Frequency Of Rescue Research Articles

966: LATE (≥ 7 DAYS) SYSTEMIC POSTNATAL CORTICOSTEROIDS FOR BRONCHOPULMONARY DYSPLASIA: A META-ANALYSIS

Introduction: One of the several complications associated with preterm birth is bronchopulmonary dysplasia (BPD), a disorder characterized by abnormal development of the lungs and subsequent breathing problems. We aim to determine the safety and efficacy of late (≥ 7 days) systemic corticosteroids for the prevention of BPD in preterm infants. Methods: We searched electronic databases, international trial registers, grey literature sources, and reference lists of articles to identify relevant randomized controlled trials (RCTs) on the use of systemic corticosteroids for the prevention of BPD. We assessed the risk of bias using the revised Cochrane “Risk of bias” tool for randomized trials (RoB 2.0), calculated risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) with 95% CI for continuous outcomes. Results: Our meta-analysis included 24 RCTs (2617 infants); 21 RCTs involved dexamethasone while 3 RCTs involved hydrocortisone. Our analysis showed that compared to the control group, late corticosteroids significantly decreased neonatal mortality at various ages: 28 days (RR 0.62, 95% CI 0.40-0.95, I2=0%), 36 weeks postmenstrual age (RR 0.73, 95% CI 0.56-0.95, I2=0%), latest reported age (RR 0.82, 95% CI 0.68-0.99, I2=0%), and before hospital discharge (RR 0.80, 95% CI 0.66-0.98, I2=0%). Late systemic corticosteroids did not significantly affect the incidence of BPD at 28 days after birth (RR 0.91, 95% CI 0.83-1.00, I2=40%) and 36 weeks postmenstrual age (RR 0.90, 95% CI 0.82-1.00, I2=27%). However, late corticosteroids decreased the frequency of late rescue with corticosteroids (RR 0.56, 95% CI 0.43-0.73, I2=61%). Late corticosteroids increased the risk of hyperglycemia, glycosuria, and hypertension. Infants who were administered corticosteroids were also found to have significantly less failure to extubate on the 3rd, 7th, and 14th day after treatment. Conclusions: The use of late systemic corticosteroids is shown to have significantly reduced the mortality in preterm infants, but had no significant effect on the incidence of BPD. More RCTs with longer follow-ups addressing the appropriate dose and timing of steroid therapy are needed.

Theory of tip structure–dependent microtubule catastrophes and damage-induced microtubule rescues

Microtubules are essential cytoskeletal polymers that exhibit stochastic switches between tubulin assembly and disassembly. Here, we examine possible mechanisms for these switches, called catastrophes and rescues. We formulate a four-state Monte Carlo model, explicitly considering two biochemical and two conformational states of tubulin, based on a recently conceived view of microtubule assembly with flared ends. The model predicts that high activation energy barriers for lateral tubulin interactions can cause lagging of curled protofilaments, leading to a ragged appearance of the growing tip. Changes in the extent of tip raggedness explain some important but poorly understood features of microtubule catastrophe: weak dependence on tubulin concentration and an increase in its probability over time, known as aging. The model predicts a vanishingly rare frequency of spontaneous rescue unless patches of guanosine triphosphate tubulin are artificially embedded into microtubule lattice. To test our model, we used invitro reconstitution, designed to minimize artifacts induced by microtubule interaction with nearby surfaces. Microtubules were assembled from seeds overhanging from microfabricated pedestals and thus well separated from the coverslip. This geometry reduced the rescue frequency and the incorporation of tubulins into the microtubule shaft compared with the conventional assay, producing data consistent with the model. Moreover, the rescue positions of microtubules nucleated from coverslip-immobilized seeds displayed a nonexponential distribution, confirming that coverslips can affect microtubule dynamics. Overall, our study establishes a unified theory accounting for microtubule assembly with flared ends, a tip structure-dependent catastrophe frequency, and a microtubule rescue frequency dependent on lattice damage and repair.

Modeling microtubule dynamic instability: Microtubule growth, shortening and pause

Microtubules (MTs) are protein polymers found in all eukaryotic cells. They are crucial for normal cell development, providing structural support for the cell and aiding in the transportation of proteins and organelles. In order to perform these functions, MTs go through periods of relatively slow polymerization (growth) and very fast depolymerization (shortening), where the switch from growth to shortening is called a catastrophe and the switch from shortening to growth is called a rescue. Although MT dynamic instability has traditionally been described solely in terms of growth and shortening, MTs have been shown to pause for extended periods of time, however the reason for pausing is not well understood. Here, we present a new mathematical model to describe MT dynamics in terms of growth, shortening, and pausing. Typically, MT dynamics are defined by four key parameters which include the MT growth rate, shortening rate, frequency of catastrophe, and the frequency of rescue. We derive a mathematical expression for the catastrophe frequency in the presence of pausing, as well as expressions to describe the total time that MTs spend in a state of growth and pause. In addition to exploring MT dynamics in a control-like setting, we explore the implicit effect of stabilizing MT associated proteins (MAPs) and stabilizing and destabilizing chemotherapeutic drugs that target MTs on MT dynamics through variations in model parameters.

Analgesia Effect of Ultrasound-Guided Transversus Abdominis Plane Block Combined with Intravenous Analgesia After Cesarean Section: A Double-Blind Controlled Trial.

Complete postoperative analgesia is very important for puerperae after cesarean section. The objective of this study was to explore the optimal postoperative analgesia after cesarean section. A total of 180 full-term puerperae who underwent cesarean section in Hanzhong People's Hospital from March 2019 to March 2020 were enrolled and were randomly divided into three groups. Group A was given 0.9% normal saline, group B and C were given 0.4% ropivacaine for transversus abdominis plane block (TAPB). Postoperative patient-controlled intravenous analgesia (PCIA) pumps were 2μg/kg sufentanil + 2.5mg droperidol, 1.5μg/kg and 1.3μg/kg sufentanil, respectively. All puerperae were given different but effective analgesia programs. The primary outcome indicators were visual analog scores (VAS), the first compression time of postoperative analgesia pump and the total number of compressions in 48h. The secondary outcome indicators were vital signs,Ramsay sedation scores, comfort scores (BCS), the frequency of analgesic rescue, postoperative side effects and satisfaction. The dynamic and static VAS scores of the puerperae in group B at T2 and T6 were significantly lower than group A and at T12, T24 and T48 were significantly lower than group C. Compared with group A, the dynamic and static VAS scores of puerperae in group C were lower at T2 and T6 and higher at T12, T24 and T48. The Ramsay score and BCS score of the puerperae in group C at T12, T24 and T48 were significantly lower than those in groups A and B. PCIA with sufentanil alone or combined with TAPB can be safely and effectively used for postoperative analgesia after cesarean section. PCIA combined with TAPB had better analgesic effect and lower incidence of side effects while reducing the dose of opioids. The results of this study provide new ideas and insights for the choice of analgesia after cesarean section.

Patient Controlled Analgesia and an Alternative Protocol: A Comparison of Outcomes After Thoracic and Lumbar Surgery.

IntroductionPatient controlled analgesia (PCA) is a common form of pain management after spine surgeries, in which patients get custom control of their opioid dose. PCA has been demonstrated as a safe form of analgesia; however, use of PCA comes with risks that can be mitigated by opting for alternative pain management. This study aimed to compare the outcomes of patients using PCA to those with an alternative analgesia protocol that does not involve PCA.MethodsA retrospective chart review from January 2017 to July 2018 was conducted. Patients included in this study were those 18 or older who were admitted to a large midwestern tertiary medical center in Wichita, Kansas, and underwent thoracic or lumbar spinal surgery from a single spine surgeon. Data from patient demographics, comorbidities, and type of procedure were collected and compared to control for possible confounding variables. Patients were divided into two groups: patients receiving a PCA pain protocol post-operatively and those receiving a non-PCA protocol. Statistical analyses were performed and all tests with p < 0.05 were considered significant.ResultsThis study found patients in the PCA protocol had similar outcomes to those in the alternative analgesia protocol. This was true for both primary and secondary outcomes. The primary outcome was patient length of stay after the operation. Secondary outcomes included readmission rates, frequency of naloxone rescue, transfers to higher levels of care, and total opioid consumption.ConclusionsThis study supported that a non-PCA protocol for post-operative pain management yields similar outcomes to a PCA protocol in the setting of thoracic and lumbar surgery.

Do wave heights and water levels increase ocean lifeguard rescues?

ObjectiveTo investigate the association of wave height and tidal water level changes with the frequency of ocean lifeguard rescues. MethodsAll ocean lifeguard rescues recorded by Newport Beach Lifeguards in 2015 and 2016 were linked by time and location to weather and ocean variables contained in other historical databases. We performed separate multivariable analyses using mixed effects negative binomial regression to evaluate the total effects of wave height, mean water level (primarily set by tidal elevation), and rising vs. falling water level, on the frequency of ocean rescue in the study location, controlling for confounding variables. ResultsNewport Beach Lifeguards made 8046 rescues during the study period. In all areas of the beach, rescue frequency increased as waves got larger (IRR: 3.25; 95%CI: 2.91–3.79) but then decreased in large surf (IRR: 0.52; 95%CI: 0.37–0.73). In two sections of beach, lifeguards made more rescues during lower water levels, but in the third section of beach, made more rescues during higher water levels. Rescue frequency increased in two sections of beach with rising water levels, but did not in the other section. ConclusionsWave height, water level, and water level direction were associated with rescue frequency, but the environmental factors included in the analysis did not fully account for most variation in rescue frequency. Other factors need to be evaluated to identify major determinants of rescue frequency.

Evolutionary Rescue

Populations that experience severe stress may avoid extinction through adaptation by natural selection. This process is called evolutionary rescue and has been studied under different names in medicine, agriculture, and conservation biology. It is a component of the emerging field of eco-evolutionary dynamics, which investigates how the ecological attributes of species may evolve rapidly under strong selection. Its distinguishing feature is to combine the evolutionary concept of relative fitness with the ecological concept of absolute fitness in a synthetic theory of persistent adaptation. The likelihood of rescue will depend both on attributes of the population, particularly abundance and variation, and on properties of the environment, particularly the rate and severity of deterioration. Medical interventions (e.g., the administration of antibiotics), agricultural practices (e.g., the application of pesticides), and population ecology (e.g., the effects of species introductions) provide numerous examples of evolutionary rescue. The general theory of rescue has been tested in laboratory experiments with microbes, in which experimental evolution shows how different treatments affect the frequency of rescue. Overall, these experiments have supported the predictions of general theory: In particular, abundance, variation, and dispersal have pronounced and repeatable effects on the rescue of populations and communities. Extending these laboratory results to the field is a major task for future research.

Circulating fibrocytes correlate with the asthma control test score

BackgroundBronchial asthma is characterised by airway inflammation and remodelling with a decline of lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that play important roles in the pathogenesis of airway remodelling. Several clinical parameters are currently being used in routine clinical practice to assess outcome of therapy in asthma including frequency of rescue with short-acting β2-agonist and the asthma control test. In this study, we hypothesised that asthma control test is associated with circulating levels of fibrocytes in bronchial asthma. MethodsThere were 20 patients with asthma and seven healthy controls. The number of CD45+Collagen I+ circulating fibrocytes was assessed in the peripheral blood by flow cytometry. ResultsThe number of circulating fibrocytes was significantly increased in asthma patients with moderate and severe disease compared to controls, and it was inversely correlated with % forced expiratory volume in one second and % forced vital capacity (%FVC). The frequency of inhalation of short-acting β2 agonist and the asthma control test score was significantly and inversely correlated with the number of circulating fibrocytes. ConclusionThe results of this study showed that the number of circulating fibrocytes is inversely correlated with clinical asthma control parameters, further supporting the relevance of measuring circulating fibrocytes as a marker of clinical control in bronchial asthma.

Effects of two analgesic regimens on the postoperative analgesia and knee functional recovery after unilateral total knee arthroplasty-a randomized controlled trial

To evaluate the efficacy of continuous femoral block on the postoperative analgesia and functional recovery after total knee arthroplasty (TKA). Two hundreds and eighty patients who underwent TKA were randomized into two groups:the group receiving continuous femoral block (CFNB) and the group receiving patient controlled intravenous analgesia (PCIA), each group included 140 participants. Femoral nerve block with ropivacaine by ultrasonic guidance was performed in group CFNB and group PCIA were administrated with patient controlled intravenous analgesia. Numerical rating scale (NRS) scores at rest and in motion at 24, 48, 72 h, 3, 6 and 12 months postoperatively, also the NRS scores at hospital discharge were recorded. The incidence of moderate-severity pain, as well as the degree of knee flexion and the WOMAC scores at 3, 6 and 12 months after surgery were analyzed. The rescue analgesic administration and analgesia-related adverse effects were also recorded. Data were expressed as mean± standard deviation (SD) for normally distributed continuous variables and total number (percent frequency) for categorical variables. If non-normally distributed, data were expressed median inter-quartile range. Student's t-test, Wilcoxon rank test were used to compare results for continuous variables, when appropriate. Chi-square test was used to compare results for categorical variable, Fisher exact test was used for categorical variables when the number of event was less than 5. NRS scores of group CFNB in motion was 3 (3-4) at discharge time, and 3 (2-4), 3 (2-3) at 3 months and 6 months postoperatively, while the scores of group PCIA was 4 (4-4), 3 (3-4), 3 (3-4), respectively. And at rest, NRS scores of group CFNB was 3 (2-3), 1 (1-2), 1 (1-1) at discharge time, and 3, 6 months postoperatively. Compared with group PCIA, NRS scores in motion of group CFNB at discharge time (Z=-5.174, P<0.05) and 3 months (Z=2.308, P=0.021), as well as 6 months postoperatively (Z=-2.495, P=0.013), were significantly lower,also for the NRS scores at rest (Z=-2.405, P=0.016; Z=-4.360, P<0.05; Z=-9.268, P<0.05). The degree of knee flexion of group CFNB at 3 and 6 months postoperatively was 92 (88-97), 103 (99-106), while the degree of knee flexion of group PCIA was 89 (86-95), 100 (97-105); the WOMAC scores of group CFNB at 3 and 6 months postoperatively was 21 (18-26), 18 (16-22), while the scores of group PCIA was 24 (20-27), 21 (17-24). WOMAC scores of group CFNB was lower compared with group PCIA at 3 (Z=-2.467, P=0.014) and 6 (Z=-2.537, P=0.011) months postoperatively while the degree of knee flexion of group CFNB was higher (Z=-2.175, P=0.030; Z=-2.471, P=0.013). Moreover, the frequency of bolus and frequency of rescue of group CFNB was 2.3 and 0.6, while the frequency of group PCIA was 2.6 and 1.1, the frequency of bolus and frequency of rescue were lower in group CFNB (t=-2.984, P=0.003; t=-3.213, P=0.002). The incidence of adverse events such muscle weakness of low limbs,nausea and vomiting were similar in two groups (P>0.05). CFNB can alleviate the postoperative pain after TKA with safety, help improving the short-middle-term functions of knee and quality of patients' lives.

Changes in the Management of Femoral Shaft Fractures in Polytrauma Patients : From Early Total Care to Damage Control Orthopedic Surgery

major fractures in patients with blunt multiple injuries continues to be discussed. The aim of this study is to investigate the clinical course of poly- trauma patients treated at a Level I trauma cen- ter within the last two decades regarding the ef- fect of changes in the management of their femoral shaft fracture. Methods: In a retrospective cohort study performed at a Level I trauma center, the pa- tient's injuries and clinical outcomes were stud- ied. Adult blunt polytrauma patients were in- cluded if a femoral shaft fracture eligible for intramedullary stabilization was stabilized (in- cluding external fixation) primarily < 8 hours after primary admission. Patients were separated according to the management strategies for the Results: The patient groups were com- parable regarding age, gender distribution, and the mechanism of injury. Primary external fixa- tion was performed significantly more frequent in the INT (23.9%) and DCO (35.6%) groups com- pared with the ETC group (16.6%) (p 0.02 ETC vs. DCO). Plating of the femur was almost abolished in the 1990s (DCO, 6.8%; ETC, 23.4%). In the subgroups categorized to I°EF (ETC, 41.1 points; INT, 37.1 points; DCO, 39.1 points), the general injury severity was higher in comparison with the I°IMN group (ETC, 38.3%; INT, 36.1%; DCO, 35.8%). Thoracic or abdom- inal injuries accounted for significantly higher numbers of patients submitted to I°EF in the INT (13.6%, p 0.03) and DCO (17.3%, p 0.01) groups, compared with the ETC (8.1%) group. A higher incidence of reamed nailing was present in the ETC group compared with the other groups (ETC, 96.1%; INT, 73.7%; DCO, 13.5%). No significant differences in the incidence of local complications were found. The incidence of mul- tiple organ failure decreased significantly from the ETC to the DCO period regardless of the type of treatment of the femoral fracture. Moreover, there was a significantly higher incidence of acute respiratory distress syndrome (ARDS) when I°IMN (15.1%) and I°EF (9.1%) in the DCO subgroup were compared. Conclusion: A significant reduction in the incidence of general systemic complications regardless of the type of femur fixation used was found when comparing the time periods of 1981 to 1989 (ETC), 1990 to 1992 (INT), and 1993 to 2000 (DCO). The change in treatment protocols to external fixation and from reamed to unreamed nailing was not associated with an increased rate of local complications (pin-track infections, delayed unions, nonunions). Among other causes for the improved general outcome during the most recent time period (DCO), an increase in the frequency of air rescue, a change from reamed to unreamed nailing, and an in- creased awareness toward thoracic and abdom- inal injuries may have played a role. Even dur- ing the DCO era, IMN was associated with a higher rate of ARDS than I°EF. In view of a lower complication rate despite higher injury severity compared with the ETC period, the introduction of DCO appears to be an adequate alternative for patients at high risk of develop- ing posttraumatic systemic complications such as ARDS and multiple organ failure.

The effect of KETODEX on the incidence and severity of emergence agitation in children undergoing adenotonsillectomy using sevoflurane based-anesthesia

BackgroundPostoperative emergency agitation (EA) is a common problem often observed in children undergoing general anesthesia. The purpose of this study was to evaluate whether a bolus of intraoperative low-dose ketamine followed by dexmedetomidine i.v. could reduce the incidence of EA in children undergoing adenotonsillectomy following sevoflurane-based anesthesia. MethodsA total of 92 children undergoing adenotonsillectomy, aged 3–7 years, were randomly allocated to receive either low-doseketamine 0.15mg/kg followed by dexmedetomidine 0.3μg/kg i.v. (KETODEX, n=45) or volume-matched normal saline (Control, n=47), about 10min before the end of surgery. Anesthesia was induced and maintained with sevoflurane. Postoperative pain and EA were assessed with objective pain score (OPS) and the Pediatric Anesthesia Emergence Delirium scale (PAED), respectively. EA was defined as a PAED≥10 points. Recovery profile and postoperative complications were recorded. ResultThe incidence and severity of EA was lower in KETODEX group than controls (11% vs. 47%) and (2% vs. 13%), respectively (P<0.05). The frequency of fentanyl rescue was lower in KETODEX group than in controls (13.3 vs. 38.3%, P<0.05). Heart rate during extubation was significantly higher in the control group compared with children who received KETODEX (P<0.05). The incidence of postoperative pain was significantly less in the KETODEX group (15.5% vs. 63.8%, P<0.05). Times to interaction and extubation were significantly longer in the KETODEX group (P<0.05). ConclusionKETODEX reduces the incidence and severity of EA in children undergoing adenotonsillectomy following sevoflurane-based anesthesia and provided smooth extubation.

Ten years of helicopter emergency medical services in Germany: Do we still need the helicopter rescue in multiple traumatised patients?

BackgroundHelicopter emergency medical service (HEMS) has been established in the preclinical treatment of multiple traumatised patients despite an ongoing controversy towards the potential benefit. Celebrating the 20th anniversary of TraumaRegister DGU® of the German Trauma Society (DGU) the presented study intended to provide an overview of HEMS rescue in Germany over the last 10 years analysing the potential beneficial impact of a nationwide helicopter rescue in multiple traumatised patients. Patients and methodsWe analysed TraumaRegister DGU® including multiple traumatised patients (ISS ≥16) between 2002 and 2012. In-hospital mortality was defined as main outcome. An adjusted, multivariate regression with 13 confounders was performed to evaluate the potential survival benefit. Results42,788 patients were included in the present study. 14,275 (33.4%) patients were rescued by HEMS and 28,513 (66.6%) by GEMS. Overall, 66.8% (n=28,569) patients were transported to a level I trauma centre and 28.2% (n=12,052) to a level II trauma centre. Patients rescued by HEMS sustained a higher injury severity compared to GEMS (ISS HEMS: 29.5±12.6 vs. ISS GEMS: 27.5±11.8). Helicopter rescue teams performed more on-scene interventions, and mission times were increased in HEMS rescue (HEMS: 77.2±28.7min. vs. GEMS: 60.9±26.9min.). Linear regression analysis revealed that the frequency of HEMS rescue has decreased significantly between 2002 and 2012. In case of transportation to level I trauma centres a decrease of 1.7% per year was noted (p<0.001) while a decline of 1.6% per year (p<0.001) was measured for level II trauma centre admissions. According to multivariate logistic regression HEMS was proven a positive independent survival predictor between 2002 and 2012 (OR 0.863; 95%-CI 0.800–0.930; Nagelkerkes-R2 0.539) with only little differences between each year. ConclusionsThis study was able to prove an independent survival benefit of HEMS in multiple traumatised patients during the last 10 years. Despite this fact, a constant decline of HEMS rescue missions was found in multiple trauma patients due to unknown reasons. We concluded that HEMS should be used more often in case of trauma in order to guarantee the proven benefit for multiple traumatised patients.

CP-125 Collaboration of the pharmacist in palliative care: analysis of patients admitted and therapeutic equivalents suggested

BackgroundPain is a common symptom that leads terminally ill patients to an emergency department. Opioids have a critical place in the management of terminal pain.PurposeTo investigate the characteristics of patients...

Low-Dose Dexmedetomidine Reduces Emergence Agitation after Desflurane Anaesthesia in Children Undergoing Strabismus Surgery

PurposeEmergence agitation (EA) is frequently observed in children undergoing general anaesthesia. This study tested whether the addition of an intra-operative low-dose infusion of dexmedetomidine to fentanyl treatment reduced the incidence of emergence delirium following desflurane anesthesia in children undergoing strabismus surgery.Materials and MethodsA total of 96 children (1-5 years old) undergoing strabismus surgery were enrolled. Anaesthesia was induced with propofol and maintained with desflurane. After induction, fentanyl (1 µg/kg) was administered to all children. During surgery, patients were infused with 0.2 µg/(kg·h)-1 dexmedetomidine (Group FD, n=47) or normal saline (Group F, n=47). Postoperative objective pain score (OPS), Paediatric Agitation and Emergence Delirium (PAED) score, and EA score were documented every 10 minutes in the post-anaesthesia care unit.ResultsThere were no significant differences between the two groups in demographic characteristics and haemodynamic changes. The mean values of maximum EA, maximum PAED, and maximum OPS score were significantly lower in Group FD than in Group F at 0, 10, and 20 minutes after arrival at the post-anaesthesia care unit (p<0.001). The frequency of fentanyl rescue was lower in Group FD than in Group F (p<0.001). The incidence of severe EA was significantly lower in Group FD than in Group F (12.8% vs. 74.5%, p<0.001).ConclusionIntra-operative low-dose infusion of dexmedetomidine in addition to fentanyl reduces EA following desflurane anaesthesia in children undergoing strabismus surgeries.

Patronin Regulates the Microtubule Network by Protecting Microtubule Minus Ends

Tubulin assembles into microtubule polymers that have distinct plus and minus ends. Most microtubule plus ends in living cells are dynamic; the transitions between growth and shrinkage are regulated by assembly-promoting and destabilizing proteins. In contrast, minus ends are generally not dynamic, suggesting their stabilization by some unknown protein. Here, we have identified Patronin (also known as ssp4) as a protein that stabilizes microtubule minus ends in Drosophila S2 cells. In the absence of Patronin, minus ends lose subunits through the actions of the Kinesin-13 microtubule depolymerase, leading to a sparse interphase microtubule array and short, disorganized mitotic spindles. In vitro, the selective binding of purified Patronin to microtubule minus ends is sufficient to protect them against Kinesin-13-induced depolymerization. We propose that Patronin caps and stabilizes microtubule minus ends, an activity that serves a critical role in the organization of the microtubule cytoskeleton.

Germ-line transmission of trisomy 21: Data from 80 families suggest an implication of grandmaternal age and a high frequency of female-specific trisomy rescue

BackgroundTrisomy of chromosome 21 (T21; Down syndrome, DS) is the most common aneuploidy in live births. Though its etiology has been intensively studied for a half of century, there are surprisingly many problems awaiting their elucidation. Some of the open questions are related directly to germ line mosaicism for T21, other problems include the prevalence of males with non-mosaic trisomy over females (skewed sex ratio, SR), the genetic predisposition to non-disjunction, etc. Studies in families of gonadal mosaicism (GM) carriers might help resolving some of these problems.Results80 families of carriers of GM, in which the sex of the offspring had been specified, were identified in the literature and in logbooks of two local genetic units. Mothers in these families were relatively young: only 8% of mothers were 35 years old and older at the time of delivery of their first affected offspring while the proportion of grandmothers on the GM carrier's side aged 35 years old and older was significantly higher (39%). Postzygotic rescue of T21 due to error in the meiosis I had been proposed as a mechanism of parental GM formation in 78% of the families with known origin of the T21. For the other 22%, rescue of errors in the meiosis II or postzygotic mitotic non-disjunction was assumed. Mosaicism for T21 in successive generations was reported in at least 12 families. The proportion of mosaics among affected female offspring (14%) is significantly higher compared to that among affected male offspring (0%). Male preponderance (SR = 1.5) is found in non mosaic liveborn offspring with either maternally- or paternally transmitted T21. Among unaffected offspring of male carriers of GM there is a notable excess of females (SR = 0.27).ConclusionBoth direct (results of cytogenetic and molecular study of the origin of trisomic line) and indirect (advanced grandmaternal age on the side of GM carrier) evidences allow to assume that significant proportion of the mosaic parents had been conceived as trisomics. Female-specific trisomy rescue and genetic predisposition to postzygotic non-disjunction has been suggested as mechanisms of formation of both GM and somatic mosaicism. Typical male preponderance in affected non mosaic offspring with either maternally- or paternally transmitted trisomy 21, indicates than meiotic events are not responsible for the skewed sex ratio in DS. However a female excess among unaffected offspring of male carriers of GM might be the result of meiotic non homologous co-orientation of chromosomes 21 and X in spermatogenesis.

Repeated Dosing Effects of Mediator Antagonists in Inhaled Corticosteroid-Treated Atopic Asthmatic Patients

The anti-inflammatory effects of repeated dosing with mediator antagonists as add-on therapy to that with inhaled corticosteroids (ICSs) in patients with asthma remain to be fully established. We elected to evaluate the effects of repeated dosing with fexofenadine (FEX) and montelukast (ML) at clinically recommended doses in ICS-treated asthmatic patients using adenosine monophosphate (AMP) bronchial challenge as the primary outcome. Eighteen atopic asthmatic patients receiving a mean (+/- SEM) dose of 631 +/- 104 micro g daily of ICSs, which remained unchanged throughout the entire study, were randomized in double-blind, cross-over fashion to receive FEX, 180 mg, ML, 10 mg, or placebo (PL) for 1 week. There was a 1-week washout period prior to each randomized treatment. Measurements of the provocative concentration of a substance (ie, AMP) causing a 20% fall in FEV(1) (PC(20)) were made after each washout period and randomized treatment period. The values for AMP PC(20) after the washout period prior to each randomized treatment were not significantly different (FEX, 74 +/- 15 mg/mL; ML, 73 +/- 18 mg/mL; PL, 71 +/- 19 mg/mL). There were significant improvements (p < 0.05) in AMP PC(20) with the use of FEX (127 +/- 38 mg/mL) and ML (121 +/- 27 mg/mL) compared to PL (78 +/- 23 mg/mL). Spontaneous recovery after AMP challenge, as determined by area under the 60-min time-response curve, was significantly enhanced (p < 0.05) with the use of ML (352 +/- 95%.min [corrected]) compared to FEX (758 +/- 140%.min) and PL (683 +/- 134%.min [corrected]). Both FEX and ML significantly suppressed (p < 0.05) the levels of exhaled nitric oxide, while only ML significantly reduced (p < 0.05) the peripheral blood eosinophil count compared to PL. Morning and evening peak expiratory flow were significantly higher (p < 0.05), and the frequency of salbutamol rescue was significantly reduced (p < 0.05) with FEX and ML compared to PL. Repeated dosing with FEX and ML as add-on therapy improved AMP PC(20) and other surrogate inflammatory markers along with asthma diary outcomes in ICS-treated atopic asthmatic patients. Further studies are indicated to evaluate the long-term add-on effects of FEX on asthma exacerbations.

Transgenic rescue of GATA-1–deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia

AbstractAssociation of GATA-1 and its cofactor Friend of GATA-1 (FOG-1) is essential for erythroid and megakaryocyte development. To assess functions of GATA-1–FOG-1 association during mouse development, we used theGATA-1hematopoietic regulatory domain to generate transgenic mouse lines expressing a mutant GATA-1, which contains a substitution of glycine 205 for valine (V205G) that abrogates its association with FOG-1. We examined whether the transgenic expression of mutant GATA-1 rescuesGATA-1germ line mutants from embryonic lethality. In high-expressor lines we observed that the GATA-1V205Grescues GATA-1–deficient mice from embryonic lethality at the expected frequency, revealing that excess GATA-1V205Gcan eliminate the lethal anemia that is due to GATA-1 deficiency. In contrast, transgene expression comparable to the endogenous GATA-1 level resulted in much lower frequency of rescue, indicating that the GATA-1–FOG-1 association is critical for normal embryonic hematopoiesis. Rescued mice in these analyses exhibit thrombocytopenia and display dysregulated proliferation and impaired cytoplasmic maturation of megakaryocytes. Although anemia is not observed under steady-state conditions, stress erythropoiesis is attenuated in the rescued mice. Our findings reveal an indispensable role for the association of GATA-1 and FOG-1 during late-stage megakaryopoiesis and provide a unique model for X-linked thrombocytopenia with inheritedGATA-1mutation.

Changes in the management of femoral shaft fractures in polytrauma patients: from early total care to damage control orthopedic surgery.

The optimal treatment of major fractures in patients with blunt multiple injuries continues to be discussed. The aim of this study is to investigate the clinical course of polytrauma patients treated at a Level I trauma center within the last two decades regarding the effect of changes in the management of their femoral shaft fracture. In a retrospective cohort study performed at a Level I trauma center, the patient's injuries and clinical outcomes were studied. Adult blunt polytrauma patients were included if a femoral shaft fracture eligible for intramedullary stabilization was stabilized (including external fixation) primarily < 8 hours after primary admission. Patients were separated according to the management strategies for the femur fracture (I degrees intramedullary nailing [I degrees IMN]; I degrees external fixation [I degrees EF]; I degrees plate osteosynthesis [I degrees plate]) followed during a certain time period: (1) early total care (ETC) (January 1, 1981-December 31, 1989) and early (< 24 hours) definitive stabilization; (2) intermediate (INT) (January 1, 1990-December 31, 1992) change in the protocol; or (3) damage control orthopedic surgery (DCO) (January 1, 1993-December 31, 2000), early (< 24 hours) temporary stabilization, and secondary conversion to intramedullary nailing in patients at risk of organ failure. The patient groups were comparable regarding age, gender distribution, and the mechanism of injury. Primary external fixation was performed significantly more frequent in the INT (23.9%) and DCO (35.6%) groups compared with the ETC group (16.6%) ( = 0.02 ETC vs. DCO). Plating of the femur was almost abolished in the 1990s (DCO, 6.8%; ETC, 23.4%). In the subgroups categorized to I degrees EF (ETC, 41.1 points; INT, 37.1 points; DCO, 39.1 points), the general injury severity was higher in comparison with the I degrees IMN group (ETC, 38.3%; INT, 36.1%; DCO, 35.8%). Thoracic or abdominal injuries accounted for significantly higher numbers of patients submitted to I degrees EF in the INT (13.6%, = 0.03) and DCO (17.3%, = 0.01) groups, compared with the ETC (8.1%) group. A higher incidence of reamed nailing was present in the ETC group compared with the other groups (ETC, 96.1%; INT, 73.7%; DCO, 13.5%). No significant differences in the incidence of local complications were found. The incidence of multiple organ failure decreased significantly from the ETC to the DCO period regardless of the type of treatment of the femoral fracture. Moreover, there was a significantly higher incidence of acute respiratory distress syndrome (ARDS) when I degrees IMN (15.1%) and I degrees EF (9.1%) in the DCO subgroup were compared. A significant reduction in the incidence of general systemic complications regardless of the type of femur fixation used was found when comparing the time periods of 1981 to 1989 (ETC), 1990 to 1992 (INT), and 1993 to 2000 (DCO). The change in treatment protocols to external fixation and from reamed to unreamed nailing was not associated with an increased rate of local complications (pin-track infections, delayed unions, nonunions). Among other causes for the improved general outcome during the most recent time period (DCO), an increase in the frequency of air rescue, a change from reamed to unreamed nailing, and an increased awareness toward thoracic and abdominal injuries may have played a role. Even during the DCO era, IMN was associated with a higher rate of ARDS than I degrees EF. In view of a lower complication rate despite higher injury severity compared with the ETC period, the introduction of DCO appears to be an adequate alternative for patients at high risk of developing posttraumatic systemic complications such as ARDS and multiple organ failure.

The Aspergillus cytoplasmic dynein heavy chain and NUDF localize to microtubule ends and affect microtubule dynamics.

Cytoplasmic dynein is a multisubunit, minus end-directed microtubule motor that uses dynactin as an accessory complex to perform various in vivo functions including vesicle transport, spindle assembly, and nuclear distribution [1]. We previously showed that in the filamentous fungus Aspergillus nidulans, a GFP-tagged cytoplasmic dynein heavy chain (NUDA) forms comet-like structures that exhibited microtubule-dependent movement toward and back from the hyphal tip [2]. Here we demonstrate that another protein in the NUDA pathway, NUDF, which is homologous to the human LIS1 protein involved in brain development [3, 4], also exhibits such dynamic behavior. Both NUDA and NUDF are located at the ends of microtubules, and this observation suggests that the observed dynamic behavior is due to their association with the dynamic microtubule ends. To address whether NUDA and NUDF play a role in regulating microtubule dynamics in vivo, we constructed a GFP-labeled alpha-tubulin strain and used it to compare microtubule dynamics in vivo in wild-type A. nidulans versus temperature-sensitive loss-of-function mutants of nudA and nudF. The mutants showed a lower frequency of microtubule catastrophe, a lower rate of shrinkage during catastrophe, and a lower frequency of rescue. The microtubules in the mutant cells also paused longer at the hyphal tip than wild-type microtubules. These results indicate that cytoplasmic dynein and the LIS1 homolog NUDF affect microtubule dynamics in vivo.