Thin-film micro-electrode stimulation of the cochlea in rats exposed to aminoglycoside induced hearing loss.

The multi-channel cochlear implant (CI) provides sound and speech perception to thousands of individuals who would otherwise be deaf. Broad activation of auditory nerve fibres when using a CI results in poor frequency discrimination. The CI also provides users with poor amplitude perception due to elicitation of a narrow dynamic range. Provision of more discrete frequency perception and a greater control over amplitude may allow users to better distinguish speech in noise and to segregate sound sources. In this research, thin-film (TF) high density micro-electrode arrays and conventional platinum ring electrode arrays were used to stimulate the cochlea of rats administered sensorineural hearing loss (SNHL) via ototoxic insult, with neural responses taken at 434 multiunit clusters in the central nucleus of the inferior colliculus (CIC). Threshold, dynamic range and broadness of response were used to compare electrode arrays. A stronger current was required to elicit CIC threshold when using the TF array compared to the platinum ring electrode array. TF stimulation also elicited a narrower dynamic range than the PR counterpart. However, monopolar stimulation using the TF array produced more localised CIC responses than other stimulation strategies. These results suggest that individuals with SNHL could benefit from micro stimulation of the cochlea using a monopolar configuration which may provide discrete frequency perception when using TF electrode arrays.

Business continuity in blood services: two case studies from events with potentially catastrophic effect on the national provision of blood components.

BACKGROUND AND OBJECTIVES: NHS Blood and Transplant (NHSBT) and the Australian Red Cross Blood Service (ARCBS) are national blood establishments providing blood components to England and North Wales, and Australia, respectively. In 2012, both services experienced potentially catastrophic challenges to key assets. NHSBT suffered a flood that closed the largest blood-manufacturing centre in Europe, whilst ARCBS experienced the failure of a data centre network switch that rendered the national blood management system inaccessible for 42 h. This paper describes both crisis events, including the immediate actions, recovery procedures and lessons learned. MATERIALS AND METHODS: Both incidents triggered emergency response plans. These included hospital reprovisioning and recovery from the incident. Once normal services had been restored, both events were subjected to root cause analysis (RCA) and production of 'lessons learned' reports. RESULTS: In both scenarios, the key enablers of rapid recovery were established emergency plans, clear leadership and the support of a flexible workforce. Product issues to hospitals were unaffected, and there were no abnormal trends in hospital complaints. RCA identified the importance of risk mitigations that require co-operation with external organizations. Reviews of both events identified opportunities to enhance business resilience through prior identification of external risks and improvements to contingency plans, for example by implementing mass messaging to staff and other stakeholders. CONCLUSIONS: Blood establishment emergency plans tend to focus on responding to mass casualty events. However, consolidation of manufacturing to fewer sites combined with a reliance on national IT systems increases the impact of loss of function. Blood services should develop business continuity plans which include prevention of such losses, and the maintenance of services and disaster recovery.

Intralaminar stimulation of the inferior colliculus facilitates frequency-specific activation in the auditory cortex.

OBJECTIVE: Auditory midbrain implants (AMI) provide inadequate frequency discrimination for open set speech perception. AMIs that can take advantage of the tonotopic laminar of the midbrain may be able to better deliver frequency specific perception and lead to enhanced performance. Stimulation strategies that best elicit frequency specific activity need to be identified. This research examined the characteristic frequency (CF) relationship between regions of the auditory cortex (AC), in response to stimulated regions of the inferior colliculus (IC), comparing monopolar, and intralaminar bipolar electrical stimulation. APPROACH: Electrical stimulation using multi-channel micro-electrode arrays in the IC was used to elicit AC responses in anaesthetized male hooded Wistar rats. The rate of activity in AC regions with CFs within 3 kHz (CF-aligned) and unaligned CFs was used to assess the frequency specificity of responses. MAIN RESULTS: Both monopolar and bipolar IC stimulation led to CF-aligned neural activity in the AC. Altering the distance between the stimulation and reference electrodes in the IC led to changes in both threshold and dynamic range, with bipolar stimulation with 400 µm spacing evoking the lowest AC threshold and widest dynamic range. At saturation, bipolar stimulation elicited a significantly higher mean spike count in the AC at CF-aligned areas than at CF-unaligned areas when electrode spacing was 400 µm or less. Bipolar stimulation using electrode spacing of 400 µm or less also elicited a higher rate of elicited activity in the AC in both CF-aligned and CF-unaligned regions than monopolar stimulation. When electrodes were spaced 600 µm apart no benefit over monopolar stimulation was observed. Furthermore, monopolar stimulation of the external cortex of the IC resulted in more localized frequency responses than bipolar stimulation when stimulation and reference sites were 200 µm apart. SIGNIFICANCE: These findings have implications for the future development of AMI, as a bipolar stimulation strategy may improve the ability of implant users to discriminate between frequencies.

Midbrain responses to micro-stimulation of the cochlea using high density thin-film arrays.

A broader activation of auditory nerve fibres than normal using a cochlear implant contributes to poor frequency discrimination. As cochlear implants also deliver a restricted dynamic range, this hinders the ability to segregate sound sources. Better frequency coding and control over amplitude may be achieved by limiting current spread during electrical stimulation of the cochlea and positioning electrodes closer to the modiolus. Thin-film high density microelectrode arrays and conventional platinum ring electrode arrays were used to stimulate the cochlea of urethane-anaesthetized rats and responses compared. Neurophysiological recordings were taken at 197 multi-unit clusters in the central nucleus of the inferior colliculus (CIC), a site that receives direct monaural innervation from the cochlear nucleus. CIC responses to both the platinum ring and high density electrodes were recorded and differences in activity to changes in stimulation intensity, thresholds and frequency coding of neural activation were examined. The high density electrode array elicited less CIC activity at nonspecific frequency regions than the platinum ring electrode array. The high density electrode array produced significantly lower thresholds and larger dynamic ranges than the platinum ring electrode array when positioned close to the modiolus. These results suggest that a higher density of stimulation sites on electrodes that effectively 'aim' current, combined with placement closer to the modiolus would permit finer control over charge delivery. This may equate to improved frequency specific perception and control over amplitude when using future cochlear implant devices.

Complications associated with distraction osteogenesis for infected nonunion of the femoral shaft in the presence of a bone defect: a retrospective series.

We undertook a retrospective study of 50 consecutive patients (41 male, 9 female) with an infected nonunion and bone defect of the femoral shaft who had been treated by radical debridement and distraction osteogenesis. Their mean age was 29.9 years (9 to 58) and they had a mean of 3.8 (2 to 19) previous operations. They were followed for a mean of 5.9 years (2.0 to 19.0). The mean duration of the distraction osteogenesis was 24.5 months (2 to 39). Pin-track infection was observed in all patients. The range of knee movement was reduced and there was a mean residual leg-length discrepancy of 1.9 cm (0 to 8) after treatment. One patient required hip disarticulation to manage intractable sepsis. In all, 13 patients had persistent pain. Bony union was achieved in 49 patients at a mean of 20.7 months (12 to 35). Although distraction osteogenesis is commonly used for the treatment of infected femoral nonunion with bone defects, it is associated with a high rate of complications.

Central bone grafting for nonunion of fractures of the tibia: a retrospective series.

Nonunion of the tibia associated with bone loss, previous infection, obliteration of the intramedullary canal or located in the distal metaphysis poses a challenge to the surgeon and significant morbidity to patients. We retrospectively reviewed the records of 24 patients who were treated by central bone grafting and compared them to those of 20 who were treated with a traditional posterolateral graft. Central bone grafting entails a lateral approach, anterior to the fibula and interosseous membrane which is used to create a central space filled with cancellous iliac crest autograft. Upon consolidation, a tibiofibular synostosis is formed that is strong enough for weight-bearing. This procedure has advantages over other methods of treatment for selected nonunions. Of the 24 patients with central bone grafting, 23 went on to radiographic and clinical union without further intervention. All healed within a mean of 20 weeks (10 to 48). No further bone grafts were required, and few complications were encountered. These results were comparable to those of the 20 patients who underwent posterolateral bone grafting who united at a mean of 31.3 weeks (16 to 60) but one of whom required below-knee amputation for intractable sepsis. Central bone grafting is a safe and effective treatment for difficult nonunions of the tibia.

Plasma concentrations of endotoxin and platelet activation in the developmental stage of oligofructose-induced laminitis.

The link between the fermentation of carbohydrate in the equine large intestine and the development of acute laminitis is poorly understood. Absorption of endotoxin (lipopolysaccharide; LPS) into the plasma has been observed in one experimental model of laminitis, but does not cause laminitis when administered alone. Thus, the potential role of endotoxin is unclear. Platelet activation has previously been demonstrated in the developmental stage of laminitis. Equine platelets are more sensitive than leukocytes to activation by endotoxin, and can be activated directly by LPS in the low pg/ml range, activating p38 MAP kinase and releasing serotonin (5-HT) and thromboxane. The objectives of this study were firstly to determine whether endotoxin and platelet activation could be measured in the plasma of horses in the developmental phase of laminitis induced with oligofructose. Secondly, the time course of events involving platelet activation and platelet-derived vasoactive mediator production was investigated. Laminitis was induced in six Standardbred horses by the administration of 10 g/kg bwt of oligofructose. Plasma samples were obtained every 4h, and platelet pellets were obtained by centrifugation. LPS was measured using a kinetic limulus amebocyte lysate assay, and platelet activation was assessed by Western blotting for the phosphorylated form of p38 MAP kinase. Plasma 5-HT was assayed by HPLC with electrochemical detection and thromboxane B(2) was measured by radioimmunoassay. Clinical signs of laminitis and histopathologic changes were observed in lamellar sections from five of the six horses. Onset of lameness was between 20 and 30 h after the administration of oligofructose. LPS increased above the limit of detection (0.6 pg/ml) to reach a peak of 2.4+/-1.0 pg/ml at 8 h. TNFalpha was also detectable in the plasma from 12 to 24 h. There was a time-dependent increase in platelet p38 MAPK phosphorylation, which peaked at approximately 12 h (3.8+/-1.3 fold increase); plasma 5-HT and thromboxane increased steadily after this time (2.9+/-0.6 and 11.3+/-5.0 fold increases, respectively). These data indicate that small quantities of endotoxin may move into the circulation from the large intestine after the sharp decrease in pH that occurs as a result of carbohydrate fermentation. Correlating these findings with in vitro studies suggests that LPS may primarily activate platelets, leading indirectly to the activation of leukocytes. Therefore, endotoxin may contribute in the initiation of the early inflammatory changes observed in experimental models of acute laminitis.

Impact of the complement cascade on posttraumatic cartilage inflammation and degradation.

The limited ability of articular cartilage to recover from injury, remains an unsolved clinical challenge in orthopaedic surgery. Persistent injury of the articular surface can lead to the development of posttraumatic osteoarthritis. The local inflammatory response contributes to the pathogenesis of osteoarthritis by inducing chondrocyte apoptosis and the de-regulation of chondrocyte matrix remodelling. The role of the complement system in contributing to secondary inflammation-mediated cartilage degradation represents a newer field of investigation. The purpose of this review article is to summarize the known complement-mediated actions in cartilage homeostasis and injury. This article focuses on the known effects of complement on secondary chondrocyte apoptosis, and the interplay of the complement system with pro-inflammatory cytokines. Pharmacological therapies related to complement inhibition will be discussed as they potentially represent a new avenue for attenuating the effect of the complement system on cartilage repair.

[The relevance of the inflammatory response in the injured brain]. / Die Bedeutung der posttraumatischen Entzündungsreaktion im verletzten Gehirn.

Research efforts in recent years have defined traumatic brain injury (TBI) as a predominantly immunological and inflammatory disorder. This perception is based on the fact that the overwhelming neuroinflammatory response in the injured brain contributes to the development of posttraumatic edema and to neuropathological sequelae which are, in large part, responsible for the adverse outcome. While the "key" mediators of neuroinflammation, such as the cytokine cascade and the complement system, have been clearly defined by studies in experimental TBI models, their exact pathways of interaction and pathophysiological implications remain to be further elucidated. This lack of knowledge is partially due to the concept of a "dual role" of the neuroinflammatory response after TBI. This notion implies that specific inflammatory molecules may mediate diverse functions depending on their local concentration and kinetics of expression in the injured brain. The inflammation-induced effects range from beneficial aspects of neuroprotection to detrimental neurotoxicity. The lack of success in pushing anti-inflammatory therapeutic concepts from"bench to bedside" for patients with severe TBI strengthens the further need for advances in basic research on the molecular aspects of the neuroinflammatory network in the injured brain. The present review summarizes the current knowledge from experimental studies in this field of research and discusses potential future targets of investigation.

Group A streptococcal skin infection outbreak in an abattoir: lessons for prevention.

During a group A streptococcus (GAS) outbreak 21 abattoir workers developed skin infections. The unusual outbreak strain (emm 108.1) was cultured from five workers and four persons in the community with links to the abattoir. The attack rate was 26% in the lamb line. Communal nailbrushes were neither routinely disinfected nor changed, and had high bacterial counts. A cohort study found a higher risk from working in the gutting area and getting cuts on hands more than weekly. Despite high bacterial counts daily nailbrush use had a lower risk, as did always wearing disposable gloves. Working in the gutting area (OR 11.44) and nailbrush use at least once a day (OR 0.04) were significant in the multivariate model. Transmission of infection is likely to have occurred on carcasses. GAS infection among abattoir workers was once common. Simple hygiene measures, such as nailbrush use, may reduce the impact of future outbreaks.

Bcl-2 family proteins are essential for platelet survival.

Platelets are relatively short-lived, anucleated cells that are essential for proper hemostasis. The regulation of platelet survival in the circulation remains poorly understood. The process of platelet activation and senescence in vivo is associated with processes similar to those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, and cell shrinkage. ABT-737, a potent antagonist of Bcl-2, Bcl-X(L), and Bcl-w, induces apoptosis in nucleated cells dependent on these proteins for survival. In vivo, ABT-737 induces a reduction of circulating platelets that is maintained during drug therapy, followed by recovery to normal levels within several days after treatment cessation. Whole body scintography utilizing ([111])Indium-labeled platelets in dogs shows that ABT-737-induced platelet clearance is primarily mediated by the liver. In vitro, ABT-737 treatment leads to activation of key apoptotic processes including cytochrome c release, caspase-3 activation, and PS externalization in isolated platelets. Despite these changes, ABT-737 is ineffective in promoting platelet activation as measured by granule release markers and platelet aggregation. Taken together, these data suggest that ABT-737 induces an apoptosis-like response in platelets that is distinct from platelet activation and results in enhanced clearance in vivo by the reticuloendothelial system.

Contraception for teenagers and young adults with cancer.

Adolescence can be an extremely stressful time for all concerned. When this period is then compounded by the development of cancer, formidable and seemingly insurmountable problems may be perceived. Cancer in adolescence is relatively uncommon, with an annual incidence rate in western populations of approximately 150-200 per million. Five-year survival of patients diagnosed around 1990 exceeded 70% in the United Kingdom (UK) and United States of America (USA), and adolescents with cancer are likely to remain fertile. Further advances in therapeutic modalities are creating a generation of adolescents and young adults with cancer who can now aspire to the same sexual and reproductive activities as their healthy peers. This then raises the issue of avoidance of undesired pregnancy during and after treatment. This article aims to address the contraceptive needs of adolescents and young adults undergoing treatment for cancer.

Iliosacral screw fixation of the posterior pelvic ring using local anaesthesia and computerised tomography.

Various techniques have been used for the fixation of the posterior pelvis, each with disadvantages specific to the technique. In this study, a new protocol involving the placement of posterior pelvic screws in the CT suite is described and evaluated. A total of 66 patients with unstable pelvic ring injuries was stabilised under local anaesthesia with sedation. The mean length of time for the procedure was 26 minutes per screw. There were no technical difficulties or misplaced screws and no cases of infection or nonunion. All patients stated that they would choose to have the CT scan procedure again rather than a procedure requiring general anaesthesia. The charges for the procedure were approximately 1840 pounds sterling (2800 dollars) per operation. CT-guided placement of iliosacral screws is a safe, feasible, and cost-effective alternative to radiologically-guided placement in the operating theatre in selected patients.

A novel mutation in KRT12 associated with Meesmann's epithelial corneal dystrophy.

BACKGROUND: The molecular basis of Meesmann's epithelial corneal dystrophy (MECD) has recently been attributed to mutations in the cornea specific keratin genes KRT3 and KRT12. The mechanisms by which these mutations cause the Meesmann's phenotype are not clear. This study presents new data, examines clinical, histological, ultrastructural, and molecular aspects of MECD, and compares the features seen in this condition with those observed in other well studied keratin diseases such as epidermolysis bullosa simplex. METHODS: A two generation family with typical features of Meesmann's epithelial corneal dystrophy (MECD) was studied. All family members were examined under a slit lamp. Biopsy material from elective keratoplasty was studied by histopathological and ultrastructural analysis using standard techniques. Direct automated sequencing of genomic DNA was used for mutation detection, mutations were confirmed by restriction digest analysis. RESULTS: The abnormal corneal epithelium was acanthotic and contained numerous dyskeratotic cells and intraepithelial vesicles. By electron microscopy abnormally aggregated and clumped keratin filament bundles were detected in basal and suprabasal keratinocytes from the centre of the cornea. Direct sequencing of the patients' genomic DNA revealed a novel missense mutation (423T>G) in exon 1 of the cornea specific keratin 12 (KRT12) gene. This mutation predicts the amino acid change N133K within the helix initiation motif of the K12 polypeptide. Comparative studies with well established keratin disorders of other human epithelia underscore the pathogenic relevance of K3 and K12 gene mutations in Meesmann's epithelial corneal dystrophy. The morphological data presented here illustrate the disruptive effects of keratin gene mutations on the integrity of corneal keratinocytes. CONCLUSIONS: A clinical, histopathological, and ultrastructural study of a previously unreported family with MECD is presented. In this family the disease is ascribed to a novel mutation in KRT12. A molecular mechanism is proposed for MECD based on the comparison with other well characterised keratin diseases.

Attitudes of orthopaedic trauma surgeons regarding current controversies in the management of pelvic and acetabular fractures.

A closed-ended questionnaire was mailed to all 363 active members of the Orthopaedic Trauma Association. It directed, toward practicing pelvic and acetabular surgeons, questions pertaining to practice demographics and preferred methods for detection and prevention of deep venous thrombosis (DVT), nerve injury, and heterotopic ossification (HO). Questionnaires were received from 226 surgeons (62 percent). Of the surgeons who responded, 181 (80 percent) perform pelvic-fracture and acetabular-fracture surgery; only questionnaires from this group were analyzed. Standard statistical methods were used to perform both univariate and multivariate analyses. Preoperative DVT screening was performed by 48 percent of the surgeons; ultrasound was the most commonly used modality (82 percent). Preoperative DVT prophylaxis was administered by 88 percent of those surveyed; the majority (78 percent) used sequential compression devices. Postoperative prophylaxis was used by 99 percent; the most commonly used modality was sequential compression devices. Analysis suggests that fellowship-trained surgeons and surgeons in practice for fewer than twenty years are more likely to use preoperative DVT prophylaxis. HO prophylaxis was administered by 88 percent; the most commonly used modality was indomethacin. Intraoperative nerve monitoring was performed by only 15 percent of the respondents. Most surgeons employed prophylactic measures to prevent DVT and HO. The wide variation in type of prophylaxis and reasons for use suggests that controversy will continue, and a standard of care for these conditions has yet to be defined. Very few surgeons use intraoperative nerve monitoring routinely.