiation exposure using alternative prostate cancer models that incorporate normal prostate and in those that are not driven by SV40 large T antigen.

False-positive TUNEL staining observed in SV40 based transgenic murine prostate cancer models.

The TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) and LADY (Probasin-large T antigen transgenic mouse) mice are widely used autochthonous models of prostate cancer. Both models utilise probasin promoters to direct androgen-regulated expression of oncogenic SV40 specifically to epithelial cells of the mouse prostate. The oncogenic processes and phenotypes which result mimic many features of human prostate cancer, making these transgenic mouse models useful experimental systems. The terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP in situ nick end labelling (TUNEL) assay is a commonly used method for the detection of cells undergoing apoptosis. In this study, we demonstrate false-positive TUNEL staining in frozen prostate tissue from TRAMP and LADY mice, which was not observed in non-transgenic control animals and is not due to non-specific binding of labelled-dUTP substrate. The false-positive signal co-localised with large SV40 T-antigen expression. False-positive signal was apparent using multiple commercial TUNEL kits with different detection systems. These results caution against the use of the TUNEL assay for detection of apoptosis in frozen prostate tissue of large T-antigen based autochthonous transgenic models of prostate cancer.

The neurosteroid allopregnanolone modulates oxytocin expression in the hypothalamic paraventricular nucleus.

Virgin, ovariectomized rats exposed to 2 wk of sequential estradiol (E(2)) and progesterone (P) followed by P withdrawal have increased hypothalamic oxytocin (OT) mRNA and peptide levels relative to sham-treated animals. This increase is prevented if P is sustained. In the central nervous system, P is metabolized to the neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), which exerts effects by acting as a positive allosteric modulator of GABA(A) receptor/Cl(-)-channel complexes. In the present study, ovariectomized rats that received sequential E(2) and P for 2 wk followed by P withdrawal were administered allopregnanolone at the time of P withdrawal. Hypothalamic and plasma allopregnanolone concentrations, serum E(2) and P concentrations, and hypothalamic OT mRNA levels were measured at death. Steroid-induced increases in OT mRNA were attenuated in animals treated with allopregnanolone at the time of P withdrawal. The results suggest that allopregnanolone plays an important modulatory role in steroid-mediated increases in hypothalamic OT.

Time course of induction of oxytocin messenger ribonucleic acid levels in the hypothalamic paraventricular nucleus of ovariectomized rats following gonadal steroid administration.

The nonapeptide oxytocin (OT) is important for uterine contractility at parturition, milk ejection during lactation, and the induction of maternal behavior. OT messenger ribonucleic acid (mRNA) levels increase in the paraventricular and supraoptic nuclei (PVN and SON) of late pregnant and lactating rats and are modulated by the steroid milieu that accompanies these states. Specifically, sequential exposure to estradiol (E2) and progesterone (P) followed by P withdrawal 48 hrs prior to sacrifice increases PVN, and to a lesser but significant degree, SON OT mRNA. To better define the time course of induction of OT mRNA levels following P withdrawal, ovariectomized Sprague-Dawley rats were treated with empty or steroid-filled capsules. On day 1, animals received an E2-filled or empty capsule, followed by P-filled or empty capsules on day 3. On day 14, P-filled or empty capsules were removed and animals were sacrificed 24, 36, or 48 hrs later. The hypothalamic PVN were analyzed for OT mRNA by in situ hybridization histochemistry. Significant differences in PVN OT mRNA were found among the groups (P<0.0001, Kruskal-Wallis). Animals in the 48 hr (P=0.007) and 36 hr (P=0.005), but not the 24 hr, steroid-treated groups had significantly increased OT mRNA relative to their respective sham-treated cohorts (Mann-Whitney U test). The relative abundance of PVN OT mRNA differed among the steroid-treated groups (Kruskal-Wallis, P<0.0003), with highest levels at 48 hr. We conclude that increases in PVN OT mRNA occur by 36 hrs, and are highest at 48 hrs, after P withdrawal in the E2-primed rat. Future studies will determine if OT-mediated changes in behavior or physiology that surround parturition are related to these changes in OT mRNA.

The absent cryptorchid testis: surgical findings and their implications for diagnosis and etiology.

On surgical exploration for impalpable testes, there is often found nothing or a nubbin of tissue at the end of the spermatic vessels. This situation is commonly referred to as an absent testis. Controversy exists on how to establish correctly this diagnosis and the degree of investigation required. In addition, there is disagreement concerning whether an absent testis results from early torsion or endocrinopathic event. What is accepted is that the spermatic vessels are singularly important in establishing testis location. In this study, the pathological findings of 117 cases of absent testis diagnosed by surgical exploration at our hospital were reviewed. This diagnosis represented 10% of 1,225 patients explored for cryptorchidism from 1985 to 1991. Average patient age at operation was 26.8 months (range 5 months to 14 years). Of these children 78 (67%) presented with an impalpable left testis. At operation 3 patients (3%) underwent laparoscopy only, while all others had groin exploration with or without transperitoneal exposure to ensure identification of spermatic vessels. In 110 cases surgical specimens or nubbins were excised. Pathological study of these remnants revealed vas deferens in 89 cases (81%), epididymal tissue in 40 (36%) and small amounts of seminiferous tubules with germinal elements in 7 (6.4%). Only 26 specimens (24%) had sufficient vascular tissue present to be suggestive of spermatic vessels. A significant number showed the presence of calcification (35.5%) and hemosiderin (30%) deposits within the remnant. A subset of patients with absent testis possesses testicular tissue of presumed increased malignant potential. Therefore, surgical exploration with spermatic vessel identification and remnant removal is the gold standard for the diagnosis and treatment of the absent testis. The surgeon continues to be responsible for spermatic vessel identification, since the vessels may be recognized at pathological examination in less than 25% of the cases. Also, the common finding of calcification and hemosiderin lends weight to the torsion etiology over endocrinopathy for an absent testis.

Endoscopic incision of ureteroceles: intravesical versus ectopic.

A total of 51 children, mostly less than 2 years old, underwent endoscopic incision of ureteroceles as a primary form of treatment. In 73% no further surgery was required. Of the patients 19 were diagnosed by prenatal ultrasound, with a urinary tract infection the usual presenting symptom in the remainder. Of 27 intravesical cases endoscopic incision resulted in decompression of the ureterocele in 93%, with preservation of upper pole function in 96%, and secondary surgical procedures were required in 7%. Reflux was created in 18% and it persisted in 2 of 4 patients. Of 24 cases of ectopic (extravesical) ureteroceles incision resulted in decompression in 75%, with upper pole function preserved in 50%. Reflux was created in 47% and a secondary surgical procedure was performed in 50%. Preservation of upper pole function was significantly better for intravesical versus ectopic ureteroceles (p < 0.01), and the requirement for secondary surgical procedure was greater with ectopic ureteroceles (p < 0.01). Three patients had intermittent bladder outlet obstruction following the incision and required further surgery. The 2 different techniques for incision of intravesical and ectopic ureteroceles are described. The role of endoscopic incision in the overall management of ureteroceles is confirmed by this review, and the need for partial nephroureterectomy may diminish.

Urethral stones: US for identification in boys with hematuria and dysuria.

There are multiple causes for hematuria in infants and children. When hematuria is accompanied by dysuria, however, one should focus attention on the lower urinary tract. Although ultrasound (US) is a well-established method for assessing the kidneys and bladder, little attention has been focused on its use for evaluating urethral abnormalities, since voiding cystourethrography or retrograde urethrography usually is used. In the cases of two young boys, sonography aided in the identification of clinically unsuspected urethral stones. US evaluation of the urethra is now included as an integral part of urinary tract sonography in male patients with hematuria accompanied by dysuria.

Managing apparent ureteropelvic junction obstruction in the newborn.

A total of 97 newborns with apparent ureteropelvic junction obstruction was evaluated from mid 1984 to 1989. Evaluation and management are described. Of these patients 39 with an affected kidney showing good initial differential function (greater than 35%) by diethylenetriaminepentaacetic acid scan and 2 showing diminished function (less than 35%) were followed nonoperatively. Six patients (15%) eventually required pyeloplasty for diminishing function (4), urinary tract infections (1) or symptoms of colic (1). The 4 patients with diminishing function improved after pyeloplasty to at least the initial level. A total of 12 patients with good initial function (greater than 35%) of the affected kidney underwent early pyeloplasty (within 6 weeks of diagnosis). They were compared to the similar group of patients managed nonoperatively and followed by sequential renal scans. Eventual changes in percentage differential function in the nonoperative and early surgery groups were +2.8% and +4.1%, respectively. Changes in extraction factor were +0.8% (nonoperative group) and +0.9% (surgery group). No statistically significant difference was found. In the kidney with apparent ureteropelvic junction obstruction and good function, an initial nonoperative approach with sequential renal scan followup and pyeloplasty as needed appears to be reasonable and has resulted in no permanent loss of function.

An absent testis is associated with contralateral testicular hypertrophy.

Surgical exploration was done in 109 boys ages birth through 9 years with unilateral impalpable testes by physical examination under anesthesia. Of the patients 51 (47%) had an absent testis and 58 had intra-abdominal testes. At open biopsy of the contralateral descended testis the 3 dimensions of the exposed testis were recorded and testicular volume was calculated. The mean volume of the contralateral descended testes of boys with an absent testis was greater than that of boys with intra-abdominal testes at all ages. The differences were significant (p = 0.0019 to 0.0117) from birth through year 4 but not from years 5 through 9. However, the standard deviations ranged from 27 to 74% of the means, and there was broad overlap of the volumes of the 2 groups. These findings indicate that, although the volume of the contralateral descended testis of boys with an absent testis is significantly greater than that of boys with intra-abdominal testes, the volume of the contralateral descended testis is not a reliable criterion for differentiating an absent testis from an intra-abdominal testis in a boy with a unilateral impalpable testis. Surgical exploration continues to be the method of choice for making the diagnosis of an absent testis.

Is lamina propria matrix responsible for normal bladder compliance?

Immunohistochemistry using monoclonal and polyclonal antibodies to extracellular matrix proteins is a highly sensitive tool for the characterization of matrix components. For the first time in the normal and noncompliant human bladder we have used antibodies to collagen types I, III and IV, and elastin to provide morphological correlation with mechanical properties noted clinically. In the normal bladder elastin and collagen types I and III showed intense localization in the lamina propria with modest localization in the detrusor layer. In contrast, lamina propria staining in the noncompliant bladder was essentially unchanged, while there was intense localization within the detrusor layer. Significantly, this intense localization consisted of collagen type III and elastin with little increase in type I. Type IV collagen is associated with basement membranes and individual smooth muscle cells, and shows commensurate increase in specimens with muscle hypertrophy and/or hyperplasia. These observations suggest that in the normal bladder the lamina propria may be a major structural capacitance layer with the smooth muscle covering it. The collagen fibers of the lamina propria may gradually unfold during filling, thus, accounting for normal compliance while in the noncompliant bladder the capacitance layer shifts outward to the infiltrated smooth muscle, thus, preventing the normal expansion of the lamina propria. The smooth muscle infiltration consists of a deposition of collagen type III and elastin with little increase of collagen type I, and it results in a loss of compliance. The pattern of localization would suggest that the smooth muscle is responsible for this accumulation.

Lithogenic properties of enterocystoplasty.

Calculi formed in 26 of 87 patients (30%) following augmentation enterocystoplasty, of which 23 formed within the reservoir, at a mean interval of 25 months postoperatively. The calculi were composed principally of triple phosphates suggesting an important etiological role of bacteriuria and the urease reaction. Open cystolithotomy was the most successful means of removing the calculi.

Early postnatal testicular maldevelopment in cryptorchidism.

It has been previously postulated that many cases of cryptorchidism are manifestations of a forme fruste of hypogonadotropic hypogonadism. In support of this theory the earliest postnatal histological abnormality in cryptorchid testes demonstrated by this morphometric study of semithin microscopic sections of testicular biopsies was hypoplasia of the Leydig cells, which was obvious from the first month of life. The second abnormality, defective transformation of gonocytes into adult dark spermatogonia, was significant from early in life. No reduction in the mean number of germ cells was detected in the first 7 months of life. The abnormal persistence of the untransformed gonocytes resulted in a total germ cell count that was similar to normal controls until the seventh month, when secondary degeneration of untransformed gonocytes led to a decrease in the total germ cell count. These findings are compatible with the hypothesis that the blunted neonatal surge of gonadotropins previously demonstrated in cryptorchid boys triggers a cascade of hormonal and secondary histological abnormalities that may culminate in a reduced fertility potential in adults. Early replacement hormonal therapy deserves further investigation as a rational approach to the treatment of germ cell maldevelopment and reduced fertility potential associated with cryptorchidism.

Gonadal differentiation: a review of the physiological process and influencing factors based on recent experimental evidence.

The sexual differentiation of a gonad is determined in normal embryology by the presence or absence of the TDF gene, a short segment of DNA localized near the tip of the short arm of the Y chromosome. Under the stimulus of this gene, the somatic cells of the genital ridge differentiate into Sertoli cells and secrete anti-müllerian hormone. This hormone inhibits the germ cells from entering meiosis and may well also trigger the formation of the primary sex cords. Once the Sertoli cells are formed, further differentiation of the gonad is independent of the TDF presence, although this gene may further contribute to the normal functioning of the male gonad. In true hermaphroditism the normal regulation of the gonadal differentiation is missing. Gonadal differentiation may revert to a more primitive evolutionary level at which the rate of growth of the gonad determines its sexual direction. When this exceeds a certain threshold a testis may develop despite the absence of the TDF gene.

Structural genitourinary defects detected in utero.

Fetal genitourinary anomalies are detected with increasing frequency due to the large numbers of fetuses that undergo screening ultrasonography (US) for nonspecific indications. One hundred seventy-seven patients were evaluated for fetal urinary abnormalities over a 2-year period. Fetal hydronephrosis accounted for 154 (87%) of the cases, with the remaining diagnoses including multicystic dysplastic kidney, autosomal recessive polycystic kidney disease, and renal agenesis or hypodysplasia. Ureteropelvic junction obstruction was the most common postnatal anatomic abnormality (29%), with a large number of cases of prenatally diagnosed hydronephrosis resolving either prenatally (33%) or postnatally (24%). Prenatal US findings were retrospectively analyzed with regard to the degree of hydronephrosis at different stages of gestation. Data showed that there is a gradual rise in anteroposterior renal pelvic diameter during gestation and that there is a correlation between this diameter and the ultimate renal outcome in regard to surgical repair. This information can provide guidance in making recommendations to parents and physicians.

Paratesticular rhabdomyosarcoma: results of therapy in 18 cases.

The management of paratesticular rhabdomyosarcoma has evolved more slowly than that for testicular germ cell tumors, mainly due to its lower incidence and the lack of standardized treatment protocols. With gradual refinements in staging and therapy the prognosis has improved. Between 1960 and 1988, 18 patients 2 to 18 years old were treated at the Children's Hospital. Management consisted of inguinal orchiectomy, staging evaluation and retroperitoneal lymph node dissection, followed by chemotherapy and radiotherapy according to the stage of the disease. In 11 patients (61%) the disease was confined to the scrotum, while 7 presented with spread to the retroperitoneal lymph nodes, including 3 children with more distant metastases. Histological study revealed predominantly embryonal characteristics except for 1 alveolar cell type. Chemotherapy consisted of actinomycin D in 2 patients, vincristine, actinomycin D and cyclophosphamide in 2, pulse vincristine, actinomycin D and cyclophosphamide in 10, and doxorubicin plus vincristine, actinomycin D and cyclophosphamide in 4. A total of 17 patients remain free of disease (median followup 4 years) with 1 death. The actuarial survival without relapse and over-all survival rate are 89 and 94%, respectively. We conclude that paratesticular rhabdomyosarcoma represents a favorable subgroup of rhabdomyosarcoma.

Prognosis of patients with stage D1 prostate carcinoma following radical prostatectomy with and without early endocrine therapy.

Early endocrine therapy after radical retropubic prostatectomy was compared to radical prostatectomy alone (nonearly endocrine therapy) for the treatment of carcinoma of the prostate with lymph node metastases. Our retrospective analysis demonstrated that the 2 cohorts were similar with respect to patient age, Gleason sum score, seminal vesicle invasion, lymph node involvement, tumor volume and pathological stage of the primary tumor. The cause-specific survival of the entire group was 84% at 60 months and 78% at 98 months. The cause-specific curves for the early and nonearly endocrine therapy group were not significantly different (p less than 0.194), although the estimated 9-year survival rates were 91 and 71%, respectively. Survival free of disease was significantly prolonged in the early endocrine therapy group (p less than 0.030), with a 9-year estimated rate free of disease of 67% versus 32% in the nonearly endocrine therapy group. Followup prostate specific antigen serum levels were analyzed and the value as a progression marker is discussed. These data suggest that a radical operation plus early endocrine therapy is effective palliation in selected patients with low volume lymph node metastases, producing clinical survival free of disease in most patients.