Amelioration of non-motor dysfunctions after transplantation of human dopamine neurons in a model of Parkinson's disease.

BACKGROUND: Patients suffering from Parkinson's disease (PD) display cognitive and neuropsychiatric dysfunctions, especially with disease progression. Although these impairments have been reported to impact more heavily upon a patient's quality of life than any motor dysfunctions, there are currently no interventions capable of adequately targeting these non-motor deficits. OBJECTIVES: Utilizing a rodent model of PD, we investigated whether cell replacement therapy, using intrastriatal transplants of human-derived ventral mesencephalic (hVM) grafts, could alleviate cognitive and neuropsychiatric, as well as motor, dysfunctions. METHODS: Rats with unilateral 6-hydroxydopamine lesions to the medial forebrain bundle were tested on a complex operant task that dissociates motivational, visuospatial and motor impairments sensitive to the loss of dopamine. A subset of lesioned rats received intrastriatal hVM grafts of ~9 weeks gestation. Post-graft, rats underwent repeated drug-induced rotation tests and were tested on two versions of the complex operant task, before post-mortem analysis of the hVM tissue grafts. RESULTS: Post-graft behavioural testing revealed that hVM grafts improved non-motor aspects of task performance, specifically visuospatial function and motivational processing, as well as alleviating motor dysfunctions. CONCLUSIONS: We report the first evidence of human VM cell grafts alleviating both non-motor and motor dysfunctions in an animal model of PD. This intervention, therefore, is the first to improve cognitive and neuropsychiatric symptoms long-term in a model of PD.

Targeted agents in ovarian cancer.

Despite recent advances in the treatment of ovarian cancer, a large majority of women with this diagnosis will die from recurrence of their disease. Targeted therapies, in the form of monoclonal antibodies and small molecule tyrosine kinase inhibitors have significantly altered the management of many solid tumors and hematologic malignancies. No such agents have been approved by the US FDA for use in ovarian cancer, although Phase II data suggests excellent single-agent activity of some of these drugs. Antiangiogenic agents in combination with chemotherapy are being evaluated in Phase III clinical trials, both in the adjuvant setting and in recurrent platinum-sensitive disease. Poly-ADP-ribose polymerase inhibitors are promising agents in BRCA1/2-mutated breast and ovarian cancers. Ongoing clinical trials are exploring the anti-tumor effect of poly-ADP-ribose polymerase inhibitors administered as single agents and in combination with chemotherapy. Many other new drugs are in earlier grades of development. In this article, we review the state of the art in targeted therapies for ovarian cancer and identify future directions for their development in the management of this often devastating disease.

Uptake of invasive testing following a positive triple test for Down's syndrome. Are midwives different counsellors compared with obstetricians?

A review of the uptake rate of diagnostic tests following a positive triple test was undertaken in the two maternity units of the Hull and East Yorkshire NHS Trust. In one unit, midwives were actively involved in counselling and in the other, counselling was performed by Consultant obstetricians. During the study period, there were 721 (7.1% positive rate) positive triple tests. Of these, 212 (29.4%) and 509 (70.6%) were counselled by midwives and Consultant obstetricians, respectively. There was no significant difference in uptake of amniocenteses or chorionic villous sampling with respect to the counsellor with an uptake of 60.4% in the midwife counselled group compared with 67.6% in the Consultant counselled group (p = NS). We believe the determinants of the uptake rate of a diagnostic test are patient centred if adequate counselling is provided. Midwives will continue to play a role in counselling and should be encouraged to do so to reduce the burden on obstetricians.

Phase II trial of carboplatin and infusional cyclosporine with alpha-interferon in recurrent ovarian cancer: a California Cancer Consortium Trial.

The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 +/- 291 microg/mL (mean +/- SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 microg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.

Uterine effects of tamoxifen: a prospective study.

The purpose of the study was to evaluate tamoxifen-associated changes in the vagina and uterus in postmenopausal breast cancer patients. Between June 1994 and December 1998, 45 patients enrolled in a prospective study before commencing tamoxifen therapy. Patients with endometrial thickness >5 mm or neoplasia were excluded. Transvaginal ultrasonography, vaginal maturation indexes (VMI), and endometrial biopsy were performed at baseline and repeated at 6 months (n= 42), 1 year (n= 39), 2 years (n= 32), 3 years (n= 26), 4 years (n= 19), and 5 years (n= 15). For the 39 patients followed for 1 year, VMI (% parabasal/intermediate/superficial) was 21/71/8 at baseline compared with 1/90/9 at 1 year (P value = 0.0008/0.001/0.78). At baseline, mean endometrial thickness and uterine volume were 2.6 mm and 64 cm(3), respectively, compared with 5.8 mm and 84 cm(3) at 1 year (P= 0.0002, 0.002). At baseline, 80% of patients had atrophic endometrium and 9% proliferative endometrium compared with 61% and 26% at 1 year, respectively (P= 0.04). No cases of endometrial hyperplasia or adenocarcinoma were detected. Findings observed at 6 months persisted through 5 years of follow-up. Tamoxifen exerts a weak estrogenic effect on the vagina and uterus in highly prescreened postmenopausal women without preexisting endometrial pathology.

Changes in cholinergic and purinergic neurotransmission in the diabetic rabbit bladder.

BACKGROUND: Diabetes mellitus (DM)-associated alterations in bladder function have been attributed to changes in autonomic receptors and alterations in detrusor structure and function. The changes in cholinergic and purinergic neurotransmission in the DM rabbit bladder were evaluated. MATERIALS AND METHODS: DM was induced with alloxan in adult male New Zealand White rabbits. At 6 months, detrusor and bladder neck muscle strips were obtained and mounted in organ baths. Transmural electrical field stimulation (EFS: supramaximal voltage, 0.1 ms duration, 10 s trains) was performed in the presence of atropine (10(-6) M) or alpha, beta-methylene ATP (10(-6) M), and after adding tetrodotoxin10(-6) M. Purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components were calculated independently and compared with those from controls. RESULTS: Both normal and DM detrusor and bladder neck strips contracted in a frequency-dependent fashion in response to transmural EFS. A plot of EFS vs. detrusor contractility showed a decrease (ANOVA < 0.001) in the cholinergic nerve-mediated component, whereas the purinergic nerve-mediated component was increased (ANOVA < 0.001) in the DM detrusor compared to the control. The total EFS- and KCl-induced responses were unaltered in the DM group compared to the controls. There was no difference in purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components in strips from the bladder neck for both normal and DM rabbits. CONCLUSION: These results suggest that an enhancement of purinergic and a reduction of cholinergic neurotransmission occur in the detrusor muscle of the diabetic rabbit. These changes may contribute to the pathophysiology of diabetic cystopathy.

HOXB4 overexpression promotes hematopoietic development by human embryonic stem cells.

Human embryonic stem cells (hESCs) are a potential source of hematopoietic cells for therapeutic transplantation and can provide a model for human hematopoiesis. Culture of hESCs on murine stromal layers or in stromal-free conditions as embryoid bodies results in low levels of hematopoietic cells. Here we demonstrate that overexpression of the transcription factor HOXB4 considerably augments hematopoietic development of hESCs. Stable HOXB4-expressing hESC clones were generated by lipofection and could be maintained in the undifferentiated state for prolonged passages. Moreover, differentiation of hESCs as embryoid bodies in serum-containing medium without the use of additional cytokines led to sequential expansion of first erythroid and then myeloid and monocytic progenitors from day 10 of culture. These cells retained the capacity to develop into formed blood elements during in vitro culture. Consistent with the development of committed hematopoietic cells, we observed the expression of transcription factors known to be critical for hematopoietic development. We thus demonstrate successful use of enforced gene expression to promote the differentiation of hESCs into a terminally differentiated tissue, thereby revealing an important role for HOXB4 in supporting their in vitro development along the hematopoietic pathway.

Radiation exposure and the urologist: what are the risks?

PURPOSE: Endourology is established in urology practice with routine use of fluoroscopic guidance. Medical personnel are rarely exposed to direct radiation exposure but secondary exposure occurs via radiation scatter. There are few reports on scatter radiation exposure and the subsequent risk to medical personnel involved in urological fluoroscopic procedures. We review the risks of scatter radiation exposure to medical personnel with reference to the routine use of fluoroscopic imaging in urological practice. MATERIALS AND METHODS: We measured staff radiation exposure during a series of ureteral endourological procedures using LiF:Mg,Ti thermoluminescent dosimeters placed at the extremities of the operating surgeon, the assistant and the scrub nurse. Doses for percutaneous nephrolithotomy (PCNL) procedures were calculated by extrapolating from the ureteral procedure thermoluminescent dosimeter data. Theoretical scattered radiation dose rates were also calculated. RESULTS: The average ureteral procedure fluoroscopy time was 78 seconds with an exposure rate of 71 kV, 2.4 mA. The surgeon received the highest radiation exposure with the lower leg (11.6 +/- 2.7 microGy) and foot (6.4 +/- 1.8 microGy) receiving more radiation than the eyes (1.9 +/- 0.5 microGy) and hands (2.7 +/- 0.7 microGy). For a predicted annual caseload of 50 ureteral cases, the dose received does not exceed 0.12% of the Ionising Radiations Regulations 1999 annual dose limit for adult workers. Radiation exposure during PCNLs is higher but does not exceed 2% of the annual dose limits even if 50 PCNLs are performed annually. CONCLUSIONS: Fluoroscopic screening results in radiation exposure of medical personnel. The estimate of maximum scatter radiation exposure to the surgeon for 50 PCNL procedures a year did not exceed 10 mGy. This amount is less than 2% of permissible annual limits of equivalent dose to the extremities. Medical personnel should be aware of scatter radiation risks and minimize radiation exposure when involved in fluoroscopic screening procedures.

A study of radiotherapy modalities combined with continuous 5-FU infusion for locally advanced gastrointestinal malignancies.

AIM: We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS: Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS: During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS: Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.

Erectile dysfunction: an underdiagnosed condition associated with multiple risk factors.

Erectile dysfunction (ED) is a common condition with a significant effect on the quality of life. The prevalence of ED rises with increasing age and other conditions (hypertension, diabetes, ischaemic heart disease, hypercholesterolaemia and depression). The MALES study is one of the largest epidemiological surveys to investigate the prevalence of ED. This study included 27839 patients spanning eight countries. In addition to the MALES study, we review the emerging link between lower urinary tract symptoms (LUTS), benign prostatic hypertrophy (BPH) and ED, including the effect of BPH treatment on sexual function. Preliminary data from the MALES II study shows a significant cascade effect in the treatment seeking behaviour and treatment adherence of patients taking sildenafil for ED. We explore the possible reasons behind the discontinuation of oral phosphodiesterase inhibitors prescribed for the long-term treatment of ED.

Down-regulation of nitric oxide synthase in the diabetic rabbit kidney: potential relevance to the early pathogenesis of diabetic nephropathy.

OBJECTIVES: Nephropathy is a well-recognised complication of diabetes mellitus (DM). The aim of this study was to investigate the effect of DM on the density and distribution of nitric oxide (NO) synthase (NOS) in the rabbit kidney. Quantification of the NOS radioligand on slide-mounted sections was compared with the nitroblue tetrazolium reaction, where the intensity of the reaction varies with the nicotinamide adenine dinucleotide diaphorase (NADPH-d) activity of NOS. MATERIALS AND METHODS: DM was induced with alloxan in six New Zealand White (NZW) rabbits. Plasma creatinine, urea and electrolytes were monitored at monthly intervals. The kidneys were removed following 6 months of DM. Transverse serial sections were cut and low-resolution autoradiography was performed using a radioligand for NOS ([(3)H]-NOARG). Histochemical localisation of NADPH-d activity was also performed. Densitometric analysis was performed on the autoradiographs and the results compared with those obtained from six age-matched control rabbits. RESULTS: There was a significant (p < 0.01) rise in plasma creatinine levels in the diabetic rabbits, although the mean values remained within the reference range. There was a significant (p < 0.0001) down-regulation of NOS binding sites in both the cortex and medulla of the DM kidney when compared with the controls. A similar decrease in NADPH-d activity was seen in the diabetic renal cortex and medulla. In addition, NADPH-d activity also appeared to be reduced in the diabetic glomeruli when compared with controls. CONCLUSIONS: NOS binding sites and NADPH-d activity are significantly decreased in the DM renal cortex and medulla. These changes are associated with a mild deterioration in renal function and may be an early event that could subsequently play a role in the progression of DM nephropathy. Manipulating the NO pathway during the early stages of DM nephropathy may be beneficial.

Height screening at school: ineffective without high standards and adequate resources.

BACKGROUND: The Coventry Consensus in 1998 recommended a single height measurement of all children at school entry or around the age of 5 years and prompt referral of children with height <0.4th centile for further assessment, in order to identify undetected and treatable asymptomatic growth disorders. AIM: To determine adherence and practicalities of following the Coventry Consensus recommendations in a community setting and the cost implications. METHODS: Anthropometric data of all children born between September 1992 and August 1993 in the Rhondda and Taff Ely area and measured in school year September 1998 to August 1999 were obtained from the National Child Health System (NCHS) and analysed in July 2000. RESULTS: Only 1592 (67.6%) of 2354 eligible children had their height measured. The NCHS could only flag up height data <2nd centile. Only five of the 15 children with height <0.4th centile were referred initially. Height measurements were not transcribed onto centiles in 75% of the case notes reviewed. When initially recalled, six of the 15 eligible children failed to attend the referral clinic. No new growth disorder was identified in any of these children. A conservative estimate of the cost to the health authority was pound 14 550 (US23 300 dollars; 20 500 euro) per annum. CONCLUSION: The study shows poor coverage and compliance together with a lack of parental awareness that short stature could be a potential health problem even in asymptomatic children. For a low yield programme to be successful and cost effective at the national level, a near 100% coverage is required. Further training of professionals in growth measurement and interpretation along with a campaign to raise both public and professional awareness is needed.

Workplace airborne hexavalent chromium concentrations for the Painesville, Ohio, chromate production plant (1943-1971).

Hexavalent chromium [Cr(VI)] is recognized as an inhalation carcinogen, based primarily on the increased incidence of lung cancer among occupationally exposed workers. To assess the carcinogenic potency of Cr(VI), both the U.S. Environmental Protection Agency and the Occupational Safety and Health Administration have relied on data from a 1930s cohort of workers from the Painesville, Ohio, chromate production plant. However, the exposure information for this cohort has several shortcomings. In an effort to provide better exposure information, we present here recently identified historical exposure data for the Painesville workers. More than 800 measurements of airborne Cr(VI) from 23 newly identified surveys conducted from 1943 to 1971 are presented. The results indicate that the highest Cr(VI) concentrations recorded at the plant occurred in shipping (e.g., bagging of dichromate), lime and ash, and filtering operations, with maximum yearly average Cr(VI) concentrations of 8.9, 2.7, and 2.3 mg/m(3), respectively. The locker rooms, laboratory, maintenance shop, and outdoor raw liquor storage areas had the lowest average Cr(VI) air concentrations over time, with yearly average concentrations that rarely exceeded the historical and current Threshold Limit Value TLV(R) of 0.05 mgCr(VI)/m(3) (0.1 mgCrO(3)/m(3)). Concentrations generally decreased in the plant over time. The average airborne concentration of Cr(VI) in the indoor operating areas of the plant in the 1940s was 0.72 mg/m(3), that from 1957 through 1964 was 0.27 mg/m(3), and that from 1965 through 1972 was 0.039 mg/m(3). Although in some ways limited, these data are of sufficient quality to allow for exposure reconstruction for workers employed at this plant from 1940 to 1972, and to provide the basis for an improved cancer risk assessment.

Endothelin-1 and nitric oxide in the pathogenesis of urinary tract disorders secondary to bladder outlet obstruction.

Bladder outlet obstruction (BOO) is a common disorder that is associated with urinary tract symptoms. Nitric oxide (NO), synthesized by NO synthase (NOS) is a potent vasodilator that is present throughout the urinary tract and the corpus cavernosum. Endothelin-1 (ET-1) conversely is a potent vasoconstrictor peptide that is similarly distributed throughout the urinary tract. ET-1 and NO as well as possessing opposing actions regulate each other's synthesis. The disruption of the balance between ET-1 and NO is associated with various vascular pathologies. However, their potential roles in the pathogenesis of urinary tract disorders, secondary to BOO, is not well established. New Zealand White rabbits with BOO are considered to be a suitable model of the human condition. Hence, using this model, we systematically investigated the potential roles of ET-1 and NO in the pathogenesis of the various urological disorders associated with BOO. In this review we discuss the results of our studies, which support the concept that an imbalance between ET-1 and NO may be associated with the pathogenesis of urinary tract disorders secondary to BOO. We also discuss the potential clinical implications of this association. This review is based on the Bard Silver Medal Lecture given (by MAK) at the 2002 British Association of Urological Surgeons (BAUS) annual meeting.

Enhanced relaxation of diabetic rabbit cavernosal smooth muscle in response to nitric oxide: potential relevance to erectile dysfunction.

New Zealand white rabbit cavernosal smooth muscle strips (n=6) were mounted in organ baths. Relaxations to nitric oxide (10(-7)-10(-4) mol/l) were measured and the same procedure was repeated on strips from rabbits 6 months after alloxan-induced diabetes (n=6). Transverse cavernosal sections were obtained from the same penises. Low and high resolution autoradiographs were prepared using [(3)H]-L-N(G)-nitroarginine (an index of nitric oxide binding sites) and analysed densitometrically. Histochemical analysis was performed on adjacent sections using NADPH diaphorase (an index of nitric oxide synthase activity). Nitric oxide relaxed control rabbit cavernosal smooth muscle strips in a concentration-dependent manner. Diabetic rabbit cavernosal smooth muscle strips were significantly (P<0.03) more sensitive to nitric oxide (mean IC(50)=3.9 x 10(-6) mol/l). Nitric oxide synthase binding sites were localised to the cavernosal endothelium and smooth muscle. Nitric oxide synthase activity was increased in 6 month diabetic cavernosal smooth muscle. These findings suggest impairments in the L-arginine-nitric oxide pathway may play a role in the pathophysiology of diabetic erectile dysfunction.