Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-ß/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier.

Central nervous system (CNS) drug delivery can be achieved by targeting drug uptake transporters such as Oatp1a4. In fact, many drugs that can improve neurologic outcomes in CNS diseases [3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (i.e., statins)] are organic anion transporting polypeptide (OATP) transport substrates. To date, transport properties and regulatory mechanisms of Oatp1a4 at the blood-brain barrier (BBB) have not been rigorously studied. Such knowledge is critical to develop Oatp1a4 for optimization of CNS drug delivery and for improved treatment of neurological diseases. Our laboratory has demonstrated that the transforming growth factor-ß (TGF-ß)/activin receptor-like kinase 1 (ALK1) signaling agonist bone morphogenetic protein 9 (BMP-9) increases functional expression of Oatp1a4 in rat brain microvessels. Here, we expand on this work and show that BMP-9 treatment increases blood-to-brain transport and brain exposure of established OATP transport substrates (i.e., taurocholate, atorvastatin, and pravastatin). We also demonstrate that BMP-9 activates the TGF-ß/ALK1 pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Overall, this study provides evidence that Oatp1a4 transport activity at the BBB is directly regulated by TGF-ß/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of OATP substrate drugs.

Intensive care medicine is 60 years old: the history and future of the intensive care unit.

Intensive care is celebrating its 60th anniversary this year. The concept arose from the devastating Copenhagen polio epidemic of 1952, which resulted in hundreds of victims experiencing respiratory and bulbar failure. Over 300 patients required artificial ventilation for several weeks. This was provided by 1,000 medical and dental students who were employed to hand ventilate the lungs of these patients via tracheostomies. By 1953, Bjorn Ibsen, the anaesthetist who had suggested that positive pressure ventilation should be the treatment of choice during the epidemic, had set up the first intensive care unit (ICU) in Europe, gathering together physicians and physiologists to manage sick patients - many would consider him to be the 'father' of intensive care. Here, we discuss the events surrounding the 1952 polio epidemic, the subsequent development of ICUs throughout the UK, the changes that have occurred in intensive care over the past 10 years and what the future holds for the specialty.

Rituximab in the treatment of three coexistent neurological autoimmune diseases: chronic inflammatory demyelinating polyradiculoneuropathy, Morvan syndrome and myasthenia gravis.

A 76-year-old man with a pre-existing diagnosis of myasthenia gravis was admitted to an intensive care unit with pneumonia and type II respiratory failure. In addition, muscle weakness, widespread myokymia, neuropsychiatric disturbance and autonomic disturbance were present. Antivoltage gated potassium channel antibodies, antistriated muscle antibodies and antiacetylcholine receptor antibodies were positive. Nerve-conduction studies demonstrated findings consistent with patchy demyelination. Electromyography confirmed widespread myokymia, and there was evidence of diffuse encephalopathy on electroencephalography. Diagnoses of Morvan syndrome and chronic inflammatory demyelinating polyradiculopathy (CIDP) were made. Treatment with intravenous immunoglobulin, plasma exchange and high-dose steroids were ineffective, and the patient remained dependent on mechanical ventilation. The coexistence of possibly three humorally mediated autoimmune diseases led to treatment with rituximab. Rituximab treatment was followed by an improvement in muscle strength, allowing successful weaning from mechanical ventilation, diminution in myokymia and improved cognition. At follow-up, there was reversal of the neuropsychiatric manifestations and normal muscle strength. This case suggests that rituximab may be useful in the treatment of autoimmune neurological disease refractory to other immunosuppressant therapies. Specifically, it adds further evidence for the use of rituximab in CIDP. As indications for rituximab in humorally mediated disease continue to expand, international multicentre randomised controlled trials are required to prove the effectiveness of this important emerging biological agent.

Randomized controlled trial of toothbrushing to reduce ventilator-associated pneumonia pathogens and dental plaque in a critical care unit.

AIM: To investigate the effect of a powered toothbrush on colonization of dental plaque by ventilator-associated pneumonia (VAP)-associated organisms and dental plaque removal. MATERIALS AND METHODS: Parallel-arm, single-centre, examiner- and analyst-masked randomized controlled trial. Forty-six adults were recruited within 48 h of admission. Test intervention: powered toothbrush, control intervention: sponge toothette, both used four times per day for 2 min. Groups received 20 ml, 0.2% chlorhexidine mouthwash at each time point. RESULTS: The results showed a low prevalence of respiratory pathogens throughout with no statistically significant differences between groups. A highly statistically significantly greater reduction in dental plaque was produced by the powered toothbrush compared with the control treatment; mean plaque index at day 5, powered toothbrush 0.75 [95% confidence interval (CI) 0.53, 1.00], sponge toothette 1.35 (95% CI 0.95, 1.74), p=0.006. Total bacterial viable count was also highly statistically significantly lower in the test group at day 5; Log(10) mean total bacterial counts: powered toothbrush 5.12 (95% CI 4.60, 5.63), sponge toothette 6.61 (95% CI 5.93, 7.28), p=0.002. CONCLUSIONS: Powered toothbrushes are highly effective for plaque removal in intubated patients in a critical unit and should be tested for their potential to reduce VAP incidence and health complications.

Anti-N-methyl-D-aspartate receptor antibodies: a potentially treatable cause of encephalitis in the intensive care unit.

OBJECTIVE: To report the occurrence of an unusual neurologic disorder requiring admission to the intensive care unit. DESIGN: Analysis of an observational cohort study of 31 patients with encephalitis admitted over a 4-yr period. SETTING: Neurologic intensive care unit in a tertiary referral center. PATIENTS: We identified N-methyl-D-aspartate receptor antibodies in six patients (two male and four female). All seropositive patients presented with a psychiatric prodrome, before developing seizures and obtundation requiring intensive care unit admission. They exhibited limb and truncal stereotypies and orofacial dyskinesias upon weaning sedation. Two patients had ovarian tumors. INTERVENTIONS: Patients were treated with sedation, antiepileptic drugs, and immunotherapy. One patient received a magnesium infusion and ketamine. MEASUREMENTS AND MAIN RESULTS: N-methyl-D-aspartate receptor antibodies were identified in serum samples by an immunofluorescent cell-based assay. Three patients made a good but slow recovery; two were left with severe neurologic deficits; and one died after return to the referring hospital. These patients accounted for approximately 20% of all patients admitted with encephalitis to this referral center. CONCLUSIONS: N-methyl-D-aspartate receptor antibodies should be tested in patients with hyperkinetic encephalitis and neuropsychiatric prodrome admitted to the intensive care unit. The disorder is probably not rare and is potentially treatable.

A pilot study of fibreoptic endoscopic evaluation of swallowing in patients with cuffed tracheostomies in neurological intensive care.

INTRODUCTION: Patients on neurological intensive care units (NICU) who require ventilatory support often suffer from co-existing bulbar dysfunction, either because of their underlying disease or because of their decreased level of consciousness. For this reason, most patients are ventilated through a cuffed tracheostomy tube, which allows a degree of protection from tracheal aspiration of saliva and gastric contents. Patients who are awake often complain of thirst, but traditionally are only offered oral fluids when the cuff of the tracheostomy tube has been deflated. Given that many patients in NICU cannot tolerate cuff deflation, a reliable technique is needed to assess the adequacy of the patient's swallow and therefore the risk of aspiration when the tracheostomy cuff is inflated. METHODS: The aim of this feasibility study was to examine the viability of Fibreoptic Endoscopic Evaluation of Swallowing (FEES) as a diagnostic tool to assess the effectiveness of swallowing in four NICU patients with cuffed tracheostomies. RESULTS: The technique was successful in all of the four patients. One patient was found to have a normal swallow. Two patients were seen to have laryngeal penetration of fluids and one patient aspirated the fluid challenge. CONCLUSION: This pilot study has demonstrated the feasibility of using the FEES technique for assessment of swallowing in patients with cuffed tracheostomy tubes; it therefore presents the prospect of allowing earlier drinking in such patients whilst helping confirm the safety of such a strategy.