Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism. INTRODUCTION: A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline. METHODS: The ~ 3-week protocol included two segments: "baseline," ≥ 10-h sleep opportunity/day × 5 days; "forced desynchrony" (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20-59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (ß) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure. RESULTS: Plasma P1NP levels declined significantly within the first 10 days of FD ([Formula: see text] = - 1.33 µg/L per 24 h, p < 0.0001) and remained lower than baseline with prolonged exposure out to 3 weeks ([Formula: see text] = - 0.18 µg/L per 24 h, p = 0.67). As previously reported, levels of a bone resorption marker (C-telopeptide (CTX)) were unchanged. CONCLUSION: Sleep restriction with concurrent circadian disruption induced a relatively rapid decline in P1NP (despite no change in CTX) and levels remained lower with ongoing exposure. These data suggest (1) even brief sleep restriction and circadian disruption can adversely affect bone metabolism, and (2) there is no P1NP recovery with ongoing exposure that, taken together, could lead to lower bone density over time.

Decreased sensitivity of the circadian system to light in current, but not remitted depression.

BACKGROUND: Misalignment of circadian timing in patients with depression has commonly been reported, but the underlying mechanisms are not known. Individual differences in the sensitivity of the circadian system to light affect how the biological clock synchronizes with the external environment and can lead to misalignment of rhythms. We investigated the sensitivity of the circadian system to light in unmedicated (for >3 months) women with a current or previous diagnosis of major depression, and healthy controls. METHODS: Baseline melatonin levels in dim light (<1 lux) were assessed, followed by melatonin levels in normal indoor lighting of 100 lux in order to determine melatonin suppression. RESULTS: Patients currently experiencing a depressive episode showed significantly lower levels of melatonin suppression to light compared to remitted patients and controls, with large effect sizes. Remitted patients and controls showed similar suppression. LIMITATIONS: The relatively small sample, and lack of long-term, within subject assessments, make it difficult to determine the potential causal role of reduced light sensitivity in the development of circadian disruption. CONCLUSIONS: We conclude that hyposensitivity of the circadian system to light may contribute to circadian misalignment in patients with depression. Interventions that increase sensitivity to light or provide stronger light cues may assist in normalizing circadian clock function.

The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose.

RATIONALE: Disturbances of the circadian system are common in depression. Though they typically subside when depression is treated with antidepressants, the mechanism by which this occurs is unknown. Despite being the most commonly prescribed class of antidepressants, the effect of selective serotonin reuptake inhibitors (SSRIs) on the human circadian clock is not well understood. OBJECTIVE: To examine the effect of the SSRI citalopram (30 mg) on the sensitivity of the human circadian system to light. METHODS: This study used a double-blind, placebo-controlled, within-subjects, crossover design. Participants completed two melatonin suppression assessments in room level light (~ 100 lx), taking either a single dose of citalopram 30 mg or a placebo at the beginning of each light exposure. Melatonin suppression was calculated by comparing placebo and citalopram light exposure conditions to a dim light baseline. RESULTS: A 47% increase in melatonin suppression was observed after administration of an acute dose of citalopram, with all participants showing more suppression after citalopram administration (large effect, d = 1.54). Further, melatonin onset occurred later under normal room light with citalopram compared to placebo. CONCLUSIONS: Increased sensitivity of the circadian system to light could assist in explaining some of the inter-individual variability in antidepressant treatment responses, as it is likely to assist in recovery in some patients, while causing further disruption for others.

Evening types demonstrate reduced SSRI treatment efficacy.

Selective serotonin reuptake inhibitors (SSRIs) have a profound effect on the circadian system's response to environmental light, which may impact treatment outcomes for patients depending on their habitual light exposure patterns. Here, we investigated the relationship between time-of-day preference, depressive symptoms and self-reported antidepressant treatment response. Evening types reported having taken a higher number of antidepressant medications in the previous 5 years and lower SSRI efficacy than morning types. While undergoing SSRI treatment, evening types also reported more depressive symptoms and suicidality. It is concluded that time-of-day preference may prove informative in predicting SSRI treatment responses.

Demographics and predictors of mortality in children undergoing resuscitation at Khayelitsha Hospital, Western Cape, South Africa

Background. The clinical outcomes of paediatric patients requiring resuscitation depend on physicians with specialised knowledge,equipment and resources owing to their unique anatomy, physiology and pathology. Khayelitsha Hospital (KH) is a government hospital located near Cape Town, South Africa, that sees ~44 000 casualty unit patients per year and regularly functions at more than 130% of the bed occupancy. Many of these patients are children requiring resuscitation.Objectives. We sought to describe characteristics of children under the age of 12 who required resuscitation upon presentation to KH,determine predictors of mortality, and compare paediatric volume to specialist physician presence in the unit.Methods. A retrospective chart review was performed on patients younger than 12 years who were treated in the resuscitation area of KH during the six-month period from 1 November 2014 to 30 April 2015.Results. A total 317 patients were enrolled in the study with a median age of 14 months. The top 5 diagnoses were: pneumonia (n=58/317);neonatal sepsis (n=40/317); seizures (n=37/317); polytrauma (n=32/317); and acute gastroenteritis complicated by septic shock (n=28/317). Overall mortality was 7% (n=21/317) and mortality in children less than 1 month of age was 12% (n=5/42). Premature birth was associated with a mortality odds ratio of 8.44 (p=0.002). More than two-thirds (73%; n=231/317) of paediatric resuscitations occurred when specialist physicians were not physically present in the unit.Conclusion. The study findings indicate that children under one month of age with a history of prematurity are at high risk and may benefit most from paediatric-specific expertise and rapid transfer to a higher level of care

24-hour profile of serum sclerostin and its association with bone biomarkers in men.

The osteocyte's role in orchestrating diurnal variations in bone turnover markers (BTMs) is unclear. We identified no rhythm in serum sclerostin (osteocyte protein). These results suggest that serum sclerostin can be measured at any time of day and the osteocyte does not direct the rhythmicity of other BTMs in men. INTRODUCTION: The osteocyte exerts important effects on bone remodeling, but its rhythmicity and effect on the rhythms of other bone cells are not fully characterized. The purpose of this study was to determine if serum sclerostin displays rhythmicity over a 24-h interval, similar to that of other bone biomarkers. METHODS: Serum sclerostin, FGF-23, CTX, and P1NP were measured every 2 h over a 24-h interval in ten healthy men aged 20-65 years. Maximum likelihood estimates of the parameters in a repeated measures model were used to determine if these biomarkers displayed a diurnal, sinusoidal rhythm. RESULTS: No discernible 24-h rhythm was identified for sclerostin (p = 0.99) or P1NP (p = 0.65). CTX rhythmicity was confirmed (p < 0.001), peaking at 05:30 (range 01:30-07:30). FGF-23 levels were also rhythmic (p < 0.001), but time of peak was variable (range 02:30-11:30). The only significant association identified between these four bone biomarkers was for CTX and P1NP mean 24-h metabolite levels (r = 0.65, p = 0.04). CONCLUSIONS: Sclerostin levels do not appear to be rhythmic in men. This suggests that in contrast to CTX, serum sclerostin could be measured at any time of day. The 24-h profiles of FGF-23 suggest that a component of osteocyte function is rhythmic, but its timing is variable. Our results do not support the hypothesis that osteocytes direct the rhythmicity of other bone turnover markers (CTX), at least not via a sclerostin-mediated mechanism.

Constraint is associated with earlier circadian phase and morningness: Confirmation of relationships between personality and circadian phase using a constant routine protocol.

Associations among personality, diurnal preference, and circadian phase were investigated using a constant routine laboratory protocol. One hundred and sixty-eight healthy participants aged 18-30 years (Women n = 68) completed either a 30- or 50-hour constant routine under dim-light conditions (<3 lux), during which circadian phase was measured from core body temperature and melatonin. Prior to laboratory admission, self-report measures of personality and diurnal preference were also obtained. The personality trait of Constraint correlated positively with morning diurnal preference and earlier circadian phase, with circadian phase partially mediating the relationship between Constraint and diurnal preference. No other personality variables correlated with circadian phase. Sex was an important covariate in several of the relationships investigated due to lower levels of Constraint and later CBT phase amongst men and was thus controlled for in all relevant analyses. Findings from this highly controlled study are consistent with previous field research in suggesting that earlier circadian phase is associated with the personality trait of Constraint.

Investigating the relationship between sleep and macronutrient intake in women of childbearing age.

BACKGROUND/OBJECTIVE: Reduced sleep is a strong and independent risk factor for weight gain and obesity. Maternal obesity preconception and throughout gestation can increase the risk of adverse pregnancy outcomes and impact on offspring health in later life. This study investigated the relationship between sleeping behaviour and macronutrient intake in childbearing aged women. SUBJECTS/METHODS: We used cross-sectional data from the Australian Longitudinal Study on Women's Health 1973-78 cohort, aged 31-36 years in 2009 (n=8200). Subjective sleeping behaviour was reported and macronutrient intake was measured using a validated food frequency questionnaire. Latent class analysis (LCA) was used to derive sleeping patterns. Multivariate regression analysis was used to investigate the relationships between sleep and macronutrient intake. RESULTS: LCA identified three sleep patterns: (LC1) average sleep (~8 h) with no adverse sleep-related symptoms (n=3570); (LC2) average sleep (~8 h) with sleeping difficulties and severe tiredness (n=2109); and (LC3) short sleep (~6 h) with sleeping difficulties and severe tiredness (n=915). In fully adjusted models, LC2 was inversely associated with percentage energy as protein (b=-0.24; P=0.01) and the protein-to-carbohydrate ratio (b=-0.01; P<0.05). LC3 was positively associated with percentage of energy as fat (b=0.29; P=0.01), saturated fat (b=0.24; P=<0.001) and monounsaturated fat (b=0.09; P=0.04). CONCLUSIONS: Sleeping behaviour patterns were associated with macronutrient intake in childbearing aged women. Improved sleep patterns, together with diet and physical activity strategies, may make it easier for women to achieve a balanced diet and optimise their weight status in preparation for pregnancy.

What is the risk of a shunt malfunction after elective intradural surgery?

OBJECT: Surgery for CSF diversion is the most common procedure performed by pediatric neurosurgeons. The failure rates for shunts remain frustratingly high, resulting in a burden to patients, families, providers, and healthcare systems. The goal of this study was to quantify the risk of a shunt malfunction in patients with an existing shunt who undergo an elective intradural operation. METHODS: All elective intradural surgeries (cranial and spinal) at Le Bonheur Children's Hospital from January 2010 through June 2014 were reviewed to identify those patients who had a functional ventricular shunt at the time of surgery. Patient records were reviewed to collect demographic, surgical, clinical, radiological, and pathologic data, including all details related to any subsequent shunt revision surgery. The primary outcome was all-cause shunt revision (i.e., malfunction or infection) within 90 days of elective intradural surgery. RESULTS: One hundred and fifty elective intradural surgeries were identified in 109 patients during the study period. There were 14 patients (12.8%, 13 male) who experienced 16 shunt malfunctions (10.7%) within 90 days of elective intradural surgery. These 14 patients underwent 13 craniotomies, 2 endoscopic fenestrations for loculated hydrocephalus, and 1 laminectomy for dorsal rhizotomy. Median time to failure was 9 days, with the shunts in half of our patients failing within 5 postoperative days. Those patients with failed shunts were younger (median 4.2 years [range 0.33-26 years] vs median 10 years [range 0.58-34 years]), had a shorter time interval from their previous shunt surgery (median 11 months [range 0-81 months] vs median 20 months [range 0-238 months]), and were more likely to have had intraventricular surgery (80.0% vs. 60.3%). CONCLUSIONS: This is the first study to quantify the risk of a shunt malfunction after elective intradural surgery. The 90-day all-cause shunt failure rate (per procedure) was 10.7%, with half of the failures occurring within the first 5 postoperative days. Possible risk factors for shunt malfunction after elective intradural surgeries are intraventricular surgical approach, shorter time since last shunt-related surgery, and young age.

Fibrinolysis for intraventricular hemorrhage: an updated meta-analysis and systematic review of the literature.

BACKGROUND AND PURPOSE: Intraventricular hemorrhage is associated with high mortality and poor functional outcome. The use of intraventricular fibrinolytic (IVF) therapy as an intervention in intraventricular hemorrhage is an evolving therapy with conflicting reports in the literature. The goal of this study is to investigate the impact of IVF on mortality, functional outcome, ventriculitis, shunt dependence, and rehemorrhage. METHODS: During March and April 2014, a systematic literature search was performed identifying 1359 articles. Of these, 24 met inclusion criteria. A random effects meta-analysis was performed using both pooled and subset analysis based on study type. RESULTS: Our meta-analysis demonstrated that IVF reduced mortality in intraventricular hemorrhage by nearly half (relative risk [RR], 0.55; 95% confidence interval [CI], 0.42-0.71; P<0.00001), increased the likelihood of good functional outcome by 66% (RR, 1.66; 95% CI, 1.27-2.19; P=0.0003), and also decreased the rate of shunt dependence (RR, 0.62; 95% CI, 0.42-0.93; P=0.02). IVF was not found to be associated with increased rates of ventriculitis (RR=1.46; 95% CI, 0.77-2.76; P=0.25) or rehemorrhage (RR=1.06; 95% CI, 0.66-1.70; P=0.80). We detected no evidence of publication bias. CONCLUSIONS: Our meta-analysis showed that IVF is safe and could be an effective strategy for the treatment of intraventricular hemorrhage. It may reduce mortality, improve functional outcome, and diminish the need for permanent ventricular shunting, while not increasing the risk of ventriculitis or rehemorrhage.

Neurosurgical checklists: a review.

Morbidity due to avoidable medical errors is a crippling reality intrinsic to health care. In particular, iatrogenic surgical errors lead to significant morbidity, decreased quality of life, and attendant costs. In recent decades there has been an increased focus on health care quality improvement, with a concomitant focus on mitigating avoidable medical errors. The most notable tool developed to this end is the surgical checklist. Checklists have been implemented in various operating rooms internationally, with overwhelmingly positive results. Comparatively, the field of neurosurgery has only minimally addressed the utility of checklists as a health care improvement measure. Literature on the use of checklists in this field has been sparse. Considering the widespread efficacy of this tool in other fields, the authors seek to raise neurosurgical awareness regarding checklists by reviewing the current literature.

Biological Rhythms Workshop IC: sleep and rhythms.

Rhythms of sleep and wakefulness (typically measured as rest/activity rhythms) are among the most prominent of biological rhythms and therefore were among the first to be recorded in early chronobiological studies. These rhythms can provide useful information about the central biological clock, although an appreciation of the problems associated with using rest/activity to infer central clock function is important in the design and interpretation of chronobiological experiments in both animals and humans. Here, we review the anatomical and neurophysiologic bases of sleep regulation in mammals as well as similarities and differences between the sleep of humans and that of other organisms. We outline how human sleep is measured, the role of the circadian system in models of human sleep regulation, and human circadian rhythm sleep disorders. Although the function of sleep is still not completely understood, sleep has a critical role for human health, and we have attempted to outline the role that the circadian timing system has in regulating human sleep and in contributing to sleep disorders.

A resorbable porous ceramic composite bone graft substitute in a rabbit metaphyseal defect model.

The success of converted corals as a bone graft substitute relies on a complex sequence of events of vascular ingrowth, differentiation of osteoprogenitor cells, bone remodeling and graft resorption occurring together with host bone ingrowth into and onto the porous coralline microstructure or voids left behind during resorption. This study examined the resorption rates and bone infiltration into a family of resorbable porous ceramic placed bilaterally in critical sized defects in the tibial metaphyseal-diaphyseal of rabbits. The ceramics are made resorbable by partially converting the calcium carbonate of corals to form a hydroxyapatite (HA) layer on all surfaces. Attempts have been made to control the resorption rate of the implant by varying the HA thickness. New bone was observed at the periosteal and endosteal cortices, which flowed into the centre of the defect supporting the osteoconductive nature of partially converted corals. The combination of an HA layer and calcium carbonate core provides a composite bone graft substitute for new tissue integration. The HA-calcium carbonate composite demonstrated an initial resorption of the inner calcium carbonate phase but the overall implant resorption and bone ingrowth behaviour did not differ with HA thickness.

Tc-99m-labeled C5a and C5a des Arg74 for infection imaging.

UNLABELLED: The complement anaphylatoxin C5a and its natural metabolite C5a des Arg(74) (C5adR) are involved in several stages of the inflammatory process. Both act on a common receptor expressed on different cell types, including neutrophils and monocytes. The receptor binding affinity of C5a is in the nanomolar range and exceeds that of C5adR by 1-2 orders of magnitude. The biologic potency of C5a is considerably higher than that of C5adR. Here we tested both proteins labeled with (99m)Tc for imaging of infection. METHODS: The proteins were labeled with (99m)Tc via the hydrazinonicotinamide (HYNIC) chelator. The preparations were tested for imaging of infection in a rabbit model of intramuscular infection. Biodistribution of the radiolabel was determined by gamma-camera imaging and by counting dissected tissues at 5 h p.i. RESULTS: C5a and C5adR showed in vivo abscess uptakes of 0.12 and 0.025%ID/g, abscess/muscle ratios of 76 and 14, abscess/blood ratios of 9.1 and 2.6, and ROI derived target-to-background ratios of 5.9 and 2.1, respectively at 5 h p.i. CONCLUSION: For infection imaging (99m)Tc-labeled C5a showed excellent in vivo characteristics. However, C5a is a very bioactive protein, impeding its clinical use as an infection imaging agent. The naturally occurring partial agonist C5adR has less biological effect but showed suboptimal imaging characteristics. The present study showed that for adequate localization of a receptor binding ligand affinities for the receptor in the nanomolar range are required.

Estrous odors and sexually conditioned neutral odors activate separate neural pathways in the male rat.

Olfactory stimuli play important roles in sexual behavior. Previous studies have demonstrated that both estrous odors and initially neutral odors paired with copulation influence the sexual behavior of male rats. The present study examines the pattern of neural activation as revealed by Fos immunoreactivity (Fos-IR) following exposure to bedding scented with either a neutral odor (almond) paired previously with copulation, estrous odors or no odor. Following exposure to estrous odors Fos-IR increased in the accessory olfactory bulb, medial amygdala, medial bed nucleus of the stria terminalis, medial preoptic area, ventromedial hypothalamus, ventral tegmental area, and both the nucleus accumbens core and shell. Conversely, following exposure to the sexually conditioned odor Fos-IR increased in the piriform cortex, basolateral amygdala, nucleus accumbens core, and the anterior portion of the lateral hypothalamic area. In addition, following exposure to almond odor Fos-IR increased in the main olfactory bulb independent of its pairing with copulation. These patterns of Fos-IR following exposure to estrous or sexually conditioned odors were not influenced by either the addition or omission of the other type of odor. These findings demonstrate that estrous and sexually conditioned odors are processed by distinct neural pathways and converge in the nucleus accumbens core, suggesting that this structure has a unique role in processing sexual stimuli of both pheromonal and olfactory natures.

Surface roughness of the proximal and distal bearing surface of mobile bearing total knee prostheses.

Proximal and distal articulations surface roughness measurements were done on 8 mobile bearing knee designs immediately after removal from sterile packaging. Roughness parameters Ra and Rp based on ISO 97, representing mean deviation from the smooth surface line and mean peak to smooth surface line, were recorded using a contact surface profilometer at 10 random sites in the anteroposterior and mediolateral direction on the femoral and tibial metal components and the proximal and distal surface of the ultra-high molecular weight polyethylene (PE) inserts. No differences were found for surface roughness values for the metal components. Surface roughness values were greater for the distal PE bearing surfaces compared with the proximal PE bearing surfaces for each design tested. The roughness values for the PE inserts showed a directional dependence. Complex kinematics of mobile bearing knees coupled with this rougher distal interface could influence the rate of generation of wear particles and total volume of particles produced especially in the early postoperative period.

The function of the posterior cruciate ligament in an anteroposterior-gliding rotating platform total knee arthroplasty.

Knee kinematics after total knee arthroplasty is dictated primarily by implant geometry and native soft tissue constraints. This study highlights the importance of a functioning posterior cruciate ligament in limiting excessive anteroposterior translation in a mobile bearing knee design that relies on native posterior cruciate ligament integrity and postarthroplasty tensioning for stability rather than any inherent mechanical design stability, such as anterior rails or stops.

Mapping the ligand-binding site on the C5a receptor: arginine74 of C5a contacts aspartate282 of the C5a receptor.

The interaction between the anaphylatoxin C5a and its receptor involves two distinct sites. One site is formed by acidic residues at the receptor N-terminus and contributes to only ligand binding. The second site, responsible for activation, is less well defined. In this study, we demonstrate that the receptor residue D(282), near the extracellular face of transmembrane domain VII, is a component of the second ligand-binding site. Mutation of D(282) to A decreases the sensitivity of the receptor to activation by intact C5a but not by its less potent metabolite, C5adR(74), which lacks the C-terminal arginine(74). The mutation of the R(74) residue of C5a to A causes a 60-fold decrease in wild-type receptor sensitivity, but only a 2-fold decrease for the receptor mutated at D(282). In contrast, the mutation of R(74) to D makes C5a completely inactive on both wild-type and A(282) C5a receptors. The mutation of D(282) to R partly restores the response to C5a[D(74)], which is a more effective ligand than C5a at the mutant receptor. A peptide mimic of the C5a activation domain with a C-terminal R potently activates the wild type but is only a weak agonist at the mutant D(282)R-C5a receptor. Conversely, a peptide with D at the C-terminus is a more effective activator of D(282)R than wild-type C5a receptors. These data indicate that the R(74) side chain of C5a makes an interaction with receptor D(282) that is responsible for the higher potency of intact C5a versus that of C5adR(74).

Regional magnetic fields as navigational markers for sea turtles.

Young loggerhead sea turtles (Caretta caretta) from eastern Florida undertake a transoceanic migration in which they gradually circle the north Atlantic Ocean before returning to the North American coast. Here we report that hatchling loggerheads, when exposed to magnetic fields replicating those found in three widely separated oceanic regions, responded by swimming in directions that would, in each case, help keep turtles within the currents of the North Atlantic gyre and facilitate movement along the migratory pathway. These results imply that young loggerheads have a guidance system in which regional magnetic fields function as navigational markers and elicit changes in swimming direction at crucial geographic boundaries.