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.

Prevention of tea-induced extrinsic tooth stain.

OBJECTIVES: The objectives of this study were to determine whether the addition of milk to tea reduces the ability of tea to stain extracted human teeth and, if so, to ascertain the component of milk that is responsible for milk's stain reducing properties. METHODS: Extracted human teeth were immersed in a tea solution, with the addition of 2% milk, 5.26% lactose, 2.7% casein or 10% fat-free milk for 24 h at 37°C. A dental spectrophotometer (VITA Easyshade Compact) was used to evaluate the colour of the teeth both before and after immersion in the tea solutions. Commission internationale de l'éclairage (CIE) L*a*b* colour space values were recorded, and the change in colour (ΔE*) was calculated. A two-tailed t-test or one-way analysis of variance (anova) was used to determine whether there were statistical differences between groups. RESULTS: Milk significantly reduces the ability of tea to stain teeth (P = 0.0225), specifically in the L* and a* dimensions (P = 0.0182 and P = 0.0124, respectively) of the colour sphere. Casein, which makes up 80% of the protein content in bovine milk, is the component of milk that is responsible for significantly reducing tea's ability to stain teeth (P < 0.0001). CONCLUSIONS: The addition of milk to tea significantly reduces the tea's ability to stain teeth. Casein was determined to be the component of milk that is responsible for preventing tea-induced staining of teeth to a similar order of magnitude that can be obtained by vital bleaching treatments.

Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004.

BACKGROUND: Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs). METHODS: This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated. RESULTS: We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)). CONCLUSION: The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.

Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004.

BACKGROUND: Retinoblastoma occurs in both a heritable and a non-heritable form. In the heritable form, there is a predisposition to the development of non-ocular tumours. OBJECTIVES: To identify the types of non-ocular tumour occurring in retinoblastoma survivors and to produce estimates of risk for these tumours. METHODS: We carried out a cohort study that included 1927 cases of retinoblastoma diagnosed in Great Britain between 1951 and 2004. Cases were ascertained through the National Registry of Childhood Tumours and followed up for the occurrence of non-ocular tumours using the routine notification system based on the National Health Service Central Registers in Britain. RESULTS: Of the 1927 cases, 809 were known to have the heritable form of the disease and 1118 assumed to have the non-heritable form. 102 of the heritable and 13 of those classified as non-heritable developed a non-ocular tumour. The cumulative risk of developing such a tumour 50 years after retinoblastoma diagnosis was 48.3% (95% confidence interval: 38.1 to 59.7%) in the heritable and 4.9% (1.9 to 12.4%) in the non-heritable cases. The main categories of non-ocular tumours observed in the heritable cases were soft-tissue sarcomas (36 of which 21 were leiomyosarcoma), osteosarcoma (32), carcinoma (13), brain and central nervous system tumours (10), melanoma (9), leukaemia (4) and others (4). There were a total of 108 non-ocular tumours in 102 cases. CONCLUSIONS: There is a high risk of non-ocular tumours occurring in survivors of heritable retinoblastoma. These results have important implications for the clinical follow-up and counselling of survivors.

Decreased mitochondrial hydrogen peroxide release in transgenic Drosophila melanogaster expressing intramitochondrial catalase.

The objective of this study was to develop strategies for manipulating oxidative stress transgenically in a multicellular organism. Ectopic catalase was introduced into the mitochondrial matrix, which is the main intracellular site of H2O2 formation and where catalase is normally absent. Transgenic Drosophila melanogaster were generated by microinjection of a P element construct, containing the genomic catalase sequence of Drosophila, with the mitochondrial leader sequence of ornithine aminotransferase inserted upstream of the coding region. Total catalase activities in whole-body homogenates of 10-day-old flies from four transgenic lines were approximately 30-160% higher than those from the parental and four vector-only control lines. Expression of catalase in the mitochondrial matrix was confirmed by immunoblotting and catalase activity assays. Mitochondrial release of H2O2 was decreased by approximately 90% in the transgenic lines when compared to levels in vector-only controls. This in vivo system provides a novel model for examining the functional significance of decreased mitochondrial H2O2 release.

The flow cytometric detection of alloantibodies in screening for renal transplantation.

Flow cytometric screening of sera using pooled chronic lymphocytic leukaemia (CLL) cells has previously been reported as a quick method for detecting HLA antibodies of the IgG class. In this study we investigated the sensitivity of this method in the detection of IgG and IgM alloantibodies, and its performance in serum screening when compared to conventional microlymphocytotoxic screening. Results indicate that flow cytometric screening is more sensitive in the measurement of IgG alloantibodies by up to five doubling dilutions, whereas the converse is true for IgM. IgM autoantibodies were found not to be detectable by flow cytometry. By testing a large number of sera by both methods in parallel, we have found that a significant proportion of sera exhibiting no activity of IgM activity alone on cytotoxic screening contain IgG antibodies detectable with a pool of CLL cells on the flow cytometer.

A highly sensitive, rapid screening method for the detection of antibodies directed against HLA class I and II antigens.

Screening of potential transplant recipients for antibodies that can cause graft rejection is an essential part of the pre-transplant monitoring carried out by tissue typing laboratories. This is a time-consuming process and the rapid reporting of results is dependent on the maintenance of frozen cell panels. The usual procedure of screening against a panel of random cells takes up to 6 weeks. In this study we have used flow cytometric analysis of pooled chronic lymphatic leukaemia (CLL) cells to detect antibodies directed against HLA antigens. We show that FACS screening of pooled cells can accurately and rapidly detect these antibodies and that the method is suitable for routine use. An estimate of the degree of patient panel reactivity can be determined within a few hours. In addition, the technique is more sensitive than those conventionally used, an advantage that may be of importance in preventing graft damage.

Clinical and socioeconomic benefits of serological HLA-DR matching for renal transplantation over three eras of immunosuppression regimens at a single unit.

The efficacy of HLA-DR matching in cadaveric renal transplantation is controversial in the cyclosporine (CsA) era. Reports have questioned both the reliability of serological HLA-DR typing as well as the benefit of matching in terms of improved graft survival. Analysis of 1,000 consecutive cadaver donor transplants performed at Oxford between 1975 and 1992 has shown that with improved immunosuppressive regimens and increased transplant success there has been a steadily diminishing influence of HLA-DR matching measured in terms of first graft outcome. For patients treated with azathioprine and prednisolone (n = 278) overall one-year first graft survival was 65%, but there was a 20% improvement associated with HLA-DR matching which has been maintained for up to 15 years. With the introduction of CsA, used either alone or in conjunction with low dose steroids (n = 96), one-year first graft survival was 69% and the difference between HLA-DR-matched and -mismatched transplants was 14%. Our current maintenance immunosuppressive protocol is triple therapy (N = 425) with an 81% one-year first graft survival for both matched and mismatched transplants. However, we do continue to find a marked correlation between HLA-DR matching and clinical course. HLA-DR-mismatched patients suffer more rejection episodes, spend a longer time in the hospital, and have higher creatinine levels at 3 months. This costs, on average, an extra 1,500 pounds for each mismatched transplant. The effect is most apparent in unsensitized males. For cadaveric regrafts, one-year graft survival for patients on triple therapy is 80% (n = 116) which does not differ from first graft survival rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-time curve regardless of concentration.

Previous studies have failed to fully establish whether ototoxicity is related in any way to the levels of an aminoglycoside antibiotic in the perilymph. To study this we exposed guinea pigs to continuously infused amikacin at four different dosing rates under conditions parallel to those used in our previous study which related ototoxicity to total plasma area under the concentration-time curve regardless of the level in plasma. It was found that at all dosing rates, levels in the perilymph and ratios of levels in perilymph/plasma remained constant as the dosing duration increased from nonototoxic to strongly ototoxic. Plasma and perilymph amikacin levels were found to be linear functions of the dosing rate even at ototoxic dosing exposures, and ratios of levels in perilymph/plasma did not differ between dosing rates. The total perilymph area under the concentration-time curve was not different between dosing rates either for a total dose associated with threshold ototoxicity or for one associated with severe ototoxicity. The results suggest that amikacin ototoxicity is related to the integral of the concentration in the perilymph over the total time of amikacin exposure regardless of the level in the perilymph.

Delay in hearing loss following drug administration. A consistent feature of amikacin ototoxicity.

The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.

Incidence of amikacin ototoxicity: a sigmoid function of total drug exposure independent of plasma levels.

A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.