Cadherin 13: human cis-regulation and selectively-altered addiction phenotypes and cerebral cortical dopamine in knockout mice.

The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5 choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

Mouse Model for Protein Tyrosine Phosphatase D (PTPRD) Associations with Restless Leg Syndrome or Willis-Ekbom Disease and Addiction: Reduced Expression Alters Locomotion, Sleep Behaviors and Cocaine-Conditioned Place Preference.

The receptor type protein tyrosine phosphatase D (PTPRD) gene encodes a cell adhesion molecule likely to influence development and connections of addiction-, locomotion- and sleep-related brain circuits in which it is expressed. The PTPRD gene harbors genome-wide association signals in studies of restless leg syndrome (Willis-Ekbom disease [WED]/restless leg syndrome [RLS]; p < 10-8) and addiction-related phenotypes (clusters of nearby single nucleotide polymorphisms [SNPs] with 10-2 > p > 10-8 associations in several reports). We now report work that seeks (a) association between PTPRD genotypes and expression of its mRNA in postmortem human brains and (b) RLS-related, addiction-related and comparison behavioral phenotypes in hetero- and homozygous PTPRD knockout mice. We identify associations between PTPRD SNPs and levels of PTPRD mRNA in human brain samples that support validity of mouse models with altered PTPRD expression. Knockouts display less behaviorally defined sleep at the end of their active periods. Heterozygotes move more despite motor weakness/impersistence. Heterozygotes display shifted dose-response relationships for cocaine reward. They display greater preference for places paired with 5 mg/kg cocaine and less preference for places paired with 10 or 20 mg/kg. The combined data provide support for roles for common, level-of-expression PTPRD variation in locomotor, sleep and drug reward phenotypes relevant to RLS and addiction. Taken together, mouse and human results identify PTPRD as a novel therapeutic target for RLS and addiction phenotypes.

Preeclampsia: an update.

Preeclampsia was formerly defined as a multisystemic disorder characterized by new onset of hypertension (i.e. systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg) and proteinuria (> 300 mg/24 h) arising after 20 weeks of gestation in a previously normotensive woman. Recently, the American College of Obstetricians and Gynecologists has stated that proteinuria is no longer required for the diagnosis of preeclampsia. This complication of pregnancy remains a leading cause of maternal morbidity and mortality. Clinical signs appear in the second half of pregnancy, but initial pathogenic mechanisms arise much earlier. The cytotrophoblast fails to remodel spiral arteries, leading to hypoperfusion and ischemia of the placenta. The fetal consequence is growth restriction. On the maternal side, the ischemic placenta releases factors that provoke a generalized maternal endothelial dysfunction. The endothelial dysfunction is in turn responsible for the symptoms and complications of preeclampsia. These include hypertension, proteinuria, renal impairment, thrombocytopenia, epigastric pain, liver dysfunction, hemolysis-elevated liver enzymes-low platelet count (HELLP) syndrome, visual disturbances, headache, and seizures. Despite a better understanding of preeclampsia pathophysiology and maternal hemodynamic alterations during preeclampsia, the only curative treatment remains placenta and fetus delivery. At the time of diagnosis, the initial objective is the assessment of disease severity. Severe hypertension (SBP ≥ 160 mm Hg and/or DBP ≥ 110 mmHg), thrombocytopenia < 100.000/µL, liver transaminases above twice the normal values, HELLP syndrome, renal failure, persistent epigastric or right upper quadrant pain, visual or neurologic symptoms, and acute pulmonary edema are all severity criteria. Medical treatment depends on the severity of preeclampsia, and relies on antihypertensive medications and magnesium sulfate. Medical treatment does not alter the course of the disease, but aims at preventing the occurrence of intracranial hemorrhages and seizures. The decision of terminating pregnancy and perform delivery is based on gestational age, maternal and fetal conditions, and severity of preeclampsia. Delivery is proposed for patients with preeclampsia without severe features after 37 weeks of gestation and in case of severe preeclampsia after 34 weeks of gestation. Between 24 and 34 weeks of gestation, conservative management of severe preeclampsia may be considered in selected patients. Antenatal corticosteroids should be administered to less than 34 gestation week preeclamptic women to promote fetal lung maturity. Termination of pregnancy should be discussed if severe preeclampsia occurs before 24 weeks of gestation. Maternal end organ dysfunction and non-reassuring tests of fetal well-being are indications for delivery at any gestational age. Neuraxial analgesia and anesthesia are, in the absence of thrombocytopenia, strongly considered as first line anesthetic techniques in preeclamptic patients. Airway edema and tracheal intubation-induced elevation in blood pressure are important issues of general anesthesia in those patients. The major adverse outcomes associated with preeclampsia are related to maternal central nervous system hemorrhage, hepatic rupture, and renal failure. Preeclampsia is also a risk factor for developing cardiovascular disease later in life, and therefore mandates long-term follow-up.

Thromboprophylaxis in microsurgery.

Microsurgical free tissue transfer has become a gold standard in a wide range of clinical situations. Thrombosis at the anastomotic site is not only the most common cause of failure of microsurgical operations, but it is also one of the factors resulting in microcirculatory intravascular thrombosis in free flaps. All conditions of thrombus formation, defined by Virchow in 1856, are encountered in free flap surgery. This literature review concerns the problem of thromboprophylaxis in microsurgery. All citations published this last ten years (1996-2005) concerning this problem are noted. Data are confronted with other specialties, particularly vascular surgery, or with large retrospective studies. Protocol used in our institution is presented at the end of this lecture.

The cervical spine in trauma: implications for the anaesthesiologist.

In this paper, the authors review the most recent literature concerning the management of the cervical spine in trauma patients. They address the main topics of concern for the anaesthesiologist including pre-hospital care, clearance of the cervical spine, neuroprotective therapies, difficult tracheal intubation, and management during general anaesthesia, in the intensive care unit and in paediatric patients. The most widely accepted strategies are provided as well as alternative options.

[Emergency practice: specifics in the management of complex multiple trauma]. / Pratique d'urgence: particularités dans la prise en charge des polytraumatisés complexes.

Almost twenty years ago, Trunkey showed that deaths due to trauma followed a trimodal distribution over time. Half of these deaths were delayed by at least one to two hours after the initiating insult. This interval (the "golden hour") can be exploited, especially in specialized trauma centers (where the most severely injured patients are cared for), to aggressively treat these patients, thereby reducing morbidity and mortality. In Belgium, this hierarchy of trauma care centers is non-existent; patients are distributed within the healthcare system randomly, depending on the localisation of the accident and the directives of the unified "100" call centre. Because this limits the number of cases any one centre treats, this type of arrangement acts to inhibit the acquisition of competency in the handling of these complex patients. The relative lack of experience of individual emergency departments leads to difficulties in establishing diagnostic and treatment priorities for the most severely injured trauma victims. The approach to these patients must follow very precise guidelines, established scientifically in order to minimize the impact of the injury on life and maximize chances of satisfactory functional recovery. In this paper, we describe the general principles of the initial approach to victims of complex multiple trauma.

[Emergency medicine: general principles governing the hospital management of victims of multiple trauma]. / Pratique d'urgence: principes généraux gouvernant la prise en charge hospitalière du polytraumatisé.

The management of the trauma victim admitted to the emergency department must be rapid and efficient. Within the first hour, vital functions must be stabilised while a systematic survey of all injuries is carried out. This survey must be as complete as possible, and depends on the patient's status and response to initial resuscitative measures. The need for urgent surgical intervention, therapeutic radiology, or other treatment modalities must be quickly established. This systematic approach, which follows a seven step sequence, can only be carried out by a well-trained team. Because at this time emergency and SMUR are often staffed with general practitioners, and because the trauma centers do not yet exist in Belgium, the application of the treatment protocol presented in this paper is a pre-requisite to quality of care for these patients. It is the only means to end, once and for all, the improvised or intuitive, and often erroneous, approach to these patients.

Management of difficult intubation.

Appropriate airway management is an essential part of the anaesthetist's role. Difficult intubation, which can now be quantified using the 'Intubation Difficulty Scale', should be anticipated whenever possible. A strategy needs to be developed in order to anticipate problems. The first part of this paper reviews the different factors that contribute to make intubation and/or ventilation difficult. Problems with intubation (or ventilation of the lungs) can be caused by abnormal laryngeal structures (e.g. tumour, stenosis), or by difficulty in seeing the glottis. The clinical history will usually help identify the former problem, while physical examination of the airway is required to reveal either disproportion between the various structures of the airway (e.g. tongue, larynx), and/or difficulties in aligning the oral, pharyngeal, and laryngeal axes. The different techniques used to diagnose these problems are described. The second part of this paper summarizes the algorithms used by the anaesthetist when management of the airway is found difficult. Three situations are considered: (a) anticipated difficult intubation, for which awake fibreoptic intubation would appear to be the technique of choice in the majority of cases, (b) unforeseen difficult intubation in a patient whose lungs can be ventilated; here, various techniques for control of the airway will be briefly described, and (c) both tracheal intubation and lung ventilation are impossible; this is a life-threatening emergency, for which three solutions are proposed. These include use of the laryngeal mask airway, the Combitube, or transtracheal ventilation. These situations will be analysed with the aim of proposing management strategies that always guarantee the safety of the patient.

Hemodynamic changes and catecholamine release during laparoscopic adrenalectomy for pheochromocytoma.

UNLABELLED: We investigated hemodynamics and plasma catecholamine concentrations in eight consecutive patients undergoing laparoscopic adrenalectomy for suspected pheochromocytoma. The same anesthesia protocol was used in all patients: a continuous infusion of sufentanil 0.5 microg x kg(-1) x h(-1) and isoflurane 0.4% (end-tidal) in 50% N2O/O2. Systolic arterial pressure was maintained between 120 and 160 mm Hg by adjusting an infusion of nicardipine, a calcium-channel blocker, while tachycardia (>100 bpm) was treated by 1-mg boluses of atenolol. Hemodynamics (thermodilution technique) and plasma catecholamine concentrations were measured before surgery, after the induction of anesthesia, after turning the patient to the lateral position, during pneumoperitoneum, during tumor manipulation, after adrenalectomy, and at the end of surgery. Two events resulted in significant catecholamine release: creation of the pneumoperitoneum and adrenal gland manipulation. As a consequence, a twofold increase in cardiac output was recorded. Adjustments of nicardipine infusion (2-6 microg x kg(-1) x min(-1)) minimized changes in mean arterial pressure. Beta-adrenergic blockade was necessary in six patients. In conclusion, laparoscopic adrenalectomy for pheochromocytoma results in marked catecholamine release during pneumoperitoneum and tumor manipulation. Titration of a nicardipine infusion allowed easy and quick control of the hemodynamic aberrancies related to these processes. IMPLICATIONS: Pneumoperitoneum during laparoscopy, now used for adrenalectomy, may complicate anesthetic management of patients with pheochromocytoma. In this study, laparoscopic adrenalectomy was associated with catecholamine release during the creation of pneumoperitoneum and tumor manipulation. Adjustments of a nicardipine infusion readily attenuated the subsequent hemodynamic aberrancies.

[Is celioscopic approach of pheochromocytoma acceptable? Reflections apropos of a prospective study of 6 personal cases]. / L'abord coelioscopique des phéochromocytomes est-il acceptable? Réflexions à propos d'une ètude prospective de 6 cas personnels.

Today, laparoscopy is for us the technique of choice for approaching presumed benign adrenal tumors. With regards to pheochromocytoma however, two major questions must be addressed. First, is it acceptable to resect potentially multifocal tumors with such a targeted approach? Second, can peroperative hemodynamic changes be anticipated and controlled by the anesthetist, taking into account the additional effects of pneumoperitoneum and catecholamine release on the cardiovascular system? The present prospective study attempts to answer these two questions. From November 1993 to November 1995 we operated on four women and two men, with ages ranging from 33 to 71 years (mean of 47) and a mean Body Mass Index of 25 kg/m2 (range 17-35). Four patients were assigned ASA (American Society of Anesthesiologists) physical status 2, one grade 1 and one grade 3. Comprehensive preoperative work-up, including a CT scan and an I131 MIBG Scan in all, a C11 Hydroxyephedrine PET Scan in 4 and a MRI in one patient, showed a solitary lesion in each case. There were four right-sided and two left-sided tumors, ranging from 30 to 60 mm in diameter. Laparoscopy was always performed transperitoneally. Systemic and pulmonary hemodynamics were thoroughly assessed. Epinephrin and norepinephrin concentrations were measured at the 10 key-time of surgery. Use of continuous intravenous infusion of nicardipine allowed tight control of hemodynamics despite impressive increases in circulating catecholamines. The mean operative time was 76 minutes (range 59-130). Blood loss was minimal. We observed neither mortality nor morbidity. Mean hospital stay ranged from 3 to 13 days (median = 3). All patients are normotensive without drug after a follow-up of 9 to 33 months. In conclusion, we think that laparoscopic removal of selected cases of pheochromocytoma may be performed safely from both the hemodynamical and oncological standpoints.

Treatment of excessive mediastinal bleeding after cardiopulmonary bypass.

BACKGROUND: Excessive mediastinal bleeding after cardiopulmonary bypass is one of the most frequently reported complications of cardiac operations. Appropriate treatment requires a rapid and effective diagnostic work-up, based on the knowledge of the pathophysiology induced by cardiopulmonary bypass. METHODS: Possible causes, diagnostic methods available, and therapeutic approaches are reviewed in the light of the literature published on excessive bleeding after cardiac operations. RESULTS: When bleeding is massive (> 250 to 300 mL/h for the first 2 hours, > 150 mL/h thereafter), immediate surgical reexploration is mandatory. When bleeding is less important (50 to 150 mL/h), the decision to reoperate should be based on the presence of hemodynamic compromise or a suspected surgical cause. Otherwise, coagulation testing should allow the correction of hemostatic defects as appropriate with protamine, platelet concentrates, fresh frozen plasma, desmopressin, or antifibrinolytics. Hypothermia and hypotension should be corrected and a trial of positive end-expiratory pressure may be considered if diffuse mediastinal oozing (especially from the bed of the mammary artery) is suspected. CONCLUSIONS: A protocol is suggested to guide treatment, taking into account the rapidity of blood loss and the suspected underlying cause.

Reduction in requirements for allogeneic blood products: pharmacologic methods.

BACKGROUND: Numerous articles describe the reduction of perioperative bleeding by the therapeutic or prophylactic administration of drugs such as prostacyclin, desmopressin, and natural or synthetic antifibrinolytics. METHODS: A review of the literature was carried out to help the reader define the indications of these drugs during cardiopulmonary bypass operations, highlight the questions that remain concerning their indications and modes of action, and suggest future studies to answer these remaining questions. RESULTS: Prostacyclin reduces platelet trauma induced by extracorporeal circulation but does not effectively reduce postoperative bleeding and transfusion requirements. Desmopressin acts as a "glue," improving platelet adhesion, and may be effective when postoperative bleeding is excessive, but its routine use in cardiac operations cannot be recommended. Natural and synthetic antifibrinolytics inhibit plasmin and plasmin-induced platelet dysfunction. These agents have been shown to decrease bleeding and the need for allogeneic transfusions after open heart operations. However, with antifibrinolytic drugs, the risk of thromboembolic phenomena cannot be neglected. With aprotinin, this risk appears to be minimal when the drug is used at concentrations high enough to inhibit plasma kallikrein also. CONCLUSIONS: Prophylactic antifibrinolytics are efficacious, but their routine use remains controversial, both for economic reasons and for fear of thromboembolic complications.

Spontaneous rupture of the iliac vein.

A spontaneous rupture of the left iliac vein is described. A 2 cm tear on the anterior surface of the left iliac vein was discovered at emergency laparotomy on a patient who was suspected of having a huge intraabdominal hemorrhage. Prodromal symptoms, cause, and treatment are discussed. The nine previously reported cases are reviewed. This case represents the seventh successful repair of an idiopathic rupture of an iliac vein.

A high-risk method for studying psychosocial antecedents of chronic pain: the prospective investigation of herpes zoster.

Although patients with chronic pain are often psychologically distressed, it has been difficult to determine whether this distress is an antecedent of chronic pain or whether it is caused by the experience of living with chronic pain. The aim of this investigation was to develop a method that would allow individuals who are at risk for the development of chronic pain to be studied before their pain has become chronic. Patients with acute herpes zoster were assessed with demographic, medical, pain, and psychosocial measures. Pain was assessed in follow-up interviews at 6 weeks and 3, 5, 8, and 12 months after these initial assessments. There were no significant differences between patients who developed short-term herpes zoster pain and patients who did not develop short-term pain for any of the measures at the initial assessment, except for one measure of pain intensity. Patients who developed chronic herpes zoster pain, however, had significantly greater pain intensity, higher state and trait anxiety, greater depression, lower life satisfaction, and greater disease conviction at the initial assessment than patients who did not develop chronic pain. In discriminant analyses, disease conviction, pain intensity, and state anxiety each made a unique contribution to discriminating patients who did and who did not develop chronic pain. This study demonstrates the feasibility of investigating psychosocial antecedents of the development of chronic pain by prospectively examining the longitudinal course of herpes zoster.