Newborn hearing screening: a regional example for national care.

Congenital Permanent Childhood Hearing Impairment (PCHI) is known to have a negative effect on language acquisition, cognitive development and social integration. Since 2000 our department has implemented a UNHS program in the West of Ireland. We describe our experience and detail our results to date. All neonates born from October 2000 to November 2007 were screened using a 2-stage protocol. Transient evoked oto-acoustic emissions (TEOAEs) were used to screen all neonates, followed by automated auditory brainstem response (AABR) in those who did not pass TEOAE, and all neonates at audiological risk. 26,281 babies were born over the eight year period. 25,742 underwent the screening process, achieving a coverage rate of 98%. The prevalence of PCHI in the population tested was 1.21/1000 live births (31/25,731). Our results show that a hospital based 2-stage UNHS protocol using TEOAEs and AABR is accurate, feasible and effective.

Functionalized silver nanoparticles depress aerobic metabolism in the absence of overt toxicity in brackish water killifish, Fundulus heteroclitus.

Engineered nanomaterials (ENMs) tend to precipitate in saline waters so the majority of aquatic toxicity studies have focused on freshwaters, where bioavailability is presumed to be higher. Recent studies have illustrated that some ENM formulations are bioavailable and bioactive in salt water and that their effects are more pronounced at the physiological than biochemical level. These findings raise concerns regarding the effects of ENMs on marine organisms. Therefore, our goal was to characterize the effects of polyvinylpyrolidone-functionalized silver ENMs (nAg) on aerobic performance in the killifish (Fundulus heteroclitus), a common euryhaline teleost. Fish were exposed to 80 µg L-1 of 5 nm nAg for 48 h in brackish water (12 ppt) and routine (MO2min) and maximum (MO2max) rates of oxygen consumption were quantified. Silver dissolution was minimal and nAg remained well dispersed in brackish water, with a hydrodynamic diameter of 21.0 nm, compared to 19.3 in freshwater. Both MO2min and MO2max were significantly lower (by 53 and 30%, respectively) in killifish exposed to nAg and a reduction in MO2 variability suggested spontaneous activity was suppressed. Neither gill Na+/K+-ATPase activity, nor various other biochemical markers were affected by nAg exposure. The results illustrate that a common ENM formulation is bioactive in salt water and, as in previous studies on functionalized copper ENMs, that effects are more pronounced at the whole animal than the biochemical level.

Oral ulceration--the importance of biopsy.

Pemphigus vulgaris is a rare cause of oral ulceration. A 34 year old male presented with a three week history of severe oral ulceration which was initially treated as aphthous ulceration. However, he failed to improve and a mucosal biopsy was performed. Histology and immunostaining confirmed pemphigus vulgaris.

Interaction of 4'-(9-acridinylamino)methanesulfon-m-anisidide with DNA and inhibition of oncornavirus reverse transcriptase and cellular nucleic acid polymerases.

4'-(9-Acridinylamino)methanesulphon-m-anisidide (AMSA) (NSC 141549), an acridine derivative with activity against a variety of laboratory tumors in vivo, is presently undergoing Phase 1 clinical evaluation. The interaction of AMSA with DNA and its effects on nucleic acid-polymerizing enzymes were examined in an attempt to define the site of cytotoxicity of AMSA. Binding of AMSA to DNA, as demonstrated by equilibrium dialysis and spectrophotometric methods, appears to be similar to other aminoacridines, in that two types of binding sites (type 1 and type 2) were observed. Fluorescence studies and thermal denaturation studies gave strong evidence that AMSA type 1 binding was by intercalation into DNA. The binding of AMSA to DNA was without marked base-pair specificity. Furthermore, the effect of AMSA on nucleic acid-polymerizing enzyme activities (mouse embryo DNA polymerase alpha, avian myeloblastosis virus reverse transcriptase, and Escherichia coli RNA polymerase) was studied. Inhibition of enzyme activity by AMSA appeared to be independent of DNA base sequence. The relatively high concentrations of AMSA required for inhibition of these enzymes as compared to the concentrations of AMSA necessary for cytotoxicity in vitro suggest that the interaction with DNA alone might not fully explain its antitumor activity.

Metabolism of 4'-(9-acridinylamino)methanesulfon-m-anisidide by rat liver microsomes.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is metabolized by a hepatic microsomal enzyme system composed of rat liver microsomes, a reduced nicotinamide adenine dinucleotide phosphate-generating system, cytosolic protein (or glutathione), and oxygen. Omission of any one of the components, or incubation under an atmosphere of CO or N2, results in inhibition of the reaction. Also, the addition of inhibitors of microsomal metabolism (alpha-naphthoflavone, metyrapone, or SKF 525-A) decreases m-AMSA metabolism. Metabolism of m-AMSA is more rapid with microsomes prepared from rats pretreated with phenobarbital or 3-methylcholanthrene. Two microsomal oxidation products of m-AMSA were isolated and identified as N1'-methanesulfonyl-N4'-(9-acridinyl)-3'-methoxy-2',5'-cyclohex adiene-1', 4'-dimine (m-AQDI) and 3'-methoxy-4'-(9-acridinylamino-2',5'-cyclohexadien-1'-one (m-AQI). m-AQDI reacts with glutathione to form a product previously identified in in vivo studies as the principal rat biliary metabolite and which is not cytotoxic to cultured L1210 cells. Thus, the end result of the microsomal metabolism of m-AMSA is detoxification. However, the two primary oxidation products (m-AQDI and m-AQI) are considerably more cytotoxic to L1210 cells in vitro than is m-AMSA. The concentration of m-AMSA required to produce a 5-log kill is 1.0 microgram/ml compared to 0.01 microgram/ml for m-AQDI and m-AQI. These results indicate that m-AMSA might undergo bioactivation to form the active cytotoxic species of the drug.

Phase I clinical and pharmacological study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide using an intermittent biweekly schedule.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA, NSC 249992), an acridine derivative, was given to 28 patients with solid tumors and one patient with Hodgkin's disease in a Phase I clinical trial. The dose schedule used was a single dose given every 14 days for three doses. The amount given ranged from 10 to 120 mg/sq m/dose. Dose-limiting toxicity was moderate to severe leukopenia which occurred at and above 70 mg/sq m. Thrombocytopenia was infrequent and did not require transfusion. Nonhematological side effects were mild and included nausea, vomiting, local irritation, and fever. Antineoplastic activity was noted in liposarcoma, adenocarcinoma of unknown primary origin, and squamous carcinoma of unknown primary origin (one patient each). Pharmacokinetics studies were done in 19 patients. Total m-AMSA and free m-AMSA concentrations showed a biphasic distribution with an initial rapid phase of t1/2 = 10 to 15 min for both, and a second slow phase of t1/2 = 8 to 9 hr for total m-AMSA and 3 hr for free m-AMSA. Phase II studies with m-AMSA, in hematological cancers are warranted, since its most consistent effect is on leukocytes. The recommended dosages for solid-tumor Phase II studies are 70 mg/sq m for good-risk patients and 50 mg/sq m for poor-risk patients, given as a single dose every other week, or 120 mg/sq m for poor-risk patients for the single-dose every-3-week schedule.

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.

Kinetics of cis-dichlorodiammineplatinum.

The cancer chemotherapeutic cis-dichlorodiammineplatinum (cis-DDP) was administered to 8 patients (1-hr intravenous infusion) at a dose of 70 mg/m2. Plasma and urine concentrations of platinum were determined by flameless atomic absorption spectrometry. Measured plasma platinum concentrations revealed a biphasic clearance of platinum with half-life values of 23 min and 67 hr. Platinum values obtained 3 wk after the infusion indicated that a third excretory phase might be present. Urinary measurements showed 17 +/- 2.7% of the administered dose excreted in the first 4 hr and 23 +/- 3.9% excreted in the first 24 hr. Renal excretion appears to be predominantly by glomerular filtration. Non-protein-bound plasma platinum values were calculated and the non-protein-bound platinum was found to be rapidly and biphasically cleared from the plasma with half-life values of 8 to 10 min and 40 to 45 min.

Effects of drug therapy on Toxoplasma cysts in an animal model of acute and chronic disease.

PURPOSE: To evaluate the effects of drug therapy on the clinical course of acute acquired Toxoplasma retinochoroiditis and on the number of Toxoplasma cysts present in the brain and ocular tissues in the hamster animal model. METHODS: The Syrian golden hamster animal model of Toxoplasma retinochoroiditis was used. In acute disease, systemically administered atovaquone was compared with conventional therapies (pyrimethamine combined with sulfadiazine; clindamycin; and spiramycin). The clinical course of the ocular disease was determined with retinal examination and photography of the fundus. The number of Toxoplasma cysts remaining after treatment was evaluated in aliquots of brain homogenate and in retinal tissue. The effect of atovaquone on cerebral Toxoplasma cyst count was also studied in chronic disease. RESULTS: None of the drugs administered altered the course of the acute disease, judged by clinical examination. Atovaquone alone significantly reduced the number of cerebral Toxoplasma cysts after acute disease. Atovaquone also significantly reduced the cerebral Toxoplasma cyst count in chronic disease. CONCLUSIONS: Tissue cysts are believed to be responsible for reactivation of Toxoplasma retinochoroiditis. Atovaquone has the potential to reduce the risk of recurrent disease.

Acquired retinochoroiditis in hamsters inoculated with ME 49 strain Toxoplasma.

PURPOSE: These studies were undertaken to establish an animal model for use in studies of ocular toxoplasmosis. An animal model is needed to examine the development, progression, and resolution of ocular Toxoplasma infections and to study the effects on the disease of currently used and experimental therapies. METHODS: Cysts of the ME 49 strain of Toxoplasma gondii were injected intraperitoneally into each of 60 golden hamsters. The hamsters' eyes were examined before inoculation and at intervals after inoculation, and fundus photographs were taken. Histologic sections were analyzed and photographed to document the ocular effects of the infection. RESULTS: Retinochoroiditis was found in both eyes of all hamsters within 2 to 3 weeks of inoculation. The disease resolved spontaneously without treatment and was quiescent in most cases at 12 weeks after inoculation. The animals remained in good general health, and those tested had high antibody titers to Toxoplasma (1:256 to 1:32,000) at 6 months after the infection. The discovery of cysts and lesions in the retina confirmed the diagnosis. CONCLUSIONS: Although the lesions were not identical to those of human disease, this animal model of ocular toxoplasmosis offers several advantages: reproducibility, short incubation time, spontaneous resolution without treatment, consistent production of cysts, and ease of inoculation intraperitoneally without intraocular injection.

Pharmacokinetic study of cerebrospinal fluid penetration of cis-diamminedichloroplatinum (II).

The ability of cis-DDP and several analogs to enter the CSF was investigated in rhesus monkeys that had subcutaneously implanted Ommaya reservoirs connected to catheters in each monkey's fourth ventricle. Plasma and CSF samples were analyzed for platinum content by atomic absorption spectroscopy. Plasma platinum curves were biphasic with a very slowly declining terminal phase. CSF platinum curves rose to maximum concentrations 30-40 min after an IV bolus injection and declined mono-exponentially (T 1/2 = 60 min) without displaying a detectable slow terminal phase. cis-DDP given as an IV bolus of 1.5 mg/kg or 3.0 mg/kg produced peak CSF concentrations of 0.35 and 0.78 microM platinum. The ratio of CSF platinum:plasma platinum never exceeded 0.04. When cis-DDP at 3.0 mg/kg was given as a 2- or 7-h infusion, the peak CSF concentrations were 0.28 and 0.17 microM platinum, respectively. The total CSF exposure, measured as concentration X time, was the same for bolus and for 2- and 7-h infusions. Studies with analogs showed that neither malonato 1,2-diaminocyclohexane platinum (II) nor 4-carboxyphthalato 1,2-diaminocyclohexane platinum (II) had better CSF penetrance than cis-DDP. Sulfato 1,2-diaminocyclohexane platinum (II) could not be detected in the CSF. The ratio of CSF platinum:plasma platinum was never greater tha 0.02-0.03 for any of the analogs.

Preservation of cochlear function in the surgery of cholesteatomatous labyrinthine fistulas and oval window tympanosclerosis.

Anakusis is reported as a not uncommon complication of the surgical treatment of cholesteatomatous fistula of the labyrinth. Likewise, although published results on the surgical treatment of tympanosclerotic ears are infrequent, most otologists are aware of greater than usual risks of severe sensorineural impairment from ossiculoplasty in this type of middle ear disease. Because of recent developments in implanted aids-to-hearing, in tympanoplasty operations, when they fail to adequately improve hearing, preservation of eighth nerve function becomes ever-increasingly important. This article concerns two types of middle ear disease in which surgical treatment threatens hair cells and neurons, to the extent that surgical complications might prejudice the eventual possible benefits of a standard hearing aid or any implanted device, if either was indicated.

Congenital vascular anomalies and persistent respiratory symptoms in children.

Congenital cardiovascular anomalies are a rare but treatable cause of stridor in the paediatric population. Despite this, we and the authors of other series have found a delay in referral for endoscopic diagnosis. The duration of symptoms prior to endoscopic diagnosis ranged from 6 weeks to 10 years. It has been estimated that up to 3% of the population have congenital anomalies of the aortic arch complex and we feel that many patients currently being diagnosed as having recurrent croup or atypical asthma must be excluded from this group. We had 16 cases of congenital vascular anomalies causing tracheobronchial compression. Fifteen were due to innominate artery compression and one was due to a double aortic arch. Presenting symptoms included stridor (100%), persistent cough (75%), chronic dyspnoea (75%), reflex apnoea (60%), recurring respiratory tract infections (56%) and dysphagia (25%). Direct laryngoscopy and bronchoscopy was diagnostic in all cases and is our investigation of choice. Eleven underwent aortopexy (69%), one had division of the non-dominant aortic arch (6%) and four were managed conservatively (25%). They were followed for up to 9 years post-operatively and 75% had complete resolution of their symptoms. We feel that only a high clinical index of suspicion will enable these potentially fatal anomalies to be diagnosed.

Surgical management of labyrinthine fistula with cholesteatoma.

From 684 cases of ear surgery for cholesteatoma performed by one surgeon, 35 had labyrinthine fistulae (incidence 5.1 per cent). Of these fistulae, 79 per cent involved the lateral semicircular canal only; the other sites involved were the other semicircular canals and the cochlea. The fistula test was positive in 54 per cent of cases overall, but in 80 per cent with an extended site fistula (ESF). Three surgical approaches were employed sequentially--staged combined approach tympanoplasty (CAT), open cavity tympanoplasty and attico-antrotomy. Surgically-induced deafness occurred in 3.3 per cent. All surgical groups showed similar hearing results, except for less conductive deafness in the CAT group. Surgical management is discussed with reference to current theories of the erosive effects of cholesteatoma.

Xenograft versus autograft in tympanoplasty.

This retrospective study compares the tympanoplasty success rate when using a xenograft (Zenoderm) or an autograft (temporalis fascia). Fifty-three ears were operated on over a three-year period. All the tympanoplasty operations were performed by the same surgeon. There were 43 ears in the temporalis fascia autograft group and 10 ears in the Zenoderm xenograft group. Both groups were similar with respect to patient age, type of tympanoplasty, area of tympanic membrane perforation and condition of the contralateral ear. The tympanoplasty success rate in the temporalis fascia autograft group was 95 per cent. The tympanoplasty success rate in the Zenoderm xenograft group was only 40 per cent. All Zenoderm tympanoplasty failures were regrafted with temporalis fascia autograft. There was a 100 per cent success rate with this salvage surgery. In conclusion, we suggest that Zenoderm is not a suitable graft material for tympanoplasty.

The influence of bismuth subgallate and adrenaline paste upon operating time and operative blood loss in tonsillectomy.

The aims of this study were to demonstrate the effect of bismuth subgallate and adrenaline paste application to the tonsillar fossae on operating time and peroperative blood loss during tonsillectomy. Ninety-eight patients were included in a prospective randomized trial. Bismuth subgallate powder is mixed with 10 ml of normal saline and 0.03 ml of 1:1000 adrenaline to make a paste. This paste is used as a topical haemostatic agent during tonsillectomy. Bismuth subgallate activates Factor XII and therefore accelerates the coagulation cascade. Adrenaline causes vasoconstriction and promotes platelet aggregation. The application of bismuth subgallate and adrenaline paste to the tonsillar fossae during tonsillectomy reduces operating time by 23 per cent for Consultant staff (p < 0.05) and 32 per cent for Junior staff (p < 0.05). Blood loss is reduced by 21 per cent (p > 0.05), for the average paediatric tonsillectomy.

Otological manifestations of a new familial polyostotic bone disorder.

Fifty members of a family with a unique autosomal dominant bone disease were investigated. Nineteen of the family members were either known to have, or were strongly suspected of having the disease. All but one of these had a hearing loss which was conductive in the younger age group and mixed in the older members. The common finding in those who had middle ear surgery was replacement of the long process of incus by a fibrous band. The histological features were similar to those found in Paget's disease. The age of onset, distribution of lesions and radiographic findings, however, were not typical of this disorder.

The role of Chlamydia pneumoniae in severe acute tonsillitis.

Chlamydia pneumoniae has been implicated as a cause of tonsillitis and pharyngitis, but the incidence has varied from one to 19 per cent in various studies. We investigated 51 patients admitted to University College Hospital, Galway, with severe tonsillitis. Throat swabs were examined for evidence of Chlamydia pneumoniae using a direct monoclonal antibody test. Blood was taken for serology from 45 patients. A further specimen was taken at six weeks. A control group of 32 blood bank sera was used. Mean hospital stay was three days (one to eight). Five patients (10 per cent) were monospot positive. Chlamydia pneumoniae was identified by direct immunofluorescence on a tonsillar swab from one patient who did not seroconvert. IgG antibody was identified in 13 cases (29 per cent) and in seven of the control group (22 per cent). No serological evidence of recent infection was found. Chlamydia pneumoniae was not found to be a cause of severe acute tonsillitis in our study group.