Where is the blood–brain barrier … really?

Few terms in the biomedical lexicon are as widely recognized as the phrase blood-brain barrier (BBB). Indeed, it immediately conjures up a "barricade" between the blood and the brain, a feature often considered more obstacle than safeguard. In truth, the BBB performs in both capacities, and it is precisely this duality that imparts such a vital role to the BBB in influencing physiological and pathophysiological processes in the CNS. Although the concept is more than a century old, the BBB continues to remain enigmatic in both substance and idea, with seemingly resolved issues once again beckoning for clarification. In this regard, recent technological advancements, such as sequencing of the human genome and development of microarray analysis, have illuminated novel aspects of vascular gene expression and provoked reconsideration of the cellular and biochemical makeup of the BBB. In light of the critical impact of the BBB in the realms of science and medicine, this Mini-Review will revisit the topic of the composition of the BBB, specifically highlighting how recent developments in endothelial biology have prompted a reevaluation of its precise vascular location. We have intentionally avoided discussing generalized features of the BBB, as these have been skillfully described elsewhere as noted.     

Linaclotide – a secretagogue and antihyperalgesic agent – what next?

Ongoing clinical trials suggest that linaclotide, a first‐in‐class, 14‐amino acid peptide guanylate cyclase‐C (GC‐C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation‐ and stress‐induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint‐induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC‐C receptors. Dose–effect relationships of linaclotide were complicated and non‐linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC‐C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress‐induced increased intestinal permeability. However, the data need to be confirmed in humans and in long‐term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide’s known effects on epithelial GC‐C receptors.     

Does it make sense to do repeated surveys? – the Lundby Study, 1947–1997

OBJECTIVE: To describe the Lundby Study and the difficulties in doing repeated surveys. METHOD: Best-estimate consensus diagnoses have been used since 1957 together with DSM-IV and ICD-10 in 1997. RESULTS: The Lundby population consisting of 3563 probands was investigated in 1947, 1957 and 1972. Sufficient information was available for 98-99%. In 1997-2000 a fourth field investigation was carried out. Attrition rate for the interviews was 13% (238/1797). About 36% (1030/2827) had died between 1972 and 1997, but data from registers, case notes and key-informants for the period 1972 and 1997 completed the information for 94% (2659/2827). The population has followed the same pattern of development as many rural populations in Sweden since the 1940s. Multiple sources of information are preferable in longitudinal studies in order to tackle the problem of changing diagnostic systems. CONCLUSION: Low attrition rates over 50 years and reasonable diagnostic uniformity make comparisons over time justifiable.     

The story of O – is oxytocin the mediator of the placebo response?

Abstract  While the placebo responses in various medical conditions have been shown to follow a few basic principles such as expectancies, reward learning and Pavlovian conditioning, the underlying neurobiology and the mediating hormonal and/or neuromodulating processing have remained obscure. We here report the collected evidence that oxytocin (OXT), a 389-amino acid polypeptide located on chromosome 3p25 that is released in the brain (hypothalamus) and in peripheral tissue, is the central mediator of the placebo response: we hypothesize that exogenous OXT via an OXT agonist will enhance the placebo response, while exogenous OXT blockade by an antagonist will reduce the placebo response in placebo analgesia and other placebo models. It is furthermore proposed that the placebo response in trials may be predicted by circulating plasma OXT levels, the OXT receptor density in the brain and/or the presence of one or more of the single nucleotide polymorphisms of the OXT promoter gene.     

Cavernous hemangioma of the spinal cord – conservative or operative management?

Once believed to be extremely uncommon, due to magnetic resonance imaging cavernous hemangiomas of the spinal cord are detected with increasing frequency. Management of both symptomatic and asymptomatic intramedullary cavernous hamangiomas is therefore of growing importance. However, experience with treatment and follow-up is very limited. In particular, patients with multiple central nervous system cavernous hemangiomas represent a therapeutical dilemma. We present a patient with a ruptured intramedullary and multiple cerebral cavernous hemangiomas and a survey of current knowledge of epidemiology, pathophysiology and treatment options. We conclude that the benefit of operative treatment possibly decreases with the number of clinically silent vascular malformations.