Selective Mapping of Deep Brain Stimulation Lead Currents Using Acoustoelectric Imaging

We describe a new application of acoustoelectric imaging for non-invasive mapping of the location, magnitude and polarity of current generated by a clinical deep brain stimulation (DBS) device. Ultrasound at 1MHz was focused near the DBS device as short current pulses were injected across different DBS leads. A recording electrode detected the high-frequency acoustoelectric interaction signal. Linear scans of the US beam produced time-varying images of the magnitude and polarity of the induced current, enabling precise localization of the DBS leads within 0.70mm, a detection threshold of 1.75mA at 1 MPa and a sensitivity of 0.52 ± 0.07 μV/(mA*MPa). Monopole and dipole configurations in saline were repeated through a human skullcap. Despite 13.8-dB ultrasound attenuation through bone, acoustoelectric imaging was still >10dB above background with a sensitivity of 0.56 ± 0.10 μV/(mA*MPa). This proof-of-concept study indicates that selective mapping of lead currents through a DBS device may be possible using non-invasive acoustoelectric imaging.     

Effect of a GP desktop resource on smoking cessation activities of general practitioners

Objectives To evaluate an intervention aimed at increasing the quantity and quality of brief opportunistic general practitioner (GP) advice to smokers encouraging and supporting quit attempts. Design Randomized controlled trial with two groups: (1) control and (2) GP desktop resource (GDR). Smoking cessation activities of GPs were assessed by an independent postal survey 1 month after distribution of resource. Subjects and setting One hundred and seven GPs in West Dorset. Main outcome measures GPs’ self‐reported rates of advising and counselling smokers on cessation over the previous week. Results The rate of opportunistic advice per week in the GDR group was 4.9 (SD = 4.1), compared with 2.8 (SD = 1.8) in the control group, F = 8.2, p = 0.0025, one‐tailed. The rate of giving counselling was also higher 2.2 (SD = 3.2) in the intervention group versus 1.0 (SD = 1.4) in the control group, F = 4.0, p = 0.025, one‐tailed. The proportion who had recommended or prescribed NRT was greater, although not significantly (54% versus 46%, Fisher’s exact p = 0.1, one‐tailed). Conclusions The findings indicate that the GDR can increase the rate of delivery of opportunistic advice and provision of counselling. Given the importance of this activity, a larger trial appears to be warranted to examine the long‐term effect and the effect on cessation rates in patients.     

Induction of immune tolerance in patients with hemophilia A and inhibitors treated with porcine VIIIC by home therapy

Home therapy with porcine factor VIIIC was safe and effective when administered to five hemophilic patients over periods of 8 1/2, 6, 4, 3 1/2, and 2 years. No significant transfusion reactions occurred. Before treatment with porcine factor VIIIC, all five had high-level, high- responding anti-human VIIIC inhibitors initially lacking anti-porcine factor VIIIC activity. Although specific anti-porcine VIIIC inhibitors arose in all patients, these were generally transient, and only one patient became refractory to treatment. We believe that porcine factor VIIIC is the treatment of choice in patients whose inhibitors do not cross-react. All five patients lost their original anti-human VIIIC inhibitors after starting treatment with porcine VIIIC, permitting the reintroduction of human VIIIC in three of them. There has been no recurrence of anti-human VIIIC inhibitor activity during 2 to 3 years of regular treatment with human VIIIC in these patients. This suggests that tolerance to human VIIIC has arisen as a result of treatment with porcine VIIIC. Porcine VIIIC may have a role in the desensitization of some factor VIIIC inhibitor patients.     

Eukaryotic and prokaryotic stomatins: the proteolytic link

The 32kD membrane protein stomatin was first studied because it is deficient from the red cell membrane in two forms of the class of haemolytic anaemias known as "hereditary stomatocytosis." The hallmark of these conditions is a plasma membrane leak to the monovalent cations Na+ and K+: the protein is missing only in the most severely leaky of these conditions. No mutation has ever been found in the stomatin gene in these conditions. Stomatin-like proteins have been identified in all three domains of biology, yet their function remains enigmatic. Although the murine knock-out is without phenotype, we have identified a family showing a splicing defect in the stomatin mRNA, in which affected children showed a catastrophic multisystem disease not inconsistent with the now-known wide tissue distribution of stomatin. We report here a study of strongly homologous stomatin-like genes in prokaryotes, which reveals a close connection with a never-studied gene erroneously known as "nfed." This gene codes for a hydrophobic protein with a probable serine protease motif. It is possible that these stomatin-like genes and those which are known as"nfed" form an operon, suggesting that the two protein products are aimed at a common function. The corollary is that stomatin could be a partner protein for a membrane-bound proteolytic process, in both prokaryotes and in eukaryotes generally: this idea is consistent with experimental evidence.     

Targeting Nitric Oxide With Drug Therapy

Increasing knowledge of the role of nitric oxide (NO) in physiology and disease has stimulated efforts to target the NO pathway pharmacologically. These therapeutic strategies include NO donors that directly or indirectly release NO and agents that increase NO bioactivity. Traditional organic nitrates such as nitroglycerin, which indirectly release NO, were believed to have limited long-term efficacy and tolerability, chiefly because of nitrate tolerance. Recent studies, however, suggest more effective ways of using these agents and new applications for them. Nicorandil, a hybrid organic nitrate that also activates potassium channels, has demonstrated significant benefits in acute coronary syndromes. Other nitrates are being investigated for use in neurodegenerative diseases. Direct NO donors include NO gas, which is useful in respiratory disorders, and the more recent classes of diazeniumdiolates, sydnonimines, and S-nitrosothiols. Preliminary data suggest that these agents may be effective as anti-atherosclerotic agents as well as in other disease states. In addition, hybrid agents that consist of an NO donor coupled with a parent anti-inflammatory drug, including nonsteroidal anti-inflammatory drugs, have demonstrated enhanced efficacy and tolerability compared with the anti-inflammatory parent drug alone in diverse experimental models. Established drugs that enhance NO bioactivity include antihypertensive agents, particularly angiotensin-converting enzyme inhibitors, calcium channel blockers, and newer vasodilating β-blockers. In addition, 3-methylglutaryl coenzyme A reductase inhibitors (statins) promote NO bioactivity, both through and independent of lipid lowering. The NO-promoting actions of these established drugs provide some insight into their known benefits and suggest possible therapeutic potential.     

Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites

During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected. Five previously protected volunteers were rechallenged 23-42 weeks after a secondary immunization, and 4 were protected. Two volunteers were protected when rechallenged with a heterologous Pf strain (7G8). In total, there was protection in 24 of 26 challenges. These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.     

The natural history of chronic hepatitis C in haemophiliacs

Most haemophiliacs treated with non-virally-inactivated clotting factor concentrates have been infected with hepatitis C virus (HCV). We have studied the natural history of chronic HCV infection by following all 138 HCV-positive patients from our centre for periods of up to 28 years. As well as the clinical and biochemical characteristics, we studied 116 liver samples from 63 patients obtained at elective biopsy ( n =103) or autopsy ( n =13). 36 (26%) of the patients were HIV positive, and three were chronic carriers of hepatitis B. Evidence of previous exposure to hepatitis A and B was found in 37.2% and 48.1% respectively. Raised transaminase levels were found in 82.6% of patients. 11 of 15 patients with normal transaminases tested by PCR for HCV RNA were positive, indicating that most patients, even in this group, have chronic hepatitis C infection. Cirrhosis was diagnosed by liver histology in 19 patients, and nine patients developed liver failure. The incidence of cirrhosis rose rapidly 15 years after HCV infection to 15.6 per 1000 person-years. Multivariate analysis showed that HIV status, length of time since HCV infection and age at HCV infection were independently associated with both the development of cirrhosis and liver failure. Two patients developed hepatocellular carcinoma; one of these was exposed only to a single batch of FVIII concentrate 11 years earlier. Chronic hepatitis C is increasingly recognized as a major cause for morbidity and mortality in haemophiliacs, especially those who are HIV positive and who were infected at an older age.     

Reduced risk of non-A, non-B hepatitis after a first exposure to ''wet heated''factor VIII concentrate

The risk of post-infusion non-A, non-B hepatitis (NANBH) in patients receiving a first exposure to unheated or conventionally 'dry heated' factor VIII concentrates approaches 100%, implying invariable contamination of these products. Amongst 18 patients who received a first treatment with a 'wet heated' commercial concentrate, five (28%) developed asymptomatic NANBH, suggesting a more efficient inactivation of NANB agent(s) by this process. 2/9 (22%) of the batches of concentrate used in the study were implicated in NANBH transmission. One of those two batches, responsible for NANBH in four patients, had been prepared from a plasma pool containing an unusually large proportion of donations with high alanine aminotransferase (ALT) levels. A resulting high level of viral contamination in this batch may have been sufficient to override the effects of the sterilization process. All patients remained anti-HIV seronegative at 17-28 months of follow-up.     

Antithrombin Sheffield: amino acid substitution at the reactive site (Arg393 to His) causing thrombosis

A Sheffield family with a predisposition towards thrombosis has been shown to have a functional abnormality of antithrombin. The abnormality was detected as reduced heparin cofactor activity, with normal antigenic levels of antithrombin. Crossed immunoelectrophoresis performed in the absence and presence of heparin was normal. The antithrombin was isolated by heparin Sepharose affinity chromatography. It had normal mobility on SDS polyacrylamide gel electrophoresis. However, the second order rate constant of inhibition of thrombin was about half that of normal, and this was compatible with a heterozygous abnormality involving the reactive site. The antithrombin was further purified by chromatography on thrombin-Sepharose (to remove the normal component), reduced, S-carboxymethylated and fragmented with cyanogen bromide. A pool containing the reactive site region was digested with trypsin and the molecular size of peptides generated determined by fast atom bombardment mass spectrometry. The two peptides adjacent to the Arg393-Ser394 bond of mass 2290 and 700 were almost absent from the mass spectrum, but an additional peptide of mass 2952 was present. Subdigestion with V8 protease reduced the mass of this peptide to 1748. These peptides generated by trypsin and V8 protease were almost identical to those obtained when another variant, antithrombin Glasgow, was treated in the same way (Erdjument et al, 1988). It is concluded that the molecular abnormality of antithrombin Sheffield is identical to that of antithrombin Glasgow, Arg393 to His.     

An evaluation of serum osteocalcin in Paget's disease of bone and its response to diphosphonate treatment

We found that serum bone gamma-carboxyglutamic acid-containing protein (BGP) (osteocalcin) had lower sensitivity and specificity for measurement of disease activity in Paget's disease of bone than other biochemical measures of disease activity. The administration of diphosphonates induced suppression of urinary hydroxyproline excretion and a subsequent decrease in alkaline phosphatase values, but no consistent change in BGP values. Serum BGP measurements have limited value as a screening test for Paget's disease or for monitoring treatment of the disorder.