Guidelines for quantification of noise-induced hearing loss in a medicolegal context.

OBJECTIVES: Guidelines published in 2000 by the authors are widely used by medical and legal professionals in the UK for diagnosis of noise-induced hearing loss in a medicolegal context. However, they cannot be used for quantification of the noise-induced hearing loss, which is required in most cases. This requirement is addressed. DESIGN: A method is developed here to quantify noise-induced hearing loss, thereby overcoming this shortcoming. SETTING: Assessment of noise-induced hearing loss in medicolegal cases. PARTICIPANTS: A consecutive series of 124 cases of noise-induced hearing loss is used for evaluation. MAIN OUTCOME MEASURE: Magnitude of noise-induced hearing loss based on hearing threshold levels averaged over the frequencies 1, 2 and 3 kHz. RESULTS: The rationale of the method, practical application and three worked examples are developed. A simpler short-cut method is developed and shown to be equivalent to the full method in most cases. CONCLUSIONS: The method offers a practical approach to quantification of noise-induced hearing loss.

Waveguide-coupled photonic crystal cavity for quantum dot spin readout.

We present a waveguide-coupled photonic crystal H1 cavity structure in which the orthogonal dipole modes couple to spatially separated photonic crystal waveguides. Coupling of each cavity mode to its respective waveguide with equal efficiency is achieved by adjusting the position and orientation of the waveguides. The behavior of the optimized device is experimentally verified for where the cavity mode splitting is larger and smaller than the cavity mode linewidth. In both cases, coupled Q-factors up to 1600 and contrast ratios up to 10 are achieved. This design may allow for spin state readout of a self-assembled quantum dot positioned at the cavity center or function as an ultra-fast optical switch operating at the single photon level.

The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of Type 1 diabetes mellitus.

AIMS: The prevalence of autoantibodies to zinc transporter 8 (ZnT8) in Czech children at the onset of Type 1 diabetes mellitus and dynamic changes in ZnT8 autoantibody levels during disease progression were studied. The value of ZnT8 autoantibody measurements in diagnosis of Type 1 diabetes was assessed. METHODS: Serum samples from 227 children with newly diagnosed Type 1 diabetes and from 101 control children without diabetes were analysed in a retrospective cross-sectional study. One hundred and seventy-one samples from 116 of the patients with diabetes were analysed in a follow-up study at (median) intervals of 1, 3, 5 and 10 years after onset of Type 1 diabetes. ZnT8 autoantibodies were measured using a bridging enzyme-linked immunosorbent assay, while antibodies to glutamic acid decarboxylase, insulinoma antigen 2 and insulin were measured by radioimmunoassays. RESULTS: ZnT8 autoantibodies were detected in 163/227 (72%) of children at Type 1 diabetes onset and in 1/101 (1%) of the control subjects. Sixteen out of 227 (7%) patients with Type 1 diabetes were antibody negative based on three antibodies (glutamic acid decarboxylase, insulinoma antigen 2 and insulin). This false-negative rate was reduced to 10/227 (4.4%) (P < 0.05) after inclusion of ZnT8 autoantibody measurements. Of the children, 142/227 (63%) were positive for at least three antibodies and the most common combination was insulinoma antigen 2, glutamic acid decarboxylase and ZnT8. ZnT8 autoantibody levels decreased over time after Type 1 diabetes onset and the presence and level of ZnT8 autoantibodies correlated with IA-2 autoantibodies. CONCLUSIONS: A ZnT8 autoantibody enzyme-linked immunosorbent assay showed 72% disease sensitivity and 99% specificity at Type 1 diabetes onset. Measurements of ZnT8 autoantibodies are important for Type 1 diabetes diagnosis and should be included in the panel of autoantibodies tested at the onset of Type 1 diabetes.

Vegetative fragment production as a means of propagule dispersal for tropical seagrass meadows.

BACKGROUND AND AIMS: Long distance dispersal (LDD) contributes to the replenishment and recovery of tropical seagrass habitats exposed to disturbance, such as cyclones and infrastructure development. However, our current knowledge regarding the physical attributes of seagrass fragments that influence LDD predominantly stems from temperate species and regions. The goal of this paper is to measure seagrass fragment density and viability in two tropical species, assessing various factors influencing their distribution. METHODS: We measured the density and viability of floating seagrass fragments for two tropical seagrass species (Zostera muelleri and Halodule uninervis) in two coastal seagrass meadows in the central Great Barrier Reef World Heritage Area, Australia. We assessed the effect of wind speed, wind direction, seagrass growing/senescent season, seagrass meadow density, meadow location and dugong foraging intensity on fragment density. We also measured seagrass fragment structure and fragment viability; i.e., potential to establish into a new plant. KEY RESULTS: We found that seagrass meadow density, season, wind direction and wind speed influenced total fragment density, while season and wind speed influenced the density of viable fragments. Dugong foraging intensity did not influence fragment density. Our results indicate that wave action from winds combined with high seagrass meadow density increases seagrass fragment creation, and that more fragments are produced during the growing than the senescent season. Seagrass fragments classified as viable for Z. muelleri and H. uninervis had significantly more shoots and leaves than non-viable fragments. We collected 0.63 (±0.08 SE) floating viable fragments 100 m-2 in the growing season, and 0.13 (±0.03 SE) viable fragments 100 m-2 in the senescent season. Over a third (38%) of all fragments collected were viable. CONCLUSION: There is likely to be a large number of viable seagrass fragments available for long distance dispersal. This study's outputs can inform dispersal and connectivity models that are used to direct seagrass ecosystem management and conservation strategies.

Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung.

We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

Asymmetric sensorineural hearing thresholds in the non-noise-exposed UK population: a retrospective analysis.

OBJECTIVES: To estimate the distribution of inter-aural sensorineural hearing threshold level differences in the non-noise-exposed adult population of the UK. SETTING: A two-stage population study carried out in 1979-1986, initially by postal questionnaire, followed up in a proportion of participants by clinical and audiological examination. PARTICIPANTS: Volunteers (n = 48 313) initially selected at random from the electoral registers of four cities, subsequently selected at random from questionnaire respondents stratified by answers to questions about hearing. MAIN OUTCOMES MEASURE: Inter-aural hearing threshold level differences measured audiometrically, as a function of age and gender. RESULTS: Tables of inter-aural threshold level differences provided as a resource with potential medicolegal, clinical and research applications. Based on the average of the frequencies 0.5, 1, 2 and 4 kHz, approximately 1% of the general UK population aged 18-80 years have an asymmetry of 15 dB or more. The prevalence is greater in older than in younger people. CONCLUSIONS: Inter-aural threshold differences greater than attributable to measurement error are not uncommon in the adult population, even after screening for conductive hearing loss and substantial noise exposure. They are typically of unknown origin.

Chirality of nanophotonic waveguide with embedded quantum emitter for unidirectional spin transfer.

Scalable quantum technologies may be achieved by faithful conversion between matter qubits and photonic qubits in integrated circuit geometries. Within this context, quantum dots possess well-defined spin states (matter qubits), which couple efficiently to photons. By embedding them in nanophotonic waveguides, they provide a promising platform for quantum technology implementations. In this paper, we demonstrate that the naturally occurring electromagnetic field chirality that arises in nanobeam waveguides leads to unidirectional photon emission from quantum dot spin states, with resultant in-plane transfer of matter-qubit information. The chiral behaviour occurs despite the non-chiral geometry and material of the waveguides. Using dot registration techniques, we achieve a quantum emitter deterministically positioned at a chiral point and realize spin-path conversion by design. We further show that the chiral phenomena are much more tolerant to dot position than in standard photonic crystal waveguides, exhibit spin-path readout up to 95±5% and have potential to serve as the basis of spin-logic and network implementations.

Purification and characterization of Escherichia coli xanthine-guanine phosphoribosyltransferase produced by plasmid pSV2gpt.

The enzyme xanthine-guanine phosphoribosyltransferase from Escherichia coli cells harboring the plasmid pSV2gpt has been purified 30-fold to near homogeneity by single-step GMP-agarose affinity chromatography. It has a Km value of 2.5, 42 and 182 microM for the substrates guanine, xanthine and hypoxanthine, respectively, with guanine being the most preferred substrate. The enzyme exhibits a Km value of 38.5 microM for PRib-PP with guanine as second substrate and of 100 microM when xanthine is used as the second substrate. It is markedly inhibited by 6-thioguanine, GMP and to a lesser extent by some other purine analogues. Thioguanine has been found to be the most potent inhibitor. The subunit molecular weight of xanthine-guanine phosphoribosyltransferase was determined to be 19 000. The in situ activity assay on a nondenaturing polyacrylamide gel electrophoresis gel has indicated that a second E. coli phosphoribosyltransferase preferentially uses hypoxanthine as opposed to guanine as a substrate, and it does not use xanthine.

Thermal regulation of FMLP receptors on human neutrophils.

Polymorphonuclear leukocytes (PMNs) from subjects diagnosed as having juvenile periodontitis (JP) have been categorized on the basis of their chemotactic (CTX) response to f-met-leu-phe (FMLP) when assayed concurrently with PMNs from periodontally healthy subjects (HP). When PMNs from JP groups demonstrating depressed CTX were assayed for lysosomal enzyme secretion (LES) in response to FMLP, there were no significant differences with respect to rate or amount. Significant differences were observed between HP and chemotactically depressed JP cells when assessed for FMLP receptor ligand binding at 23 degrees C, but not at 4 degrees C. Receptor differences observed at 23 degrees C in HP cells included an increase in amount of total binding, number of receptors, and available displaceable binding sites, compared with the chemotactically depressed JP PMNs, whereas the receptor affinities were similar. These data suggest that differences in FMLP receptor density in JP PMN that are chemotactically depressed may be related to processes that modulate receptor mobility and/or expression.

Factors affecting bone density in young adults.

A 14-y follow-up of 581 children who took part in a randomized controlled trial of the effect of a milk supplement on growth of children was conducted to investigate the supplement's effect on adult bone mineral content (BMC) and density (BMD). BMC and BMD of the nondominant forearm were measured by single-photon absorptiometry in 371 subjects (64%) aged 20-23 y, at a proximal site (shaft of radius and ulna) and at a distal site near the wrist. BMCs and BMDs tended to be higher in the intervention group (NS). Cross-sectionally, BMD was positively associated with body weight (P less than 0.01) in both sexes; inversely associated with alcohol consumption (P less than 0.05), and positively with manual occupation (NS) in men; positively associated with current intakes of calcium (P less than 0.05), vitamin D (P less than 0.01), and sports activity during adolescence (P less than 0.01), and inversely with parity (NS) in women. In multiple linear-regression analysis body weight and sports activity during adolescence were stronger determinants of female BMD than was diet.

Molecular mechanisms of cataractogenesis: IV. Evidence of phospholipid . malondialdehyde adduct in human senile cataract.

Lipid extracts of the human cataractous and normal lenses were analyzed by thin-layer chromatography (TLC) using a solvent system consisting of CHCl3/CH3OH/CH3COOH/H2O (50:25:7:3 by vol.). A novel phospholipid having a Rf intermediate between phosphatidyl ethanolamine (PE) and phosphatidyl serine (PS) was detected besides the four major phospholipids viz., PE, PS, phosphatidyl choline (PC) and sphingomyelin (SP). The novel phospholipid was found to be molybdenum positive and ninhydrin negative having a characteristic fluorescence of Schiff-base conjugate formed between PE, malondialdehyde (MDA) and PS. It was possible to resolve this adduct into PE and PS after acid hydrolysis using two dimensional TLC with CHCl3/CH3OH/NH3 (7 M) (65:25:4 by vol.) as the second solvent. In cataract PE . MDA . PS adduct increased significantly as did diene conjugates and MDA. In plasma membrane lipid extract of cataractous lenses there was a marked increase in fluorescence at 460 nm when excited at 365 nm showing a characteristic fluorescence of a typical Schiff-base conjugate. The evidence suggests that peroxidation of lenticular plasma membrane lipids is one of the molecular mechanisms involved in cataract in the human.

A rat granulosa cell plasminogen activator bioassay for FSH in human serum.

A previously described in-vitro rat granulosa cell plasminogen activator bioassay for FSH has been modified and applied in the assay of human serum. This modified method consists of exposing the diethylstilboestrol-stimulated granulosa cells from 25- to 26-day-old rats to FSH or test substance for 3.5 h in wells coated with 125I-labelled fibrinogen and treated with thrombin. Following stimulation with FSH, the dose-related production of plasminogen activator was measured as the degree of 125I-labelled fibrinolysis in the presence of added plasminogen. Using the urinary FSH/LH bioassay reference preparation as the assay standard, the useful range of the assay was 0.3-15 IU/l, with an assay sensitivity of 0.3 IU/l. As determined using purified glycoprotein hormone preparations, the assay was highly specific for FSH. The minor degree of FSH bioactivity measured in some of the hormone preparations was accounted for by the amount of FSH contamination in these preparations. To abolish interference caused by unknown serum factors, we heat-treated the serum samples for 15 min at 56 degrees C before the assay. The results indicated that neither immunoreactivity nor bioactivity was affected by this treatment. Furthermore, heat-treated human sera gave responses parallel to the standard curve at the three dose levels (2, 4 and 8 microliters) studied. We used this bioassay to estimate the FSH-like bioactivity in 15 human serum samples. The estimates of immunoreactive FSH in these samples correlated well with the corresponding FSH bioactivity (r = 0.745, n = 15 and P less than 0.05). The results indicate that with this sensitive and rapid (completed within 24 h) bioassay, it should be possible to measure FSH bioactivity in heat-treated human serum samples.

Adoptive transfer of cytotoxic T lymphocytes for the treatment of transplant-associated lymphoma.

BACKGROUND: Immunocompromised organ transplant recipients have a high incidence of B cell lymphomas (BCL). Severe combined immunodeficient (SCID) mice develop human BCL when engrafted with Epstein-Barr virus (EBV) transformed and immortalized B lymphoblastoid cell lines (BLCL). Because a lack of effective EBV-specific cytotoxic T lymphocytes (EBV-CTL) is thought to lead to lymphoma development, the SCID mouse model was used to determine the relationship between EBV-infected B cells and EBV-specific CTL in BCL development in vivo. METHODS: EBV-CTL were generated by in vitro stimulation of peripheral blood leukocytes with autologous BLCL. CD8+ CTL were isolated from CTL populations by depletion of CD4+ cells. SCID mice were engrafted with BLCL, EBV-CTL were adoptively transferred into engrafted SCID mice either immediately or 7 days after engraftment, and the animals were monitored for the development of BCL. Statistical significance was determined by the log rank test. RESULTS: SCID mice engrafted with BLCL rapidly developed BCL (mean, 20 days). SCID mice engrafted with BLCL and human leukocyte antigen-identical EBV-CTL or CD8+ EBV-CTL had a significant delay in BCL development (p < 0.05), whereas some mice did not develop BCL. In contrast, human leukocyte antigen-nonidentical EBV-CTL did not significantly delay BCL development. CONCLUSIONS: This study showed the role of EBV-CTL in inhibiting the development of BCL. A greater understanding of the cellular and viral interactions leading to B-cell transformation and malignancy may allow the development of specific interventional therapies in patients who have received immunosuppressants.

12-O-tetradecanoyl-phorbol-13-acetate down-regulates the Huntingtin promoter at Sp1 sites.

We have studied the effects of the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on Huntington's disease (HD) gene transcription in neuronal and non-neuronal cell lines, to investigate pathways regulating HD gene expression. TPA reduced transcription from the HD gene promoter in SK-N-SH (neuroblastoma) and HeLa cells but not in JEG3 (choriocarcinoma) cells. In SK-N-SH cells, the responsible cis-acting promoter sequences comprise the tandemly duplicated Sp1 sites in the region from -213 to -174, relative to the translation start site. The TPA-down-regulating region in HeLa cells was mapped to the sequence from -141 to -126. In conclusion, this demonstrates that HD gene transcription can be down-regulated in vitro in a cell-specific manner.

Retroviral gene transduction of circulating progenitor cells in patients with metastatic breast cancer.

The use of somatic gene therapy for the treatment of breast cancer has many potential applications. Because chemotherapeutic protocols for breast cancer are commonly limited by bone marrow toxicity, transduction of genes into pleuripotent stem cells may allow the generation and maintenance of immune responses in the presence of lymphocytotoxic agents. The practical utility of stem cell isolation and transduction would be enhanced if stem cells circulating in the peripheral blood could be isolated in patients, however this approach has been limited by the small numbers of such cells in the circulation. In these studies, recombinant granulocyte colony stimulating factor (G-CSF) was administered to patients with metastatic breast cancer to increase the number of circulating stem cells. Stem cells in the peripheral blood were then isolated and a retroviral vector (LXSN) was used to transduce the neomycin phosphotransferase gene into these cells. Gene transduction was demonstrated by resistance to the toxic effects of a neomycin analog (G418) and the detection of retroviral DNA from transduced cells. A practical method of transfer of exogenous genes into the circulating pleuripotent stem cells of patients with metastatic breast cancer is documented by these experiments. Application of these findings may allow the generation of cells resistant to anti-neoplastic agents or unique lymphoid effector cells with potent immune functions for the treatment of patients with metastatic breast cancer.

Effects of cyclosporine on human B-cell lymphoma development in vivo.

Cyclosporine (CsA) is a potent immunosuppressive agent primarily affecting T-lymphocyte function. Patients receive CsA following organ transplantation to prevent rejection. These patients are at high risk for developing Epstein-Barr virus (EBV)-induced lymphoproliferative disease (LPD) or B-cell lymphoma (BCL). Severe Combined Immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (PBL) develop fatal B-cell lymphomas of human origin following latent or active infection with EBV. This model was utilized to determine the role of CsA in the development of human BCL. SCID mice were reconstituted with PBL, latently or actively infected with EBV, and treated with CsA. Following active EBV infection, mice developed human BCL with or without CsA treatment. In contrast, treatment with CsA prevented the development of BCL in mice latently infected with EBV. This suggests a T-cell interaction with latently infected B-cells which is perturbed by CsA. Further understanding of this interaction and the occurrence of human BCL may allow the development of strategies to prevent, detect, or treat malignancies associated with immunosuppression.

The moral education of medical students.

The author begins his essay by discussing George Eliot's novel Middlemarch, in which a doctor, early in his career, wanders from his idealistic commitment to serving the poor. Although he establishes a prominent practice, he considers himself a failure because "he had not done what he once meant to do." The essay explores how many of us (physicians included) forsake certain ideals or principles--not in one grand gesture, but in moment-to-moment decisions, in day-to-day rationalizations and self-deceptions, until we find ourselves caught in lives whose implications we have long ago stopped examining, never mind judging. Medical education barrages students with information, fosters sometimes ruthless competition, and perpetuates rote memorization and an obsession with test scores--all of which stifle moral reflection. Apart from radically rethinking medical education (doing away with the MCAT, for example, as Lewis Thomas proposed), how can we teach students to consider what it means to be a good doctor? Calling upon the work of Eliot, Walker Percy, and others, the author discusses how the study of literature can broaden and deepen the inner lives of medical students and encourage moral reflectiveness.

Image comparison techniques for use with megavoltage imaging systems.

In this paper we describe software facilities for enabling patient positioning studies using the megavoltage imaging system developed at the Royal Marsden Hospital and Institute of Cancer Research. The study focuses on the use of the system for three purposes: patient position verification (by comparing images taken at treatment simulation with megavoltage images taken at treatment time); reproducibility studies (by analysing a set of megavoltage images); and set-up correction (by adjusting the set-up until the megavoltage image obtained at treatment registers with the simulation image). The need is discussed for suitably presented simulator images, a method of determining field boundaries and the possibility of delineating soft-tissue interfaces. Several algorithms of different types, developed specifically for the purpose of intercomparison of planar projection images, are presented. The techniques employed and their usefulness, in both the qualitative and the quantitative sense, are discussed. The results are presented of a phantom and clinical study, to evaluate the rigour and reproducibility of the algorithms. These results indicate that measurements can be made to an accuracy of about 1-2 mm, with a similar value for interobserver reproducibility for the best image comparison techniques available.

Children who become parents: a challenge to physicians.

Adolescent pregnancy is a major adolescent health concern in the United States today, yet physicians often lack the knowledge and time to care properly for pregnant adolescents. this study examined the health concerns of pregnant adolescents and the ways in which the modern medical system deals with those concerns. Interviews with adolescents and health care workers in rural and urban neighborhoods showed that many adolescents are unaware of certain important personal matters that affect their health; the same holds true for some of those who work with these young people. All too often physicians are not trained to deal with many of the problems they encounter with pregnant adolescents. Many of the problems and concerns associated with adolescent pregnancy which directly affect the medical well-being of the mother and baby are not considered traditional medical problems: family experiences, superstitions, folk beliefs, culturally sanctioned interests, eating and sleeping habits. For the physician to successfully care for the adolescent mother and her child, these important concerns must be understood and addressed.

Masking of the non-test ear in speech audiometry.

Masking of the non-test ear is often needed in speech audiometry but the methods for such masking have not been well defined. 'White' or 'speech' noise is commonly provided by audiometers for this purpose, and the many problems and uncertainties in their calibration and effectiveness are discussed; data on these aspects are presented with respect to some current audiometers and Fry's and AB(S) PB-word lists. Formulae are given for estimating the possible need for masking, calculating the required dial level of masking noise for a given dial level of speech signal, and assessing the extent to which cross-masking may be affecting the results. The formulae presented are applicable for earphone listening only.