Ethanol inhibits dopamine uptake via organic cation transporter 3: Implications for ethanol and cocaine co-abuse.

Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.

Cohorts for the study of HIV­1-exposed but uninfected individuals: benefits and limitations.

Since the late 1980s, with the first identification of individuals who were exposed to human immunodeficiency virus type 1 (HIV-1) yet remained uninfected, or "HIV-1-resistant" individuals, a large number of cohorts that include HIV-exposed seronegative (HESN) subjects have been identified globally for the purpose of investigating the genetic, immunologic, and environmental factors that may help alter susceptibility to HIV-1. In this article, in light of the recent International Symposium on Natural Immunity to HIV, we review the characteristics of different groups with respect to their relative risks and briefly summarize the known cohorts that include exposed uninfected subjects worldwide.

IgA1 antibodies specific for outer membrane protein PorA modulate the interaction between Neisseria meningitidis and the epithelium.

Despite high carriage rates of Neisseria meningitidis, incidence of meningococcal disease remains low, partially due to development of natural immunity. We have previously demonstrated an inverse relationship between salivary anti-meningococcal IgA and disease incidence, but little is known about the contribution of IgA to immunity at mucosal surfaces. Here we show strong immunoreactivity by human salivary IgA against the meningococcal outer membrane porin, PorA. Monomeric anti-PorA IgA1 (humanized chimeric antibodies) but not IgG increased the association of unencapsulated serogroup B N. meningitidis (H44/76) with Chang (conjunctival) but not with either Detroit (pharyngeal) cells or with A549 (alveolar) epithelial cells. Association of encapsulated N. meningitidis was not increased. Epithelial binding of IgA was Fc fragment dependent and not inhibited by IgM. Together these data suggest the presence of a specific epithelial IgA receptor that could influence the effect of both naturally acquired and vaccine induced IgA antibodies at the epithelial surface.

Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and 'schizophrenia-related' behaviors.

There is growing evidence implicating dysfunctional glutamatergic neurotransmission and abnormal interactions between the glutamate and dopamine (DA) systems in the pathophysiology of various neuropsychiatric disorders including schizophrenia. The present study evaluated knockout (KO) mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) GluR1 receptor subunit for a range of behaviors considered relevant to certain symptoms of schizophrenia. KO showed locomotor hyperactivity during exposure to open field and in response to a novel object, but normal activity in a familiar home cage. Open field locomotor hyperactivity in KO was effectively normalized to WT levels by treatment with the DA antagonist and neuroleptic haloperidol, while locomotor stimulant effects of the NMDA receptor antagonist MK-801 were absent in KO. Social behaviors during a dyadic conspecific encounter were disorganized in KO. KO showed deficits in prepulse inhibition of the acoustic startle response. In vivo chronoamperometric measurement of extracellular DA clearance in striatum demonstrated retarded clearance in KO. These data demonstrate behavioral abnormalities potentially pertinent to schizophrenia in GluR1 KO, together with evidence of dysregulated DA function. Present findings provide novel insight into the potential role of GluR1, AMPA receptors and glutamate x DA interactions in the pathophysiology of schizophrenia and other neuropsychiatric conditions.

Blood group isoantibody stimulation in man by feeding blood group-active bacteria.

It was investigated whether or not the human blood group isoantibodies A and B could be induced by immunogenic stimuli via natural routes with a kind of antigenic substance to which all humans are commonly exposed, or if the appearance of these antibodies is independent of antigenic stimuli as has long been believed. Escherichia coli O(86), which possess high human blood group B and faint A activity in vitro, were fed to healthy humans and those with intestinal disorders. 80% of the sick individuals of blood group O and A responded with a significant rise of anti-B antibodies which was frequently de novo in infants; significant increase of anti-A isoantibodies among blood group O individuals was less frequent. Over one-third of the healthy individuals also had a significant isoantibody increase. Intestinal lesions favor isoantibody stimulation by intestinal bacteria; this view was supported by the study of control infants. Persons of blood group A responded more frequently with anti-B and anti-E. coli O(86) antibody production than those of blood group O. Isoantibody increase was accompanied with antibody rise against E. coli O(86). Inhalation of E. coli O(86) or blood group AH(O)-specific hog mucin also evoked isoantibodies. The induced isoantibodies were specifically inhibited by small amounts of human blood group substances. E. coli O(86)-induced anti-blood group antibodies in germ-free chickens and preexisting blood group antibodies in ordinary chickens were neutralized by intravenous injection of E. coli O(86) lipopolysaccharide. This study demonstrates that human isoantibodies A and B are readily elicited via physiological routes, by blood group-active E. coli, provided the genetically determined apparatus of the host is responsive. Antibodies against a person's own blood group were not formed. Interpretation of these results permits some careful generalizations as to the origin of so-called natural antibodies.

Pulsed Doppler angiography in lower limb arterial ischemia.

A 30-channel pulsed Doppler vessel imaging system (MAVIS, GEC Medical, Middlesex, England), was used to obtain images and maximal Doppler velocity time waveforms in the diagnosis of stenosis of the origin of the profunda femoris artery (PFA) and in the detection of structural changes within Dacron arterial grafts. In PFA scans of 33 limbs in 22 patients (mean age, 52 years), PFA stenosis of more than 50% at operation was invariably associated with a damping factor of the maximal Doppler velocity-time waveform of greater than 1.5 (eight limbs). In 12 limbs with a normal PFA at operation, the damping factor was always less than 1.4, and in 13 limbs of normal patients without arterial disease, the damping factor was always less than 1.34. In studies of 10 mm arterial grafts, the internal diameter of 14 iliopopliteal grafts scanned just above the popliteal anastomosis was strikingly reduced as compared with the femoral anastomosis of 14 aortoiliofemoral grafts and seven axillobifemoral grafts. These preliminary results suggest that MAVIS studies can be used noninvasively to detect PFA stenosis and to identify luminal narrowing of iliopopliteal grafts.

A review of the pharmacoeconomics of pharmaceutical care.

Numerous studies have demonstrated that the therapeutic use of drugs results in adverse outcomes and contributes to high rates of morbidity and mortality. The causes of drug-related problems are multifactorial and their assessment has been based on factors such as inappropriate prescribing, inappropriate delivery, inappropriate patient behaviour, patient idiosyncrasy and inappropriate monitoring. The cost in the ambulatory setting has been estimated to exceed total prescription pharmaceutical use. Pharmaceutical care is defined as the responsible provision of drug therapy for the purpose of achieving definite outcomes that improve a patient's quality of life. It describes the process through which a pharmacist cooperates with a patient and other healthcare professionals in designing, implementing and monitoring a therapeutic plan that will produce specific therapeutic outcomes for the patient. This article evaluates published studies related to the economic analysis of pharmaceutical care in enhancing the value of pharmaceuticals. While numerous descriptive articles exist, our review found no studies which met accepted pharmacoeconomic criteria. A small number of studies measured process variables and/or quality of life, but only one considered costs. Barriers to optimising the economic value of pharmaceutical care were also explored. Common methodological shortcomings indicated a need for improvement in future studies. There is little published research to date which demonstrates the pharmacoeconomic benefits of pharmaceutical care. Evidence does exist that clinical pharmacy services have positive economic benefits, and it is this evidence that, at present, supports the assertion that pharmaceutical care has potential to increase the value of pharmaceuticals in society by minimising drug-related morbidity and mortality. Thus, well conducted research is required to determine the economic impact of pharmaceutical care.

Iliopopliteal Dacron graft in treatment of advanced ischaemia of the leg.

This is a preliminary report of 14 patients treated for advanced ischaemic disease by iliopopliteal Dacron graft. In all the patients either the saphenous vein was not available for use or the occlusion was too long to be bypassed by saphenous vein. In these circumstances no alternative treatment exists other than amputation. The operation is not difficult and preliminary results are very favourable.

Localized thrombus complicating saphenous vein grafts.

Recurrence of symptoms after a long saphenous vein graft may be due to a variety of causes. When the graft pulse can still be felt the presence of a localized thrombus partially occluding the lumen must be considered. After arteriographic confirmation such a thrombus can be easily removed.

A randomised controlled trial to compare local with general anaesthesia for short-stay inguinal hernia repair.

A series of 117 consecutive unselected patients with clinically reducible unilateral inguinal herniae were admitted for short-stay repair. Seven expressed a strong preference for one form of anaesthesia (6 general (GA)) local (LA) and 7 were unfit for GA; these were excluded from the trial. The remaining 103 patients were allocated at random to receive either LA or GA in order to compare the two methods of anaesthesia. The resulting groups (53 LA, 50 GA) were well matched for age and obesity. Perand postoperative symptoms were assessed with linear analogues self-assessment questionnaires. Statistically significant differences were demonstrated between the groups; those patients having LA were able to walk, eat, and pass urine earlier than those having GA, who experienced more nausea, vomiting, sore throat, and headache. The postoperative course and additional symptoms were otherwise similar. Forty-five LA patients experienced mild pain during the operation, but nevertheless 85% of the total group said they would consent to its use again. Ninety-three patients (90%) were discharged at 24 h. LA was applicable to all types of clinically reducible inguinal hernia and was an acceptable, safe, and satisfactory alternative to GA.

Long grafts in the treatment of critical ischaemia.

Forty-two woven 10-mm Dacron grafts were implanted from the common iliac artery to the distal popliteal artery in 38 patients with rest pain or gangrene. The long-term patency at 5 years was 50%, using life-table analysis. These results show that iliopopliteal Dacron grafts are effective in preventing major amputations of severely ischaemic limbs.