Monro-Kellie 2.0: The dynamic vascular and venous pathophysiological components of intracranial pressure

For 200 years, the ‘closed box’ analogy of intracranial pressure (ICP) has underpinned neurosurgery and neuro-critical care. Cushing conceptualised the Monro-Kellie doctrine stating that a change in blood, brain or CSF volume resulted in reciprocal changes in one or both of the other two. When not possible, attempts to increase a volume further increase ICP. On this doctrine’s “truth or relative untruth” depends many of the critical procedures in the surgery of the central nervous system. However, each volume component may not deserve the equal weighting this static concept implies. The slow production of CSF (0.35 ml/min) is dwarfed by the dynamic blood in and outflow (∼700 ml/min). Neuro-critical care practice focusing on arterial and ICP regulation has been questioned. Failure of venous efferent flow to precisely match arterial afferent flow will yield immediate and dramatic changes in intracranial blood volume and pressure. Interpreting ICP without interrogating its core drivers may be misleading. Multiple clinical conditions and the cerebral effects of altitude and microgravity relate to imbalances in this dynamic rather than ICP per se. This article reviews the Monro-Kellie doctrine, categorises venous outflow limitation conditions, relates physiological mechanisms to clinical conditions and suggests specific management options

Emergency burr holes:" How to do it"

This paper describes a simple approach to emergency burr hole evacuation of extra-axial intracranial haematoma that can be used in the uncommon situation when life saving specialist neurosurgical intervention is not available

Nitric oxide binds to the proximal heme coordination site of the ferrocytochrome c/cardiolipin complex: formation mechanism and dynamics.

Mammalian mitochondrial cytochrome c interacts with cardiolipin to form a complex (cyt. c/CL) important in apoptosis. Here we show that this interaction leads to structural changes in ferrocytochrome c that leads to an open coordinate site on the central iron, resulting from the dissociation of the intrinsic methionine residue, where NO can rapidly bind (k = 1.2 x 10(7) m(-1) s(-1)). Accompanying NO binding, the proximal histidine dissociates leaving the heme pentacoordinate, in contrast to the hexacoordinate nitrosyl adducts of native ferrocytochrome c or of the protein in which the coordinating methionine is removed by chemical modification or mutation. We present the results of stopped-flow and photolysis experiments that show that following initial NO binding to the heme, there ensues an unusually complex set of kinetic steps. The spectral changes associated with these kinetic transitions, together with their dependence on NO concentration, have been determined and lead us to conclude that NO binding to cyt. c/CL takes place via an overall scheme comparable to that described for cytochrome c' and guanylate cyclase, the final product being one in which NO resides on the proximal side of the heme. In addition, novel features not observed before in other heme proteins forming pentacoordinate nitrosyl species, include a high yield of NO escape after dissociation, rapid (<1 ms) dissociation of proximal histidine upon NO binding and its very fast binding (60 ps) after NO dissociation, and the formation of a hexacoordinate intermediate. These features all point at a remarkable mobility of the proximal heme environment induced by cardiolipin

The Brain at Altitude: The Cerebral Vasculature, Hypoxia and Headache

This thesis studies the effect of hypoxia (at rest and during exercise) on the arterial and venous cerebral circulation, investigating the venous system role in high altitude headache. Methods: 1) Hypobaric hypoxic studies investigated 198 trekkers and 24 Investigators to 5300m, 14 to 6400m and 8 to 8848m. 2) Normobaric hypoxic studies used Magnetic Resonance Imaging (MRI)) at sea-level. Four domains were addressed: i. Arterial: Hypobaric hypoxia: (n=24) Transcranial Doppler (TCD) measured middle cerebral artery diameter (MCAD) and blood velocity (MCAv). Sea-Level normobaric hypoxia: (n=7) A hypoxicator (FiO2 = 11%) for 3 hours with a 3Tesla MRI scan measured MCAD and MCAv. ii. Brain Oxygenation: Near Infrared Spectroscopy (NIRS) monitored Regional Brain Oxygenation (rSO2). iii. Venous: Retinal imaging at altitude and MRI at sea-level assessed the venous system. iv. Headache: A daily diary recorded headache burden. Results: Arterial: Hypobaric and normobaric hypoxia induced MCA dilatation. Mean (±(SEM)) MCAD increased in hypoxia (from 5.23(±0.23)mm (at 5300m) to 9.34(±0.88)mm (at 7950m)(p<0.001) (TCD). At sea-level, (after 3 hours FiO2 = 11%) MCAD increased from 3.04(±0.13)mm to 3.27(±0.13)mm (MRI). Brain Oxygenation: rSO2 decreased more than peripheral arterial saturation (SaO2), especially during exercise. The relative percentage reduction in resting SaO2 and rSO2 from 75m to 5300m was -22.23 ±0.56% and -30.61 ±1.28% (p<0.001) respectively. Venous: Hypoxia induced retinal and cerebral venous distension. Twenty-three of 24 subjects exhibited retinal venous distension (range 5 to 44%). Degree of distension correlated with headache (r = 0.553, p=0.005). Possession of a narrow transverse sinus strongly related to retinal and cerebral venous distension and headache. Headache: Headache Severity Index (HSI) (headache score x duration) correlated inversely to both lateral and third ventricular volumes summed (r = -0.5, p = 0.005) and pericerebellar CSF volume (r = -0.56, p = 0.03). Conclusions: Large cerebral arteries dilate and veins distend with hypoxia. This suggests an important influence of cerebral venous anatomy and physiology on headache, with implications for pathophysiological states and their management

Three and half million year history of moisture availability of South West Africa: Evidence from ODP site 1085 biomarker records

Ocean Drilling Program Site 1085 provides a continuous marine sediment record off southern South West Africa for at least the last three and half million years. The n-alkane ∂13 C record from this site records changes in past vegetation and provides an indication of the moisture availability of SW Africa during this time period. Very little variation, and no apparent trend, is observed in the n-alkane δ13C record, suggesting stable long-term conditions despite significant changes in East African tectonics and global climate. Slightly higher n-alkane δ13C values occur between 3.5 and 2.7 Ma suggesting slightly drier conditions than today. Between 2.5 and 2.7 Ma there is a shift to more negative n-alkane δ13C values suggesting slightly wetter conditions during a ~ 0.2 Ma episode that coincides with the intensification of Northern Hemisphere Glaciation (iNHG). From 2.5 to 0.4 Ma the n-alkane δ13C values are very consistent, varying by less than ± 0.5‰ and suggesting little or no long-term change in the moisture availability of South West Africa over the last 2.5 million years. This is in contrast to the long-term drying trend observed further north offshore from the Namib Desert and in East Africa. A comparison of the climate history of these regions suggests that Southern Africa may have been an area of long-term stability over the last 3.5 Myrs

Assessment of best single sample for finding chlamydia in women with and without symptoms: a diagnostic test study

Objective: to compare vulvovaginal swabs with endocervical swabs as optimal diagnostic sample for detection of Chlamydia trachomatis infection. Design: a diagnostic test study. Setting: an urban sexual health centre. Participants: 3973 women aged ≥16 years requesting testing for sexually transmitted infections. Interventions: participants took a vulvovaginal swab before routine examination, and clinicians took an endocervical swab during examination. Main outcome measure: diagnosis of chlamydia infection with samples analysed using the Aptima Combo-2 assay; positive results confirmed with the Aptima CT assay. Results: of the 3973 participants, 410 (10.3%) were infected with C trachomatis. Infected women were significantly younger (22 v 25 years, P<0.0001) and more likely to have symptoms suggestive of a bacterial sexually transmitted infection (53% v 41%, odds ratio 1.63 (95% CI 1.30 to 2.04)), be a contact of someone with a sexually transmitted infection (25% v 5%, odds ratio 6.18 (4.61 to 8.30)), clinically diagnosed with cervicitis (17% v 4%, odds ratio 4.92 (3.50 to 6.91)), and have pelvic inflammatory disease (9% v 3%, odds ratio 2.85 (1.87 to 4.33)). When women co-infected with gonorrhoea were included in the analysis, there was an association with mixed ethnicity (10% v 7%, odds ratio 1.53 (1.07 to 2.17)); but when those with gonorrhoea were removed, women of white ethnicity were significantly more likely to have chlamydia (85% v 80%, odds ratio 1.40 (1.03 to 1.91)). On analysis of complete paired results, vulvovaginal swabs were significantly more sensitive than endocervical swabs (97% (95% CI 95% to 98%) v 88% (85% to 91%), P<0.00001); corresponding specificities were 99.9% and 100%. In women with symptoms suggestive of a bacterial sexually transmitted infection, vulvovaginal swabs were significantly more sensitive than endocervical swabs (97% (93% to 98%) v 88% (83% to 92%), P=0.0008), as they were in women without symptoms (97% (94% to 99%) v 89% (84% to 93%), P=0.002). Conclusions: vulvovaginal swabs are significantly better than endocervical swabs at detecting chlamydia in women with and without symptoms suggestive of sexually transmitted infections. In those with symptoms, using endocervical samples rather than vulvovaginal swabs would have missed 9% of infections, or 1 in every 11 cases of chlamydia

A change in the NICE guidelines on antibiotic prophylaxis

Since 2008, NICE clinical guidelines have stated: ‘Antibiotic prophylaxis against infective endocarditis is not recommended for people undergoing dental procedures’. This put UK guidance at odds with guidance in the rest of the world, where antibiotic prophylaxis is recommended for patients at high-risk of infective endocarditis undergoing invasive dental procedures. Many dentists also felt this wording prohibited the use of antibiotic prophylaxis, regardless of the wishes of the patient or their personal risk of infective endocarditis and made it difficult for them to use their clinical judgment to deliver individualised care in the best interests of their patients. NICE have now changed this guidance to ‘Antibiotic prophylaxis against infective endocarditis is not recommended routinely for people undergoing dental procedures.’ This article examines the implications of this small but important change

Structured sequence learning across sensory modalities in humans and nonhuman primates

Structured sequence processing tasks inform us about statistical learning abilities that are relevant to many areas of cognition, including language. Despite the ubiquity of these abilities across different tasks and cognitive domains, recent research in humans has demonstrated that these cognitive capacities do not represent a single, domain-general system, but are subject to modality-specific and stimulus-specific constraints. Sequence processing studies in nonhuman primates have provided initial insights into the evolution of these abilities. However, few studies have examined similarities and/or differences in sequence learning across sensory modalities. We review how behavioural and neuroimaging experiments assess sequence processing abilities across sensory modalities, and how these tasks could be implemented in nonhuman primates to better understand the evolution of these cognitive systems

The influence of perfusion solution on renal graft viability assessment

BACKGROUND: Kidneys from donors after cardiac or circulatory death are exposed to extended periods of both warm ischemia and intra-arterial cooling before organ recovery. Marshall’s hypertonic citrate (HOC) and Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) preservation solutions are cheap, low viscosity preservation solutions used clinically for organ flushing. The aim of the present study was to evaluate the effects of these two solutions both on parameters used in clinical practice to assess organ viability prior to transplantation and histological evidence of ischemic injury after reperfusion. METHODS: Rodent kidneys were exposed to post-mortem warm ischemia, extended intra-arterial cooling (IAC) (up to 2 h) with preservation solution and reperfusion with either Krebs-Hensleit or whole blood in a transplant model. Control kidneys were either reperfused directly after retrieval or stored in 0.9% saline. Biochemical, immunological and histological parameters were assessed using glutathione-S-transferase (GST) enzymatic assays, polymerase chain reaction and mitochondrial electron microscopy respectively. Vascular function was assessed by supplementing the Krebs-Hensleit perfusion solution with phenylephrine to stimulate smooth muscle contraction followed by acetylcholine to trigger endothelial dependent relaxation. RESULTS: When compared with kidneys reperfused directly post mortem, 2 h of IAC significantly reduced smooth muscle contractile function, endothelial function and upregulated vascular cellular adhesion molecule type 1 (VCAM-1) independent of the preservation solution. However, GST release, vascular resistance, weight gain and histological mitochondrial injury were dependent on the preservation solution used. CONCLUSIONS: We conclude that initial machine perfusion viability tests, including ischemic vascular resistance and GST, are dependent on the perfusion solution used during in situ cooling. HTK-perfused kidneys will be heavier, have higher GST readings and yet reduced mitochondrial ischemic injury when compared with HOC-perfused kidneys. Clinicians should be aware of this when deciding which kidneys to transplant or discard

Utility of Whole Genome Sequencing in Assessing and Enhancing Partner Notification of Neisseria gonorrhoeae Infection

Background: Gonorrhea is a sexually transmitted infection of global concern. We investigated whole genome sequencing (WGS) as a tool to measure and enhance partner notification (PN) in gonorrhea management. / Methods: Between May-November 2018, all N. gonorrhoeae isolated from patients attending Leeds Sexual Health, UK, underwent WGS. Reports listing sequences within 20 single nucleotide polymorphisms (SNPs) of study isolates within a database containing select isolates from April 1 2016 to November 15 2018 were issued to clinicians. The proportion of cases with a potential transmission partner identified by PN was determined from patient and PN data. WGS reports were reviewed to identify additional cases within ≤6 SNPs and verified for PN concordance. / Results: 380 isolates from 377 cases were successfully sequenced; 292 had traceable/contactable partners and 69 (18%) had a potential transmission partner identified by PN. Concordant PN and WGS links were identified in 47 partner pairs. Of 308 cases with no transmission partner by PN, 185 (60%) had a case within ≤6 SNPs; examination of these cases’ PN data identified seven partner pairs with previously unrecognized PN link, giving a total of 54 pairs; all had ≤4 SNP differences. WGS clusters confirmed gaps in partner finding, at individual and group levels. Despite the clinic providing sexual health services to the whole city, 35 cases with multiple partners had no genetically related case, suggesting multiple undiagnosed infections. / Conclusions: WGS could improve gonorrhea PN and control by identifying new links and clusters with significant gaps in partner finding