Cardiopulmonary Exercise Performance in the Pediatric and Young Adult Population Before and During the COVID-19 Pandemic.

Physical activity (PA) decreased and sedentary behavior (SB) increased in the pediatric population during the Coronavirus Disease 2019 (COVID-19) pandemic. We examined the effects of PA and SB on cardiopulmonary exercise performance in children, adolescents and young adults both with and without underling cardiac disease, and hypothesized that there will be a change in aerobic and physical working capacity during the pandemic. This was a single-center retrospective longitudinal cohort study in patients age 6-22 years who underwent serial maximal cardiopulmonary exercise stress testing before and during the COVID-19 pandemic. Metabolic variables were obtained; PA and SB data were extracted from clinic notes. A total of 122 patients (60% male) underwent serial exercise testing with a median age of 14 years at the first CPET. Predicted peak aerobic capacity significantly decreased among both females and males during the pandemic, even after adjusting for changes in somatic growth. There was no significant change in physical working capacity during the pandemic. Patients who were more aerobically fit experienced a greater decrease in aerobic capacity during the pandemic compared to those less fit. In conclusion, cardiopulmonary exercise performance, notably aerobic activity, decreased during the COVID-19 pandemic in children, adolescents and young adults compared to pre-pandemic values. This decline was most notable in those with the highest pre-pandemic aerobic capacity values and was independent of somatic growth or changes in BMI. This study has public health implications and demonstrates the importance of PA on overall cardiovascular health.

Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders.

BACKGROUND: Deficits in gamma aminobutyric acid (GABA) neuron-related markers, including the GABA-synthesizing enzyme GAD67, the calcium-binding protein parvalbumin, the neuropeptide somatostatin, and the transcription factor Lhx6, are most pronounced in a subset of schizophrenia subjects identified as having a 'low GABA marker' (LGM) molecular phenotype. Furthermore, schizophrenia shares degrees of genetic liability, clinical features and cortical circuitry abnormalities with schizoaffective disorder and bipolar disorder. Therefore, we determined the extent to which a similar LGM molecular phenotype may also exist in subjects with these disorders. METHOD: Transcript levels for GAD67, parvalbumin, somatostatin, and Lhx6 were quantified using quantitative PCR in prefrontal cortex area 9 of 184 subjects with a diagnosis of schizophrenia (n = 39), schizoaffective disorder (n = 23) or bipolar disorder (n = 35), or with a confirmed absence of any psychiatric diagnoses (n = 87). A blinded clustering approach was employed to determine the presence of a LGM molecular phenotype across all subjects. RESULTS: Approximately 49% of the subjects with schizophrenia, 48% of the subjects with schizoaffective disorder, and 29% of the subjects with bipolar disorder, but only 5% of unaffected subjects, clustered in the cortical LGM molecular phenotype. CONCLUSIONS: These findings support the characterization of psychotic and bipolar disorders by cortical molecular phenotype which may help elucidate more pathophysiologically informed and personalized medications.

Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping.

Pycnodysostosis is an autosomal recessive sclerosing skeletal dysplasia of unknown aetiology which is inherited with complete penetrance. The clinical features, fully delineated in 1962 by Maroteaux & Lamy and by Andrén et al., include osteosclerosis, acro-osteolysis of the distal phalanges, bone fragility, clavicular dysplasia, reduced stature and skull deformities with delayed suture closure. Although rare, pycnodysostosis has attained prominence because the French artist Henri de Toulouse-Lautrec was retrospectively diagnosed as having been affected with this disorder. For rare autosomal recessive traits, homozygosity mapping provides a powerful approach to disease gene mapping. We have now used this approach to map the locus for pycnodysostosis. Following a genome-wide search in a large Arab family with 16 affected relatives, we established linkage to a narrow region on chromosome 1q21, with a maximal lod score of 11.72. A single marker, D1S498, was homozygous-by-descent in all affecteds and defined the gene locus to a region of 4 cM. Two candidate genes in the region--the interleukin-6 receptor gene (IL6R) and the myeloid cell leukaemia-1 gene (MCL1)--are involved in the differentiation of monocyte/macrophages into osteoclasts, the most likely site of the primary defect in pycnodysostosis.

The influence of mechanical Circulatory support on post-transplant outcomes in pediatric patients: A multicenter study from the International Society for Heart and Lung Transplantation (ISHLT) Registry.

BACKGROUND: Mechanical circulatory support (MCS) is increasingly being used as a bridge to transplant in pediatric patients. We compare outcomes in pediatric patients bridged to transplant with MCS from an international cohort. METHODS: This retrospective cohort study of heart-transplant patients reported to the International Society for Heart and Lung Transplantation (ISHLT) registry from 2005-2017 includes 5,095 patients <18 years. Pretransplant MCS exposure and anatomic diagnosis were derived. Outcomes included mortality, renal failure, and stroke. RESULTS: 26% of patients received MCS prior to transplant: 240 (4.7%) on extracorporeal membrane oxygenation (ECMO), 1,030 (20.2%) on ventricular assist device (VAD), and 54 (1%) both. 29% of patients were <1 year, and 43.8% had congenital heart disease (CHD). After adjusting for clinical characteristics, compared to no-MCS and VAD, ECMO had higher mortality during their transplant hospitalization [OR 3.97 & 2.55; 95% CI 2.43-6.49 & 1.42-4.60] while VAD mortality was similar [OR 1.55; CI 0.99-2.45]. Outcomes of ECMO+VAD were similar to ECMO alone, including increased mortality during transplant hospitalization compared to no-MCS [OR 4.74; CI 1.81-12.36]. Patients with CHD on ECMO had increased 1 year, and 10 year mortality [HR 2.36; CI 1.65-3.39], [HR 1.82; CI 1.33-2.49]; there was no difference in survival in dilated cardiomyopathy (DCM) patients based on pretransplant MCS status. CONCLUSION: Survival in CHD and DCM is similar in patients with no MCS or VAD prior to transplant, while pretransplant ECMO use is strongly associated with mortality after transplant particularly in children with CHD. In children with DCM, long term survival was equivalent regardless of MCS status.

Effects of Border Crops and Intercrops on Control of Cucurbit Virus Diseases.

In five field trials over 3 years, control of aphid-transmitted, nonpersistent virus diseases on pumpkin, caused mostly by the potyviruses Watermelon mosaic virus (WMV) and Papaya ringspot virus type-W (PRSV-W), was achieved by intercropping with grain sorghum, as opposed to clean tillage. Reductions in disease incidence ranged from 43 to 96% (P ≤ 0.05). Surrounding pumpkin plots with borders of peanut, soybean, or corn was not effective. Borders of grain sorghum were effective, but disease control was generally less than for the intercrop treatment. Intercropping soybean and peanut with pumpkin reduced disease incidence by 27 to 60% (P ≤ 0.05), but disease control generally was less than for grain sorghum. Peak periods of alate aphid immigration generally preceded virus disease outbreaks by 7 to 14 days. However, alate landing rates, as measured in green tile traps, did not differ among treatments. Marketable yield was not increased by the intercrop treatments, and yield was reduced by up to 50% for the intercrop treatment with grain sorghum in two trials. The use of grass-selective herbicide applied along pumpkin rows, reduced seeding rates of the intercrops, or mowing did not alleviate the adverse effects of competition between pumpkin and the grain sorghum intercrop on yield.

Spatial pattern and sequential sampling of squash bug (Heteroptera: Coreidae) adults in watermelon.

Spatial distribution patterns of adult squash bugs were determined in watermelon, Citrullus lanatus (Thunberg) Matsumura and Nakai, during 2001 and 2002. Results of analysis using Taylor's power law regression model indicated that squash bugs were aggregated in watermelon. Taylor's power law provided a good fit with r2 = 0.94. A fixed precision sequential sampling plan was developed for estimating adult squash bug density at fixed precision levels in watermelon. The plan was tested using a resampling simulation method on nine and 13 independent data sets ranging in density from 0.15 to 2.52 adult squash bugs per plant. Average estimated means obtained in 100 repeated simulation runs were within the 95% CI of the true means for all the data. Average estimated levels of precision were similar to the desired level of precision, particularly when the sampling plan was tested on data having an average mean density of 1.19 adult squash bugs per plant. Also, a sequential sampling for classifying adult squash bug density as below or above economic threshold was developed to assist in the decision-making process. The classification sampling plan is advantageous in that it requires smaller sample sizes to estimate the population status when the population density differs greatly from the action threshold. However, the plan may require excessively large sample sizes when the density is close to the threshold. Therefore, an integrated sequential sampling plan was developed using a combination of a fixed precision and classification sequential sampling plans. The integration of sampling plans can help reduce sampling requirements.

Vitamin D stimulates DNA synthesis in alveolar type-II cells.

Alveolar type-II cells are responsible for alveolar epithelial cell proliferation during growth and development and in response to lung injury. Based on the observation of abnormal lung development in rachitic rat pups and the expression of receptors for vitamin D by fetal alveolar epithelial cells, the present study examined the influence of 1,25-dihydroxy vitamin D (DHD) on the proliferation of primary cultures of fetal, neonatal and adult alveolar epithelial cells. The ontogony of vitamin D responsiveness was examined, using fetal (days 18, 19 and 22 = term), neonatal (days 7 and 18) alveolar epithelial cells as well as adult alveolar type-II cells. Maximal stimulation of [3H]thymidine incorporation occurred in neonatal d18 cells: (250 +/- 4.8%, n = 4, P < 0.05). Incubation of adult type-II cells, in the presence of 10(-9) M DHD increased thymidine incorporation into DNA (149.1 +/- 33.2%, mean +/- S.E., n = 3, P < 0.001) compared to control cells maintained in basal medium. Exposure to DHD also increased thymidine incorporation after stimulation with a mixture of conventional progression factors (insulin (10 micrograms/ml) (I), cholera toxin (10 micrograms/ml) (C) and EGF (20 ng/ml) (E)) (349.4 +/- 42.9% vs. 213.5 +/- 23.6%, n = 6, P < 0.005). Autoradiographic labeling indices of adult type-II cells increased from 3.1 +/- 0.6% for cells cultured in basal medium to 7.2 +/- 1.7% in cells exposed to DHD from the time of plating and I, C, E from 20-68 h in culture (n = 4, P < 0.05). Although no increase in the number of adult type-II cells was observed in these experiments, flow cytometric analysis of nuclear DNA content revealed an increased proportion of cells in the S and G2 phases of the cell cycle (basal: S = 2.6%, G2/M = 3.0%, DHD+GF: S = 4.7%, G2/M = 5.6%, P < 0.05 for each comparison). These data demonstrate that vitamin D3 is a growth factor for alveolar type-II cells and suggest the possibility that local elaboration of vitamin D may provide a novel mechanism of modulation of epithelial proliferation in the context of lung development and repair.

The clinical assessment of severe asthma.

Thorough and ongoing clinical assessment is the foundation of modern asthma management. The history delineates the severity, circumstances, and time course of the present attack, placing it in the clinical context of the patient and his disease. A physical examination disclosing airflow obstruction, tissue hypoxia, respiratory muscle fatigue, and complications of therapy, in conjunction with simple objective measures of airflow obstruction and arterial gas tensions, allows the physician to make informed management decisions in the care of these severely ill patients.

Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation.

Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast-mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate-resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross-links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast-mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.

Amrinone metabolism.

High-performance liquid chromatographic methods for the analysis of amrinone in plasma and for both amrinone and its N-acetyl metabolite in urine were developed and applied to measure specimens obtained from a number of healthy men who had received intravenous or oral amrinone. The intravenous doses ranged from 0.8 to 2.2 mg/kg. Terminal elimination of amrinone from the bloodstream followed apparent first-order kinetics. Half-life, after the drug had distributed to the tissues, was estimated by a log-linear least-squares regression; mean half-life was 2.6 +/- 1.4 hr. During the first 24 hr after medication, unchanged amrinone excreted in the urine of these subjects represented 10% to 40% of the dose. N-Acetyl metabolite in the urine represented less than 2% of the dose. In the oral study, doses ranged from 25 to 250 mg (0.31 to 3.5 mg/kg) and the maximum plasma concentration attained was proportional to the dose. The first order terminal elimination half-life was possibly dose-related. In only one subject were there unequivocal amounts of the N-acetyl metabolite in the plasma.

Dose proportionality of amrinone.

Amrinone was given to 18 healthy subjects in doses of 75, 150, and 225 mg in a randomized crossover design. Plasma levels were shown to rise in proportion to dose. The mean plasma AUC, extrapolated to infinite time, was determined for each dose level; the values obtained were 4, 8.18, and 12.35 micrograms . hr/ml for the 75-, 150-, and 225-mg doses. Mean maximum observed plasma concentrations were 1.03, 1.74, and 2.58 micrograms/ml. At higher doses the extrapolated AUC is more variable, but it is linear over the range of 0.73 to 3.81 mg/kg. The apparent first-order terminal elimination rate is not dose dependent and corresponds to a t1/2 of 3.85 hr.

Effect of the acetylator phenotype on amrinone pharmacokinetics.

Ten healthy male subjects were phenotyped with isoniazid for their acetylator status and then received intravenous amrinone at a dose of 75 mg during a period of 10 minutes. Blood samples were drawn at specified times during a 24-hour period after dosing. Plasma concentrations of amrinone were determined by a specific HPLC method. The plasma concentration data were fitted to a biexponential model by nonlinear regression. The mean apparent first-order elimination t1/2 for amrinone in the slow acetylators was 4.4 hours, whereas it was 2.0 hours in the fast acetylators (P less than 0.05). There was little difference in the volume of distribution at steady state. Clearance was lower in the slow acetylators, 16.6 L/hr, than in the fast acetylators, 37.2 L/hr (P less than 0.05). The AUC was higher for the slow acetylators, 4.96 micrograms X hr X ml-1, than for the fast acetylators, 2.20 micrograms X hr X ml-1 (P less than 0.01). Concentrations of amrinone and its N-acetyl metabolite in the urine from each volunteer were determined. The ratio of N-acetylamrinone to amrinone was calculated and, as expected, the fast acetylators had a higher ratio than did the slow acetylators (P less than 0.01).

Relationship between amrinone plasma concentration and cardiac index.

Amrinone was given to 14 patients with congestive heart failure as an intravenous bolus (1 mg/sec) at doses ranging from 0.5 to 3.5 mg/kg. Simultaneous determinations of cardiac index were made by thermodilution and of amrinone plasma concentration by high-performance liquid chromatography. A relationship between improvement in cardiac index and increasing plasma concentrations of amrinone was demonstrated for 13 of the 14 patients. The percentage increase in cardiac index correlated with amrinone plasma concentration (r = 0.81; p less than 0.001). Amrinone was given to four patients as an intravenous bolus dose of 1.5 mg/kg followed by a constant infusion of 10 micrograms/kg/min for 10 hr; simultaneous determinations of cardiac index and circulating levels of amrinone indicated that both declined after the initial rise. The plasma concentration of amrinone remained relatively constant during the infusion at about 1.7 micrograms/ml. In all cases, despite the relatively constant plasma levels there was a decline in cardiac index after about 4 to 5 hr of infusion, although the cardiac index remained above the baseline; during the constant infusion the cardiac index rose again and was maintained at a reasonably constant level for the last 3 hr. Seven patients received oral doses of amrinone of about 3 mg/kg, and simultaneous determinations of cardiac index and plasma concentration showed a relationship between amrinone level and rise in cardiac index (p less than 0.05). In 16 patients after amrinone orally sufficient blood samples were taken to estimate the apparent first-order terminal elimination t 1/2. The t 1/2 as estimated by log-linear regression ranged from about 3 to 15 hr; mean +/- SEM value was 8.3 (+/- 1.1) hr.

Blood levels, tissue distribution and the duration of action in rats of ciprofibrate, a new hypolipidemic agent.

The blood levels, distribution and duration of action of ciprofibrate, an orally active hypolipidemic agent, was investigated in rats. Serum concentrations of 30 micrograms of ciprofibrate/ml are associated with significant reductions in both serum cholesterol and triglycerides in rats on a hyperlipidemic diet. Increasing the plasma concentrations of ciprofibrate to 69 micrograms/ml resulted in only a modest incremental reduction in serum lipids. The distribution of radioactivity from [14C]ciprofibrate within rat tissues was not affected by prior treatment for 14 days with ciprofibrate at either 1.5 or 3.0 mg/kg/day. Varying the dosage regimen of ciprofibrate at 30 mg/kg, with medication at intervals of one, 2 or 3 days resulted in similar peak plasma levels of about 300 micrograms/ml, 4 h after medication. The half-life of ciprofibrate, during the terminal disposition phase, was about 82 h. Levels of serum cholesterol remained suppressed up to 3 days after medication with ciprofibrate was discontinued; triglyceride levels returned to control values more slowly.

The effect of low-potassium-dextran versus Euro-Collins solution for preservation of isolated type II pneumocytes.

Limited availability of donor organs is a major factor restricting the clinical application of lung transplantation. Improvements in preservation techniques are essential for prolonging storage time and improving lung function following transplantation. The present investigation used primary cultures of adult rat alveolar type II cells as a model for evaluating lung-preservation solutions. Type II cells were plated onto tissue-culture plastic at a density 5 x 10(5) cells/cm2 and maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (D10) for 40 hr. Cells were then exposed to Euro-Collins solution or a low-potassium-dextran solution (LPD). At designated time points, measurements of lactate-dehydrogenase (LDH) release, protein content, and incorporation of 3H-thymidine into cellular DNA were made. During 12 hr of "storage" at 37 degrees C, cells maintained in LPD released less LDH (14.3 +/- 1.2% of cellular total, mean +/- SEM, n = 5) than their counterparts stored in EC (20.6 +/- 1.6%, P less than 0.05). During the 36 hr following a 6-hr exposure to preservative solutions, LPD-treated cells incorporated more thymidine per mg of protein (2566 +/- 419.8 cpm/micrograms protein, mean +/- SEM, n = 6) compared with cells maintained continuously in D10 (1431 +/- 351, P less than 0.05). By contrast, cells exposed to EC incorporated less thymidine (82.2 +/- 62.8 cpm/micrograms protein) than either cells maintained in LPD or D10 (P less than 0.01 for each comparison). These results suggest that LPD solution is less cytotoxic than EC and that LPD enables higher levels of metabolic activity in recovering epithelial cells. In vitro cultures of type II epithelial cells are a useful model system for the study of lung preservation and posttransplantation lung injury.

The effect of the cold pressor test on vasopressin secretion in man.

Stress has been thought to induce the release of arginine vasopressin (AVP). We evaluated this claim by studying the effects of a modified cold pressor test on plasma AVP, plasma cortisol, blood pressure, pulse rate, and a number of variables known to affect AVP secretion. In a cross-over study design, test and control values were obtained in seven male subjects. The pressor test was found to induce painful stress as evidenced by subjective reports and the objective findings of increased mean arterial pressure (13.9 +/- 3.1 mm Hg; p less than 0.004), pulse rate (9.2 +/- 2.8 beats/min; p less than 0.02), and plasma cortisol (3.5 +/- 0.8 micrograms/dl; p less than 0.005). In contrast, there were no significant changes in plasma AVP that could be attributed to the cold pressor test. There also were no changes in plasma osmolality, measured plasma solutes, hematocrit or body temperature. An unexpected finding was a premonitory drop in plasma AVP occurring just prior to the pressor test (2.5 +/- 2.0 pg/ml; p less than 0.04) and at the comparable time point in the control study (3.1 +/- 1.2 pg/ml; p less than 0.001). There were no changes in any of the other measured variables which could account for this drop. We conclude that the cold pressor test is not a stimulus to AVP release and that anticipation of stress may inhibit secretion of this hormone.

Bronchogenic carcinoma in patients seropositive for human immunodeficiency virus.

The purpose of this report is to describe an association between bronchogenic carcinoma and HIV. Three HIV-seropositive patients are described who developed bronchogenic cancer (two large cell, one adenocarcinoma) before developing an AIDS-defining illness. A critical review of the literature revealed 22 other patients in which the association of HIV infection and lung cancer is reported. These patients are characterized by a relatively young age at diagnosis (median, 43 years) and prevalence of the adenocarcinoma subtype (13 of 25 patients). Twenty of 21 patients had a history of smoking. Among 21 patients for whom data were available, 6 patients (28 percent) had AIDS at time of diagnosis of lung cancer while 11 patients (55 percent) did not have AIDS or AIDS-related complex at diagnosis.

A radioimmunoassay for danazol (17alpha-pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol).

A method is described for the radioimmunoassay of circulating levels of the pituitary inhibiting agent, danazol. An antigen for danazol was prepared by reacting a 17-carboxy-methyloxime derivative of danazol with bovine serum albumin. By immunizing rabbits with this antigen, antiserum was generated which shows excellent specificity for danazol relative to its known metabolites as well as to many natural steroids. A radioimmunoassay was developed, without using separation or extraction techniques, involving competition for the antiserum between danazol in plasma and 14C-danazol. This assay has been successfully used to measure danazol in a series of normal human subjects receiving the drug at either 100 or 200 mg b.i.d. for 2 weeks. A significant relationship was seen between dosage of danazol and plasma concentrations.

Concentration of perfluorohexyl bromide in dog plasma and selected tissues.

Beagle dogs received single perfluorohexyl bromide doses, either 30.2 g/kg po or 3.8 g/kg intratracheally. The apparent first-order plasma half-life during the terminal elimination phase was approximately 8 hr after oral treatment and greater than 8 hr after intratracheal administration. Tissue analysis showed the highest mean concentration of the compound in abdominal fat 1 week after intratracheal administration. One dog had detectable levels in abdominal fat 4 weeks after treatment by either administration route.

Pharmacokinetics of iohexol, a new nonionic radiocontrast agent, in humans.

Sixteen healthy men received iohexol intravenously at a concentration of 346 mg of iodine/mL. Doses of 500, 750, 1000, and 1500 mg of iodine/kg of body weight were administered to four volunteers each. Neither clearance nor percent of dose excreted in the urine showed any significant correlation with size of the dose. The overall mean (+/- SD) renal and total body clearances were 120 +/- 18.6 and 131 +/- 18.6 mL/min, respectively. The overall mean apparent volume of distribution was 165 (+/- 30.7) mL/kg. Urine contained 92.3 +/- 4.4% of the dose. Most of the drug (89.9%) was excreted within the first 12 h. An open three-compartment body model gave the best fit to the experimental data. The mean apparent first-order terminal elimination (gamma-phase) half-life was 12.6 h.