A 'cure' for Down syndrome: what do parents want?

Recent advancements in molecular genetics raise the possibility that therapeutics or a 'cure' for Down syndrome (DS) may become available. However, there are no data regarding how parents of children with DS perceive the possibility of mitigating specific manifestations such as the intellectual disability (ID) associated with DS, or curing the condition entirely. To explore these issues, we distributed a questionnaire to members of the Lower Mainland Down Syndrome Society in British Columbia, Canada. Questionnaires were completed by 101 parents (response rate=41%). A majority (61%) viewed the possibility of reversing ID in DS positively, but only 41% said that they would 'cure' their child of DS if it were possible. Twenty-seven percent of respondents said they would not 'cure' their child, and 32% were unsure if they would 'cure' their child. The most commonly cited motivation for opting for a 'cure' was to increase their child's independence. However, parental attitudes' towards a 'cure' for DS were complex, affected by ethical issues, perceived societal values, and pragmatic factors such as the age of the individual and long-term care-giving burden. These findings could be used by healthcare professionals supporting families who include a member with DS and to direct future research.

Long-term followup after endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer in patients with neurogenic bladder.

PURPOSE: Subureteral injection of dextranomer/hyaluronic acid copolymer is a minimally invasive method to treat vesicoureteral reflux. We report short and long-term success in treating secondary vesicoureteral reflux in patients with neurogenic bladder dysfunction or severe voiding dysfunction. MATERIALS AND METHODS: We performed a retrospective chart review of all subureteral injection procedures done to identify patients with neurogenic bladder or severe voiding dysfunction. Short (less than 12 months) and long-term vesicoureteral reflux results for patients and ureters were recorded. Preoperative urodynamics and radiographic findings were reviewed. Preoperative factors were evaluated to identify patients with greater chances of success. RESULTS: A total of 12 patients (17 ureters) were identified (10 with neurogenic bladder and 2 with Hinman syndrome). Short-term success (no vesicoureteral reflux) was achieved in 50% of patients and 58% of ureters. At a median followup of 4.5 years (range 1 to 9) success decreased to 35% of ureters. Overall, long-term success was found in 25% of patients who were free of vesicoureteral reflux and required no additional surgery. Of the patients 41% required additional urological surgery for vesicoureteral reflux or related conditions. CONCLUSIONS: With long-term followup many patients who had initial improvement in vesicoureteral reflux ultimately experienced treatment failure and recurrence of reflux. At a median of 4.5 years 25% of patients with neurogenic bladder and vesicoureteral reflux were successfully treated with endoscopic injection of dextranomer/hyaluronic acid copolymer.

Depression during pregnancy: the potential impact of increased risk for fetal aneuploidy on maternal mood.

Depression during pregnancy can have serious consequences for families. Indications of fetal aneuploidy can induce maternal stress, a risk factor for depression. Few studies have assessed symptoms of depression in pregnant women soon after they receive results indicating increased risk for fetal aneuploidy. We compared symptoms of depression in women who had increased risks for fetal aneuploidy with two other groups of pregnant women at similar gestational ages: controls, and women taking antidepressant medications (MEDS). Eighty-one women attending the British Columbia (BC) Medical Genetics (MG) Program regarding positive maternal serum screens or ultrasound soft marker findings completed the Edinburgh Postnatal Depression Scale (EPDS). Control (n = 41) and MEDS (n = 41) groups were recruited from the community or the BC Reproductive Mental Health program. A threshold score of 12 on the EPDS was used to calculate percentages of women likely to be depressed. Mean EPDS scores were compared using anova, followed by post-hoc tests. In the control, MG, and MEDS groups, 2.4%, 35%, and 52.4% of women, respectively, scored above 12. Mean EPDS score was significantly higher in the MG group than in the control group (p < 0.0001). These results suggest a place for depression screening in prenatal genetic counseling.

Factors associated with delay in undescended testis referral.

INTRODUCTION: Undescended testis (UDT) is one of the most common congenital disorders and is associated with infertility and testicular cancer. Multiple guidelines internationally have recommended orchiopexy by 18 months. Multiple large retrospective studies published in the last decade have found persistent delay in timing of orchiopexy. OBJECTIVE: The aim of the study was to determine timing at which UDTs are referred at the tertiary pediatric hospital and assess factors that are associated with delay in UDT referral. STUDY DESIGN: Based on clinical observations and previous data, a series of clinical and socio-economic variables were constructed to design a prospective database. All patients who underwent orchiopexy for UDT from March 1, 2017, to August 31, 2018, were reviewed for demographic and clinical data. Referral appointments after 18 months were considered delayed. Factors associated with delay in UDT referral were analyzed using univariate and multivariate analysis with logistic regression. RESULTS: One hundred seventy-eight patients underwent orchiopexy for UDT. The median age was 44 months, and 64% of them had delay in referral. On univariate analysis, normal birth testicular examination, diagnosis of 'retractile testicle,' long gap without seeing pediatrician, diagnosis by a new physician, and primary language non-English were associated with delayed UDT referral. On multivariate analysis, delayed referral was associated with normal testicular examination at birth, history of 'retractile testis,' diagnosis not by the regular primary care provider, and other health or social issues that may have led to delay. DISCUSSION: This is the first prospective study analyzing timing of referral for boys with cryptorchidism. It was found that timing of treatment of UDT with orchiopexy has not improved over the last decade. Major causes in delay in referral may be due to poor of education of families and lack of routine testicular examinations by referring providers. Secondary ascent may account a significant number of delayed orchiopexy cases. CONCLUSION: Most patients at Doernbecher had delayed referral of cryptorchidism. Factors associated with delay were determined. To improve treatment of cryptorchidism, quality-based interventions and the importance of education and routine testicular examinations need to be focused on.

Viral vector delivery in solid-state vehicles: gene expression in a murine prostate cancer model.

BACKGROUND: Although there are increasingly more clinical trials involving gene therapy, efficient gene transfer remains a major hurdle to success. To enhance the efficiency of delivery of viral vectors in gene therapy protocols, we evaluated the effect of various matrices to act as a vehicle for recombinant virus during intratumoral injection. METHODS: The ability of several vehicles (catgut spacer, polyglycolic acid, chromic catgut, and gelatin sponge matrix) to deliver the canarypox virus ALVAC to the cells of the murine prostate cancer cell line RM-1 was studied in vitro and in vivo. ALVAC recombinants encoding the murine cytokines interleukin 2 (IL-2), interleukin 12 (IL-12), and tumor necrosis factor-alpha (TNF-alpha) were used to assess enhancement of antitumor activity after intratumoral inoculation. Confirmatory experiments were conducted by use of another mouse prostate cancer cell line, RM-11, and a mouse bladder cancer cell line, MB-49. All statistical tests were two-sided. RESULTS: The gelatin sponge matrix proved to be the most effective solid-state vehicle for delivering viral vectors to cells in culture. In addition, this matrix statistically significantly enhanced expression of ALVAC-delivered reporter genes in tumor models when compared with fluid-phase delivery of virus (P =.037 for the RM-1 model and P =.03 for the MB-49 model). Statistically significant growth inhibition of established tumors was observed when a combination of the three recombinant ALVAC viruses expressing IL-2, IL-12, and TNF-alpha was delivered with the matrix in comparison with 1) fluid-phase intratumoral injection of the ALVAC recombinants, 2) no treatment, or 3) treatment with parental ALVAC (all P<.05). CONCLUSIONS: Viral vector delivery in a solid-state vehicle resulted in improved recombinant gene expression in vivo and translated to greater inhibition of tumor growth in an immunotherapy protocol for heterotopic tumor nodules. The efficient delivery of reporter genes described herein may prove useful in many solid tumor gene therapy protocols.

Substrate polarization by residues in delta 5-3-ketosteroid isomerase probed by site-directed mutagenesis and UV resonance Raman spectroscopy.

delta 5-3-Ketosteroid isomerase (KSI: EC 5.3.3.1) of Pseudomonas testosteroni catalyzes the isomerization of delta 5-3-ketosteroids to delta 4-3-ketosteroids by the stereospecific transfer of the steroid 4 beta-proton to the 6 beta-position, using Tyr-14 as a general acid and Asp-38 as a base. Ultraviolet resonance Raman (UVRR) spectra have been obtained for the catalytically active double mutant Y55F + Y88F, which retains Tyr-14 as the only tyrosine residue (referred to as the Y14(0) mutant), and the Y14F mutant, which has 50,000-fold lower activity. The UVRR results establish that binding of the product analog and competitive inhibitors 19-nortestosterone or 4-fluoro-19-nortestosterone to the Y14(0) mutant does not result in the formation of deprotonated Tyr-14. The UVRR spectra of the steroid inhibitors show large decreases in the vinyl and carbonyl stretching frequencies on binding to the Y14(0) enzyme but not on binding to the Y14F enzyme. These changes cannot be mimicked by protonation of the steroids. For 19-nortestosterone, the vinyl and carbonyl stretching frequencies shift down (with respect to the values in aqueous solution) by 18 and 27 cm-1, respectively, on binding to Y14(0) KSI. It is proposed that the changes in the steroid resonance Raman spectrum arise from polarization of the enone moiety via the close proximity of the charged Asp-38 side chain to the vinyl group and the directional hydrogen bond between Tyr-14 and the 3-carbonyl oxygen of the steroid enone. The 230-nm-excited UVRR spectra do not, however, show changes that are characteristic of strong hydrogen bonding from the tyrosine hydrogen. It is proposed that this hydrogen bonding is compensated by a second hydrogen bond to the Tyr-14 oxygen from another protein residue. UVRR spectra of the Y14(0) enzyme obtained using 200 nm excitation show enhancement of the amide II and S Raman bands. The secondary structure of KSI was estimated from the amide II and S intensities and was found to be low in alpha-helical structure. The alpha-helix content was estimated to be in the range of 0-25% (i.e., 10 +/- 15%).

Early and late risk of mitral valve replacement. A 12 year concomitant comparison of the porcine bioprosthetic and prosthetic disc mitral valves.

A consecutive series of 706 mitral valve replacements was performed from January, 1972, to January, 1984. The follow-up ranged from 6 to 150 months with a mean of 50 and a median of 43 months. Seven percent (50) of the patient were lost to follow-up. There were 243 men and 463 women, whose ages ranged from 17 to 86 years (mean 58). A porcine bioprosthetic valve was implanted in 528 patients (514 Hancock and 14 Carpentier-Edwards valves) and a prosthetic disc valve in 178 patients (102 standard disc Björk-Shiley, 34 Beall, and 42 Harken disc valves). Seven patients were in Functional Class II, 325 in Class III, and 374 in Class IV. A concomitant operative procedure was performed in 253 of the 706 patients (36%). Mitral regurgitation was the primary hemodynamic lesion in 363 and mitral stenosis in 343. Operative mortality figures were as follows: 77 of 706 (11%) for the overall group, 34 of 453 (7.5%) for isolated mitral valve replacement, 30 of 169 (17.5%, p = 0.001) for mitral replacement plus coronary bypass, 49 of 528 (9%) for the bioprosthetic valve group, and 28 of 178 (16%) for the prosthetic disc valve group (p = 0.01). After the operation, 262 patients were in Functional Class I, 99 in Class II, and 18 in Class III. The long-term survival rate was significantly lower in patients who had an associated procedure (45% +/- 6%), who had mitral regurgitation rather than mitral stenosis (53% +/- 5% versus 67% +/- 4%) (p = 0.002), who were in Functional Class IV rather than Classes I to III (51% +/- 4% versus 70% +/- 4%) (p = 0.001), and who received a prosthetic disc valve rather than a bioprosthesis (40% +/- 6% versus 67% +/- 4%) (p = 0.001). Thromboembolic rates were significantly higher with prosthetic valves than with bioprosthetic valves (4.6% +/- 0.22% versus 2.4% +/- 0.5% per patient-year of follow-up), and the incidence of anticoagulant-related hemorrhage was significantly higher in the prosthetic valve group (1.65% versus 0.43% per patient-year). Primary valve dysfunction was significantly more common in the bioprostheses (1.23% versus 0.40% per patient-year).(ABSTRACT TRUNCATED AT 400 WORDS)

Blood gas pH and pulmonary response to the inhalation of low osmolar contrast media iopamidol and ioxaglate.

Effects of inhalation of diluted low-osmolar ionic ioxaglate and nonionic iopamidol 200 water-soluble radiographic contrast media on neonatal pig lung were evaluated. Our purpose was to assess the suitability of these substances for the radiologic investigation of upper gastrointestinal problems in human neonates in whom aspiration may occur. We used two-week-old baby piglets weighing 2.5-3.5 kg as the experimental model because they are similar in weight and size to a human neonate. The effects of intratracheal instillation of isosmolar contrast media were evaluated using the parameters of (1) blood gas exchange, (2) clinical status, (3) radiology, and (4) histopathology. The piglets showed no clinical or radiologic abnormality; blood gas exchange, initially impaired, rapidly returned to normal. Long-term (four days) follow up showed mild, self limiting but persistent infiltrates in the lungs at histology. We conclude that these diluted contrast media are suitable for upper gastrointestinal examination in neonates.

Inotropic response of the salvaged myocardium after acute coronary occlusion.

We determined the response of the reperfused myocardium to inotropic stimulation with dobutamine hydrochloride. The middle part of the left anterior descending coronary artery (LAD) was occluded in 15 greyhounds for 3 hours. Group 1 (N = 8) was reperfused for 3 hours in the beating, working heart. Group 2 (N = 7) was put on cardiopulmonary bypass (CPB) for 1 hour, received 500 ml of potassium cardioplegia in the aortic root and in the area of ischemia through an internal mammary-LAD graft, and the LAD was reperfused off CPB for 3 hours. After 3 hours of reperfusion, dobutamine was given at 10 micrograms/kg/min for 20 minutes. Regional myocardial function was determined with subendocardial ultrasonic crystals in the area of ischemia and in the base of the heart; segmental contractility was determined from the ratio of peak left ventricular pressure to end-systolic segment length; and global contractility was determined by the slope of the ventricular pressure wave at a developed pressure of 40 mm Hg. Measurements were made prior to LAD occlusion (control), at the end of 3 hours of reperfusion (6 hours from the beginning of occlusion), and after 20 minutes of dobutamine infusion. Dobutamine infusion improved segmental function in all animals compared with 3 hours of reperfusion. The study shows that the reperfused myocardium responds favorably to inotropic stimulation after 3 hours of occlusion and 3 hours of reperfusion, and that the contractile response both to reperfusion and to inotropic stimulation is greatly affected by the method of reperfusion.

The effects of cavity smear layer removal on experimental marginal leakage around amalgam restorations.

Unvarnished freshly-packed dental amalgam restorations leak initially. However, with time, a marginal seal is usually effected. It is not known whether the smear layer which forms during cavity preparation is associated with this leakage pattern. This study was undertaken to evaluate experimental marginal leakage around amalgam restorations (left in situ for one and 12 wk) which had been placed in cavities prepared with and without removal of the smear layer in vital and devitalized teeth. The cavities were obturated with two types of dental amalgams, a conventional and a dispersed-phase amalgam. The excised teeth restorations were subjected to a fluorescent dye marginal leakage experiment. All of the short-term specimens leaked severely, but some of the long-term specimens displayed significant sealing properties. No significant differences were found between the two types of amalgams. However, the non-vital tooth specimens and cavities without smear layers displayed significantly improved sealing properties.

Treatment of esophageal cancer: the continued need for surgical resection.

We conclude that preoperative radiotherapy and chemotherapy is very likely to improve the length of survival in patients with squamous cell carcinoma undergoing surgical resection and decreases the incidence of symptomatic local recurrence requiring additional palliative treatment. A favorable tumor response to adjuvant therapy, however, did not significantly improve the survival curves in our study, does not guarantee complete tumor regression, and should not be cited as a basis for elimination of esophagectomy in treatment protocols. Adenocarcinoma treated with surgical resection has a better prognosis than similarly treated squamous cell carcinoma, but has a poorer prognosis than squamous cell carcinoma treated with preoperative adjuvant therapy and surgical resection.

Factors predicting failure of medical therapy for gastric ulcers.

We reviewed the charts of all patients admitted with a diagnosis of gastric ulcer from January 1970 to December 1980. Multiple risk factors were recorded in patients receiving medical treatment and compared in those patients successfully treated medically versus those requiring operation after a failed course of medical treatment. One hundred patients were treated medically without surgical intervention, and 34 patients underwent operation after medical therapy failed. Significant risk factors in patients requiring operative therapy included smoking (p = 0.03), multiple trauma and sepsis (p = 0.02), large ulcers (p = 0.03), and multiple ulcers (p = 0.02). We have identified a set of factors associated with a high risk of failure of medical therapy. Patients with any of these risk factors may be treated most effectively by a limited trial of medical therapy with close follow-up. If their ulcer disease does not respond readily to standard medical therapy, they should be considered for early elective surgery.

A phase II study of [90Y] yttrium-capromab pendetide in the treatment of men with prostate cancer recurrence following radical prostatectomy.

There is currently no curative therapy for men who have disseminated prostate cancer following failed radical prostatectomy. The purpose of this trial was to investigate systemic radioimmunotherapy in these men. Eight patients with occult metastatic prostate cancer following radical prostatectomy as evidenced solely by a rising serum PSA and evidence of soft tissue lesions outside the prostatic fossa detected by an [111I]indiumcapromab pendetide scan received an infusion of 10 mg of capromab pendetide labeled with 9 mCi/m2 of [90Y]yttrium. Serum PSA was used to measure response rate. There were no complete or partial responses by PSA criteria. Significant unexpected bone marrow toxicity developed in the first 6 of 8 patients treated. The last two patients received co-infusion of edetate calcium disodium in an effort to decrease marrow suppression. In these two patients less marrow toxicity was seen. Repeat 111In-capromab pendetide scans were uninterpretable due to grossly altered whole-body biodistribution of the radioimmunoconjugate. Retrospective analysis of serial PSA values after closure of the study showed a decrease in the log slope PSA for seven of eight patients following radioimmunotherapy, with a statistically significant change in the mean log slope (p = 0.01). The clinical significance of this small but measurable change is uncertain. We conclude that radioimmunotherapy for occult metastatic prostate cancer using 90Y-capromab-pendetide at the dose described does not lower serum PSA, is associated with significant hematologic toxicity, and leads to complexation of the immunoconjugate following subsequent capromab pendetide infusion.

Scanning electron microscope observations on the tubule content of freeze-fractured peripheral vervet monkey dentine (Cercopithecus pygerythrus).

Pulp tissue in the incisors was fixed in situ by perfusion. Cervical thirds of the tooth crowns were excised by sectioning the teeth transversely and cryofractured through the long axis of the tooth in a bucco-lingual mid-axial plane to expose the dentine from the pulp to the enamel-dentine junction. Specimens were freeze-dried and the fracture surfaces examined by scanning electron microscopy. Flattened tubular processes were noted protruding from the open ends of transversely fractured dentinal tubules in the outer third of the dentine. These structures were present in fractured tubules to within 20 microns of the enamel-dentine junction. These observations suggest that odontoblast processes traverse the full length of dentinal tubules.

Neuroradiologic evaluation of sacral abnormalities in imperforate anus complex.

Neurologic impairment and sacral spinal anomalies are a finding in children with imperforate anus. The neurologic deficits previously had been considered static rather than progressive. Recent experience at this institution has documented the frequent association of imperforate anus patients having bony sacral and other spinal deformities with progressive neurologic dysfunction. These deficits are related to underlying spinal cord anomalies, which may be amenable to neurosurgical correction. To investigate the nature and frequency of such lesions, spinal cord imaging was done in these patients. From July 1976 to June 1985, 106 patients with imperforate anus were screened with plain radiographs of the sacral spine; 37 (35%) patients had abnormalities. Of these, 26 have been evaluated with a variety of spinal cord imaging techniques, including magnetic resonance imaging (18), digital metrizamide myelotomography (14), computed tomography (10), metrizamide myelography (5), or ultrasound (4). Four patients were lost to follow-up, and seven have not yet been studied. Fifteen of the 26 patients (53%) had one or more abnormal studies. Thirteen were considered to have progressive dysfunction with operable lesions and have undergone neurosurgical correction. At follow-up, there was improved leg function in five patients and improved bladder function in two patients. No patient had additional neurologic deficits after surgery. Because of the high incidence of progressive but potentially correctable myelodysplasias in patients with coexisting anorectal and sacral anomalies, routine radiographic screening of the spine is recommended, followed by spinal cord imaging and neurosurgical evaluation if warranted.

The role of laboratory animals in dental research.

In dental research, in common with other forms of scientific research, the use of laboratory animals is necessary to carry out many investigations that may not be undertaken on man, and to control biological variability. In South Africa the main experimental animals used in dental research are rats and vervet monkeys, although other species such as dogs and baboons have been used. This paper lists examples of published dental research carried out in laboratory animals in South Africa in the fields of bone healing, dental caries, dental materials, growth studies, oral cancer, oral mucosa and periodontal disease investigations.

Current status and future options for the development of laboratory animal technology and the training of laboratory animal technicians.

Laboratory animal technology has evolved into a specialised field of expertise which is associated with the production, care and use of laboratory animals in biomedical teaching and research. A survey of laboratory animal facilities and supporting personnel was undertaken to assess the uses of laboratory animals in relation to the administrative and technical staffing of animal facilities. The results of this study indicate that there is a need for training in laboratory animal science at both the technical and professional levels. Options for the development of formal training in laboratory animal technology are reviewed.

The Japanese quail (Coturnix coturnix japonica) as a laboratory animal.

The use of the Japanese quail as a laboratory animal was first reported in 1959. Since then this species has been increasingly used as an avian model for biomedical research. A quail colony was recently established in the Dental Research Institute to provide adult birds for teratogenicity and toxicity studies. These birds are not widely used for biological research in South Africa at present. The housing, husbandry, breeding and nutrition of this species is described, together with the biomethodology which is applicable to this species.

Design and use of an inhalation chamber for air pollution studies in small animals.

Environmental chambers provide a convenient means of studying the toxicology of gases in experimental animals. The specialised equipment needed for these studies is not commercially available. This paper reports on the design, construction and performance of a simple, and inexpensive, inhalation chamber and gas mixing unit for air pollution studies in small laboratory animals. Provision has been made for controlling the mixing of gases, the ventilation rate, the even distribution of gases in the chamber and for the removal of vented gases to prevent the hazard of air pollution in the laboratory animal facility. No significant differences were found between the food and water consumption and body mass gain of a group of rats housed in the chamber for 5 days and a control group housed im similar cages located in a rodent room and managed under conventional laboratory conditions. The chamber fulfills all the requirements for an animal inhalation system.