Subarachnoid pharmacodialysis for central nervous system disorders

We postulate that alternating use of microcontroller-regulated delivery and drain pumps connected to one or more sealed subarachnoid fluid exchange ports can maintain localized bi-directional molecular fluxes across pia mater covering multiple diseased areas of the cerebral cortex or spinal cord. This system enables local irrigation with drugs and drainage of endogenous neurotoxic molecules normalizing regional neurochemistry and restoring physiological function. Viewing the pia mater as an endogenous dialysis membrane, testing this hypothesis requires demonstrating: (a) benefits of removing neurotoxic molecules from diseased cerebral cortical or spinal areas via subarachnoid dialysis, (b) neuropharmacological effects of subarachnoid drug delivery and (c) evaluating additive effects of combining the two, as a novel, “pharmacodialysis” procedure. Our supporting experimental data show that this procedure can drain proinflammatory cytokines from the neocortex to the subarachnoid cerebrospinal fluid in rats and can prevent focal seizures in monkeys through subarachnoid delivery of muscimol to their neocortex. Subarachnoid pharmacodialysis allows effective site-specific treatment and microcontroller-regulated timing responsive to the evolving course of a disease and can be performed with bedside systems or fully implanted devices. The procedure provides a two-pronged, combined therapy for traumatic brain and spinal cord injuries, cortically localized epilepsy, stroke and tumors as well as psychiatric disorders such as Alzheimer’s disease with pathology of the association cortex. Therapeutic subarachnoid pharmacodialysis drainage of endogenous molecules from the neocortical interstitial space offers unprecedented opportunities to gain new insights into the neurochemistry of the human neocortex in real-life conditions over months or even years.     

The effect of ovariectomy and oestrogen replacement on small artery biomechanics in the rat

Objective To determine the effects of oestrogen deficiency and hormone replacement therapy on the biomechanical properties of a small artery.
Sample Thirty non-pregnant female Sprague-Dawley rats.
Methods Twenty animals were pharmacologically ovariectomised by triptorelin and received either oestradiol propionate or its vehicle. Ten other animals received only the vehicle for the same period of time (control group). After 12 weeks of treatment, cylindrical segments of the saphenous artery were isolated and cannulated at both ends. Pressure-diameter curves were recorded from segments in normal Krebs-Ringer, using norepinephrine, and then with papaverine. The vessel segment close to the examined one was histologically evaluated. Serum levels of oestradiol and cortisol were determined.
Main outcome measures Biomechanical parameters based on the pressure-diameter curves.
Results Pharmacological ovariectomy decreased the passive diameter of the arteries and oestrogen replacement therapy prevented this. Decreased reactivity to norepinephrine was also restored by oestrogen treatment. Pressure induced myogenic tone was decreased significantly by oophorectomy and increased after oestradiol treatment. No significant changes were found in wall thickness, distensibility, elastic modulus or tangential stress. No significant histological alterations were seen in the vessel wall. Oestradiol levels were significantly decreased in the castrated animals compared with the other two groups.
Conclusions These results suggest that oestrogen deficiency decreases and oestrogen replacement increases the passive diameter of small peripheral arteries, and that oestrogen enhances the reactivity of vascular smooth muscle. These responses may provide the background mechanisms for the increased incidence of arterial hypertension and hot flushes during the menopause and the ability of oestrogen substitution to prevent them.     

Inhaled nitric oxide therapy in adults: European expert recommendations

BACKGROUND: Inhaled nitric oxide (iNO) has been used for treatment of acute respiratory failure and pulmonary hypertension since 1991 in adult patients in the perioperative setting and in critical care. METHODS: This contribution assesses evidence for the use of iNO in this population as presented to a expert group jointly organised by the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists. CONCLUSIONS: Expert recommendations on the use of iNO in adults were agreed on following presentation of the evidence at the expert meeting held in June 2004.     

A role for mannose-binding lectin, a component of the innate immune system in pre-eclampsia

Problem Mannose‐binding lectin (MBL) is a pattern‐recognition receptor that activates complement and modulates inflammation. Homozygosity for the most common allele of the MBL2 gene that is associated with high MBL serum concentrations is more prevalent among patients with pre‐eclampsia. The objective of this study was to determine maternal plasma MBL concentrations in normal pregnant women and patients with pre‐eclampsia. Method of study This cross‐sectional study included normal pregnant women (n = 187) and patients with pre‐eclampsia (n = 99). Maternal plasma MBL concentrations were determined by ELISA. Results Women with pre‐eclampsia had a higher median maternal plasma MBL concentration than normal pregnant women. MBL concentration distribution curves were three‐modal, the subintervals in normal pregnancy were low (<143.7), intermediate (143.7–1898.9) and high (>1898.9 ng/mL). The proportion of normal pregnant women was larger in the low subinterval, while the proportion of patients with pre‐eclampsia was larger in the high subinterval (P = 0.02). Normal pregnant women in the high subinterval had a larger rate of placental underperfusion than those in the low and intermediate subintervals (P = 0.02). Conclusions The median maternal plasma MBL concentration is elevated in patients with pre‐eclampsia and a larger proportion of these patients are in the high subinterval than normal pregnant women, suggesting that this component of the innate immune system is involved in the mechanisms of disease in pre‐eclampsia.