Association of intraoperative changes in brain-derived neurotrophic factor and postoperative delirium in older adults.

BACKGROUND: Delirium is common after surgery, although the aetiology is poorly defined. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in neurotransmission and neuroplasticity. Decreased levels of BDNF have been associated with poor cognitive outcomes, but few studies have characterized the role of BDNF perioperatively. We hypothesized that intraoperative decreases in BDNF levels are associated with postoperative delirium. METHODS: Patients undergoing spine surgery were enrolled in a prospective cohort study. Plasma BDNF was collected at baseline and at least hourly intraoperatively. Delirium was assessed using rigorous methods, including the Confusion Assessment Method (CAM) and CAM for the intensive care unit. Associations of changes in BDNF and delirium were examined using regression models. RESULTS: Postoperative delirium developed in 32 of 77 (42%) patients. The median baseline BDNF level was 7.6 ng ml -1 [interquartile range (IQR) 3.0-11.2] and generally declined intraoperatively [median decline 61% (IQR 31-80)]. There was no difference in baseline BDNF levels by delirium status. However, the percent decline in BDNF was greater in patients who developed delirium [median 74% (IQR 51-82)] vs in those who did not develop delirium [median 50% (IQR 14-79); P =0.03]. Each 1% decline in BDNF was associated with increased odds of delirium in unadjusted {odds ratio [OR] 1.02 [95% confidence interval (CI) 1.00-1.04]; P =0.01}, multivariable-adjusted [OR 1.02 (95% CI 1.00-1.03); P =0.03], and propensity score-adjusted models [OR 1.02 (95% CI 1.00-1.04); P =0.03]. CONCLUSIONS: We observed an association between intraoperative decline in plasma BDNF and delirium. These preliminary results need to be confirmed but suggest that plasma BDNF levels may be a biomarker for postoperative delirium.

The impact of phone calls on follow-up rates in an online depression prevention study.

BACKGROUND: Automated Internet intervention studies have generally had large dropout rates for follow-up assessments. Live phone follow-ups have been often used to increase follow-up completion rates. OBJECTIVE: To compare, via a randomized study, whether receiving phone calls improves follow-up rates beyond email reminders and financial incentives in a depression prevention study. METHOD: A sample of 95 participants (63 English-speakers and 32 Spanish-speakers) was recruited online to participate in a "Healthy Mood" study. Consented participants were randomized to either a Call or a No Call condition. All participants were sent up to three email reminders in one week at 1, 3, and 6 months after consent, and all participants received monetary incentives to complete the surveys. Those in the Call condition received up to ten follow-up phone calls if they did not complete the surveys in response to email reminders. RESULTS: The follow-up rates for Call vs. No Call conditions at 1, 3, and 6 months, respectively, were as follows: English speakers, 58.6% vs. 52.9%, 62.1% vs. 52.9%, and 68.9% vs. 47.1%; Spanish speakers, 50.0% vs. 35.7%, 33.3% vs. 21.4%, and 33.3% vs. 7.1%. The number of participants who completed follow-up assessments only after being called at 1-, 3- and 6 months was 2 (14.3%), 0 (0%), and 3 (25.0%) for English speakers, and 2 (18.9%), 0 (0%), and 1 (7.7%) for Spanish speakers. The number of phone calls made to achieve one completed follow-up was 58.8 in the English sample and 57.7 and Spanish-speaking sample. CONCLUSIONS: Adding phone call contacts to email reminders and monetary incentives did increase follow-up rates. However, the rate of response to follow-up was low and the number of phone calls required to achieve one completed follow-up raises concerns about the utility of adding phone calls. We also discuss difficulties with using financial incentives and their implications.

Attenuated hypothalamic responses to α-melanocyte stimulating hormone during pregnancy in the rat.

KEY POINTS: Increased appetite and weight gain occurs during pregnancy, associated with development of leptin resistance, and satiety responses to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) are suppressed. This study investigated hypothalamic responses to α-MSH during pregnancy, using c-fos expression in specific hypothalamic nuclei as a marker of neuronal signalling, and in vivo electrophysiology in supraoptic nucleus (SON) oxytocin neurons, as a representative α-MSH-responsive neuronal population that shows a well-characterised α-MSH-induced inhibition of firing. While icv injection of α-MSH significantly increased the number of c-fos-positive cells in the paraventricular, supraoptic, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, this response was suppressed in pregnant rats. Similarly, SON oxytocin neurons in pregnant rats did not demonstrate characteristic α-MSH-induced inhibition of firing that was observed in non-pregnant animals. Given the known functions of α-MSH in the hypothalamus, the attenuated responses are likely to facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy. ABSTRACT: During pregnancy, a state of positive energy balance develops to support the growing fetus and to deposit fat in preparation for the subsequent metabolic demands of lactation. As part of this maternal adaptation, the satiety response to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) is suppressed. To investigate whether pregnancy is associated with changes in the response of hypothalamic α-MSH target neurons, non-pregnant and pregnant rats were treated with α-MSH or vehicle and c-fos expression in hypothalamic nuclei was then examined. Furthermore, the firing rate of supraoptic nucleus (SON) oxytocin neurons, a known α-MSH responsive neuronal population, was examined in non-pregnant and pregnant rats following α-MSH treatment. Intracerebroventricular injection of α-MSH significantly increased the number of c-fos-positive cells in the paraventricular, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, but no significant increase was observed in any of these regions in pregnant rats. In the SON, α-MSH did induce expression of c-fos during pregnancy, but this was significantly reduced compared to that observed in the non-pregnant group. Furthermore, during pregnancy, SON oxytocin neurons did not demonstrate the characteristic α-MSH-induced inhibition of firing rate that was observed in non-pregnant animals. Melanocortin receptor mRNA levels during pregnancy were similar to non-pregnant animals, suggesting that receptor down-regulation is unlikely to be a mechanism underlying the attenuated responses to α-MSH during pregnancy. Given the known functions of α-MSH in the hypothalamus, the attenuated responses will facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy.

Reproductive Regulation of Gene Expression in the Hypothalamic Supraoptic and Paraventricular Nuclei.

Oxytocin secretion is required for successful reproduction. Oxytocin is synthesised by magnocellular neurones of the hypothalamic supraoptic and paraventricular nuclei and the physiological demand for oxytocin synthesis and secretion is increased for birth and lactation. Therefore, we used a polymerase chain reaction (PCR) array screen to determine whether genes that might be important for synthesis and/or secretion of oxytocin are up- or down-regulated in the supraoptic and paraventricular nuclei of late-pregnant and lactating rats, compared to virgin rats. We then validated the genes that were most highly regulated using real time-quantitative PCR. Among the most highly regulated genes were those that encode for suppressors of cytokine signalling, which are intracellular inhibitors of prolactin signalling. Prolactin receptor activation changes gene expression via phosphorylation of signal transducer and activator of transcription 5 (STAT5). Using double-label immunohistochemistry, we found that phosphorylated STAT5 was expressed in almost all oxytocin neurones of late-pregnant and lactating rats but was almost absent from oxytocin neurones of virgin rats. We conclude that increased prolactin activation of oxytocin neurones might contribute to the changes in gene expression by oxytocin neurones required for normal birth and lactation.

Oxytocin Neurones: Intrinsic Mechanisms Governing the Regularity of Spiking Activity.

Oxytocin neurones of the rat supraoptic nucleus are osmoresponsive and, with all other things being equal, they fire at a mean rate that is proportional to the plasma sodium concentration. However, individual spike times are governed by highly stochastic events, namely the random occurrences of excitatory synaptic inputs, the probability of which is increased by increasing extracellular osmotic pressure. Accordingly, interspike intervals (ISIs) are very irregular. In the present study, we show, by statistical analyses of firing patterns in oxytocin neurones, that the mean firing rate as measured in bins of a few seconds is more regular than expected from the variability of ISIs. This is consistent with an intrinsic activity-dependent negative-feedback mechanism. To test this, we compared observed neuronal firing patterns with firing patterns generated by a leaky integrate-and-fire model neurone, modified to exhibit activity-dependent mechanisms known to be present in oxytocin neurones. The presence of a prolonged afterhyperpolarisation (AHP) was critical for the ability to mimic the observed regularisation of mean firing rate, although we also had to add a depolarising afterpotential (DAP; sometimes called an afterdepolarisation) to the model to match the observed ISI distributions. We tested this model by comparing its behaviour with the behaviour of oxytocin neurones exposed to apamin, a blocker of the medium AHP. Good fits indicate that the medium AHP actively contributes to the firing patterns of oxytocin neurones during non-bursting activity, and that oxytocin neurones generally express a DAP, even though this is usually masked by superposition of a larger AHP.

Hospital discharge instructions: comprehension and compliance among older adults.

BACKGROUND: Little is known regarding the prevalence or risk factors for non-comprehension and non-compliance with discharge instructions among older adults. OBJECTIVE: To quantify the prevalence of non-comprehension and non-compliance with discharge instructions and to identify associated patient characteristics. RESEARCH DESIGN: Prospective cohort study. SUBJECTS: Four hundred and fifty adults aged ≥ 65 admitted to medical and surgical units of a tertiary care facility and meeting inclusion criteria. MEASURES: We collected information on demographics, psycho-social factors, discharge diagnoses, and medications using surveys and patient medical records. Domains within discharge instructions included medications, follow-up appointments, diet, and exercise. At 5 days post-discharge, we assessed comprehension by asking patients about their discharge instructions, and compared responses to written instructions from medical charts. We assessed compliance among patients who understood their instructions. RESULTS: Prevalence of non-comprehension was 5 % for follow-up appointments, 27 % for medications, 48 % for exercise and 50 % for diet recommendations. Age was associated with non-comprehension of medication [odds ratio (OR) 1.07; 95 % confidence interval (CI) 1.04, 1.12] and follow-up appointment (OR 1.08; 95 % CI 1.00, 1.17) instructions. Male sex was associated with non-comprehension of diet instructions (OR 1.91; 95 % CI 1.10, 3.31). Social isolation was associated with non-comprehension of exercise instructions (OR 9.42; 95 % CI 1.50, 59.11) Depression was associated with non-compliance with medication (OR 2.29; 95 % CI 1.02, 5.10) and diet instructions (OR 3.30; 95 % CI 1.24, 8.83). CONCLUSIONS: Non-comprehension of discharge instructions among older adults is prevalent, multi-factorial, and varies by domain.

Glial regulation of extrasynaptic NMDA receptor-mediated excitation of supraoptic nucleus neurones during dehydration.

Magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) project to the posterior pituitary gland where they release the hormones, vasopressin and oxytocin into the circulation to maintain plasma osmolality. Hormone release is proportionate to SON MNC action potential (spike) firing rate. When activated by ambient extracellular glutamate, extrasynaptic NMDA receptors (eNMDARs) mediate a tonic (persistent) depolarisation to increase the probability of action potential firing. In the present study, in vivo single-unit electrophysiological recordings were made from urethane-anaesthetised female Sprague-Dawley rats to investigate the impact of tonic eNMDAR activation on MNC activity. Water deprivation (for up to 48 h) caused an increase in the firing rate of SON MNCs that was associated with a general increase in post-spike excitability. To determine whether eNMDAR activation contributes to the increased MNC excitability during water deprivation, memantine, which preferentially blocks eNMDARs, was administered locally into the SON by microdialysis. Memantine significantly decreased the firing rate of MNCs recorded from 48-h water-deprived rats but had no effect on MNCs recorded from euhydrated rats. In the presence of the glial glutamate transporter-1 (GLT-1) blocker, dihydrokainate, memantine also reduced the MNC firing rate in euhydrated rats. Taken together, these observations suggest that GLT-1 clears extracellular glutamate to prevent the activation of eNDMARs under basal conditions and that, during dehydration, eNMDAR activation contributes to the increased firing rate of MNCs.

Physiological regulation of magnocellular neurosecretory cell activity: integration of intrinsic, local and afferent mechanisms.

The hypothalamic supraoptic and paraventricular nuclei contain magnocellular neurosecretory cells (MNCs) that project to the posterior pituitary gland where they secrete either oxytocin or vasopressin (the antidiuretic hormone) into the circulation. Oxytocin is important for delivery at birth and is essential for milk ejection during suckling. Vasopressin primarily promotes water reabsorption in the kidney to maintain body fluid balance, but also increases vasoconstriction. The profile of oxytocin and vasopressin secretion is principally determined by the pattern of action potentials initiated at the cell bodies. Although it has long been known that the activity of MNCs depends upon afferent inputs that relay information on reproductive, osmotic and cardiovascular status, it has recently become clear that activity depends critically on local regulation by glial cells, as well as intrinsic regulation by the MNCs themselves. Here, we provide an overview of recent advances in our understanding of how intrinsic and local extrinsic mechanisms integrate with afferent inputs to generate appropriate physiological regulation of oxytocin and vasopressin MNC activity.

Socio-demographic inequalities in stage of cancer diagnosis: evidence from patients with female breast, lung, colon, rectal, prostate, renal, bladder, melanoma, ovarian and endometrial cancer.

BACKGROUND: Understanding socio-demographic inequalities in stage at diagnosis can inform priorities for cancer control. PATIENTS AND METHODS: We analysed data on the stage at diagnosis of East of England patients diagnosed with any of 10 common cancers, 2006-2010. Stage information was available on 88 657 of 98 942 tumours (89.6%). RESULTS: Substantial socio-demographic inequalities in advanced stage at diagnosis (i.e. stage III/IV) existed for seven cancers, but their magnitude and direction varied greatly by cancer: advanced stage at diagnosis was more likely for older patients with melanoma but less likely for older patients with lung cancer [odds ratios for 75-79 versus 65-69 1.60 (1.38-1.86) and 0.83 (0.77-0.89), respectively]. Deprived patients were more likely to be diagnosed in advanced stage for melanoma, prostate, endometrial and (female) breast cancer: odds ratios (most versus least deprived quintile) from 2.24 (1.66-3.03) for melanoma to 1.31 (1.15-1.49) for breast cancer. In England, elimination of socio-demographic inequalities in stage at diagnosis could decrease the number of patients with cancer diagnosed in advanced stage by ∼5600 annually. CONCLUSIONS: There are substantial socio-demographic inequalities in stage at diagnosis for most cancers. Earlier detection interventions and policies can be targeted on patients at higher risk of advanced stage diagnosis.

Variation in advanced stage at diagnosis of lung and female breast cancer in an English region 2006-2009.

BACKGROUND: Understanding variation in stage at diagnosis can inform interventions to improve the timeliness of diagnosis for patients with different cancers and characteristics. METHODS: We analysed population-based data on 17,836 and 13,286 East of England residents diagnosed with (female) breast and lung cancer during 2006-2009, with stage information on 16,460 (92%) and 10,435 (79%) patients, respectively. Odds ratios (ORs) of advanced stage at diagnosis adjusted for patient and tumour characteristics were derived using logistic regression. RESULTS: We present adjusted ORs of diagnosis in stages III/IV compared with diagnosis in stages I/II. For breast cancer, the frequency of advanced stage at diagnosis increased stepwise among old women (ORs: 1.21, 1.46, 1.68 and 1.78 for women aged 70-74, 75-79, 80-84 and ≥85, respectively, compared with those aged 65-69 , P<0.001). In contrast, for lung cancer advanced stage at diagnosis was less frequent in old patients (ORs: 0.82, 0.74, 0.73 and 0.66, P<0.001). Advanced stage at diagnosis was more frequent in more deprived women with breast cancer (OR: 1.23 for most compared with least deprived, P=0.002), and in men with lung cancer (OR: 1.14, P=0.011). The observed patterns were robust to sensitivity analyses approaches for handling missing stage data under different assumptions. CONCLUSION: Interventions to help improve the timeliness of diagnosis of different cancers should be targeted at specific age groups.

The association of diagnosis in the private or NHS sector on prostate cancer stage and treatment.

BACKGROUND: To examine associations of private healthcare with stage and management of prostate cancer. METHODS: Regional population-based cancer registry information on 15 916 prostate cancer patients. RESULTS: Compared with patients diagnosed in the National Health Service (NHS) (94%), those diagnosed in private hospitals (5%) were significantly more affluent (69 versus 52% in deprivation quintiles 1-2), younger (mean 69 versus 73 years) and diagnosed at earlier stage (72 versus 79% in Stages

Glial regulation of neuronal function: from synapse to systems physiology.

Classically, glia have been regarded as non-excitable cells that provide nourishment and physical scaffolding for neurones. However, it is now generally accepted that glia are active participants in brain function that can modulate neuronal communication via several mechanisms. Investigations of anatomical plasticity in the magnocellular neuroendocrine system of the hypothalamic paraventricular and supraoptic nuclei led the way in the development of much of our understanding of glial regulation of neuronal activity. In this review, we provide an overview of glial regulation of magnocellular neurone activity from a historical perspective of the development of our knowledge of the morphological changes that are evident in the paraventricular and supraoptic nuclei. We also focus on recent data from the authors' laboratories presented at the 9th World Congress on Neurohypophysial Hormones that have contributed to our understanding of the multiple mechanisms by which glia modulate the activity of neurones, including: gliotransmitter modulation of synaptic transmission; trans-synaptic modulation by glial neurotransmitter transporter regulation of neurotransmitter spillover; and glial neurotransmitter transporter modulation of excitability by regulation of ambient neurotransmitter levels and their action on extrasynaptic receptors. The magnocellular neuroendocrine system secretes oxytocin and vasopressin from the posterior pituitary gland to control birth, lactation and body fluid balance, and we finally speculate as to whether glial regulation of individual magnocellular neurones might co-ordinate population activity to respond appropriately to altered physiological circumstances.

Do contact precautions cause depression? A two-year study at a tertiary care medical centre.

Contact precautions, used to reduce the transmission of infectious diseases, include the wearing of gowns and gloves for room entry. Previous small studies have shown an association between contact precautions and increased symptoms of depression and anxiety. A retrospective cohort of all patients admitted to a tertiary care centre over two years was studied to assess the relationship between contact precautions and depression or anxiety. During the two-year period, there were 70,275 admissions including 28,564 unique non-intensive-care-unit (ICU), non-psychiatric admissions. After adjusting for potential confounders, contact precautions were associated with depression [odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2-1.5] but not with anxiety (OR 0.8, 95% CI 0.7-1.1) in the non-ICU population. Depression was 40% more prevalent among general inpatients on contact precautions.

How safe is it to transplant organs from deceased donors with primary intracranial malignancy? An analysis of UK Registry data.

Patients dying from primary intracranial malignancy are a potential source of organs for transplantation. However, a perceived risk of tumor transfer to the organ recipient has limited their use. We evaluated the risk of tumor transmission by reviewing the incidence in patients transplanted in the UK. Information from the UK Transplant Registry was combined with that from the national cancer registries of England, Wales and Northern Ireland to identify all organ donors between 1985 and 2001 inclusive with a primary intracranial malignancy and to identify the occurrence of posttransplant malignancy in the recipients of the organs transplanted. Of 11,799 organ donors in the study period, 179 were identified as having had a primary intracranial malignancy, including 33 with high-grade malignancy (24 grade IV gliomas and 9 medulloblastomas). A total of 448 recipients of 495 organs from 177 of these donors were identified. No transmission of donor intracranial malignancy occurred. Organs from patients dying from primary intracranial malignancy, including those with high-grade tumors, should be considered for transplantation and the small risk of tumor transmission should be balanced against the likely mortality for potential recipients who remain on the transplant waiting list.

State-dependent plasticity in vasopressin neurones: dehydration-induced changes in activity patterning.

Moderate dehydration impairs concentration and co-ordination, whereas severe dehydration can cause seizures, brain damage or death. To slow the progression of dehydration until body fluids can be replenished by drinking, the increased body fluid osmolality associated with dehydration increases vasopressin (antidiuretic hormone) secretion from the posterior pituitary gland. Increased vasopressin secretion reduces water loss in the urine by promoting water reabsorption in the collecting ducts of the kidney. Vasopressin secretion is largely determined by action potential discharge in vasopressin neurones, and depends on both the rate and pattern of discharge. Vasopressin neurone activity depends on intrinsic and extrinsic mechanisms. We review recent advances in our understanding of the physiological regulation of vasopressin neurone activity patterning and the mechanisms by which this is altered to cope with the increased secretory demands of dehydration.

Treatment and survival in breast cancer in the Eastern Region of England.

BACKGROUND: The reasons for variation in survival in breast cancer are multifactorial. METHODS: From 1999 to 2003, the vital status of 9051 cases of invasive breast cancer was identified in the Eastern Region of England. Survival analysis was by Cox proportional hazards regression. Data were analysed separately for patients aged <70 years and those older due to differences in treatment policies. RESULTS: Overall 5-year survival was 78%. In patients aged <70 years, significant differences in survival lost their formal significance after adjustment for detection mode and node status, although this remained close to statistical significance with some residual differences between relative hazards. There was significant negative ecological correlation between proportion with nodes positive or not examined and 9-year survival rates. Patients with estrogen receptor (ER) status unknown were at significantly higher risk of dying than ER-positive patients. There was a clear trend of increasing hazard of dying with increasing deprivation. Survival differences in women aged > or =70 years were related to whether surgery was included as part of treatment. CONCLUSION: This variation in treatment and survival may be attributed to lack of information, in particular nodal and ER status, thereby impacting on staging and prescription of adjuvant therapy.

Radiological staging in breast cancer: which asymptomatic patients to image and how.

BACKGROUND: Approximately 4% of patients diagnosed with early breast cancer have occult metastases at presentation. Current national and international guidelines lack consensus on whom to image and how. METHODS: We assessed practice in baseline radiological staging against local guidelines for asymptomatic newly diagnosed breast cancer patients presenting to the Cambridge Breast Unit over a 9-year period. RESULTS: A total of 2612 patients were eligible for analysis; 91.7% were appropriately investigated. However in the subset of lymph node negative stage II patients, only 269 out of 354 (76.0%) investigations were appropriate. No patients with stage 0 or I disease had metastases; only two patients (0.3%) with stage II and < or =3 positive lymph nodes had metastases. Conversely, 2.2, 2.6 and 3.8% of these groups had false-positive results. The incidence of occult metastases increased by stage, being present in 6, 13.9 and 57% of patients with stage II (> or =4 positive lymph nodes), III and IV disease, respectively. CONCLUSION: These results prompted us to propose new local guidelines for staging asymptomatic breast cancer patients: only clinical stage III or IV patients require baseline investigation. The high specificity and convenience of computed tomography (chest, abdomen and pelvis) led us to recommend this as the investigation of choice in breast cancer patients requiring radiological staging.