Clinical and molecular evaluation of SHOX/PAR1 duplications in Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS).

CONTEXT: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity. OBJECTIVE: The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS. DESIGN AND METHODS: Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications. RESULTS: During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5' flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals. CONCLUSION: MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.

CDKN1C mutations in HELLP/preeclamptic mothers of Beckwith-Wiedemann Syndrome (BWS) patients.

Preeclampsia is the development of new-onset hypertension with proteinuria after 20 weeks of gestation. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is a severe form of preeclampsia with high rates of neonatal and maternal morbidity. In recent years, loss of function of cdkn1c (a tight-binding inhibitor of G1 cyclin/cyclin-dependent kinase complexes and a negative regulator of cell proliferation) has been observed in several mouse models of preeclampsia. In this paper, we report on three women with HELLP/preeclampsia who had children with Beckwith Wiedemann syndrome, a complex genetic disorder characterised, among other findings, by overgrowth, omphalocele and macroglossia. All three children displayed mutations in CDKN1C predicted to generate truncated proteins. Two of the mutations were maternally inherited while the third was de novo. This finding suggests a fetal contribution to the maternal disease. To the best of our knowledge this is the first report of CDKN1C mutations in children born to women with preeclampsia/HELLP syndrome, thus suggesting the involvement of an imprinted gene in the pathophysiology of preeclampsia.

A comparison of isoflurane versus fentanyl as primary anesthetics for mitral valve surgery.

We conducted a randomize study of fentanyl compared to isoflurane anesthesia in patients with pulmonary hypertension undergoing mitral valve surgery. Patients were premedicated and randomly assigned to one of two groups: 21 patients had anesthesia induced with thiopental and maintained with isoflurane; 23 patients had anesthesia induced with a fentanyl bolus and maintained with a fentanyl infusion. Adjustments of fentanyl infusion and isoflurane concentration, as well as fentanyl boluses and vasoactive/positive inotropic medication, were administered to maintain preoperative arterial blood pressure. Both groups exhibited similar demographics, similar duration of cardiopulmonary bypass (CPB) surgery, anesthesia, and time from entrance into the surgical intensive care unit (SICU) to endotracheal extubation. However, the time from entrance into the SICU to awake was significantly (P < 0.05) shorter in patients given isoflurane anesthesia. Hemodynamic variables were recorded at baseline and 12 surgical events and compared between and within groups. Significant changes from baseline were demonstrated in both groups upon institution and discontinuation of CPB. Patients receiving isoflurane anesthesia exhibited cardiovascular depression as compared to their baseline. There were no deaths in either patient group. Adequate hemodynamic profiles were achieved in both groups with comparable use of inotropic and vasoactive medication, with the exception of norepinephrine that was administered intraoperatively to significantly (P < 0.05) more patients in the isoflurane-based anesthesia group. Neither technique was associated with acute improvement of right heart performance or pulmonary hypertension, in large part because of morphologic changes of the pulmonary arterial bed, occurring with long-standing mitral valve disease. We conclude that isoflurane-based anesthesia is adequate for this type of surgery, although there is a higher anesthetic algorithm failure rate than with fentanyl-based anesthetic technique.

Effect of oral clonidine premedication on anesthetic requirement, hormonal response, hemodynamics, and recovery in coronary artery bypass graft surgery patients.

STUDY OBJECTIVE: To examine how premedication with clonidine affects opioid use, hemodynamic effects, hormonal responses, and recovery effects. DESIGN: Double blind, placebo-controlled study. SETTING: Operating room and surgical intensive care unit of a university medical center. PATIENTS: 54 patients undergoing elective coronary artery bypass graft (CABG) surgery. INTERVENTIONS: Patients received approximately 5 micrograms/kg of oral clonidine or a placebo together with 40 micrograms/kg lorazepam 90 minutes prior to titrated sufentanil induction of anesthesia. Thirty minutes prior to cardiopulmonary bypass, a second dose of either approximately 5 micrograms/kg clonidine or placebo was given as a slurry via a nasogastric tube. MEASUREMENTS AND MAIN RESULTS: Opioid use, hemodynamic effects, hormonal responses, and recovery effects were recorded. Values for ten hemodynamic variables were compiled on the evening prior to surgery, prior to induction, and during seven additional events and compared. Catecholamines and beta-endorphins were measured prior to induction, after intubation, and after sternotomy. The amount of sufentanil used for induction, maintenance, and total opioid were compared. The times to awakening and response to verbal commands were compared. The two groups exhibited similar patient demographics, cardiopulmonary bypass time, and duration of surgery. Patients receiving clonidine required significantly (p < 0.04) less sufentanil for induction (clonidine: 2.19 +/- 0.95 micrograms/kg vs. placebo: 2.93 +/- 1.07 micrograms/kg) and total amount of sufentanil (clonidine: 9.1 +/- 3.9 micrograms/kg vs. placebo: 11.7 +/- 4.6 micrograms/kg). Patients receiving clonidine required significantly (p < 0.01) less isoflurane (9.7 +/- 6.8 MAC min vs. 19.7 +/- 9.9 MAC min) to maintain heart rate (HR) and mean arterial pressure (MAP) to within 15% of baseline without significant differences in other vasoactive drugs. Catecholamine concentrations were significantly (p < 0.02) lower in patients receiving clonidine without any difference in beta-endorphin concentrations. Patients receiving clonidine had significantly (p < 0.02) lower HR, systolic arterial pressure, MAP, and systemic vascular resistance prior to induction than patients receiving placebo without differences in other hemodynamic variables. CONCLUSION: Clonidine decreases opioid use and lowers hormonal response while maintaining stable hemodynamics in patients undergoing CABG with sufentanil anesthesia.

A comparison of pentamorphone and fentanyl in balanced anaesthesia during general surgery.

The purpose of our randomized, double-blind study of 64 unpremedicated healthy patients undergoing surgical procedures with a duration of at least 60 min was to compare 0.75 micrograms.kg-1 and 1 microgram.kg-1 pentamorphone with 5 micrograms.kg-1 and 7.5 micrograms.kg-1 fentanyl to determine which dose of opioid would reduce the requirement for isoflurane supplementation needed to maintain haemodynamic stability. At 21 points during the procedure, the haemodynamic variables of heart rate and systolic, diastolic, and mean arterial pressures were recorded. The use of isoflurane was quantified; the number of patients requiring inhaled anaesthetic, concentration peaks, MAC minutes, and duration of isoflurane use were noted. The number of equal-volume supplemental opioid analgesic doses, postoperative analgesics, occurrence of postoperative nausea, emesis, and antiemetic doses were compared. The four groups exhibited similar patient demographics, total dose of muscle relaxants, types of surgical procedures, and duration of surgery or anaesthesia. Haemodynamic variables were stable with no difference among the four study groups. The patients given pentamorphone demonstrated both delayed requirement (P < 0.05) and shorter duration (P < 0.05) of isoflurane supplementation. Patients given either 5 micrograms.kg-1 or 7.5 micrograms.kg-1 fentanyl needed isoflurane supplementation within 12 +/- 16 min and 12 +/- 17 min from induction respectively; while patients given either 0.75 micrograms.kg-1 or 1 microgram.kg-1 pentamorphone did not require isoflurane supplementation for 37 +/- 10 min and 43 +/- 26 min respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative and postoperative effects of vancomycin administration in cardiac surgery patients: a prospective, double-blind, randomized trial.

OBJECTIVES: In response to an increased frequency of Staphylococcus epidermidis infections in postoperative cardiac surgery patients, antibiotic prophylaxis was changed to include both vancomycin and cefazolin pre- and intraoperatively. Subsequent to the addition of vancomycin prophylaxis, clinical impression and retrospective analysis supported a correlation between vancomycin administration and post-cardiopulmonary bypass norepinephrine use. DESIGN: A prospective, double-blind, randomized study. SETTING: Tertiary care center in a university hospital. PATIENTS: A total of 58 patients undergoing elective coronary artery bypass surgery under high-dose fentanyl anesthesia. INTERVENTIONS: Patients were randomized to receive cefazolin and either vancomycin or normal saline pre-, intra-, and postoperatively in a double-blinded protocol. MEASUREMENTS AND MAIN RESULTS: Hemodynamic profiles and doses of administered vasoactive agents were calculated and recorded for all patients for both intra- and postoperative time periods. Hypotension consistent with vasodilation was treated with a norepinephrine infusion. The rate and frequency of norepinephrine infusions were tabulated for both groups. Hemodynamic profiles that were obtained after the administration of the initial dose of vancomycin or normal saline and before the induction of general anesthesia and those profiles obtained after the induction of general anesthesia until the initiation of cardiopulmonary bypass showed no difference between groups and no evidence of vasodilation secondary to vancomycin administration. However, subsequent doses of vancomycin in the intra- and postoperative periods were associated with a significantly greater frequency of norepinephrine infusions to maintain normal hemodynamic indices. In the vancomycin group, 50% of patients received a norepinephrine infusion in the intra- and/or postoperative period as compared with 14% in the normal saline group (p < .01). Furthermore, the group of patients who received vancomycin and subsequently required a norepinephrine infusion had significantly lower mean systolic arterial pressure, mean arterial pressure, and systemic vascular resistance as compared with all other groups. There were no differences between groups in the use of vasopressors (other than norepinephrine) or fluid balance. CONCLUSIONS: The results show that a significantly greater number of patients who received vancomycin required a norepinephrine infusion and that, despite norepinephrine infusion therapy, systemic vascular resistance was not normalized in this group of patients. The study supports the conclusion that perioperative administration of vancomycin in cardiac surgery patients may result in hypotension requiring the use of a vasopressor in an attempt to normalize hemodynamic indices.

Intravenous immunoglobulin for prophylaxis of neonatal sepsis in premature infants.

The incidence of sepsis, mortality due to sepsis, total mortality, and minor infections was evaluated in a group of 46 premature newborn infants who were treated with intravenous immunoglobulins. They were compared with an untreated control group. No significant differences were observed between the two groups.

[Early diagnosis of sepsis in the preterm neonate]. / Diagnosi precoce di sepsi nel neonato pretermine.

The usefulness of the neutrophil blood cell count, the ratio of band forms to total neutrophils, the platelet count, the quantitative determination of serum IgM, C-reactive protein, alpha-1-acid glycoprotein and haptoglobin for the early identification of the serious neonatal infections was evaluated in 70 preterm newborns: 15 with sepsis, 2 with serious infections, 53 without infections. None of these tests has proved sensitive and predictive enough to be used as a single measure. The combination of 2 or more of them had improve the sensitivity (76.4%) and the predictive value of negative test (91.6%). The authors suggest that the greatest potential value of the tests is to exclude infections, with a more than 90% probability, if they are negative.