The relationship between obstructive sleep apnoea and postoperative delirium and pain: an observational study of a surgical cohort.

Patients with obstructive sleep apnoea are at increased risk of adverse postoperative outcomes, such as cardiac and respiratory complications. It has been hypothesised that obstructive sleep apnoea also increases the risk for postoperative delirium and acute postoperative pain. We conducted a retrospective, observational study investigating the relationship of obstructive sleep apnoea with postoperative delirium and acute postoperative pain severity. Patients were classified as being at high risk for obstructive sleep apnoea if they had been diagnosed with this condition, or if they were positive for more than four factors using the 'STOP-BANG' screening tool. Adjusted logistic regression was used to investigate the association between obstructive sleep apnoea and postoperative delirium, and multivariable linear regression to study the relationship between obstructive sleep apnoea and postoperative pain severity. The incidence of postoperative delirium was 307 in 1441 patients (21.3%; 95%CI 19.2-23.5%). In unadjusted analysis, high risk for obstructive sleep apnoea was associated with delirium, with an odds ratio (95%CI) of 1.77 (1.22-2.57; p = 0.003). After adjustment for pre-specified variables, the association was not statistically significant with odds ratio 1.34 (0.80-2.23; p = 0.27). The mean (SD) maximum pain (resting or provoked) reported for the entire cohort was 63.8 (27.9) mm on a 0-100 mm visual analogue scale. High risk for obstructive sleep apnoea was not associated with postoperative pain severity (ß-coefficient 2.82; 95%CI, -2.34-7.97; p = 0.28). These findings suggest that obstructive sleep apnoea is unlikely to be a strong risk factor for postoperative delirium or acute postoperative pain severity.

Protocol for the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study: a pragmatic, randomised clinical trial.

INTRODUCTION: Postoperative delirium, arbitrarily defined as occurring within 5 days of surgery, affects up to 50% of patients older than 60 after a major operation. This geriatric syndrome is associated with longer intensive care unit and hospital stay, readmission, persistent cognitive deterioration and mortality. No effective preventive methods have been identified, but preliminary evidence suggests that EEG monitoring during general anaesthesia, by facilitating reduced anaesthetic exposure and EEG suppression, might decrease incident postoperative delirium. This study hypothesises that EEG-guidance of anaesthetic administration prevents postoperative delirium and downstream sequelae, including falls and decreased quality of life. METHODS AND ANALYSIS: This is a 1232 patient, block-randomised, double-blinded, comparative effectiveness trial. Patients older than 60, undergoing volatile agent-based general anaesthesia for major surgery, are eligible. Patients are randomised to 1 of 2 anaesthetic approaches. One group receives general anaesthesia with clinicians blinded to EEG monitoring. The other group receives EEG-guidance of anaesthetic agent administration. The outcomes of postoperative delirium (≤5 days), falls at 1 and 12 months and health-related quality of life at 1 and 12 months will be compared between groups. Postoperative delirium is assessed with the confusion assessment method, falls with ProFaNE consensus questions and quality of life with the Veteran's RAND 12-item Health Survey. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 95% CIs and will be considered statistically significant at a two-sided p<0.05. ETHICS AND DISSEMINATION: Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) is approved by the ethics board at Washington University. Recruitment began in January 2015. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media. TRIAL REGISTRATION NUMBER: NCT02241655; Pre-results.

Alpha-fodrin is cleaved by caspase-3 in a chronic ocular hypertensive (COH) rat model of glaucoma.

PURPOSE: alpha-Fodrin is a neuronal cytoskeletal protein and a known caspase-3 target. We sought to determine whether caspase-3 cleaves alpha-fodrin in COH rat retinas and whether this process is reduced by adeno-associated virus (AAV)-induced retinal ganglion cell expression of baculovirus inhibitory repeat-containing 4 (BIRC4), a potent caspase-3 inhibitor. METHODS: Ocular hypertension was induced unilaterally in five rat eyes by limbal injection of hypertonic saline. In a similar experiment, ocular hypertension was induced in four eyes pre-treated with an intravitreal injection of AAV-BIRC4 to assess alpha-fodrin cleavage. Western immunoblotting was performed on all retinas. RESULTS: Caspase-3 cleavage of alpha-fodrin yields a specific 120kDa protein fragment. COH retina immunoblots indicated significantly more caspase-3 cleavage of alpha-fodrin than controls (P < 0.01, paired t-test). Inhibition of retinal caspase-3 activity with BIRC4 reduced caspase-3-mediated alpha-fodrin cleavage compared to controls. CONCLUSIONS: This confirms our previous finding of caspase-3 cleavage of alpha-fodrin in COH retinas and parallels pathology seen in Alzheimer's disease, in which neurons undergo chronic caspase activation, slow build-up of cleavage products, and delayed apoptosis. If caspase activation in glaucoma leads to protracted rather than rapid retinal ganglion cell apoptosis, a much longer therapeutic window exists for apoptosis inhibition with caspase inhibitors such as BIRC4.

Evaluation of oral ro70-0004/003, an alpha1A-adrenoceptor antagonist, in the treatment of male erectile dysfunction.

Alpha-adrenoceptor antagonists have been used for the treatment of male erectile dysfunction (MED). Ro70-0004/003 (Ro70-0004) is a selective and orally active alpha1A-adrenoceptor antagonist. The objective of this study was to: (1) pharmacologically elucidate the alpha1-adrenoceptor subtype mediating norepinephrine-induced contraction of human isolated corpus cavernosal tissue and (2) conduct a clinical proof-of-concept study with Ro70-0004 to test the hypothesis that selective alpha1A-adrenoceptor blockade would improve erectile function in patients with MED. In vitro organ bath studies were conducted with strips of human isolated corpus cavernosal tissue obtained from patients undergoing penile prosthesis implantation. Prazosin, cyclazosin, RS-100329 and Ro70-0004/003 antagonized norepinephrine-induced contractile responses with affinity estimates (pK(B) or pA2) of 8.4, 7.3, 9.2 and 8.8, respectively, consistent with the singular involvement of alpha1A-adrenoceptor subtype. A clinical study (single center, observer-blind, randomized, placebo-controlled, extended period Latin-Square crossover design) was conducted in 24 male patients (mean age 44 y) with MED of no established organic cause to evaluate the efficacy of a 5-mg oral dose of Ro70-0004. The primary efficacy endpoint was the duration of rigidity > 60% at the base of the penis measured between 0.5 and 2.5 h post-dose. Rigidity was assessed by penile plethysmography using the RigiScan Plus device during visual sexual stimulation. The safety and efficacy of Ro70-0004 was also assessed. A 50-mg dose of sildenafil was included as a positive control. For the primary efficacy endpoint, the mean duration of erection was 9.69 min following administration of placebo, 8.28 min following Ro70-0004, and 22.64 min following sildenafil. Only the difference between sildenafil and placebo reached statistical significance (P < 0.05). A similar pattern was observed when measuring a duration of rigidity > 80% at the base of the penis (secondary endpoint). Ro70-0004 was safe and generally well tolerated (only two out of 20 patients reported at least one adverse event). The highly selective alpha1A-adrenoceptor antagonist, Ro70-0004, given at a single dose of 5 mg, did not improve erectile function when compared to placebo.

Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats.

PURPOSE: To determine whether acute experimental glaucoma in rats obstructs retrograde transport of brain-derived neurotrophic factor (BDNF) to retinal ganglion cells (RGCs). METHODS: Forty rats had unilateral injection of either (125)I-BDNF (20 animals) or a mixture of (125)I-BDNF and 100-fold excess nonradiolabeled BDNF (20 animals). In each group of 20 animals, eyes contralateral to injection had either normal intraocular pressure (IOP; 10 animals) or IOP elevated to 25 mm Hg below the systolic blood pressure of the eye (10 animals). In each group of 20 rats, ipsilateral eyes had IOP set at systolic blood pressure (4 eyes), had optic nerve transection (10 eyes), or had normal IOP (6 eyes). Six hours after injection, animals were killed and tissues were fixed, embedded, and sectioned for autoradiography. Grain counts were performed over retina and optic nerve using automated image analysis. RESULTS: IOP elevation to 25 mm Hg below systolic blood pressure (perfusion pressure [PP] 25) decreased median retinal nerve fiber layer (NFL) grains by 38% compared with controls (P: < 0.001). Competition by cold BDNF reduced NFL grains by 28% (P: = 0.013). Considering only the radioactivity representing specific retrograde transport of BDNF, IOP elevation to PP25 reduced transport by 74%, whereas elevation to PP0 (equaling systolic blood pressure) reduced specific transport by 83%. CONCLUSIONS: BDNF is transported retrogradely from the superior colliculus in adult rats, and this transport is substantially inhibited by acute IOP elevation. Deprivation of BDNF among RGCs may contribute to neuron loss in glaucoma.

Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma.

PURPOSE: In both animal model system and in human glaucoma, retinal ganglion cells (RGCs) die by apoptosis. To understand how RGC apoptosis is initiated in these systems, the authors studied RGC neurotrophin transport in experimental glaucoma using acute intraocular pressure (IOP) elevations in rats and chronic IOP elevation and unilateral optic nerve transections in monkeys. METHODS: Eyes were studied in masked fashion by light and electron microscopy and by immunohistochemistry with antibodies directed against the tyrosine kinase receptors (TrkA, B, and C) and against brain-derived neurotrophic factor (BDNF), as well as by autoradiography to identify retrograde axonal transport of 125I-BDNF injected into the superior colliculus. RESULTS: With acute glaucoma in the rat, RGC axons became abnormally dilated, accumulating vesicles presumed to be moving in axonal transport at the optic nerve head. Label for TrkB, but not TrkA, was relatively increased at and behind the optic nerve head with IOP elevation. Abnormal, focal labeling for TrkB and BDNF was identified in axons of monkey optic nerve heads with chronic glaucoma. With acute IOP elevation in rats, radiolabeled BDNF arrived at cells in the RGC layer at less than half the level of control eyes. CONCLUSIONS: Interruption of BDNF retrograde transport and accumulation of TrkB at the optic nerve head in acute and chronic glaucoma models suggest a role for neurotrophin deprivation in the pathogenesis of RGC death in glaucoma.

Systemic diseases involving the orbit.

A variety of systemic pathological processes may involve the eye and the surrounding orbital adnexae. CT and MRI of the orbit have become useful clinical adjuvants, not only in establishment of the diagnosis, but also in suggesting the appropriate clinical treatment, sometimes preventing needless biopsy. Grave's disease, Wegener's granulomatosis, and sarcoidosis may all present initially with orbital disease before the onset of systemic manifestations. Idiopathic inflammatory disease of the orbit and lymphoproliferative disease of the orbit continue to remain radiological and clinical challenges. The article discusses the CT and MRI appearance of many of the common systemic diseases in adults with attention to features useful in clinical practice as well as in differential diagnosis.

Biocompatibility response to modified Baerveldt glaucoma drains.

Glaucoma implants are designed to increase fluid outflow from the eye in order to decrease intraocular pressure and prevent damage to the optic nerve. The implant consists of a silicone tube that is inserted into the anterior chamber at one end and is attached at the other end to a silicone plate that is sutured to the outside of the globe beneath the conjunctiva. The glaucoma "implant" becomes a "drain" over the first 3 to 6 postoperative weeks as the silicone plate is enclosed by a fibrous capsule that allows a space to form into which fluid can drain and from which fluid can be absorbed by the surrounding tissues. Ideally, the size and thickness of the capsule (the filtering bleb) that surrounds the plate is such that the amount of fluid that passes through the capsule is identical to the amount of fluid produced by the eye at an intraocular pressure of 8 to 14 mmHg. The most common long-term complication of these implants is failure of the filtering bleb 2 to 4 years after surgery due to the formation of a thick fibrous capsule around the device. Micromovement of the smooth drainage plate against the scleral surface may be integral to the mechanism of glaucoma implant failure by stimulating low-level activation of the wound healing response, increased collagen scar formation, and increased fibrous capsule thickness. To test this hypothesis, we modified seven Baerveldt implants by adding porous cellular ingrowth material to the posterior surface of the drainage plate. Seven modified and five unmodified implants were placed in adult rabbit eyes. After 6 months, we found that the fibrous capsule around the modified implants was significantly thinner than the capsule surrounding the unmodified implants (p < 0.05), particularly on the surface between the porous ingrowth material and the sclera (p < 0.05). Although type I collagen predominated in the fibrous capsules around both types of implants, the amount of type III collagen in the capsules around the modified implants was significantly less than the amount around the unmodified implants (p < 0.05). We believe that these data suggest a reduction in the wound healing response to the modified implants, with greater stability of capsule thickness. Long-term studies are needed to verify that the stability of the capsules around the modified implants persists over a period of years, in which case this type of modification may prove useful in prolonging the functional life of these devices in the surgical treatment of glaucoma.

Anatomy of the cerebral veins, dural sinuses, sella, meninges, and CSF spaces.

This article discusses the composition, pathways, and mechanisms of some of the intricate systems within the head and neck. The anatomy of several regions are demonstrated on computed tomography scans and T1-weighted and T2-weighted magnetic resonance images. Major emphasis is given to the consonance of this system.

Echographic diagnosis of scleral fold in hypotony.

PURPOSE: To report the echographic appearance of a scleral fold in hypotony. METHOD: We performed ultrasonography on a patient who, after trabeculectomy with mitomycin C, had an intraocular pressure of 1 mm Hg, an opaque cataract, and suspected hypotonous maculopathy in the left eye. RESULTS: An area of dome-shaped eyewall thickening was noted near the tendon of the lateral rectus muscle in primary gaze. This thickening increased substantially in lateral gaze, mimicking a foreign body or a tumor. CONCLUSION: Recognizing this abnormality is important to avoid erroneous diagnosis of an intraocular foreign body or a tumor in hypotonous eyes.

Glaucoma, apoptosis, and neuroprotection.

The demise of the retinal ganglion cell represents the final common pathway of glaucomatous vision loss. Various studies demonstrate that ganglion cells die by the mechanism of apoptosis in conditions such as experimental animal models of glaucoma and optic nerve transection, and in human glaucoma. Apoptosis is a basic cell death mechanism noted in a number of neurodegenerative conditions. It constitutes a genetically coded "suicide" program activated when cells are no longer needed or have been seriously damaged, and is typified by rapid phagocytosis without inflammation. These cells demonstrate characteristic morphological changes on electron microscopy: nuclear chromatin condensation, compaction of cytoplasmic organelles, and membrane blebbing. Neurotrophin withdrawal and excitotoxic neurotransmitters have been implicated in apoptosis in ganglion cells damaged by glaucoma. Understanding the cellular and molecular biological events involved in ganglion cell death may lead to novel approaches to the treatment of glaucoma.

Frequency analysis of cytotoxic T lymphocyte precursors--possible relevance to HLA-matched unrelated donor bone marrow transplantation.

HLA-matched unrelated donor (MUD) bone marrow transplants and transplants between HLA mismatched family members are associated with an increased incidence and severity of graft-versus-host disease (GVHD) in comparison with HLA-identical sibling transplants. A limiting dilution analysis system was set up to measure the frequency of alloreactive cytotoxic T lymphocyte precursors (CTL-p) in normal individuals and in potential donor/patient pairs selected for bone marrow transplantation. The donor/recipient pairs were divided into four groups depending on their degree of HLA disparity. A distinct range of CTL-p frequencies was obtained for each group and these showed a hierarchy of response related to the degree of HLA disparity between donors and recipients in that particular group. This assay system may be of value in selecting potential matched unrelated and mismatched family donor/patient pairs for those at lower risk of GVHD.

Misonidazole and CCNU chemotherapy for recurrent primary brain tumor.

CCNU chemotherapy prolongs survival of patients with primary brain tumor when given at the time of tumor progression following radiation therapy. Used as single agent, response rates of 30 to 80 per cent have been reported with median response durations of five to six months. Experimentally, tumor cytotoxicity is enhanced using the combination of misonidazole and CCNU, without increasing myelotoxicity. In this phase I/II study, 23 patients with primary brain tumor which progressed following radiation therapy were treated with combined CCNU and misonidazole. In all patients either the diagnosis of high grade glioma was made at the time of initial diagnosis prior to radiation therapy or the tumor transformed from low grade to high grade glioma at the time of progression following radiation therapy. CCNU 120 mg/M2 was given four hours following misonidazole 3.5 g/M2 every six weeks, with dosage adjustments for myelotoxicity. Treatment was continued for one year or until tumor progression. Of the 17 patients in the study for one year or more, 11 (65 per cent) survived for one year, and six (35 per cent) remained free of tumor progression for one year. Median time to tumor progression from start of CCNU plus misonidazole chemotherapy was 27 weeks and median survival was 80 weeks. No severe complications resulted from myelotoxicity. One patient developed mild peripheral neuropathy which disappeared following discontinuation of misonidazole.

Reactions of college students to speech disorders.

This study investigated the reactions of college students to audiotaped speech samples of a woman simulating moderate speech disorders of stuttering, hypernasality, and lateral lisping, as well as presenting normal speech. Student reactions to these recordings were measured by a figure placement task and a 30-item semantic differential instrument. The students reacted to the speech disorders with a tendency of increased social distance in addition to judgments of lower evaluation, lower understandability, and higher anxiety. These findings suggest that students react negatively to speech disorders. Awareness of such reactions could facilitate clinical effectiveness and prepare clinicians to protect clients' rights.

Transplantation of unpurged autologous bone-marrow in acute myeloid leukaemia in first remission.

Twelve consecutive patients aged 18-53 were given autologous remission bonemarrow and cyclophosphamide and total-body irradiation to maintain first remission of acute myeloid leukaemia. Follow-up lasted at least 6 months. Seven patients remain in complete unmaintained remission 26-140 weeks post-autograft with overall remissions of 42-202 weeks. The prediction of leukaemia-free survival based on these results is 58% at 3 years. The procedure was well tolerated and resulted in little morbidity and no mortality.