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The Women's and Children's Hospital experience with Luque spinal fusion in Duchenne's muscular dystrophy was reviewed from its commencement in 1983 to the present with a view to assessing the clinical and radiologic outcome and safety of the procedure. Seventeen boys have undergone spinal fusion. L-rod instrumentation was used in 10, six of whom had significant problems with sitting imbalance or progression of the scoliosis or both. In seven cases, distal instrumentation was taken to the pelvis with a Galveston construct and rigid crosslinking. Apart from some progression and sitting imbalance in the L-rod group, there were few complications. In the Galveston group, pelvic obliquity was corrected by a mean of 63%, and there was better maintenance of correction. There were no pseudoarthroses or instrument failures in the Galveston group. Of the total group, four patients had forced vital capacity (FVC) values < 25% predicted, and two required ventilation postoperative (< 48 h). There were no other respiratory complications. The effect of surgery on respiratory function remains uncertain. Spinal fusion with the Luque rod construct and pelvic fixation is a safe procedure. It provided a mean correction of 60% and control of pelvic obliquity without significant postoperative deterioration. In our experience, surgery can be safely performed with FVC value down to 20% predicted. On the basis of these data, one current practice is to instrument to the pelvis with a Galveston construct and Texas Scottish Rite Hospital cross-linking.

BACKGROUND--The effect on subsequent respiratory function of spinal stabilisation for scoliosis in Duchenne muscular dystrophy is unclear. In order to clarify this clinical problem, changes in the forced vital capacity of a group of children with Duchenne muscular dystrophy who had undergone spinal surgery were measured and compared with a group of children with Duchenne muscular dystrophy who had not had surgery. METHODS--In this retrospective study 17 boys with Duchenne muscular dystrophy who underwent spinal stabilisation at a mean age of 14.9 years (surgical group) were compared with 21 boys with Duchenne muscular dystrophy who had not had surgery (non-surgical group). The mean (SD) Cobb angle of the surgical group at 14.9 years was 57 (16.4) degrees, and of the non-surgical group at 15 years was 45 (29.9) degrees. Forced vital capacity expressed as percentage predicted (% FVC) was measured in total over a seven year period in the surgical group and over 6.5 years in the non-surgical group, and regression equations were calculated. Survival curves for both groups were also constructed. RESULTS--No difference was found between spinal stabilisation (surgical group) and the non-surgical group in the rate of deterioration of % FVC which was 3-5% per year. There was no difference in survival in either group. CONCLUSIONS--Spinal stabilisation in Duchenne muscular dystrophy does not alter the decline in pulmonary function, nor does it improve survival.

The dose limiting toxicities of the short infusion trial of the dacarbazine analog, CB10-277, were nausea and vomiting which appeared to be related to the peak plasma level of the parent drug. In addition, based on mouse studies, these dose limiting toxicities occurred at a less than optimal level of the monomethyl metabolite, the presumed species required for antitumour activity. An alternative schedule that would avoid the parent drug peak plasma levels of short infusion, while possibly allowing an increase in the amount of monomethyl metabolite produced was considered. Thus, a 24 h continuous infusion schedule, repeated every 21 days was explored. Twenty-two patients received 42 courses with a dose range of 4,700-15,000 mg m-2. The dose limiting toxicity was myelosuppression (leucopenia and thrombocytopenia). Although nausea and vomiting also occurred, it was manageable with routine antiemetic therapy. Other toxicities included diarrhoea, hallucinations, malaise, muscle ache, headache and flushing and all were < or = WHO grade 2. Pharmacokinetic studies were performed with 13 courses which included all dose levels. The mean t1/2 of the parent drug was 178 min. Area under the concentration x time curve (AUC) at the highest dose for the parent drug and the monomethyl metabolite were 2,350 and 9 mM x minutes, respectively. This monomethyl metabolite AUC and the associated myelosuppression showed a more favourable comparison to the preclinical data determined in mice than the results from the short infusion trial of CB10-277. Therefore, the recommended Phase II dose and schedule of this drug was 12,000 mg m-2 given by 24 h continuous infusion.

Decarbazine is an imidazole dimethyltriazene with reproducible activity in patients with metastatic melanoma. CB10-277 is a phenyl dimethyltriazene which, like dacarbazine, requires metabolic activation to its corresponding monomethyl species for antitumour activity. In preclinical models (human melanoma xenografts and transplantable rodent tumours) CB10-277 showed a similar spectrum and level of activity when compared to dacarbazine. Pharmacokinetic studies were performed with CB10-277 in mice treated i.v. at the LD10 (750 mg m-2) and plasma analysed by HPLC. The parent drug area under the plasma concentration vs time curve (AUC) was 142 mM x minutes. Drug metabolism occurred as evidenced by the HPLC identification of the monomethyl species (AUC = 8 mM x minutes) as well as other metabolites. A Phase I trial using a short infusion with doses repeated every 21 days has been performed. Thirty-six patients received 80 courses over a dose range of 80-6,000 mg m-2. The dose limiting toxicity was nausea and vomiting which occurred in 80% of the evaluable courses > or = 900 mg m-2. The only other common side effect was a flushing or warm sensation, which occurred in over 75% of courses at > or = 1,350 mg m-2. There were no hemodynamic consequences. Responses occurred in patients with melanoma (one complete, two partial, one mixed/11), sarcoma (one mixed/6) and carcinoid (one partial/l). Pharmacokinetics were performed in 46 courses. The CB10-277 AUC increased linearly with dose (r = 0.9203, P < 0.001) up to 700 mM x minutes at 6,000 mg m-2). Evidence of CB10-277 metabolism was observed, as in mice, by detection of the monomethyl species and other metabolites. However, the plasma levels of the monomethyl species in patients (1.8 and 3.7 mM x minutes at 6,000 mg m-2) were less than those predicted from studies in mice. Despite this, antitumour activity in dacarbazine sensitive histologies was observed and additional studies with CB10-277 are recommended.

The development of new drugs in early clinical trials is currently based upon the results of preclinical antitumour and toxicity studies in animals. More recently, the use of preclinical pharmacokinetic information in mice has been proposed to also provide information that might expedite early clinical trials and more specifically phase I studies. The anthrapyrazole CI-941 was one of three chosen for phase I anticancer drug development. In addition, because of the predictability of the preclinical dose limiting toxicity and linear CI-941 pharmacokinetics in mice; a pharmacokinetically guided dose escalation scheme was attempted during the phase I trial, but had to be abandoned. 44 patients were entered who received 95 courses of treatment using a bolus injection every 21 days. The dose range was 5–55 mg/m 2 . The dose limiting toxicity was leucopenia and other toxicities, which included nausea and vomiting, mucositis, diarrhoea, alopecia and skin discolouration were either mild or manageable. Pharmacokinetic studies were performed with 27 courses. There were wide interpatient variations in the dose-AUC relationship ( r = 0.7496) that hampered application of the proposed pharmacokinetically guided dose escalation scheme as planned. No complete or partial responses were observed. The recommended phase II dose using this schedule is 50 mg/m 2 .

Comparative studies of oral and intravenous administration of tritiated dextran sulfate in rats showed markedly different distribution patterns. Following IV dosing about 50 per cent of the radioactivity was recovered in feces and urine within 24 h. The major portion of the recoverable dose was eliminated in the urine as dextran sulfate within 3 h after administration. In orally treated rats only about 32 per cent of the 3H was recovered in the feces and urine, the major fraction being associated with unabsorbed dextran sulfate in the feces. The remainder of the dose in both treatment groups has apparently distributed throughout the rat body with some accumulation in the liver, kidney and spleen. Consequently, the disposition of about 67 per cent or the oral dose could not be fully accounted for by these excretion routes. However, separation with Sephadex columns showed similarities in the 24 h plasma and urine profiles of the IV and orally dosed rats which suggest that while the oral dose was absorbed as dextran sulfate, it underwent rapid metabolism to small molecular weight products prior to entering the systemic circulation which were then widely distributed within the rat.

The aim of this paper is to document experience in the management of cases of child abuse with suspected osseous injury, at the Adelaide Children's Hospital, during the period January 1974-December 1986. The study is a retrospective review of the casenotes, radiographs and radiologists' report of 108 consecutive cases with suspected osseous injuries. Information regarding the osseous injuries sustained and the pyschosocial environment surrounding the circumstances of the patients admitted was recorded. Of 108 cases of suspected osseous injuries, 90% had confirmed osseous injury, of whom 56 cases (52%) had multiple fractures. Twenty of the 41 cases of single osseous injury were due to skull fractures. In children less than 12 months of age, long bone injuries were the most common form of presentation, and in 83% of these the injuries were multiple. Metaphyseal injury in association with other fractures was present in 14% of cases, and 8% of cases showed evidence of periosteal reaction to injury. There were two deaths during the period of this study, as a direct consequence of abuse. The main cause of death in both of these cases was the combination of cerebral haemorrhage and liver trauma. There were 10 other deaths not associated with fracture during this period. The analysis of psychosocial factors demonstrated that 48% of the children were first-born and 67% of parents were unemployed. Of the alleged abuser, the mother was known to be responsible in 50% of cases. In 10% of cases, the parent responsible for the injury admitted to the offence at the time of presentation at the hospital.(ABSTRACT TRUNCATED AT 250 WORDS) Language: en

CI-994 (N-acetyl dinaline, PD 123654) is a novel oral agent active in a broad variety of murine and human tumor xenografts. While cytotoxic in the Brown Norway (BN) rat leukemia model, growth inhibition in other murine and human tumor xenografts is predominantly cytostatic. Its specific mechanism of action remains unknown. Following CI-994 administration, inhibition of both histone deacetylation and cellular proliferation at the G1 to S transition phase of the cell cycle are observed. This Phase 1 study in patients with solid tumors was carried out to determine a maximum tolerated daily oral dose (MTD) for CI-994 administered on a chronic basis.Fifty-three patients received CI-994 daily for treatment durations ranging from 2 to 10 weeks. Dosage escalation proceeded in 2 phases; an Acute Dosing Phase (n = 11) to define the MTD for CI-994 administered over 2 weeks and a Chronic Dosing Phase (n = 29) to define the MTD for daily administration for 8 weeks. Upon completion of the Chronic Dosing Phase, a third cohort of patients (n = 13) received CI-994 at the recommended Phase 2 dose and schedule with 2 additional single doses of drug administered separated by a 1-week washout to assess the effect of food on CI-994 pharmacokinetics.Thrombocytopenia was dose limiting at the MTD of 8 mg/m2/day for 8 weeks. Other toxicities included fatigue and gastrointestinal effects such as nausea, vomiting, diarrhea, constipation and mucositis. Pharmacokinetic studies revealed that peak plasma levels and AUC's generally increased with dose and that food intake did not affect the rate or extent of drug absorption. One patient with heavily pre-treated adenocarcinoma of the lung achieved a Partial Response (PR) lasting over 2 years and 3 additional patients achieved Stable Disease (SD), 1 each with non-small cell lung, colorectal, and renal cancer.The recommended Phase 2 starting dose is 8 mg/m2/day for 8 weeks repeated after a 2-week drug-free interval.

In patients with localized prostate cancer, radical prostatectomy and radiation therapy, although effective in controlling localized disease, are often associated with significant side effects attributable to injury of adjacent tissues. Moreover, patients with metastatic disease eventually fail systemic hormonal or chemotherapy because of the development of progressive, refractory disease. In this study, we evaluated the safety and efficacy of a novel suicide gene therapy that could potentially spare normal tissue while bypassing molecular mechanisms of apoptosis resistance by using chemically inducible effector caspases to trigger apoptosis in prostate cancer cells. Initially, we compared the ability of a panel of inducible Fas signaling intermediates to kill human and murine prostate cancer cell lines. On the basis of the superior killing by downstream caspase-1 and caspase-3, replication-deficient adenoviral vectors expressing conditional caspase-1 (Ad-G/iCasp1) or caspase-3 (Ad-G/iCasp3), regulated by nontoxic, lipid-permeable, chemical inducers of dimerization (CID), were constructed. Upon vector transduction followed by CID administration, aggregation and activation of these recombinant caspases occur, leading to rapid apoptosis. In vitro, both human (LNCaP and PC-3) and murine (TRAMP-C2 and TRAMP-C2G) prostate cancer cell lines were efficiently transduced and killed in a CID-dependent fashion. In vivo, direct injection of Ad-G/iCasp1 into s.c. TRAMP-C2 tumors caused focal but extensive apoptosis without evidence for a bystander effect at the maximal viral dose (i.e., 2.5 x 10(10) viral particles/25 microl) in host animals that also received CID compared with control animals. Treatment with Ad-G/iCasp1 plus CID resulted in a transient, yet significant, reduction both in tumor growth and volume compared with tumors treated with vector but not CID (P0.035) or vector-diluent plus CID (P0.022), both of which grew more rapidly. These results demonstrate that CID-regulated, caspase-based suicide gene therapy is safe and can inhibit the growth of experimental prostate cancer in vitro and in vivo through potent induction of apoptosis, providing a rationale for further development.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

Free fat graft interposition has been used extensively in management of physeal injuries with established growth disturbances. The use of this technique as part of the management of acute physeal injuries has not been reported. Here we report on its application in acute physeal injuries, where it has prevented the formation of an anticipated physeal arrest.

We have previously shown that antibodies to CTLA-4, an inhibitory receptor on T cells, can be effective at inducing regression of transplantable murine tumors. In this study, we demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Treatment of TRAMP mice at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. Histopathological analysis revealed that treated mice had a lower tumor grade with significant accumulation of inflammatory cells in interductal spaces when treated with anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor-expressing vaccine. Vaccination of nontransgenic mice with this regimen resulted in marked prostatitis accompanied by destruction of epithelium, indicating that the immune response was, at least in part, directed against normal prostate antigens. These findings demonstrate that this combinatorial treatment can elicit a potent antiprostate response and suggest potential of this approach for treatment of prostate cancer.

The objective of the current study was to describe a multidisciplinary transition program for following young adult survivors of childhood cancer in an adult-based ambulatory medical setting and to report the late effects with grades of toxicity diagnosed in all adult survivors followed in the program.The study population was comprised of all young adult survivors (n = 96) of childhood cancer who were seen in the After the Cancer Experience (ACE) Young Adult Program prior to January 31, 1999. The median age of the survivors was 22.8 years (range, 17-34 years) and the median interval from the time of cancer diagnosis was 15.2 years (range, 6-25 years). Primary cancer groups included: leukemia, 33%; sarcoma, 24%; Hodgkin disease, 15%; non-Hodgkin lymphoma, 12%; Wilms' tumor, 9%; and other, 7%. Late effects were graded using the Common Toxicity Criteria, Version 2 (CTCv2), developed by the National Cancer Institute.Approximately 69% of the patients (66 of 96) had at least 1 late effect. Thirty-three percent of patients had a single late effect whereas 36% had/= 2 late effects. Thirty percent of patients had a CTCv2 Grade 3 or 4 late effect.The current study represents an example of a successful multidisciplinary transition program in an ambulatory, adult setting for young adult survivors of childhood cancer. Late effects of cancer treatment are common in young adult survivors, with approximately 33% being moderate to severe. Further studies are needed to modify CTCv2 with the aim of developing a reliable and valid tool to assess late effects in long term survivors of childhood cancer.

Prostate cancer is the leading form of newly diagnosed cancer cases in men in the United States. However, the molecular mechanisms contributing to the initiation, progression and ultimate development of metastatic and androgen independent disease are poorly understood. This is due in part to the difficulty in obtaining clinical samples representing early disease and the lack of animal models that recapitulate the full spectrum of the clinical disease. To this end we have developed and characterized the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model that expresses the oncogene SV40 T antigen specifically in the epithelium of the prostate. TRAMP develops spontaneous autochthonous prostate cancer compelte with distant site metastasis and can progress to androgen independent disease. Changes in the fibroblast growth factor (FGF) axis and the insulin-like growth factor (IGF) axis have been examined during prostate cancer progression utilizing the TRAMP model and these data generally support observations reproted in the clinical disease. Moreover, we report novel changes in the FGF axis and IGF axis utilizing TRAMP. Thus, TRAMP can be used as a potent tool in understanding the mechanism of prostate cancer initiation and progression.

We have characterized the temporal expression of the insulin-like growth factor (IGF) axis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model as prostate cancer progression in this model closely mimics that observed in the human disease, and the model provides samples representing the earliest stages of prostate cancer that are clinically the most difficult to obtain. We report that prostate-specific IGF-I mRNA expression increased during prostate cancer progression in TRAMP mice and was elevated in the accompanying metastatic lesions, whereas prostatic IGF-I mRNA remained at nontransgenic levels in androgen-independent disease. Expression of IGF-II mRNA, however, was reduced in primary prostate cancer, metastatic lesions, and androgen-independent disease. Expression of type-1 IGF receptor (IGF1R) mRNA, encoding the cognate receptor for both IGF-I and IGF-II, as well as type-2 IGF receptor (IGF2R) mRNA was not found to be altered during primary prostate cancer progression in intact TRAMP mice but was dramatically reduced in metastatic lesions and in androgen-independent disease. Similar to reports from clinical disease, serum IGF-I levels were observed to increase precociously in TRAMP mice early in disease progression but remained at nontransgenic levels after castration. Elevated serum levels of IGF-binding protein 2 were observed to correlate with advanced prostate cancer in the TRAMP model. Together these observations implicate IGF-I as an important factor during the initiation and progression of primary prostate cancer and provide evidence that there is a strong selection against expression of IGF1R and IGF2R in metastatic and androgen-independent disease.

The studies presented herein quantitated ductal branching morphogenesis in the anterior prostate (AP) of the newborn rat. Four parameters were measured: epithelial area, epithelial perimeter, node number, and form factor. Nine natural and synthetic androgens were tested for their effectiveness in inducing postnatal prostatic development using 808 newborn rat APs in 68 dose-response experiments. Based on these studies it was shown that testosterone (T) was slightly more effective than dihydrotestosterone (DHT) in supporting ductal branching morphogenesis in the developing rat AP. Furthermore, the activity of T could not be accounted for simply by conversion of T to DHT. Synthetic androgens, 7alpha-methyl-19-nortestosterone and methyltrienolone (R1881), which cannot be 5alpha-reduced to DHT, also induced extensive ductal branching and elicited responses less than those to T and not statistically different from those to DHT. This suggests that although DHT is sufficient for prostatic development, it is not necessary for postnatal ductal branching morphogenesis and growth of the prostate. 5Alpha-androstan-3alpha,17beta-diol was particularly potent in inducing ductal branching, eliciting a response greater than or comparable to those of T and DHT. Androsterone, androstanedione, 5alpha-androstan-3beta,17beta-diol and 5beta-androstan-3alpha,17beta-diol induced ductal branching, but to a lesser extent than either T or DHT. These studies challenge the assumption that DHT is essential for prostatic development, specifically during ductal branching morphogenesis of the neonatal rat prostate.

The purpose of this study was to determine how family physicians in the United States treat acute bronchitis in an otherwise healthy adult.A 33-item questionnaire on the diagnosis and treatment of acute bronchitis was mailed to a random sample of 500 physicians who are members of the American Board of Family Practice.Thirty-two of the 500 sampled physicians could not be located by mail; 265 of those who received the questionnaire responded. The response rate was 57% (265/468). Sixty-three percent of responding physicians indicated that antibiotics are their first choice of treatment for the otherwise healthy, nonsmoking adult with acute bronchitis. The decision to use antibiotics as the first choice of treatment did not vary by physician's sex, age, years in practice, practice location, practice type, or percentage of HMO patients. Only 6% of responding physicians reported using beta 2 agonist bronchodilators as their first choice of treatment. Physicians in this study stated that they prescribe an antibiotic 75% of the time in treating nonsmoking patients with acute bronchitis (first choice or otherwise). If the patient is a smoker, physicians reported that they prescribe antibiotics 90% of the time (F = 110.25; df = 1; P.0001). Physicians reported that for patients who smoke it takes longer for coughs to totally resolve and longer for them to return to a normal activity level than for nonsmokers.Family physicians report that antibiotics are their most common treatment for acute bronchitis in the otherwise healthy adult. Previous clinical trials have shown only marginal improvement in symptoms when patients with this condition are treated with an antibiotic. With antibiotic resistance emerging as a major global health problem, it is essential that other methods of treatment be evaluated.

The purpose of this study was to determine how family physicians in the United States diagnose acute bronchitis in otherwise healthy adults.A 33-item questionnaire on the diagnosis and treatment of acute bronchitis was mailed to a random sample of 500 physicians who are members of the American Board of Family Practice.Two hundred sixty-five physicians responded. Of those who did not respond, 32 could not be located. Of those who did respond, 10 were either retired or were practicing in another specialty. The net response rate was 56% (255/458). Responding physicians stated that character of cough and sputum production are the most important items used in diagnosing acute bronchitis. Fifty-eight percent indicated that the cough should be productive, and 60% stated that the sputum should be purulent. Seventy-two percent of respondents did not feel that wheezing or rhonchi need to be present. Younger physicians and those who selected antibiotics as their first treatment choice were more likely to define acute bronchitis as the presence of a productive cough with purulent sputum (P.05). Physicians from an academic setting were more likely to define acute bronchitis as a productive cough (P.05). Thirty-six percent of physicians from practices serving populations withor = 60% managed care patients included wheezing or rhonchi in the definition of acute bronchitis, compared with 26% of all others (P.05).Variations in the diagnosis of acute bronchitis in otherwise healthy adults can be attributed to physician age, treatment choice, and practice setting. A significant number of family physicians did not require a productive cough as part of the diagnostic criteria for acute bronchitis. This finding needs to be considered in studies evaluating treatment. Additional qualitative studies are necessary to identify other factors involved in diagnosing acute bronchitis.

To develop a syngeneic transplantable system to study immunotherapeutic approaches for the treatment of prostate cancer, three cell lines were established from a heterogeneous 32 week tumor of the transgenic adenocarcinoma mouse prostate (TRAMP) model. TRAMP is a transgenic line of C57BL/6 mice harboring a construct comprised of the minimal -426/+28 rat probasin promoter driving prostate-specific epithelial expression of the SV40 large T antigen. TRAMP males develop histological prostatic intraepithelial neoplasia by 8-12 weeks of age that progress to adenocarcinoma with distant metastases by 24-30 weeks of age. The three cell lines (TRAMP-C1, TRAMP-C2, and TRAMP-C3) express cytokeratin, E-cadherin, and androgen receptor by immunohistochemical analysis and do not appear to have a mutated p53. Although TRAMP-C1 and TRAMP-C2 are tumorigenic when grafted into syngeneic C57BL/6 hosts, TRAMP-C3 grows readily in vitro but does not form tumors. The T antigen oncoprotein is not expressed by the cell lines in vitro or in vivo. The rationale for establishing multiple cell lines was to isolate cells representing various stages of cellular transformation and progression to androgen-independent metastatic disease that could be manipulated in vitro and, in combination with the TRAMP model, provide a system to investigate therapeutic interventions, such as immunotherapy prior to clinical trials.

Organ culture methods have long been used in the study of the prostate because effects of drugs and hormones can be examined in the absence of systemic effects.Neonatal rat ventral prostates (VP) were grown on Millipore filters floating on fluid medium composed of Dulbecco's modified Eagle's medium/Ham's F-12 supplemented with insulin, transferrin, and hydrocortisone, and in the presence or absence of testosterone (T, 10(-8)M).In the presence of T, ductal lumen formation occurred, ductal branching was extensive, and basal and luminal epithelial cells were identified by immunocytochemistry based on their distinctive cytokeratin profile. In the absence of T, ductal lumen formation did not occur, basal and luminal epithelial cells failed to differentiate, and there was a marked decrease in prostatic organ size relative to glands grown with T. Interestingly, DNA synthesis, as measured by counts per min (CPM) for 3H-thymidine incorporation, showed that DNA synthesis per microgram DNA at 7 days of organ culture was not inhibited by lack of T. Androgen receptor expression is another marker of prostatic epithelial differentiation, and it occurred in both the presence and absence of T.Growth and differentiation of the neonatal rat prostate in vitro occur in a manner similar to that of the developing prostate in vivo, demonstrating that organ cultures of neonatal rat ventral prostates provide a faithful model for studying rat prostatic development and differentiation under serum-free conditions.

The xenobiotic oxidation polymorphism associated with cytochrome P450 2D6 (CYP2D6) was investigated in 152 genetically related and unrelated healthy Inuit subjects living in the High Arctic of eastern Canada. Phenotyping was based on HPLC determination of the CYP2D6-related dextromethorphan metabolic ratio in overnight urine samples after oral administration of 30 mg dextromethorphan hydrobromide. The log metabolic ratio was bimodally distributed, with three subjects classified as poor metabolizers (PMs). In subjects unrelated in the first degree, the incidence of the PM phenotype was 3 of 90 or 3.3%. PCR-based analyses of DNA for variants of the CYP2D6 gene demonstrated that the PMs of dextromethorphan had the defective allele CYP2D6*4. The estimated frequency of the CYP2D6*4 allele was 0.067-0.083, which is lower than the frequency in Caucasians but higher than the frequency in Oriental populations. The CYP2D6*3 and the CYP2D6*6 alleles were not detected in the Inuit population. The CYP2D6*10 allele was present in only four unrelated subjects, classified as extensive metabolizers (EMs), resulting in an estimated allele frequency of 0.022, which is much lower than in Oriental populations. This study demonstrated the existence of the CYP2D6 polymorphism in Canadian Inuit, while the frequencies of allelic variants of CYP2D6 point to the uniqueness of this population. Several important therapeutic drugs that are being prescribed in Arctic communities will have altered pharmacokinetics in PMs of CYP2D6.

Prostatic growth occurs through ductal elongation and branching into the mesenchyme. Ductal branching morphogenesis in the prostate is elicited by androgens via mesenchymal-epithelial interactions mediated by paracrine influences from mesenchyme. The role of keratinocyte growth factor (KGF) was investigated in the developing prostate as KGF has been suggested to be a paracrine acting factor. KGF transcripts were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in neonatal rat ventral prostates (VPs) in vivo, in VPs cultured in vitro, and in isolated VP mesenchyme. KGF receptor was detected in VP's by RT-PCR and was localized specifically to the epithelium by in situ hybridization. KGF was investigated as a potential paracrine mediator during androgen-induced prostatic development by examining neonatal rat VPs cultured for 6 days under serum-free conditions using a basal medium supplemented only with insulin and transferrin. When testosterone (10(-9) to 10(-8) M) was added to the basal medium, VPs grew and underwent ductal branching morphogenesis similar to that in situ. Neutralization of endogenous KGF with a monoclonal antibody to KGF (anti-KGF) or a soluble KGF receptor peptide inhibited androgen-stimulated VP growth (DNA content) and reduced the number of ductal end buds after 6 days of culture. When KGF (50 or 100 ng/ml) was added to the basal medium in the absence of testosterone, VP growth and ductal branching morphogenesis were stimulated. The number of ductal end buds was about 70% of that obtained with an optimal dose of testosterone (10(-8)M), and DNA content of VP's cultured with 100 ng/ml KGF was equivalent to that of glands cultured with testosterone. The stimulatory effect of KGF was partially blocked by cyproterone acetate, a steroidal anti-androgen. These data imply that KGF plays an important role as a mesenchymal paracrine mediator of androgen-induced epithelial growth and ductal branching morphogenesis in the rat VP.

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Physicians' prevention practices often differ from guidelines published by national authorities. Effective preventive services are most needed in inner city settings that suffer disproportionately from preventable diseases. This study examined the impact of a multifaceted physician prevention education program on the provision of preventive services in an inner city municipal hospital.The study used a controlled intervention comparative design at two inner city municipal hospitals--Harlem Hospital Center, New York, NY (intervention site) and Kings County Hospital, Brooklyn, NY (comparison site)--serving predominantly African-American patient populations. The intervention site received prototype materials for physicians, patients, and the office setting from the US Public Health Service's Put Prevention Into Practice campaign and a series of prevention lectures from November 1991 through April 1992. Change in physician prevention practices and knowledge was assessed by self-administered questionnaires and change in patients' reports of preventive services received was assessed by structured interviews.Physicians at Harlem Hospital Center reported a greater postintervention increase in prevention practices and demonstrated a greater increase in prevention knowledge in comparison with physicians at Kings County Hospital. Patients at Harlem Hospital Center reported receiving increased preventive services from physicians after the intervention, while patients at Kings County Hospital did not report any significant change in preventive services received.A multifaceted physician education program using prototype materials from the Put Prevention Into Practice campaign with prevention lectures significantly increased the prevention knowledge and practices reported by physicians and the preventive services reported received by patients at an inner city municipal hospital.

In an unselected series of 55 cases of slipped capital femoral epiphysis (SCFE) we observed an incidence of 25% of epiphyseal reduction, mostly unintentional. Reduction indicated physeal instability and was associated with an effusion, detected by sonography on admission, and inability to bear weight. The true prevalence of instability may be higher since an effusion was noted in 33 cases (60%) on the initial sonographic assessment. Serial radiographs showed reduction in 12 (22%), with an average change of 15.1 degrees in the head-neck angle. Serial sonography showed reduction in 7 out of 20 cases (35%), with an average change of 3.7 mm in displacement. In two cases reduction was seen on sonography but not on radiography. Of the hips which showed subsequent reduction, 12 had had a bone scan on admission; three showed initial epiphyseal avascularity but only one progressed to symptomatic avascular necrosis. All stable hips had normal epiphyseal vascularity on the initial bone scan. This indicates the importance of injury from the initial displacement in causing avascular necrosis, rather than effusion, vascular compromise or iatrogenic injury from gentle repositioning. Physeal instability in SCFE is common and should be assessed clinically on admission. It is indicated by joint effusion or inability to bear weight. A slip is very unlikely to be unstable in a child able to bear weight and with no sonographic effusion.

Pharmacokinetic studies that consisted of measuring the plasma drug profile, tissue drug distribution, and elimination in urine and feces were performed in female C57BL/6 x DBA/2 (hereafter called B6D2F1) and male B6D2F1A/2 and C57BL/6 x CH3 (hereafter called B6C3F1) mice following treatment with a 1-h i.v. infusion of the PZA, PD115934 (NSC 366140). This drug is the first of a new class of cytotoxic agents and was selected for clinical trials because of both its broad antitumor activity in vivo against murine solid tumors and human xenografts, and its in vivo toxicity profile that was predictable based on drug dose and schedule of administration. The pharmacokinetic results obtained here in mice have been used to facilitate the dose escalations during the Phase I trial and to determine pharmacokinetic drug exposure targets for its acute and sub-acute toxic effects. Plasma samples from three to four mice per time point were pooled, and then individual tissue samples from the same mice were collected at specified times following treatment. All samples were prepared using solid-phase extraction and assayed using high pressure liquid chromatography. The acute dose-limiting toxicity was neurological and occurred immediately after treatment at 300 mg/m2. The peak plasma level range at the acute maximum tolerated dose was 1040-1283 ng/ml. Thus, peak plasma levels1000 ng/ml were the acute toxicity target. Variations in the area under the plasma drug concentration x the time curve were observed that did not appear to be related to sex or age. The previously defined subacute dose-limiting toxicity was myelosuppression that occurred at a maximum tolerated dose of 600 mg/m2 (300 mg/m2 x 2) in B6D2F1 females. Thus, the area under the plasma drug concentration x the time curve in B6D2F1 females at this dose (1048 microg/ml x min) was the area under the plasma drug concentration x the time curve target. Drug levels were detected at 60 min following treatment in all tissues examined with a plasma:tissue ratio as high as 1:500. The organs with the highest levels were kidney, pancreas, liver, lung, and brain. Fecal excretion was low (range, 0.04-0.20% of the dose administered) and was not clearly different between males and females. Urinary excretion was higher (range, 5-28% of the dose administered) and did show evidence of sex-related differences, with male urinary drug excretion being higher than female urinary drug excretion. The drug was/=95% protein bound. Preliminary evidence for drug metabolism was found in urine and feces and will be further explored.

Androgen-dependent male urogenital development occurs via mesenchymal-epithelial interactions in which mesenchyme induces epithelial morphogenesis, regulates epithelial proliferation, and evokes expression of tissue-specific secretory proteins. Mesenchymal-epithelial interactions continue to be important into adulthood. For example, mesenchyme of the urogenital sinus (UGM) and seminal vesicle (SVM) induce dramatic morphologic and functional changes in various adult epithelia. Since adult epithelial cells are unquestionably responsive to mesenchymes that can elicit expression of alternative morphologic and functional phenotypes, established carcinomas might also be influenced by their connective tissue environment. In this regard, Dunning prostatic tumor has been induced by UGM or SVM to differentiate into tall columnar secretory epithelial cells. This change in cytodifferentiation is associated with a reduction in growth rate and loss of tumorigenesis. The role of soluble growth factors in the mechanism of mesenchymal-epithelial interactions is discussed.

Twenty-seven patients with Legg-Calve-Perthes disease were treated by innominate osteotomy. Satisfactory results were achieved in 96% of the patients, with a mean follow-up period of 9.3 years. Eleven patients included in assessment seven years previously were reassessed. Ten of these 11 patients showed improvement with continued growth in the shape of the affected femoral heads. A preoperative center-edge angle of less than 20 degrees is of prognostic importance. The presence or absence of a subchondral fracture before and at the time of surgery has not been found to influence the long-term results significantly.

Seventy-two patients with Legg-Calvé-Perthes disease were studied to assess the interference with proximal femoral growth as a result of the disease itself and of surgical treatment. Twenty-five patients were treated nonoperatively, 20 were treated by femoral varus derotation osteotomy, and 27 by innominate osteotomy. All patients were studied clinically for evidence of abductor weakness and leg-length discrepancy. They were also studied roentgenographically for evidence of femoral head deformity and trochanteric overgrowth. The overall results showed a 6% incidence of leg-length discrepancy greater than 2 cm after both operative and nonoperative treatment. The articulo-trochanteric distance (ATD) was less than +5 mm in 23% of patients, of which 43% had a positive Trendelenburg sign. A significantly lower mean ATD was found in patients treated by femoral varus osteotomy, which should be avoided in patients over eight years of age. The study also demonstrated a strong association between coxa magna and growth disturbance of the proximal femoral physis manifesting itself as either a leg-length discrepancy or as a low ATD. The significant effects of growth disturbance after treatment must be considered, as well as the sphericity of the healed femoral head, in the final assessment in Legg-Calvé-Perthes disease.

The technetium phosphate bone scans of 106 children with suspected septic arthritis were reviewed to determine whether the bone scan can accurately differentiate septic from nonseptic arthropathy. Only 13% of children with proved septic arthritis had correct "blind" scan interpretation. The clinically adjusted interpretation did not identify septic arthritis in 30%. Septic arthritis was incorrectly identified in 32% of children with no evidence of septic arthritis. No statistically significant differences were noted between the scan findings in the septic and nonseptic groups and no scan findings correlated specifically with the presence or absence of joint sepsis.

A new technique for evaluation of skeletal pathology is described. The use of three-dimensional reformations based on conventional computed tomographic imaging is a technique that has been used by craniofacial surgeons since 1982 and more recently by orthopedic surgeons at the Adelaide (Australia) Children's Hospital for evaluation of pediatric skeletal pathology. Four cases are presented that demonstrate our early experience with the technique. Three-dimensional reformation is an effective method of translating conventional computed tomographic scans into a readily understood three-dimensional image. We believe that the method will be of increasing value in the evaluation of pediatric skeletal pathology.

Intraocular mycotic infection is rare, and it usually necessitates enucleation of the affected eye. We recently encountered three instances of fulminating fungus endophthalmitis occurring as a postsurgical complication of cataract extraction, in which a pure culture of the Volutella species * was isolated from each of the infected eyes. We believe that these cases are the first of this kind to be reported. In two cases the infection failed to respond to conventional therapy and was terminated only by enucleation of the eye. In an effort to check the progress of infection in the third eye, a new antifungal antibiotic, amphotericin B,† was administered by parenteral, conjunctival, and intraocular routes. This clinical trial of amphotericin B for ocular infection, together with the experimental use of the antibiotic in the eyes of rabbits, is the subject of this report. Amphotericin B is a polyene antifungal antibiotic which was isolated in 1955 by

The effects of Moloney Sarcoma Virus (MSV) induced tumor growth dynamics on the blastogenic responsiveness of lymphocytes from BALB/c mice were investigated. Lymphocytes from spleen, thymus and lymph node pools were tested for responsiveness to phytohemagglutinin (PHA) and concanavalin A (Con A). Results showed a significant decrease in PHA-induced blastogenesis of all lymphocytes tested at the time of maximal tumor volume, with a return to normal responsiveness as the tumor regressed. In contrast, a differential dose dependent Con A response occurred in spleen and thymus lymphocytes. A decreased 3H-thymidine uptake occurred at optimal Con A dose, correlating with the PHA decrease. However, at a lower Con A dose an increased response was observed, beginning shortly before the PHA depression and continuing until regression of tumor began. This phenomena was not observed in lymph node lymphocytes. Based upon these observations, we suggest that the cell or cells responsible for the transient suppression of PHA responsiveness may be Con A responsive T lymphocytes.

One hundred premature femoral neck physeal closures in 430 hips with Perthes' disease have occurred in two patterns central and lateral. Abnormal physeal growth can be demonstrated early by a narrowed physeal plate with overlying avascular epiphysis and marked metaphyseal reaction below. Subsequently, a bony bridge forms between the metaphysis and epiphysis. If the physeal closure is central, the mature hip will have a short femoral neck, a relatively round femoral head, a trochanter that has overgrown the femoral head, a short leg, and a mildly deformed acetabulum. If the physeal closure is lateral, the mature hip will have a femoral head that is externally tilted as the medial neck lengthens and the lateral neck remains short, a trochanter that has overgrown the femoral head, an oval femoral head, a short leg, and a deformed acetabulum. A physeal arrest is a contraindication for a varus osteotomy because it accentuates the deformity, especially in the greater trochanter. The leg-length discrepancy may be treated by epiphysiodesis of the contralateral femur, when necessary, and the abductor muscle insufficiency may be treated by an exercise program or distal and lateral transfer of the greater trochanter.

A new treatment protocol has been developed at the Alfred I. duPont Institute by an evaluation of 480 hips affected with Legg-Calvé-Perthes disease. One hundred fifty hips have been followed up to skeletal maturity and show deformities of coxa magna (58%), coxa brevis (21%), coxa irregularis (18%), and osteochondritis dissecans (3%). Treatment is prescribed using a new classification--Class I: predeformed epiphysis (200 hips), for which treatment is needed if the patient is older than six years of age or has greater than 50% epiphyseal necrosis; Class II: deformed epiphysis prior to reossification (134 hips), for which treatment by containment is recommended; Class III: reossification (83 hips), for which reconstructive procedures may be considered if the patient is younger than seven years of age; and Class IV: mature/maturing (28 hips), in which the patients have symptoms of leg-length discrepancy, trochanteric overgrowth, osteochondritis dissecans, and degenerative joint disease. Analysis of containment methods in 192 hips reveals that Petri casts (69), Scottish Rite orthosis (44), the AIDI brace (15), varus osteotomy (34), and innominate osteotomy (30) produce comparable results.