Assessment of neurotoxicity of pharmacological compounds during early neural development of human embryonic stem cells.

Human embryonic stem cells (hESCs), with the potential for differentiation, have been used to evaluate the embryotoxicity of various compounds. The effects of pharmacological compounds (cytosine arabinoside, 5-fluorouracil, hydroxyurea, indomethacin, and dexamethasone) on neurogenesis of hESCs over 28 days were examined based on cytotoxicity (half-maximal inhibitory concentration of viability, IC50) and expression of neural markers. Cytosine arabinoside, 5-fluorouracil, and hydroxyurea showed strong cytotoxicity (IC50 < 10 µM), whereas indomethacin and dexamethasone had weaker cytotoxic effects. Dose-dependent expression profiles of neural markers in the compound-treated groups are presented in triangular charts to allow comparison with the standard expression levels in the control group. Differences in compound-specific reductions in expression patterns of GAD1, OLIG2, FABP, and NES were similar to the differences in cytotoxic strength. Cytosine arabinoside diminished nestin and ß3-tubulin in neural differentiated hESCs. The results of this study extend the understanding of how differentiated hESCs may be useful for assessment of cell viability or neurogenesis impairment by chemicals that could have effects during the embryonic stage, particularly during neurogenesis.

Post-transplant assessment of consciousness in acute-on-chronic liver failure patients undergoing liver transplantation using bispectral index monitoring.

PURPOSE: Deterioration of consciousness is a critical situation for liver transplantation (OLT) recipients. The bispectral (BIS) index based on electroencephalographic parameters, is primarily used to monitor the depth of unconsciousness. The present study sought to assess the usefulness of posttransplant BIS index to monitor acute-on-chronic liver failure patients. METHODS: This 1-year retrospective study of 28 adult patients with acute-on-chronic liver failure was performed from July 2011 to June 2012, using post-transplant BIS monitoring. RESULTS: The mean patient age was 51 ± 8 years. Their mean pretransplant Child-Turcotte-Pugh score was 12.3 ± 1.4, and the mean Model for End-stage Liver Disease score, 36.4 ± 5.9. After OLT, the mean initial Glasgow Coma Scale (GCS) score and BIS index were 3.4 ± 1.7 and 43.5 ± 9.1, respectively. After 6 hours the mean GCS and BIS values rose to 8.6 ± 4.0 and 52.4 ± 10.3 and after 12 hours to 9.7 ± 3.4 and 61.3 ± 15.7 respectively. Eye opening in response to a voice occurred at a mean of 8.9 ± 6.7 hours after arrival in the intensive care unit regardless of graft function. The mean GCS and BIS values were 10.6 ± 2.8 and 69.1 ± 13.5, respectively. The endotracheal tube was removed after a median of 140 hours; 9 patients required a tracheostomy. Among them 2 died within the first 3 months after OLT. CONCLUSIONS: BIS monitoring is a noninvasive, simple, easy-to-interpret method to measure consciousness among patients intubated with an endotracheal tube.

Outcomes of management for potential deceased donors.

BACKGROUNDS: Potential deceased donor management optimization is important for organ recovery maximization. Before optimization, the current state of donor management and predictors for organ recovery require analysis. METHODS: We retrospectively analyzed organ procurement activity and medical management for 2005 to 2010 potential brain death donors at Seoul National University Hospital. RESULTS: Of 316 contacts for potential brain-dead donors, 129 (39.7%) patients were transferred to the donor management team. Among the causes of transfer failure, issues related to proper donor management affected 33%. Expanded criteria donors were 17.9% of transferred donors. Organ recovery was successful in 111 (90.2%) donors. A total of 360 organs were recovered, corresponding to a mean of 2.92 ± 1.37 organs per donor. The absence of organ demand was an important cause of recovery failure among less transplanted organs. Brain death-related complications were identified as follows: acute kidney injury (AKI), defined by AKI network criteria, occurred in 19 (15.4%); cardiopulmonary resuscitation in 5 (3.1%); bacteremia in 12 (9.7%); thrombocytopenia in 24 (19.5%); and diabetes insipidus in 42 (34.1%). AKI was a significant independent risk factor for organ recovery failure in both the liver and kidney (odds ratio [OR] 0.147, 95% confidence interval [0.045, 0.473], P = .001; OR 0.096, 95% confidence interval [0.023, 0.392], P = .001, for kidney and liver, respectively). CONCLUSIONS: Both the transfer success rate and rate of organs transplanted per donor of potential deceased donors remained low in Korea. AKI during potential donor management was a risk factor for kidney and liver recovery failure.

Incidence and management of postoperative abdominal bleeding after liver transplantation.

PURPOSE: To assess the incidence and management of postoperative abdominal bleeding after orthotopic liver transplantation (OLT) and to identify risk factors for abdominal bleeding. METHODS: We retrospectively reviewed the medical records of 1039 patients who underwent OLT at our institution from January 2008 to December 2010 seeking to identify subjects with posttransplantation abdominal bleeding, defined as any hemorrhage requiring radiologic intervention or laparotomy within the first month. RESULTS: Among the 1039 patients, 94 (9%) showed abdominal bleeding, occurring at a mean of 6.1 days (range, day 1 to 21 days). Active bleeding was controlled by endovascular interventional techniques (n = 37; 39%), by surgical ligation or vascular reconstruction (n = 43; 46%), or by sequential combinations of endovascular intervention and surgery (n = 14; 15%). The most frequent bleeding sites for radiologic intervention were the right inferior phrenic artery (n = 14), right and left epigastric arteries (n = 7), intercostal artery (n = 5) and right renal capsular artery (n = 4). The most frequent bleeding sites requiring laparotomy were the hepatic artery (n = 9), diaphragm (n = 8), inferior vena cava (n = 5), abdominal drain insertion site (n = 4), portal vein anastomosis site (n = 4), abdominal wall (n = 3), liver graft cut surface (n = 3), hilar plate (n = 3), and greater omentum (n = 3). Bleeding episodes were associated with greater patient age and increased intraoperative blood loss. CONCLUSIONS: The risk of bleeding from coagulopathy and iatrogenic injury is high during the early posttransplantation period. This risk of bleeding can be minimized by meticulous surgical dissection and bleeding control.

The addition of an upper-extremity curriculum in medical school education and its assessment.

This study assessed the impact of changes made to address the inadequate upper-extremity education through preclinical medical school curriculum reform. After the administration of a new upper-extremity curriculum, which also increased the time devoted to three preclinical medical school courses from 7.25 to 21.25 hours, second-year medical students were evaluated for mastery of these concepts through a national validated objective examination, and attitude and skill through clinical confidence and subjective surveys. After implementation of the new upper-extremity curriculum, students had significantly greater confidence in their ability to perform a physical examination but not in identifying differential diagnoses of the upper-extremity. Students were more satisfied with the amount of time spent on the musculoskeletal system but their performance in the national examination did not change.

Functional and genetic assessment of IFN-gamma receptor in patients with clinical tuberculosis.

OBJECTIVE: The molecular basis of the genetic vulnerability underlying the most common form of clinical tuberculosis (TB) remains largely unknown. We speculated that mild genetic defects in the interferon-gamma (IFN-gamma) signalling pathway caused a subtle functional impairment of IFN-gamma which would explain susceptibility to Mycobacterium tuberculosis in clinical TB. DESIGN: A case-control study. RESULTS: We evaluated functional responsiveness to IFN-gamma in monocytes from patients with clinical TB (n = 10), and analysed the genetic sequences of the IFN-gamma receptor 1 (IFN-gammaR1) and STAT1 genes in patients with disseminated TB (n = 18). IFN-gamma stimulated an increase in the expression of HLA-DR and CD64 on monocytes of both controls and patients; the rate of increase in expression was the same in both groups. Treatment with IFN-gamma before lipopolysaccharide (LPS) stimulation further increased tumour necrosis factor-alpha (TNF-alpha) production as compared to TNF-alpha production with LPS stimulation alone; the rate of increase in TNF-alpha production was the same in both groups. The known mutations in the coding sequences of the IFN-gammaR1 and STAT1 genes were not found in the patients with disseminated tuberculosis. CONCLUSION: These results suggest that impairment of the IFN-gamma signalling pathway did not account for cases of clinical TB in this study.

Intraoperative assessment of hepatic venous congestion with direct clamping of the hepatic vein trunk for living donor liver transplantation.

We devised a hepatic vein clamping method to assess the amount of hepatic venous congestion (HVC) before liver transection. From February 2003 to May 2003, this method was applied to 5 of 58 living donor livers especially to assess donor safety. The left portal vein and proper hepatic artery as well as the middle hepatic vein (MHV)-left hepatic vein (LHV) trunk were clamped simultaneously to assess the HVC in the remnant right lobe before performing extended left lobectomy. As three donors demonstrated the extent of the HVC equivalent to about 40% of the right lobe volume (RLV), their operations proceeded according to the preoperative plan. The territory of HVC after liver transection was the same as that observed with direct clamping of the hepatic vein. However, one donor showed massive HVC more than 50% of RLV and the operative plan was adjusted to harvest only the left lobe without the MHV trunk for donor safety. To assess the HVC in the remnant left lobe, the isolated LHV trunk was occluded after clamping the donor's proper hepatic artery. The whole left lobe except for a small area at the anterior portion of the medial segment became discolored on LHV clamping: the opposite demarcation appeared on MHV clamping. The amount of HVC was so small that we harvested the right lobe with the MHV trunk. All donors and recipients recovered uneventfully. We believe that this direct clamping method makes the assessment of HVC feasible before parenchymal transection of a donor liver.

A case study of dissolved air flotation for seasonal high turbidity water in Korea.

A DAF (Dissolved-Air-Flotation) process has been designed considering raw water quality characteristics in Korea. Although direct filtration is usually operated, DAF is operated when freshwater algae blooms occur or raw water turbidity becomes high. Pre-sedimentation is operated in case when the raw water turbidity is very high due to rainstorms. A main feature of this plant is that the operation mode can be changed (controlled) based on the characteristics of the raw water to optimize the effluent quality and the operation costs. Treatment capacity (surface loading rate) and efficiency of DAF was found to be better than the conventional sedimentation process. Moreover, low-density particles (algae and alum flocs) are easily separated while the removal of them by sedimentation is more difficult. One of the main concerns for DAF operation is a high raw water turbidity. DAF is not adequate for raw water, which is more turbid than 100 NTU. In order to avoid this problem, pre-sedimentation basins are installed in the DAF plant to decrease the turbidity of the DAF inflow. For simulation of the actual operation, bench and full-scale tests were performed for highly turbid water conditions. Consequently, it is suggested that pre-sedimentation with optimum coagulation prior to DAF is the appropriate treatment scheme.

Comprehensive follow-up care and life-threatening illnesses among high-risk infants: A randomized controlled trial.

CONTEXT: Inner-city high-risk infants often receive limited and fragmented care, a problem that may increase serious illness. OBJECTIVE: To assess whether access to comprehensive care in a follow-up clinic is cost-effective in reducing life-threatening illnesses among high-risk, inner-city infants. DESIGN: Randomized controlled trial. SETTING AND PARTICIPANTS: A total of 887 very-low-birth-weight infants born in a Texas county hospital between January 1988 and March 1996 and followed up in a children's hospital clinic. One hundred four infants who became ineligible or died after randomization but before nursery discharge were excluded from the analysis. INTERVENTIONS: Infants were randomly assigned to receive routine follow-up care (well-baby care and care for chronic illnesses; n = 441) or comprehensive care (which included the components of routine care plus care for acute illnesses, with 24-hour access to a primary caregiver; n = 446). MAIN OUTCOME MEASURES: Life-threatening illnesses (ie, causing death or hospital admission for pediatric intensive care) occurring between nursery discharge and age 1 year, assessed by blinded evaluators from inpatient charts and state Medicaid and vital statistics records; and hospital costs (estimated from department-specific cost-to-charge ratios). RESULTS: Comprehensive care resulted in a mean of 3.1 more clinic visits and 6.7 more telephone conversations with clinic staff (P<.001 for both). One-year outcomes were unknown for fewer comprehensive-care infants than routine-care infants (9 vs 28; P =.001). Identified deaths were similar (11 in comprehensive care vs 13 in routine care; P =.68). The comprehensive-care group had 48% fewer life-threatening illnesses (33 vs 63; P<.001), 57% fewer intensive care admissions (23 vs 53; P =.003), and 42% fewer intensive care days (254 vs 440; P =.003). Comprehensive care did not increase the mean estimated cost per infant for all care ($6265 with comprehensive care and $9913 with routine care). CONCLUSION: Comprehensive follow-up care by experienced caregivers can be highly effective in reducing life-threatening illness without increasing costs among high-risk inner-city infants. JAMA. 2000;284:2070-2076.

Problematic formulations of SAS PROC.MIXED models for repeated measurements.

The work reported in this article was undertaken to evaluate the utility of SAS PROC.MIXED for testing hypotheses concerning GROUP and TIME x GROUP effects in repeated measurements designs with drop-outs. If dropouts are not completely at random, covariate control over informative individual differences on which dropout data patterns depend is widely recognized to be important. However, the inclusion of baseline scores and time-in-study as between-subject covariates in an otherwise well formulated SAS PROC.MIXED model resulted in inadequate control over type I error in simulated data with or without drop-outs present. The inadequate model formulations and resulting deviant test sizes are presented here as a warning for others who might be guided by the same information sources to employ similar model specifications when analyzing data from actual clinical trials. It is important that the complete model specification be provided in detail when reporting applications of the general linear mixed-model procedure. A single random-coefficients model produced appropriate test sizes, but it provided inferior power when informative covariates were added in the attempt to adjust for dropouts. As an alternative, the incorporation of covariate controls in simpler two-stage endpoint or random regression analyses is documented to be effective in dealing with dropouts under specifiable conditions.

Cost and outcome of osteocutaneous free-tissue transfer versus pedicled soft-tissue reconstruction for composite mandibular defects.

Thirty-nine patients underwent reconstruction of composite mandibular defects following resection for squamous cell carcinoma. Thirty-four underwent immediate reconstruction, while 5 were reconstructed secondarily. Twenty-one received soft-tissue reconstruction only with a pectoralis major myocutaneous flap, 14 underwent osteocutaneous free-tissue transfer, and 4 received a reconstruction plate with free-tissue transfer for soft-tissue coverage. The mandibular defects in the pectoralis major myocutaneous flap group tended to be posterolateral, while free-tissue transfer defects were more severe, usually involving the anterior mandible. Length of surgery and duration of intensive care unit care were significantly longer for free-tissue transfer patients, while flap complications were more common in the pectoralis major myocutaneous flap patients. Facial appearance scores were higher for the free-tissue transfer group by both patient and physician assessment. Social function, speech, and oral function did not differ significantly. Patients reconstructed secondarily with free-tissue transfer reported significant improvement in appearance, oral continence, and social function, with little change in speech intelligibility, deglutition, or diet tolerance. The cost of the main hospitalization was significantly higher in the free-tissue transfer group than in the pectoralis major myocutaneous flap group, although when the costs of subsequent hospitalizations are included, the difference in total cost narrows. Despite more adverse defects, free-tissue transfer provided more predictable aesthetic results and expeditious return to normal social function than did pectoralis major myocutaneous flap reconstruction. The fiscal impact of these complex reconstructions is, however, significant. Cost-containment issues are presented and recommendations are made.

Depressive symptoms and mortality in elderly persons.

Studies on the relationship between depression and mortality in elderly community populations have yielded contradictory findings, although an association frequently is found in studies of elderly psychiatric patients. These different results may be due to differences in the measures of depression, the populations under study, the covariates in the analysis, or to sample attrition. In this study of elderly residents of an urban neighborhood, depressive symptoms are measured at two time points. People are classified as consistently nonsymptomatic (N-N), with emergent symptoms (N-D), in remission (D-N), or persistently symptomatic (D-D). Symptoms of depression, sociodemographic characteristics, and measures of changes in health, functional status, number of chronic medical conditions, and social support are examined in relation to mortality in multivariate Cox regression models. Although symptoms of depression are not found to be related to time-to-death, older people, those with declines in health and functional status, and men have greater relative risks of mortality over a three-year follow-up.