Intraoperative force and electrocochleography measurements in an animal model of cochlear implantation.

To preserve residual hearing, techniques for monitoring and reducing the effects of trauma during cochlear implant surgery are being developed. This study examines the relationships between intraoperative recordings (electrode insertion force and electrocochleography), trauma, and hearing loss after cochlear implantation. The study also evaluated the efficacy of intravenous steroids for reducing hearing loss after implantation. Thirty-two normal-hearing guinea pigs were randomly implanted with electrode arrays of differing stiffness ('hard' or 'soft'). These arrays used an intracochlear electrode to record electrode insertion force and electrocochleography responses to a multi-frequency acoustic stimulus during implantation. Additionally, sub-cohorts of animals were administered intravenous saline ('control') or dexamethasone ('steroid') prior to surgery. Subsequent hearing loss was assessed using electrocochleography recordings from the round window membrane prior to surgery and 4 weeks after implantation. After 4 weeks, cochleae were harvested and imaged with thin sheet laser imaging microscopy. After 4 weeks, compound action potential (CAP) thresholds did not differ between steroid and control groups. The CAP amplitude at low-mid frequencies decreased after implantation with a hard electrode, an effect which was partly negated by administering steroids. A decrease in the 'intraoperative' CAP amplitude preceded the reporting of insertion resistance by the surgeon by 5.94 s (±4.03 s SEM). Intraoperative CAP declines were also correlated with higher grades of trauma (r = 0.56, p < 0.01) and greater hearing loss (r = 0.56, p < 0.01). This relationship was not repeated with intraoperative cochlear microphonics. A rise in intraoperative force, which preceded the reporting of resistance by 0.71 s (±0.15 s SEM), was correlated with trauma (r = 0.400, p = 0.04) but not hearing loss (r = 0.297, p = 0.27). Preserving intraoperative CAP amplitudes during implantation was predictive of an atraumatic insertion and reduced post-implantation hearing loss. A rise in force usually preceded the reporting of resistance, although by less than 1 s. These results suggest that intraoperative CAPs may offer a more robust feedback mechanism for improving hearing preservation rates than cochlear microphonic and electrode insertion force recordings, especially considering the rapid changes in insertion force and relatively slow human reaction times. Pre-operative steroids were effective in reversing loss of CAP amplitude with hard electrodes and evoked by lower frequency tones, which suggests a possible role in reducing synaptopathy.

Endolymphatic hydrops is prevalent in the first weeks following cochlear implantation.

AIM: To explore morphological or electrophysiological evidence for the presence of endolymphatic hydrops (EH) in guinea pig cochleae in the first 3 months after cochlear implantation. METHODS: Dummy silastic electrodes were implanted atraumatically into the basal turn of scala tympani via a cochleostomy. Round window electrocochleography (ECochG) was undertaken prior to and after implantation. Animals survived for 1, 7, 28 or 72 days prior to a terminal experiment, when ECochG was repeated. The cochleae were imaged using micro-CT after post-fixing with osmium tetroxide to reveal the inner ear soft tissue structure. EH was assessed by visual inspection at a series of frequency specific places along the length of the cochlea, and the extent to which Reissner's membrane departed from its neutral position was quantified. Tissue response volumes were calculated. Using ECochG, the ratio of the summating potential to the action potential (SP/AP ratio) was calculated in response to frequencies between 2 and 32 kHz. RESULTS: There was minimal evidence of electrode trauma from cochlear implantation on micro-CT imaging. Tissue response volumes did not change over time. EH was most prevalent 7 days after surgery in implanted ears, as determined by visual inspection. Scala media areas were increased, as expected in cases of EH, over the first month after cochlear implantation. SP/AP ratios decreased immediately after surgery, but were elevated 1 and 7 days after implantation. CONCLUSIONS: EH is prevalent in the first weeks after implant surgery, even in the absence of significant electrode insertion trauma.

Gentamicin administration on the stapes footplate causes greater hearing loss and vestibulotoxicity than round window administration in guinea pigs.

Clinically, gentamicin has been used extensively to treat the debilitating symptoms of Mèniére's disease and is well known for its vestibulotoxic properties. Until recently, it was widely accepted that the round window membrane (RWM) was the primary entry route into the inner ear following intratympanic drug administration. In the current study, gentamicin was delivered to either the RWM or the stapes footplate of guinea pigs (GPs) to assess the associated hearing loss and histopathology associated with each procedure. Vestibulotoxicity of the utricular macula, saccular macula, and crista ampullaris in the posterior semicircular canal were assessed quantitatively with density counts of hair cells, supporting cells, and stereocilia in histological sections. Cochleotoxicity was assessed quantitatively by changes in threshold of auditory brainstem responses (ABR), along with hair cell and spiral ganglion cell counts in the basal and second turns of the cochlea. Animals receiving gentamicin applied to the stapes footplate exhibited markedly higher levels of hearing loss between 8 and 32 kHz, a greater reduction of outer hair cells in the basal turn of the cochlea and fewer normal type I cells in the utricle in the vestibule than those receiving gentamicin on the RWM or saline controls. This suggests that gentamicin more readily enters the ear when applied to the stapes footplate compared with RWM application. These data provide a potential explanation for why gentamicin preferentially ablates vestibular function while preserving hearing following transtympanic administration in humans.

Relations between cochlear histopathology and hearing loss in experimental cochlear implantation.

This study reviews the cochlear histology from four hearing preservation cochlear implantation experiments conducted on 73 guinea pigs from our institution, and relates histopathological findings to residual hearing. All guinea pigs had normal hearing prior to surgery and underwent cochlear implantation via a cochleostomy with a silastic-platinum dummy electrode. Pure tone auditory brainstem response (ABR) thresholds from 2 to 32 kHz were recorded prior to surgery, and at one and four weeks postoperatively. The cochleae were then fixed in paraformaldehyde, decalcified, paraffin embedded, and mid-modiolar sections were prepared. The treatment groups were as follows: 1) Systemic dexamethasone, 0.2 mg/kg administered 1 h before implantation, 2) Local dexamethasone, 2% applied topically to the round window for 30 min prior to cochlear implantation, 3) Local n-acetyl cysteine, 200 µg applied topically to the round window for 30 min prior to implantation, 4) inoculation to keyhole-limpet hemocyanin (KLH) prior to implantation, and 5) untreated controls. There was a significant correlation between the extent of the tissue reaction in the cochlea and the presence of foreign body giant cells (FBGCs), new bone formation and injury to the osseous spiral lamina (OSL). The extent of the tissue response, as a percentage of the area of the scala tympani, limited the best hearing that was observed four weeks after cochlear implantation. Poorer hearing at four weeks correlated with a more extensive tissue response, lower outer hair cell (OHC) counts and OSL injury in the basal turn. Progressive hearing loss was also correlated with the extent of tissue response. Hearing at 2 kHz, which corresponds to the region of the second cochlear turn, did not correspond with loco-regional inner hair cell (IHC), OHC or SGC counts. We conclude that cochlear injury is associated with poorer hearing early after implantation. The tissue response is related to indices of cochlear inflammation and injury. An extensive tissue response limits hearing at four weeks, and correlates with progressive hearing loss. These latter effects may be due to inflammation, but would also be consistent with interference of cochlear mechanics.

Direct entry of gadolinium into the vestibule following intratympanic applications in Guinea pigs and the influence of cochlear implantation.

Although intratympanic (IT) administration of drugs has gained wide clinical acceptance, the distribution of drugs in the inner ear following IT administration is not well established. Gadolinium (Gd) has been previously used as a marker in conjunction with magnetic resonance imaging (MRI) to visualize distribution in inner ear fluids in a qualitative manner. In the present study, we applied gadolinium chelated with diethylenetriamine penta-acetic acid (Gd-DTPA) to the round window niche of 12 guinea pigs using Seprapack(TM) (carboxlmethylcellulose-hyaluronic acid) pledgets which stabilized the fluid volume in the round window niche. Gd-DTPA distribution was monitored sequentially with time following application. Distribution in normal, unperforated ears was compared with ears that had undergone a cochleostomy in the basal turn of scala tympani and implantation with a silastic electrode. Results were quantified using image analysis software. In all animals, Gd-DTPA was seen in the lower basal scala tympani (ST), scala vestibuli (SV), and throughout the vestibule and semi-circular canals by 1 h after application. Although Gd-DTPA levels in ST were higher than those in the vestibule in a few ears, the majority showed higher Gd-DTPA levels in the vestibule than ST at both early and later time points. Quantitative computer simulations of the experiment, taking into account the larger volume of the vestibule compared to scala tympani, suggest most Gd-DTPA (up to 90%) entered the vestibule directly in the vicinity of the stapes rather than indirectly through the round window membrane and ST. Gd-DTPA levels were minimally affected by the implantation procedure after 1 h. Gd-DTPA levels in the basal turn of scala tympani were lower in implanted animals, but the difference compared to non-implanted ears did not reach statistical significance.

Methylprednisolone applied directly to the round window reduces dizziness after cochlear implantation: a randomized clinical trial.

This prospective, double-blind controlled, randomized clinical trial of 43 adults showed that topical methylprednisolone applied to the round window during cochlear implantation was effective in protecting inner ear function. Postoperative vestibular disturbance was significantly lower in the steroid group (5%) than the control group (29%). Electrode impedances from the middle portion of the electrode array (electrodes 10-13) were significantly reduced in steroid-treated recipients compared to controls. Hearing and vestibular function analyses were under-powered to detect any drug changes due to limited participant data.

Beta-defensin evolution: selection complexity and clues for residues of functional importance.

We have examined the evolution of the genes at the major human beta-defensin locus and the orthologous loci in a range of other primates and mammals. For the first time, these data allow us to examine selective episodes in the more recent evolutionary history of this locus as well as in the ancient past. We have used a combination of maximum-likelihood-based tests and a maximum-parsimony-based sliding window approach to give a detailed view of the varying modes of selection operating at this locus. We provide evidence for strong positive selection soon after the duplication of these genes within an ancestral mammalian genome. During the divergence of primates, however, variable selective pressures have acted on beta-defensin genes in different evolutionary lineages, with episodes of both negative and, more rarely, positive selection. Positive selection appears to have been more common in the rodent lineage, accompanying the birth of novel rodent-specific beta-defensin gene clades. Sites in the second exon have been subject to positive selection and, by implication, are important in functional diversity. A small number of sites in the mature human peptides were found to have undergone repeated episodes of selection in different primate lineages. Particular sites were consistently implicated by multiple methods at positions throughout the mature peptides. These sites are clustered at positions that are predicted to be important for the function of beta-defensins.

Single nucleotide polymorphisms in the leptin receptor gene: studies in anorexia nervosa.

Anorexia nervosa is an eating disorder of unknown aetiology. There is significant evidence for a genetic component in the pathogenesis of this disorder. A region on chromosome 1 has been identified as a susceptibility locus. The leptin receptor has been mapped to a similar region, further upstream of this susceptibility locus. Leptin and its receptor are known to be important factors in the control and regulation of body weight. Single nucleotide polymorphisms (SNPs) in the leptin receptor are associated with measures of body weight. In the present study, SNPs in the coding region of the leptin receptor were analysed and their possible association with anorexia nervosa was investigated. Two cohorts of young women, 176 Caucasian anorexia nervosa patients and 152 normal Caucasian females, were genotyped for three SNPs in the leptin receptor. There was no significant difference in allele or genotype frequency, for any SNP, between the normal controls and the cohort of anorexia subjects. There were no significant associations with any genotype and body mass index in either the control or anorexic cohorts. When the anorexic cohort was subdivided into restricting and bingeing/purging behaviours, we found no significant association with any genotype. Analysis of haplotypes showed no significant evidence of association with anorexia. In summary, leptin receptor SNPs do not appear to be important factors in the regulation of body weight in young, pre-menopausal women or have any significant association with anorexia nervosa.

A qualitative study of Australian GPs' attitudes and practices in the diagnosis and management of attention-deficit/hyperactivity disorder (ADHD).

BACKGROUND: The importance of general practice involvement in the care of attention-deficit/ hyperactivity disorder (ADHD) is increasing due to the rising numbers of patients who present with the disorder. It has been suggested by consensus bodies that GPs should be identifying and referring patients at the severe end of the ADHD spectrum and managing those with less severe symptoms. However, GPs' views of their role in ADHD care are unknown. OBJECTIVE: Our aim was to explore the attitudes and practices of Australian GPs towards the diagnosis and management of ADHD. METHODS: We conducted a series of focus groups to explore GPs' beliefs regarding the causes of ADHD, their perceived role in ADHD diagnosis and management and their views on the role of behaviour therapies and pharmacotherapies in ADHD management. The subjects were 28 GPs in six focus groups. RESULTS: GPs in this study did not want to be the primary providers of care for patients with ADHD. Participants indicated a preference to refer the patient to medical specialists for diagnosis and treatment of ADHD, and expressed low levels of interest in becoming highly involved in ADHD care. Concerns about overdiagnosis and misdiagnosis of the disorder, diagnostic complexity, time constraints, insufficient education and training about the disorder, and concerns regarding misuse and diversion of stimulant medications were the reasons cited for their lack of willingness. CONCLUSIONS: The Australian GPs in this study identify a role for themselves in ADHD care which is largely supportive in nature, and involves close liaison with specialist services.

Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-1 trials.

OBJECTIVE: To investigate the effectiveness of valerian for the management of chronic insomnia in general practice. DESIGN: Valerian versus placebo in a series of n-of-1 trials, in Queensland, Australia. RESULTS: Of 42 enrolled patients, 24 (57%) had sufficient data for inclusion into the n-of-1 analysis. Response to valerian was fair for 23 (96%) participants evaluating their "energy level in the previous day" but poor or modest for all 24 (100%) participants' response to "total sleep time" and for 23 (96%) participants' response to "number of night awakenings" and "morning refreshment". As a group, the proportion of treatment successes ranged from 0.35 (95% CI 0.23, 0.47) to 0.55 (95% CI 0.43, 0.67) for the six elicited outcome sleep variables. There was no significant difference in the number (P=0.06), distribution (P=1.00) or severity (P=0.46) of side effects between valerian and placebo treatments. CONCLUSIONS: Valerian was not shown to be appreciably better than placebo in promoting sleep or sleep-related factors for any individual patient or for all patients as a group.

Attitudes and practices of general practitioners in the diagnosis and management of attention-deficit/hyperactivity disorder.

OBJECTIVE: To assess understanding of, and actual and potential roles in management of attention-deficit/hyperactivity disorder (ADHD) among GPs. METHODS: A cross-sectional questionnaire survey of Queensland GPs selected randomly from the Royal Australian College of General Practitioners directory of members was carried out. Main outcome measures were knowledge levels of ADHD, current management practices, referral patterns and self-perceived information and training needs. RESULTS: Three hundred and ninety-nine GPs returned a completed questionnaire (response rate 76%). Roles identified by GPs were: the provisional diagnosis of ADHD and referral to specialist services for confirmation of the diagnosis and initiation of management; assistance with monitoring progress once a management plan was in place; education of the child and their family regarding the disorder; and liaison with the school where necessary. Perceived barriers to increased involvement of GPs were: time and resource constraints of general practice; concerns regarding abuse and addiction liability of prescription stimulants; complex diagnostic issues associated with childhood behavioural problems; and lack of training and education regarding ADHD. CONCLUSIONS: General practitioners identify a role for themselves in ADHD care that is largely supportive in nature and involves close liaison with specialist services.

Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa.

There is significant evidence for genetic factors in the susceptibility to anorexia nervosa (AN). Previously genetic variation in the estrogen receptor 2 gene (ESR2) has been studied, however no strong evidence of association with AN has been found. In the present study variation in the estrogen receptor 1 (ESR1) and ESR2 genes was examined. Estrogen receptors have been localised to areas of the brain involved in behaviour and regulation of food intake. The anorexic effects of estrogen are accentuated by stress and thus it is postulated that variation in the estrogen receptors may contribute to the genetic susceptibility to AN in females. A cohort of 170 female, Caucasian AN sufferers and 152 female controls were typed for dinucleotide repeat polymorphisms in both ESR1 and ESR2 and two further SNPs at each locus. Variation at ESR1 was not associated with AN. However an association was found at the ESR2 locus with the heterozygous genotype of the G1082A polymorphism and AN but not with any of the other ESR2 polymorphisms analysed. Analysis of haplotypes at ESR1 and ESR2 showed no significant evidence of association with AN suggesting that the variability in ESR2 alone may contribute to the genetic susceptibility to AN.

Complementary therapies: the appeal to general practitioners.

Pragmatism--among consumers seeking a cure and among general practitioners seeking clinical results and more patients--is not a complete explanation for the burgeoning of complementary and alternative medicine (CAM) in Western societies. Instead, this growth is substantially a result of pervasive and rapid social change, alternatively termed 'globalisation' and 'postmodernisation'. Globalisation and postmodernisation are creating a new social reality, of which a prominent characteristic is the proliferation of consumer choice. GPs are enmeshed in this social change and subject to the trend to greater choice--both their patients' and their own. On the one hand, GPs are reacting to social change as "economic pragmatists", responding to consumers' increasing demand for CAM. On the other hand, GPs themselves are acting as agents of social change by acknowledging the limitations of orthodox biomedical treatments and promoting CAM as part of their service delivery. Lack of scientific validation of CAM has not prevented GPs' use of such therapies. The phrase "clinical legitimacy" can be seen as a trump card that overrides "scientific legitimacy". It is the shibboleth of a postmodern movement among GPs towards healing and the "art" of medicine, as opposed to the "science" of medicine per se.

Re-evaluation of two simple prognostic scores of outcome after proximal femoral fractures.

The Belfast and Newcastle simple prognostic scores of outcome after treatment of proximal femoral fractures were recorded shortly after admission on 250 patients. All patients were then followed until discharge, with 87 of those who were the more physically and socially dependent before admission being transferred after surgery for rehabilitation in a geriatric unit. The hospital mortality rate, a hospital stay of over 6 weeks and two measures of rehabilitation outcome, i.e. a delay of over 3 weeks after the operation in regaining independent mobility and any functional decline on discharge compared with the preadmission situation, were recorded for each patient. The prediction of a higher hospital mortality rate and a delay in reaching independent mobility in more dependent patients with both scores reached statistical significance. Longer hospital stays in the more dependent patients did not occur in a situation where care facilities for dependent patients were readily available. The scores, in particular the Belfast score, can be used to compare the casemix of patients with proximal femoral fractures within and between units over time and can predict mortality and delay in achieving independent mobility. They may be helpful in the early selection of patients for transfer to a geriatric unit or orthogeriatric unit for rehabilitation.

A comparison of the psychosocial aspects of AIDS and cancer-related bereavement.

OBJECTIVE: This study compares the psychological symptoms and bereavement distress of individuals bereaved by AIDS with a group bereaved by a cancer death, and addresses the question of whether an AIDS death is associated with a higher rate of adverse psychosocial factors that may increase risk of psychological morbidity in the bereaved individuals. METHOD: AIDS (n = 28) and cancer (n = 30) bereaved individuals (all within 3 months of the bereavement) completed measures of psychological morbidity and measures addressing a range of other adverse factors, e.g., number of losses, levels of social support and stigma. RESULTS: The cancer and AIDS bereaved were essentially similar on all psychological symptom measures. The AIDS group reported lower levels of social support in response to the bereavement than cancer bereaved individuals; a greater number of bereavements, were more likely to conceal the cause of death from significant others including their own family and perceived, in some instances, a greater level of rejection from others. The AIDS group reported higher levels of social support from friends than from family. CONCLUSIONS: At three months following bereavement, AIDS and cancer bereaved were similar in levels of distress. While this may change with the progress of grief over time, it suggests essentially similar early bereavement responses. Those bereaved by AIDS reported a range of other adverse factors such as a greater number of losses, lower social support, stigma, and less open disclosure of the cause of death.

Pain and its control in patients with fractures of the femoral neck while awaiting surgery.

A survey, by two methods, of the pain felt preoperatively by 100 elderly patients with an acute fracture of the femoral neck showed that most felt a great deal of pain and that a painless fracture was exceptional. No relationship was found between pain appreciation and the patient's fracture type or their age. One of the methods suggested that elderly patients with preserved mental function felt more pain, and the other that less pain was felt by those taking regular prefracture analgesia. The amount of analgesic drugs given to the patients in this survey seemed inadequate for their levels of perceived pain; accordingly regular measurement by nurses of the degree of pain felt preoperatively by patients with this condition is recommended, together with a greater medical review of the medication being prescribed.

Detrusor hyperreflexia--are there two types?

The concept that elderly patients with urinary incontinence due to detrusor hyperreflexia can be divided into two groups with differing natural histories on the basis of the detrusor contractility found on cystometry is reassessed. Thirty patients shown to have hyperreflexia on urodynamic study for persistent urinary incontinence following a recent neurological lesion had their contractility measured by the suggested criteria of the residual urine following a hyperreflexic contraction and the rate of increase of detrusor pressure. The consistency of contractility on cystometry was also measured by repeating this three times on the same occasion. A spectrum of values for the post-contraction volumes and the rate of increase of detrusor pressure was found. On repetitive cystometry 11 out of 30 patients showed a variable post-contraction residual volume. While impaired contractility is common in detrusor hyperreflexia, the concept of two subgroups is not supported by these results. In some patients cystometric measures of contractility vary considerably on repeating the study on the same occasion.

The social consequences of surgical complications for patients with proximal femoral fractures.

A case-matched study was performed to assess the social effects of surgical complications of operative fixation of fractures of the proximal femur. Fifty-two patients aged over sixty-five, half with deep wound infection, the remainder with serious early mechanical problems requiring revision surgery to correct these, had their hospital fatality, length of stay, mobility and social dependency at admission and on discharge compared with patients free from such complications. Deep wound infection was associated with a high fatality and in the survivors a prolonged period in hospital, a marked decline in mobility and without exception a great increase in social dependency; patients having revision surgery had a longer hospital admission, considerable alteration in social circumstances but a little decline in mobility and no significant increase in fatality when compared with matched cases.

Proximal femoral fractures in the elderly: does operative delay for medical reasons affect short-term outcome?

Forty patients over 65 years of age with fractures of the proximal femur, whose operation was delayed more than 24 hours after admission for medical reasons, were studied. Length of post-operative stay on the orthopaedic wards, mobility after one month and need for continuing supervision by the geriatric services, after discharge from the orthopaedic wards, were compared with a matched group in whom there was no delay. There were no significant differences between the results of the two groups, suggesting that, if medical conditions are adequately treated before operative fixation of fractures of the proximal femur in elderly patients, the short-term outcome is not adversely affected.

Delayed diagnosis of femoral-neck fractures in the elderly.

A survey of a district population presenting to a trauma unit with fractured femoral necks over a year, showed that, out of a total of 374 elderly patients with this fracture, in 33 the diagnosis was delayed for over 24 hours from the onset of disabling symptoms. This was due to late presentation in eight patients, difficulty in confirming the suspected diagnosis in five, and in 20 to initial failure of doctors to make the diagnosis. By comparing this latter group with controls, it was found that medical error was most likely in patients who were either confused, dependent and subject to falls, or alternatively had suffered a spontaneous fracture which had not displaced.