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.

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.

Sustained augmentation of cardiac alpha1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes.

We previously reported that transgenic (TG) mice with cardiac-restricted alpha(1A)-adrenergic receptor (alpha(1A)-AR)-overexpression showed enhanced contractility, but no hypertrophy. Since chronic inotropic enhancement may be deleterious, we investigated if long-term, cardiac function and longevity are compromised. alpha(1A)-TG mice, but not their non-TG littermates (NTLs), showed progressive loss of left ventricular (LV) hypercontractility (dP/dt(max): 14,567+/-603 to 11,610+/-915 mmHg/s, P<0.05, A1A1 line: 170-fold overexpression; and 13,625+/-826 to 8322+/-682 mmHg/s, respectively, P<0.05, A1A4 line: 112-fold overexpression, at 2 and 6 months, respectively). Both TG lines developed LV fibrosis, but not LV dilatation or hypertrophy, despite activation of hypertrophic signaling pathways. Microarray and real time RT-PCR analyses revealed activation of matricellular protein genes, including those for thrombospondin 1, connective tissue growth factor and tenascin C, but not transforming growth factor beta1. Life-span was markedly shortened (mean age at death: 155 days, A1A1 line; 224 days, A1A4 line compared with NTLs: >300 days). Telemetric electrocardiography revealed that death in the alpha(1A)-AR TG mice was due to cardiac standstill preceded by a progressive diminution in QRS amplitude, but not by arrhythmias. The QRS changes and sudden death could be mimicked by alpha(1)-AR activation, and reversed preterminally by alpha(1)-AR blockade, suggesting a relationship to stress- or activity-associated catecholamine release. Thus, long-term augmentation of cardiac alpha(1A)-adrenergic drive leads to premature death and progressive LV fibrosis with reactivation of matricellular protein genes. To our knowledge this is the first evidence in vivo for a role of the alpha(1A)-AR in ventricular fibrosis and in pathological cardiac remodeling.

Emergency thoracotomy in thoracic trauma-a review.

Thoracic trauma is one of the leading causes of death in all age groups and accounts for 25-50% of all traumatic injuries. While the majority of patients with thoracic trauma can be managed conservatively, a small but significant number requires emergency thoracotomy as part of their initial resuscitation. The procedure has been advocated for evacuation of pericardial tamponade, direct control of intrathoracic haemorrhage, control of massive air-embolism, open cardiac massage and cross-clamping of the descending aorta. Emergency thoracotomy can be defined as thoracotomy "occurring either immediately at the site of injury, or in the emergency department or operating room as an integral part of the initial resuscitation process". Following emergency thoracotomy, the overall survival rates for penetrating thoracic trauma are around 9-12% but have been reported to be as high as 38%. The survival rate for blunt trauma is approximately 1-2%. The decision to perform emergency thoracotomy involves careful evaluation of the scientific, ethical, social and economic issues. This article aims to provide a review of the current literature and to outline the pathophysiological features, technical manoeuvres and selective indications for emergency thoracotomy as a component of the initial resuscitation of trauma victims with thoracic injury.

Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy.

Activation of the alpha(1A)-adrenergic receptor (alpha(1A)-AR)/Gq pathway has been implicated as a critical trigger for the development of cardiac hypertrophy. However, direct evidence from in vivo studies is still lacking. To address this issue, transgenic mice with cardiac-targeted overexpression of the alpha(1A)-AR (4- to 170-fold) were generated, using the rodent alpha-myosin heavy chain promoter. Heterozygous animals displayed marked enhancement of cardiac contractility, evident from increases in dP/dt(max) (80%, P<0.0001), dP/dt(max)/LVP(inst) (76%, P<0.001), dP/dt(max):dP/dt(min) (104%, P<0.0001), and fractional shortening (33%, P<0.05). Moreover, changes in the dP/dt(max)-end-diastolic volume relationship provided load-independent evidence of a primary increase in contractility. Blood pressure and heart rate were largely unchanged, and there was a small increase in (-)norepinephrine-stimulated, but not basal, phospholipase C activity. Increased contractility was directly related to the level of receptor overexpression and could be completely reversed by acute alpha(1A)- but not beta-AR blockade. Despite the robust changes in contractility, transgenic animals displayed no morphological, histological, or echocardiographic evidence of left ventricular hypertrophy. In addition, apart from an increase in atrial natriuretic factor mRNA, expression of other hypertrophy-associated genes was unchanged. To our knowledge, these data provide the first in vivo evidence for an inotropic action of the alpha(1A)-AR.

A policy of elective delayed sternal closure does not improve the outcome after arterial switch.

BACKGROUND: Delayed sternal closure is regularly used in the immediate management of hemodynamic instability after neonatal cardiac procedures. The aim of this study was to assess whether the routine, elective use of delayed sternal closure would reduce morbidity in neonates undergoing arterial switch for transposition of the great arteries. METHODS: A retrospective statistical analysis was performed on 52 neonates operated on from 1991 to 1998. Until 1994, chest closure was routinely attempted in all patients after arterial switch; the policy was then changed to delayed sternal closure in all cases in the latter half of the study period. RESULTS: Delayed sternal closure did not significantly alter the mean duration of ventilation (2.7 +/- 2.37 versus 2.7 +/- 1.3 days) nor intensive care stay (4.1 +/- 2.8 versus 5.7 +/- 10.0 days; p = 0.46). There was no increase in the incidence of wound sepsis (7.7% versus 3.8%; p = 0.55), and mortality was unchanged (7.7% in both groups). There was an increase in the incidence of urgent reexploration (7.7% versus 19.2%; p = 0.22), which did not reach significance. CONCLUSIONS: This study does not support the hypothesis that elective delayed sternal closure reduces the morbidity after arterial switch in neonates but does, however, confirm the safety and efficacy of the procedure.

Targeted inactivation of Gh/tissue transglutaminase II.

The novel G-protein, G(h)/tissue transglutaminase (TGase II), has both guanosine triphosphatase and Ca(2+)-activated transglutaminase activity and has been implicated in a number of processes including signal transduction, apoptosis, bone ossification, wound healing, and cell adhesion and spreading. To determine the role of G(h) in vivo, the Cre/loxP site-specific recombinase system was used to develop a mouse line in which its expression was ubiquitously inactivated. Despite the absence of G(h) expression and a lack of intracellular TGase activity that was not compensated by other TGases, the Tgm2(-/-) mice were viable, phenotypically normal, and were born with the expected Mendelian frequency. Absence of G(h) coupling to alpha(1)-adrenergic receptor signaling in Tgm2(-/-) mice was demonstrated by the lack of agonist-stimulated [alpha-(32)P]GTP photolabeling of a 74-kDa protein in liver membranes. Annexin-V positivity observed with dexamethasone-induced apoptosis was not different in Tgm2(-/-) thymocytes compared with Tgm2(+/+) thymocytes. However, with this treatment there was a highly significant decrease in the viability (propidium iodide negativity) of Tgm2(-/-) thymocytes. Primary fibroblasts isolated from Tgm2(-/-) mice also showed decreased adherence with culture. These results indicate that G(h) may be importantly involved in stabilizing apoptotic cells before clearance, and in responses such as wound healing that require fibroblast adhesion mediated by extracellular matrix cross-linking.

An in vitro method for predicting the efficacy of WBC separation using different starch preparations and anticoagulant ratios.

BACKGROUND: Separation of blood components depends on a number of factors, including the viscosity of the plasma and the number and size of the various cellular elements. To enhance granulocyte collection, it is common practice to alter the plasma environment by the addition of sedimenting agents such as hydroxyethyl starch. Recently, because of its prolonged persistence in the circulation, the higher-molecular-weight form of hydroxyethyl starch, Hespan (HP), has been replaced by the lower-molecular-weight form, pentastarch (PS). However, the yield appears to be lower. A rapid in vitro approach was used to permit comparison of the efficiency of separation of WBCs by the use of PS and HP and different ratios of anticoagulants that also alter the sedimenting characteristics of blood. STUDY DESIGN AND METHOD: Blood from individual persons was collected into sodium citrate at ratios of 1:8, 1:12, and 1:16. Samples were evaluated either before or after the addition of PS or HP and after centrifugation. RESULTS: The addition of HP increased the sedimentation rate to at least four times that of plasma (10.9 vs. 47.9 mm); PS approximately doubled the rate. Viscosity was altered by the introduction of either starch. These changes (ranging from a rate of 4.2 in HP with a 1:16 anticoagulant to 3.6 in PS with a 1:8 ratio of anticoagulant) reflected the anticipated effects of anticoagulant dilution and carbohydrate addition. Granulocyte recovery was highest, with a 1:12 anticoagulant ratio in all tests with HP producing the greatest yield (HP, 101%; PS, 89%; control, 78%). CONCLUSION: HP is far more effective than its lower-molecular-weight substitute PS in the generation of granulocytes in the buffy coat of whole blood. This method provides a simple, rapid, in vitro approach to evaluating the separating efficiency of solutions.

Early results with the Carbo-seal composite valve conduit for aortic root replacement.

BACKGROUND AND AIMS OF THE STUDY: Composite graft replacement of the aortic root is still a complex operation, transgraft hemorrhage being one of the most severe complications. The aim of the study was to evaluate early results with the Carbo-seal composite conduit for aortic root replacement. METHODS: A retrospective review of 21 patients operated on for ascending aortic aneurysm and/or dissection with the open technique between August 1993 and February 1998 is presented; 12 patients had Marfan syndrome and nine were non-Marfan. RESULTS: There were two operative deaths (9.5%) due to low cardiac output. Two patients were re-explored for bleeding which was not due to transgraft hemorrhage. Postoperative complications were one hemothorax, one pneumothorax and two pericardial effusions. During the follow up, one patient died of rupture of a descending aortic aneurysm, and one patient in atrial fibrillation had a transient ischemic attack. At the closing of the follow up, the remaining patients were well and free of complications. CONCLUSIONS: Carbo-seal may be considered a reliable device for use in aortic root replacement, though a longer follow up and a larger patient population are necessary to confirm these positive early results.

Late results of patch repair of coarctation of the aorta in adults using autogenous arterial wall.

BACKGROUND: Interposition grafting or patch repair of adult coarctations of the aorta are the standard methods of surgical treatment. Both involve use of prosthetic material, and patch repair using prosthetic material may lead to aneurysm formation in the long term. METHODS: Four patients aged 17 to 29 years had been investigated for systemic hypertension and had coarctation of the aorta diagnosed on cardiac catheterization. Between March and November 1984, all 4 underwent a corrective operation. The lesions were widely incised and a broad patch of ipsilateral mammary or Abbott's artery was fashioned across the narrowing. The arteries had been enlarged in diameter because of prolonged exposure to high blood pressure as collateral vessels, although none was intrinsically diseased. RESULTS: After 12 years of follow-up, only 1 patient remains on antihypertensive therapy. Spiral computed tomographic reconstructions revealed only very mild residual stenosis in 1 patient, confirmed by subsequent aortography. CONCLUSIONS: In adult patients with coarctation of the aorta, the use of the enlarged internal mammary artery as a patch graft is a simple, quick procedure, which may give lasting relief of obstruction. Spiral computed tomographic scanning is an ideal noninvasive method of follow-up.

Assessment of outcome after thoracoscopic sympathectomy for hyperhidrosis in a specialized unit.

Transthoracic endoscopic electrocautery of the sympathetic chain is increasingly being used as a technique for producing the effects of upper thoracic sympathectomy. In November 1990 we introduced this operation as a regional service in Northern Ireland and have assessed the results in patients with idiopathic hyperhidrosis of the palms and axillae. There were 92 sympathectomics carried out for hyperhidrosis on 47 patients between 26 November 1990 and 6 September 1993. Full follow-up was possible in 45 patients (96%) at a median of 13 months (range 3-36) after the operation. Symptoms were improved in 43 patients (96%) at review. In three patients surgery failed to control symptoms on one side, and in two there was bilateral recurrence at 4 and 8 months after initial good results. Compensatory hyperhidrosis occurred in 35 patients (56%) and was severe in 4 (9%). Nine of 34 patients (34%) with plantar symptoms reported improvement in these post-operatively. This paper, with its high level of full follow-up, confirms thoracoscopic sympathectomy to be effective treatment for both palmar and axillary hyperhidrosis. Patient selection, however, is important and the risk of compensatory hyperhidrosis must be fully explained.

Surgical anatomy of the phrenic nerve and internal mammary artery.

Dissection of the thoracic inlet was performed on 22 cadavers to determine the relationship of the phrenic nerve to the internal mammary artery as it passes from lateral to medial behind the first rib. On the left the nerve was found to cross superior to the artery and then medial to it in 14 of 22 specimens; on the right this was found in ten of 22 specimens. In all other specimens, it crossed inferior to the internal mammary artery. These findings demonstrate that there is no constant relationship between these structures, and emphasize the need for caution when dissecting the internal mammary artery at or above the level of the first rib.

Life history prototypes in the study of human individuality.

Using biographical data collected in late adolescence and young adulthood, prototypes or subgroups of individuals with similar patterns of prior behaviors and experiences were empirically identified. The prototypes are described, and the pathways taken by the prototypes from adolescence to adulthood are examined. Focusing on the various pathways or trajectories followed by different prototypes, we discuss implications of prototype membership for continuity and change in personality.

Studies of the nuclear 5 alpha-reductase of human prostatic tissue: comparison of enzyme activities in hyperplastic, malignant, and normal tissues.

The nuclear conversion of testosterone (T) to dihydrotestosterone (DHT) was compared in hyperplastic (n = 40), malignant (n = 20), and normal (n = 3) prostatic tissues. Standard assay conditions were 2 microM testosterone, 2.0 mM EDTA, 1.0 mM NADPH, and the nuclear fraction equivalent to 200 mg of prostatic tissue, in 0.1 M N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer (pH 7.4). The Km values were 0.6, 0.5, and 0.3 microM, respectively, for the enzymes in hyperplastic, malignant, and normal tissues. The Vmax values were 42 +/- 17, 4.2 +/- 1.8, and 3.9 +/- 0.9 pmol/mg protein per 30 min of incubation, respectively, for the hyperplastic, malignant, and normal tissues. When DHT formation was measured at T concentrations equivalent to reported endogenous levels, it was found that enzyme activity in the hyperplastic tissue was still greater than that in the other two tissues. The enzyme in the malignant prostate was less efficient than the enzyme in normal tissue in converting T to DHT. These results would suggest that differences in the conversion of T to DHT may explain, at least in part, the higher DHT levels seen in hyperplastic tissue than in either the normal or the malignant prostate and the higher T levels seen in the malignant prostate than in the other two tissues.