A robotic Intelligent Towing Tank for learning complex fluid-structure dynamics.

We describe the development of the Intelligent Towing Tank, an automated experimental facility guided by active learning to conduct a sequence of vortex-induced vibration (VIV) experiments, wherein the parameters of each next experiment are selected by minimizing suitable acquisition functions of quantified uncertainties. This constitutes a potential paradigm shift in conducting experimental research, where robots, computers, and humans collaborate to accelerate discovery and to search expeditiously and effectively large parametric spaces that are impracticable with the traditional approach of sequential hypothesis testing and subsequent train-and-error execution. We describe how our research parallels efforts in other fields, providing an orders-of-magnitude reduction in the number of experiments required to explore and map the complex hydrodynamic mechanisms governing the fluid-elastic instabilities and resulting nonlinear VIV responses. We show the effectiveness of the methodology of "explore-and-exploit" in parametric spaces of high dimensions, which are intractable with traditional approaches of systematic parametric variation in experimentation. We envision that this active learning approach to experimental research can be used across disciplines and potentially lead to physical insights and a new generation of models in multi-input/multi-output nonlinear systems.

Increased aggression and lack of maternal behavior in Dio3-deficient mice are associated with abnormalities in oxytocin and vasopressin systems.

Thyroid hormones regulate many aspects of brain development and function, and alterations in the levels of thyroid hormone action lead to abnormal anxiety- and depression-like behaviors. A complement of factors in the brain function independently of circulating levels of hormone to strictly controlled local thyroid hormone signaling. A critical factor is the type 3 deiodinase (DIO3), which is located in neurons and protects the brain from excessive thyroid hormone. Here, we examined whether a local increase in brain thyroid hormone action secondary to DIO3 deficiency is of consequence for social behaviors. Although we did not observe alterations in sociability, Dio3-/- mice of both sexes exhibited a significant increase in aggression-related behaviors and mild deficits in olfactory function. In addition, 85% of Dio3-/- dams manifested no pup-retrieval behavior and increased aggression toward the newborns. The abnormal social behaviors of Dio3-/- mice were associated with sexually dimorphic alterations in the physiology of oxytocin (OXT) and arginine vasopressin (AVP), 2 neuropeptides with important roles in determining social interactions. These alterations included low adult serum levels of OXT and AVP, and an abnormal expression of Oxt, Avp and their receptors in the neonatal and adult hypothalamus. Our results demonstrate that DIO3 is essential for normal aggression and maternal behaviors, and indicate that abnormal local regulation of thyroid hormone action in the brain may contribute to the social deficits associated with neurodevelopmental disorders.

Perivascular stromal cells as a potential reservoir of human cytomegalovirus.

Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality among both solid organ and hematopoietic stem cell transplant recipients. Identification of cells throughout the body that can potentially serve as a viral reservoir is essential to dissect mechanisms of cell tropism and latency and to develop novel therapies. Here, we tested and compared the permissivity of liver-, brain-, lung (LNG)- and bone marrow (BM)-derived perivascular mesenchymal stromal cells (MSC) to HCMV infection and their ability to propagate and produce infectious virus. Perivascular MSC isolated from the different organs have in common the expression of CD146 and Stro-1. While all these cells were permissive to HCMV infection, the highest rate of HCMV infection was seen with LNG-MSC, as determined by viral copy number and production of viral particles by these cells. In addition, we showed that, although the supernatants from each of the HCMV-infected cultures contained infectious virus, the viral copy number and the quantity and timing of virus production varied among the various organ-specific MSC. Furthermore, using quantitative polymerase chain reaction, we were able to detect HCMV DNA in BM-MSC isolated from 7 out of 19 healthy, HCMV-seropositive adults, suggesting that BM-derived perivascular stromal cells may constitute an unrecognized natural HCMV reservoir.

Corneal oxygen distribution with contact lens wear.

PURPOSE: Since 1991, multilayer mathematical in vivo oxygenation models have been created to predict normal corneal oxygenation with contact lens wear. From these models, there have been assertions that most hydrogel contact lenses allow 97%-98% of normal corneal oxygenation compared to no contact lens wear. In light of hydrogel lens-induced neovascularization and limbal hyperemia, to clinicians, this finding seems counterintuitive. This work seeks to validate or refute those preexisting models and estimate the impact of contact lens wear on the oxygen distribution profile across the cornea. To this end, to estimate the impact of contact lens wear on the 3-dimensional (3-D) oxygen distribution profile within the cornea as a function of the oxygen permeability of the contact lens, a two-dimensional axisymetric finite element analysis (FEA) model was constructed for contact lenses, on the cornea, both having varying thickness profiles. METHODS: A two dimensional (2-D) axi-symetric finite element analysis (FEA) model of a -3.00 D contact lens on eye was constructed. The model included the varying thickness profiles of the contact lens and cornea. By symmetry, this 2-D model is equivalent to a full 3-D model. The oxygen permeability, material thickness profile, and oxygen consumption coefficients from Brennan (Optometry and Vision Science, June 2005) were used for this validation. Several different oxygen consumption profiles were also considered. Oxygen partial pressure, flux, and consumption profiles were generated. RESULTS: Profiles of the oxygen partial pressure, flux, and consumption were generated from the central cornea to the limbal junction. CONCLUSION: This FEA model reproduced Brennan 8-layer model (BEL model) results at the central cornea. However, BEL model parameters yielded regions of oxygen deficiency in the corneal periphery, even in the open eye with no contact lens. If the BEL model cannot account for oxygenation across the whole cornea, it may be incorrect or incomplete. This assertion calls into question any conclusions from the BEL model regarding the minimum contact lens transmissibility needed to fully oxygenate the eye.

Improving preventive service delivery through office systems.

OBJECTIVE: Rates of childhood immunizations and other preventive services are lower in many practices than national goals and providers' own estimates. Office systems have been used in adult settings to improve the delivery of preventive care, but their effectiveness in pediatric practices is unknown. This study was designed to determine whether a group of primary care practices in 1 community could implement office-based quality improvement systems that would significantly improve their delivery of childhood preventive services. The study was part of a larger community-wide intervention study reported in a preceding study. METHODS: All the major providers of primary care to children in 1 community were recruited and agreed to participate (N = 8 practices). Project staff worked on-site with improvement teams in each practice to develop tailored systems to assess and improve the delivery of immunizations and screening for anemia, tuberculosis, and lead exposure. Office-based quality improvement systems typically involved some combination of chart prescreening, risk assessment forms, Post-it prompts, flow-sheets, reminder/recall systems, and patient education materials. Office systems also often involved redistributing responsibilities among office staff. RESULTS: All 8 participating practices created improvement teams. Project staff met with the practices 10 to 15 times over 12 months. After the period of office assistance, the overall rates for all preventive services except tuberculosis screening increased by amounts that were both clinically and statistically significant. Absolute percent improvements included: complete immunizations at 12 months, 7%; complete immunizations at 24 months, 12%; anemia screening, 30%; lead screening, 36%. The amount of improvement achieved varied considerably between practices. CONCLUSIONS: Office systems and the principles of quality improvement that underlie them seem to be effective in improving the delivery of childhood preventive services. Important predisposing factors may exist within practices that affect the likelihood that an individual practice will make significant improvements. prevention, immunizations, improvement, office systems, primary care.

Carbon monoxide exposure from cooking in snow caves at high altitude.

OBJECTIVE: To determine the physiological consequences of acute CO exposure from cooking in snow caves at 3,200 m. We hypothesized that ambient CO and serum carboxyhemoglobin (COHb) levels would increase and that even low levels of COHb would be associated with symptoms of CO poisoning at high altitude. METHOD: This was a prospective observational study. Twenty-two healthy volunteers age 18 years or older were recruited during a winter camping trip at 3,200 m. Subjects filled out symptom questionnaires, and heart rate (HR), oxygen saturation (SaO2), serum COHb, and ambient CO were all measured before and after cooking inside snow caves. RESULTS: Median age of subjects was 32 years, and 87% were male. The median ambient CO level increased by 17 ppm (IQR, 2-27 ppm), P = .005. Mean serum COHb level rose from 0.3% (IQR, 0.2%-0.4%) to 1.2% (IQR, 0.7%-2.6%) after cooking, for a difference of 1% (IQR, 0.4%-2.3%), P < .001. There were no differences in symptom scores before and after cooking, and there was no significant effect on HR or SaO2. CONCLUSION: A single exposure to CO at 3,200 m increases ambient CO and COHb but not to clinically important levels. Further studies are needed to examine the risks of longer exposures at higher altitudes.

Ability in perceiving nonnative contrasts: performance on natural and synthetic speech stimuli.

The perception of the distinction between /r/ and /l/ by native speakers of American English and of Japanese was studied using natural and synthetic speech. The American subjects were all nearly perfect at recognizing the natural speech sounds, whereas there was substantial variation among the Japanese subjects in their accuracy of recognizing /r/ and /l/ except in syllable-final position. A logit model, which additively combined the acoustic information conveyed by F1-transition duration and by F3-onset frequency, provided a good fit to the perception of synthetic /r/ and /l/ by the American subjects. There was substantial variation among the Japanese subjects in whether the F1 and F3 cues had a significant effect on their classifications of the synthetic speech. This variation was related to variation in accuracy of recognizing natural /r/ and /l/, such that greater use of both the F1 cue and the F3 cue in classifying the synthetic speech sounds was positively related to accuracy in recognizing the natural sounds. However, multiple regression showed that use of the F1 cue did not account for significant variance in natural speech performance beyond that accounted for by the F3 cue, indicating that the F3 cue is more important than the F1 cue for Japanese speakers learning English. The relation between performance on natural and synthetic speech also provides external validation of the logit model by showing that it predicts performance outside of the domain of data to which it was fit.

Chronic hypoxia diminishes pregnancy-associated DNA synthesis in guinea pig uteroplacental arteries.

Enlargement of the uterine artery (UA) during pregnancy is diminished in women residing at a high altitude. We asked whether chronic hypoxia alters the rise in DNA synthesis in uteroplacental vessels and, if so, whether the reduction is related to the intrauterine growth retardation (IUGR) observed under conditions of chronic hypoxia. We used bromodeoxyuridine (BrdU) labelling to measure DNA synthesis in all vascular layers of the UA, mesometrial arteries (MA), thoracic aorta and mesenteric artery of guinea pigs, residing throughout pregnancy at a low (1600 m) or high (3962 m) altitude. Pregnancy increased DNA synthesis throughout the UA at both altitudes, yet the maximal value was less at high than low altitude (P<0.05). Likewise, pregnancy increased DNA synthesis throughout the MA, yet at high altitude pregnancy elevated levels returned to non-pregnant values after 42 days of gestation, whereas at low altitude DNA synthesis continued to be elevated until near term. Fetal weights were lower (P=0.01) and placental/fetal weight ratios tended to be greater in high than low altitude, near term pups (P = 0.09). We conclude that a diminished growt response by the uteroplacental vasculature to pregnancy may contribute to the previously reported reduced uterine artery blood flow and resulting IUGR at high altitude.

Late-onset renal failure after liver transplantation: role of posttransplant alcohol use.

BACKGROUND: Late-onset renal failure is being increasingly recognized as a complication in patients undergoing liver transplantation for hepatitis C virus (HCV). However, its precise incidence, predisposing risk factors, and impact on outcome after liver transplantation, have not been defined. METHODS: The development of late-onset renal failure (defined as serum creatinine persistently >2.0 mg/dl, occurring more than 6 months posttransplant) was assessed in 120 consecutive liver transplant recipients who survived at least 6 months after transplantation. Fifty-seven percent (68/120) of the patients had undergone transplantation for liver disease due to HCV. The median follow-up was 5 years. RESULTS: Late-onset renal failure developed in 28% (33/120)of the patients. Posttransplant alcohol use (P=0.0001), posttransplant diabetes (P=0.0042), and recurrent HCV hepatitis (P=0.019) were significantly associated with late onset renal failure. In multivariate analysis, alcohol use (O.R. 10.7, 95%; CI 2.4-35.9, P=0.001) and diabetes (O.R. 2.1, 95%; CI 1.1-9.9, P=.03) were independently significant predictors of late onset renal failure. When only patients transplanted for HCV were analyzed, posttransplant alcohol use (P=0.004) was the only significant independent predictor of late-onset renal failure. HCV genotype 1b, as compared with other HCV genotypes, was associated with a higher rate of late-onset renal failure in patients with HCV; 70% of the patients with genotype 1b versus 32% of those with 1a and 33% of those with 2b, developed late onset renal failure (P=0.03). At a median follow up of 5 years, mortality in patients with HCV with late-onset renal failure was 52% as compared with 2% in those without renal failure (P=.0001). CONCLUSION: Late-onset renal failure in patients with HCV portended a grave outcome. Alcohol use was an independent predictor of late-onset renal failure in patients with HCV and represents a potentially modifiable risk factor for late-onset renal failure in these patients.

Ultrasound-guided brachial and basilic vein cannulation in emergency department patients with difficult intravenous access.

STUDY OBJECTIVE: Emergency department patients who require intravenous access but lack peripheral intravenous sites frequently require central line placement. Blind percutaneous brachial vein cannulation has been proposed as an alternative in these patients but is associated with high failure and complication rates. We evaluated an ultrasound-guided approach to percutaneous deep brachial vein or basilic vein cannulation in ED patients with difficult intravenous access. METHODS: We prospectively enrolled ED patients who required intravenous access in whom there had been 2 unsuccessful attempts at establishing a peripheral intravenous line. Using a 7.5-MHz ultrasound probe, the deep brachial vein or basilic vein was identified and then cannulated with a 2-in, 18- to 20-gauge intravenous catheter. Time from probe placement to cannulation, number of attempts, and complications were recorded. RESULTS: One hundred one patients were enrolled, of whom 50 were injection drug users and 21 were obese. Cannulation was successful in 91 patients (91%) and accomplished on the first attempt in 73 (73%). The mean (+/-SD) time required for cannulation was 77 seconds (+/-129, range 4 to 600 seconds). The line infiltrated or fell out within 1 hour of cannulation in 8 (8%) patients. One patient reported severe pain. There were 2 (2%) cases of brachial artery puncture. CONCLUSION: Ultrasound-guided brachial and basilic vein cannulation is safe, rapid, and has a high success rate in ED patients with difficult peripheral intravenous access.

Mycobacterium malmoense infections in the United States, January 1993 through June 1995.

Mycobacterium malmoense is a nontuberculous mycobacterium rarely encountered in the United States. However, isolations of M. malmoense from 73 patients (11 in 1992, 35 in 1993, and 27 in 1994) were reported to the Centers for Disease Control and Prevention. We contacted state mycobacteriology laboratories and health care providers of patients whose M. malmoense isolations were reported from January 1993 through June 1995. To assign disease status for these patients, we used the criteria of the American Thoracic Society. Of 60 evaluable patients with disease status, only six (10%) had disease due to M. malmoense (five adults with pulmonary disease and one child with cervical lymphadenitis). We conclude that the number of patients with disease due to M. malmoense remains low. Increased isolation of this species may be due to the increased use of more sensitive and specific laboratory methods. For surveillance purposes, multiple M. malmoense isolates and age of younger than 10 years appear to be the best predictors for M. malmoense disease.

Effect of K+ATP channel inhibition on total and regional vascular resistance in guinea pig pregnancy.

Decreased vascular resistance and vasoconstrictor response during pregnancy enables an increase in cardiac output and regional blood flow to the uterine circulation. We sought to determine whether inhibition of vascular smooth muscle ATP-sensitive potassium (K+ATP) channel activity during pregnancy increased systemic and/or regional vascular resistance and resistance response to ANG II. A total of 32 catheterized, awake, pregnant or nonpregnant guinea pigs were treated with either the K+ATP channel inhibitor glibenclamide (3.5 mg/kg) or vehicle (DMSO) (n = 8/group). In nonpregnant and pregnant animals, glibenclamide raised blood pressure and systemic, uterine, and coronary vascular resistance, diminishing cardiac output and organ blood flow. Glibenclamide produced a greater rise in coronary vascular resistance in the pregnant than nonpregnant groups and increased renal and cerebral vascular resistance in the pregnant animals only. ANG II infusion raised blood pressure and systemic and renal vascular resistance and lowered cardiac output and renal blood flow in vehicle-treated animals. Glibenclamide augmented ANG II-induced systemic vasoconstriction in the nonpregnant and pregnant groups and the rise in uteroplacental vascular resistance in the pregnant animals. We concluded that K+ATP channel activity likely modulates systemic, uterine, and coronary vascular resistance and opposes ANG II-induced systemic vasoconstriction in nonpregnant and pregnant guinea pigs. Pregnancy augments K+ATP channel activity in the uterine, coronary, renal, and cerebral vascular beds and the uteroplacental circulation during ANG II infusion. Thus increased K+ATP channel activity appears to influence regional control of vascular resistance during guinea pig pregnancy but cannot account for the characteristic decrease in systemic vascular resistance and ANG II-induced systemic vasoconstrictor response.

Prolactin is an antagonist of TGF-beta activity and promotes proliferation of murine B cell hybridomas.

Prolactin (PRL) is an immunomodulator that has been demonstrated to enhance immune responses both in vitro and in vivo. Prolactin enhances the proliferative response of lymphoid cells to both nonspecific mitogens and specific antigens and increases their production of IL-2 and interferon-gamma. Studies were performed to examine whether recombinant human prolactin (r-hPRL) also acts as a growth factor for B cell hybridomas. Prolactin was able to stimulate proliferation of murine B cell hybridomas in a dose-dependent manner and enhanced their proliferation in response to IL-4, IL-5, and IL-6. This increase in proliferation resulted in an overall increase in antibody production. Studies were also undertaken to examine the effect of PRL with transforming growth factor beta (TGF-beta), an immunosuppressive cytokine. Hybridoma cell lines incubated with TGF-beta demonstrated a dose-dependent decrease in proliferation. Variability in the degree of inhibition was observed among the various hybridomas in their responsiveness to TGF-beta. The addition of r-hPRL to the cultures reversed the antiproliferative effects of TGF-beta. The mechanism by which PRL can overcome the anti-proliferative effect of TGF-beta is under investigation. These findings provide an additional rationale for using r-hPRL clinically in immunosuppressed patients in certain disease settings such as AIDS and cancer, where overexpression of TGF-beta has been implicated in disease development and progression.

Use of insulin-like growth factor I (IGF-I) and IGF-binding protein measurements to monitor feeding of premature infants.

To determine whether peptides of the insulin-like growth factor (IGF) system might be useful indicators of nutritional adequacy in premature infants, we studied 50 premature (25-34 weeks gestation) infants prospectively to define the relationship between nutrient intake and serum concentrations of IGF-I, IGF-binding protein-2 (IGFBP-2), and IGFBP-3. Each infant was monitored for at least 2 weeks. Nutrient intake was quantified from daily logs; weight was determined daily, and measurements of IGF-I, IGFBP-2, and IGFBP-3 in serum were made twice weekly. Serum IGF-I correlated strongly with length of gestation, increasing 4.03 +/- 0.95 ng/mL for each additional week of gestation (P < 0.0001) and 0.36 +/- 0.07 ng/mL day each day since birth (P < 0.0001). A higher intake of calories increased IGF-I by 0.07 +/- 0.01 ng/mL for each calorie per kg ingested over the previous 3 days (P < 0.0001). IGF-I increased quadratically as protein intake increased. For each change of 1% in calories as protein squared, IGF-I increased 0.36 +/- 0.11 ng/mL (P < 0.0001). Serum IGFBP-3 concentrations also correlated with length of gestation, increasing 25.06 +/- 11.83 micrograms/L.wk (P = 0.035) and 4.14 +/- 1.33 micrograms/.day since birth (P = 0.003). Unlike IGF-I, variation in the amount of protein supplied did not change IGFBP-3. As calorie intake increased, IGFBP-3 increased by 0.54 +/- 0.17 microgram/L for each calorie per kg consumed over the previous 3 days (P = 0.0015). In contrast to IGF-I and IGFBP-3, IGFBP-2 declined as the length of gestation increased (56.12 +/- 16.92 ng/mL.week; P = 0.001) and with each additional day of life (7.57 +/- 2.44 ng/mL.day; P = 0.003). Dietary protein, the predominant regulator of IGFBP-2, caused a decrease of 33.22 +/- 9.00 ng/mL with each percent increase in dietary calories as protein (P < 0.0003). Calorie intake had less effect on IGFBP-2 than protein intake. These results indicate that each of the three peptides studied is regulated in premature infants by nutritional intake, and that their regulatory patterns are qualitatively similar to those observed in older individuals. Measurements of these peptides in premature infants may be useful indicators of nutritional status and adequacy of nutrient intake.

Urinary cotinine and parent history (questionnaire) as indicators of passive smoking and predictors of lower respiratory illness in infants.

Studies of the effects of passive smoking on lower respiratory illness (LRI) have relied on questionnaires to measure exposure. We studied the association between two measures of passive smoking and the incidence of acute LRI in infants. We analyzed data from a community-based cohort study of respiratory illness during the first year of life in North Carolina. The incidence of LRI was determined by telephone calls at 2-week intervals. Environmental, demographic, and psychosocial risk factors for LRI were measured during home interviews. Tobacco smoke exposure was measured as the mean number of cigarettes smoked per day in the infant's presence. Smoke absorption by the infants was measured by the urinary cotinine/ creatinine ratio. Of the 485 infants in the study, 325 (67%) had telephone follow-up and at least two home interviews. In bivariate analyses, reported tobacco smoke exposure and urinary cotinine were associated with LRI. Only the association between reported exposure and LRI remained significant after adjusting for confounders, [adjusted incidence of LRI (episodes/child-year) non-exposed: 0.6; < or = 10 cigarettes/day: 0.9 (RR 1.5, 95% CI: 1.1, 2.0); > 10 cigarettes/day: 1.3 (RR 2.2, 95% CI: 1.3, 3.8)]. We conclude that infants reportedly exposed to tobacco smoke have an increased incidence of LRI. There are differences between questionnaire and biochemical measures of passive smoking. Urinary cotinine will not necessarily improve the validity of studies of the relationship of passive smoking to LRI in infants.