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Purpose: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations., Patients and Methods: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels., Results: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer., Conclusions: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557., (©2023 American Association for Cancer Research.)

Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

A problem of multivariate probability density function estimation by exploiting linear independent components analysis (ICA) is addressed. Historically, ICA density estimation was initially proposed under the name projection pursuit density estimation (PPDE) and two basic methods, named forward and backward, were published. We derive a modification of the forward PPDE method, which avoids a computationally demanding optimization involving Monte Carlo sampling of the original method. The results of the experiments show that the proposed method presents an attractive choice for density estimation, which is pronounced for a small number of training observations. Under such conditions, our method usually outperforms model-based Gaussian mixture model. We also found that our method obtained better results than the backward PPDE methods in the situation of nonfactorizable underlying density functions. The proposed method has demonstrated a competitive performance compared with the support vector machine and the extreme learning machine in some real classification tasks.

Ultrasonic pulse-echo methods have been used extensively in non-destructive testing of layered structures. In acoustic measurements on thin layers, the resulting echoes from two successive interfaces overlap in time, making it difficult to assess the individual echo parameters. Over the last decade sparse approximation methods have been extensively used to address this issue. These methods employ a large dictionary of elementary functions (atoms) and attempt to select the smallest subset of atoms (sparsest approximation) that represent the ultrasonic signal accurately. In this paper we propose the cluster-enhanced sparse approximation (CESA) method for estimating overlapping ultrasonic echoes. CESA is specifically adapted to deal with a large number of signals acquired during an ultrasonic scan. It incorporates two principal algorithms. The first is a clustering algorithm, which divides a set of signals comprising an ultrasonic scan into groups of signals that can be approximated by the same set of atoms. The second is a two-stage iterative algorithm, which alternates between update of the atoms associated with each cluster, and re-clustering of the signals according to the updated atoms. Because CESA operates on clusters of signals, it achieves improved results in terms of approximation error and computation time compared with conventional sparse methods, which operate on each signal separately. The superior ability of CESA to approximate highly overlapping ultrasonic echoes is demonstrated through simulation and experiments on adhesively bonded structures.

SIRT1, the mammalian homolog of yeast Sir2, is a founding member of a family of 7 protein and histone deacetylases that are involved in numerous biological functions. Previous studies revealed that SIRT1 deficiency results in genome instability, which eventually leads to cancer formation, yet the underlying mechanism is unclear. To investigate this, we conducted a proteomics study and found that SIRT1 interacted with many proteins involved in replication fork protection and origin firing. We demonstrated that loss of SIRT1 resulted in increased replication origin firing, asymmetric fork progression, defective intra-S-phase checkpoint, and chromosome damage. Mechanistically, SIRT1 deacetylates and affects the activity of TopBP1, which plays an essential role in DNA replication fork protection and replication origin firing. Our study demonstrated that ectopic over-expression of the deacetylated form of TopBP1 in SIRT1 mutant cells repressed replication origin firing, while the acetylated form of TopBP1 lost this function. Thus, SIRT1 acts upstream of TopBP1 and plays an essential role in maintaining genome stability by modulating DNA replication fork initiation and the intra-S-phase cell cycle checkpoint.

In this paper, we propose a method for P-variate probability density estimation assuming a Gaussian mixture model (GMM). Our method exploits a regularization technique for improving the estimation accuracy of the GMM component covariance matrices. We derive an expectation maximization algorithm for fitting our regularized GMM (RGMM), which exploits an analytical Ledoit-Wolf-type shrinkage estimation of the covariance matrices. Our method is compared with recent model-based and variational Bayes approximation methods using synthetic and real data sets. The obtained results show that the proposed RGMM method achieves a significant improvement in the performance of multivariate probability density estimation with respect to other methods on both the synthetic and the real data sets.

Human artificial chromosomes (HACs) represent a novel promising episomal system for functional genomics, gene therapy, and synthetic biology. HACs are engineered from natural and synthetic alphoid DNA arrays upon transfection into human cells. The use of HACs for gene expression studies requires the knowledge of their structural organization. However, none of the de novo HACs constructed so far has been physically mapped in detail. Recently we constructed a synthetic alphoid(tetO)-HAC that was successfully used for expression of full-length genes to correct genetic deficiencies in human cells. The HAC can be easily eliminated from cell populations by inactivation of its conditional kinetochore. This unique feature provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This work describes organization of a megabase-size synthetic alphoid DNA array in the alphoid(tetO)-HAC that has been formed from a ~50 kb synthetic alphoid(tetO)-construct. Our analysis showed that this array represents a 1.1 Mb continuous sequence assembled from multiple copies of input DNA, a significant part of which was rearranged before assembling. The tandem and inverted alphoid DNA repeats in the HAC range in size from 25 to 150 kb. In addition, we demonstrated that the structure and functional domains of the HAC remains unchanged after several rounds of its transfer into different host cells. The knowledge of the alphoid(tetO)-HAC structure provides a tool to control HAC integrity during different manipulations. Our results also shed light on a mechanism for de novo HAC formation in human cells.

Ultrasonic pulse-echo methods have been used extensively in measuring the thickness of layered structures as well as those of thin adhesive interface layers. When acoustically measuring thin layers, the resulting echoes from two successive interfaces overlap in time, limiting the minimum thickness that can be resolved using conventional pulse-echo techniques. In this paper, we propose a method, named support matching pursuit (SMP), for resolving the individual echoes. The method is based on the concept of sparse signal approximation in an overcomplete dictionary composed of Gabor atoms (elementary functions). Although the dictionary enables highly flexible approximations, it is also overcomplete, which implies that the approximation is not unique. We propose a method for approximation in which each ultrasonic echo is principally represented by a single atom and therefore has a physical interpretation. SMP operates similarly to the sparse matching pursuit (MP) method. It iteratively improves the approximation by adding, at each iteration, a single atom to the solution set. However, our atom selection criterion utilizes the time localization nature of ultrasonic echoes, which causes portions of a multi-echo ultrasonic signal to be composed mainly from a single echo. This leads to accurate approximations in which each echo is characterized by a set of physical parameters that represent the composing ultrasonic echoes. In the current research we compare SMP to other sparse approximation methods such as MP and basis pursuit (BP). We perform simulations and experiments on adhesively bonded structures which clearly demonstrate the superior performance of the SMP method over the MP and BP methods.

Biological Pathway Exchange (BioPAX) is a standard language to represent biological pathways at the molecular and cellular level and to facilitate the exchange of pathway data. The rapid growth of the volume of pathway data has spurred the development of databases and computational tools to aid interpretation; however, use of these data is hampered by the current fragmentation of pathway information across many databases with incompatible formats. BioPAX, which was created through a community process, solves this problem by making pathway data substantially easier to collect, index, interpret and share. BioPAX can represent metabolic and signaling pathways, molecular and genetic interactions and gene regulation networks. Using BioPAX, millions of interactions, organized into thousands of pathways, from many organisms are available from a growing number of databases. This large amount of pathway data in a computable form will support visualization, analysis and biological discovery.

Sex differences in systolic and diastolic blood pressure levels and trends with age have been consistently observed in both industrialized and unindustrialized populations. However, the impact of sex on pulse pressure, an index of vascular aging, in unindustrialized populations has not been addressed. The objective of this report was to characterize sex differences in aging trends of pulse pressure within unindustrialized populations. Using PubMed and Medline, we identified 60 articles with blood pressure data from unacculturated or partially acculturated populations. Data on 27 populations from 22 articles were included for analysis, on the basis of adequate description of study design and blood pressure measurement. Blood pressure means of adult age groups were modeled by linear and polynomial regression. The pulse pressure levels of women were lower than those of men in early adulthood and higher in older ages. Women had a steeper, steady increase in pulse pressure with age than men (P<0.001), whereas men had a stronger curvilinear upswing in pulse pressure with age (P=0.006). Partially acculturated populations had higher pulse pressures than unacculturated populations. Sex had a stronger effect on pulse pressure than acculturation. Pulse pressure trajectories of unindustrialized populations were slightly attenuated compared with those seen in National Health and Nutritional Examination Surveys III and IV of the US population. A sex effect on pulse pressure trends with age prevails across unacculturated and acculturated populations. Accordingly, the biological principles of arterial aging, as expressed in pulse pressure, are the same in all humans, regardless of demography.

A recently published generalized growing and pruning (GGAP) training algorithm for radial basis function (RBF) neural networks is studied and modified. GGAP is a resource-allocating network (RAN) algorithm, which means that a created network unit that consistently makes little contribution to the network's performance can be removed during the training. GGAP states a formula for computing the significance of the network units, which requires a d-fold numerical integration for arbitrary probability density function p(x) of the input data x (x in R(d)) . In this work, the GGAP formula is approximated using a Gaussian mixture model (GMM) for p(x) and an analytical solution of the approximated unit significance is derived. This makes it possible to employ the modified GGAP for input data having complex and high-dimensional p(x), which was not possible in the original GGAP. The results of an extensive experimental study show that the modified algorithm outperforms the original GGAP achieving both a lower prediction error and reduced complexity of the trained network.

A five-year-old boy was evaluated for fever, abdominal pain, vomiting, and diarrhea lasting two days. Chest radiograph revealed a left bronchopneumonia. Metabolic work-up demonstrated phosphaturia, glucosuria, calciuria, proteinuria, profound hypophosphatemia, hypouricemia, borderline hypomagnesemia, and normoglycemia. Creatine phosphokinase values were elevated, a finding consistent with rhabdomyolysis. Serum pH was normal and urine pH was 5. Serum urea and creatinine levels were normal. The child was treated with ceftriaxone and azithromycin. Oral phosphate was administered, followed by a rapid normalization of its serum level. Re-evaluation one and three months after discharge, while being off any therapy, showed the resolution of all metabolic abnormalities. We believe that the metabolic disturbances in this child were due to an acute and transient tubular dysfunction, possibly secondary to inflammatory/infectious induced tubulointerstitial nephritis (TIN). TIN presenting with an isolated tubular functional impairment, in the absence of any evidence of functional glomerular impairment, does not appear to have been described before.

Unlabelled: Pseudomonas aeruginosa (PA) is considered to be bacteria with a low capability to produce nitrite., Objective: To investigate the incidence of a positive urine nitrite test in community-acquired urinary tract infections (UTI) in children, caused by PA., Methods: The medical records of 38 children (18 females) admitted for febrile PA UTI during a period of 7 years were reviewed. Urine nitrite tests were carried out using dipstrips, and results were reported as positive or negative., Results: Of the 38 patients, 17 had a positive nitrite test and 21 had a negative test (proportion of positive 0.45, 95% confidence interval 0.29 to 0.61). Pyuria was detected in 13/17 patients with a positive nitrate test vs. 5/21 with a negative test (p=0.003). Data regarding renal ultrasound (US) were available for 35 patients, and in 20 abnormalities were detected, 14/17 in the positive vs. 6/18 in negative nitrite group (p = 0.001)., Conclusion: The urine nitrite test may be positive in PA UTI, therefore, a positive test does not rule out Pseudomonas UTI.

Objectives: Little is known about the relationship between the renal and gastrointestinal excretion of potassium in humans. This information is important in light of strong associations of potassium intake with hypertension and occlusive stroke., Methods: We determined the relationship between fecal and urinary excretion of potassium under both fixed and variable potassium intakes using our unpublished archival data and published data of others. Twenty-five subjects were evaluated., Results: On a fixed, low oral potassium intake (61.2 +/- 4.7 mmol/day; mean +/- SD), there was an inverse relationship between fecal and urinary potassium excretion (r = -0.66, p = 0.040). In studies in which potassium intake varied between 61-135 mmol/day, fecal and urinary potassium excretions were positively correlated (r = 0.58, p = 0.024). Considerable within-and-between-subject variation was observed in the relationship between fecal and urinary potassium excretion., Conclusions: Inter-individual variation in fecal potassium excretion may arise from both variation in dietary potassium intake and intrinsic individual differences in the renal versus gastrointestinal handling of potassium.

Background/aims: High sodium consumption has been repeatedly reported to exert deleterious effects on severe chronic renal failure progression, mainly via glomerular mechanisms. However, the role of high sodium intake in renal function deterioration in a model of moderate chronic tubulointerstitial disease has not yet been addressed. We evaluated the effects of exaggerated dietary sodium and the resultant increase in proteinuria on renal function deterioration in experimental tubulointerstitial disease in rats., Methods: In 48 Sprague-Dawley rats, moderate renal failure (approximately 50% of normal glomerular filtration rate) was induced by administration of lithium chloride in drinking water. The animals were divided into three groups fed low (<0.2% Na(+)), normal (0.5% Na(+)), or high (8% Na(+)) sodium diets., Results: Animals in all groups remained normotensive with a similar course of GFR downslope and 100% survival, irrespective of sodium regimen. Rats consuming high sodium diets developed significantly greater proteinuria compared to their counterparts fed normal or low sodium chow., Conclusions: (1) Deterioration of renal function in a lithium-induced model of normotensive moderate chronic renal failure was not affected by dietary sodium. (2) Unlike in some other human or experimental renal failure models, the magnitude of proteinuria had no adverse effect on the progression of renal deterioration.

The objective of this study was to assess the frequency of symptomatic urinary tract infections (UTIs) following voiding cystourethrography (VCUG) while using prophylactic antibiotics. Medical records of 421 patients who underwent a VCUG during a period of 4 years were reviewed. Three hundred forty-nine had a VCUG following a febrile UTI, and 72 had the test for evaluation of hydronephrosis. All received prophylactic antibiotics and were evaluated within 7-10 days following the VCUG. One hundred seventy-two children (41%) had an abnormal VCUG. Seven of 421 children (1.7%) had symptoms suggestive of UTI. Two had culture negative pyuria; one had Escherichia Coli UTI, and four had Pseudomonas aeruginosa UTI. On multivariate logistic regression analysis, the risk factors contributing to the development of UTI following VCUG were the presence of vesicoureteral reflux (VUR) and its severity (odds ratio [OR] 2.52; 95% confidence interval [CI] 2.24, 2.83, p =0.001; and OR 2.32; 95% CI 2.05,2.62, p =0.04, respectively). The incidence of VCUG-induced UTI in children receiving prophylactic antibiotic therapy is low. There is a relatively high rate of Pseudomonas UTI, especially in children with moderate to severe reflux. We recommend that children with symptoms suggesting a UTI following a VCUG should be treated for Pseudomonas aeruginosa pending culture results.

Background/aim: Hypertension induced by exaggerated sodium consumption accelerates the progression of renal failure. We investigated the effects of a high-sodium (HS) diet on the progression of renal failure in rats maintained normotensive by angiotensin-converting enzyme inhibition or AT-1 blockade., Methods: In 70 Sprague-Dawley rats, renal failure was induced by five-sixths nephrectomy. They were fed isocaloric normal-sodium (NS), low-sodium (LS), or HS diets. HS rats prone to develop hypertension were divided into three subgroups: treated to normotension by irbesartan (HS-1) or captopril (HS-2) or left untreated (HS-0)., Results: All HS animals developed significant proteinuria which strongly correlated with the 24-hour sodium excretion. HS-0 rats demonstrated severe hypertension, rapid deterioration of the renal function, and 100% mortality after 3 weeks. In irbesartan-treated HS-1 rats, mortality and decline of the glomerular filtration rate were similar to those of normal- or low-sodium-fed animals (100% mortality after week 12). In captopril-treated HS-2 rats, glomerular filtration rate decline and mortality were significantly blunted as compared with all other groups (50% mortality after week 12)., Conclusions: (1) In five-sixths-nephrectomized uremic rats maintained normotensive by either irbesartan or captopril, the rate of deterioration of the renal function was not aggravated by exaggerated sodium consumption. (2) In this experimental setting, captopril treatment yielded a better survival outcome as compared with irbesartan, despite the similar hypotensive effect.

Background: Amphotericin B may cause acute reduction in renal function. N-acetylcysteine (NAC) has a renoprotective activity in several nephrotoxic renal insults, but its effect on amphotericin-induced renal failure has not been investigated yet., Methods: Acute renal failure was induced in 30 Sprague-Dawley rats by a single intraperitoneal injection of amphotericin B (50 mg/kg). NAC (10 mg/kg) in isotonic saline or isotonic saline alone were administered daily for 4 days, starting 1 day before the amphotericin B injection. Glomerular filtration rate (GFR) was assessed using 99m-technetium diethylene triaminepentaacetic acid. Before and following amphotericin B administration, a 24-hour urine collection was performed for sodium, potassium and magnesium determination. The kidneys were preserved for pathologic examination., Results: Amphotericin B induced a significant decrease of GFR in both groups. Four days after amphotericin injection the GFR in the NAC-treated group was significantly higher than in the control group (0.62 +/- 0.20 vs. 0.46 +/- 0.14 ml/min, p = 0.042). Histologic signs of acute tubular necrosis were attenuated in the NAC-treated group. There were no significant differences between the groups in sodium, potassium and magnesium urine excretion after amphotericin injection., Conclusions: NAC treatment exerted a renoprotective effect on deterioration of GFR in a rat model of amphotericin-induced renal failure. No functional protection on tubular function, as obviated by similar polyuria and urine losses of potassium and magnesium in both groups, was observed., (Copyright (c) 2005 S. Karger AG, Basel.)

Objectives: Pseudohypoaldosteronism type 1 (PHA1) is a rare inherited disorder characterized by salt-wasting due to target organ unresponsiveness to mineralocorticoids. PHA1 comprises two clinically and genetically distinct entities; isolated renal and systemic forms., Design: The aim of this study was to investigate red blood cell (RBC) Na+,K+-ATPase activity and nasal potential difference (PD) in two pairs of unrelated dyzygous twins; one with the systemic form of the disease (PHA1-S) and the second with the isolated renal form (PHA1-R). Total and ouabain-sensitive ATPase activities were measured spectrophotometrically by a method that couples ATP hydrolysis with NADH oxidation. Maximal PD and response to amiloride perfusion were evaluated by a standard technique., Results: In the twins with PHA1-S, persistently low activity of RBC Na+,K+-ATPase was found during a 6-year follow-up. Normalization of plasma renin activity (PRA) and plasma aldosterone was observed at the end of the first year of life. Maximal nasal PD was low and there was no significant response to amiloride. In the twins with PHA1-R, RBC Na+,K+-ATPase activity was very low at the time of diagnosis and normalized at the age of 6-8 months. PRA reverted gradually to normal values, whereas aldosterone levels remained high during the 6 years of follow-up. Maximal nasal PD and response to amiloride were normal., Conclusions: The observed differences in RBC Na+,K+-ATPase activity and nasal PD response to amiloride between the two pairs of twins support the contention of different basic pathogenic mechanisms in the two forms of PHA1.

Objective: To assess the frequency of urinary tract anomalies in male neonates <8 weeks old who presented with urinary tract infection (UTI), and to evaluate a suitable imaging approach after the initial infection., Design: During a period of 4.5 years, from July 1994 through December 1998, 45 male neonates <8 weeks old (range: 5-56 days; mean: 23.77 days) with UTI were hospitalized. All patients had an ultrasound (US) and a voiding cystourethrogram (VCUG), except 1 neonate in whom VCUG was unsuccessful because of technical problems. A dimercaptosuccinic acid (DMSA) scan was recommended to all patients but was performed only in 30 of 45, most of them with an abnormal VCUG. The renal scan was performed at least 4 months after the UTI., Results: Urinary tract abnormalities were observed in 22 of 45 male neonates. Nineteen had vesicoureteral reflux (VUR), 1 had VUR and a double collecting system, 1 had VUR and a posterior urethral valve, and 1 had an ureteropelvic junction stricture. Renal atrophy or scars, as demonstrated by DMSA scan, were detected almost exclusively in neonates with VUR grade 3 and above. Only 1 neonate with VUR grade 1 had a pathologic DMSA, and the US of this male also demonstrated renal atrophy. Escherichia coli was the pathogen in 62% (28 of 45), and 9 boys had bacteremia., Conclusion: We suggest that US and VCUG should be performed routinely after the initial UTI in male neonates. Renal scan should be reserved for those cases in which the US suggests renal parenchymal damage or when VCUG detects VUR grade 3 and above.

We aimed to investigate, by means of dimercaptosuccinic acid (DMSA) scan, the relations between vesicoureteral reflux (VUR) and its degree, pyelonephritis during infancy, and renal parenchymal findings. Seventy-four infants with pyelonephritis, 44 girls and 30 boys (mean age at their first pyelonephritic episode 4.12 months, median 3 months), were enrolled in the study. Voiding cystourethrography (VCU) and ultrasonography (US) were performed within 6 weeks following the infection. DMSA was performed at least 4 months after the urinary tract infection (UTI). The renal parenchymal pathology was defined as focal or multifocal defects or as a split renal uptake of less than 45%. DMSA scintigraphy revealed that 19% (14/74) of the children had renal damage. Renal parenchymal findings were observed only when VUR was present, and its grade was above 3/5. No abnormality was found in 51 renal units without reflux, 9 with VUR grade 1/5, and 54 with grade 2/5. Renal pathology was observed in 9/24 renal units with VUR grade 3, 3/8 with grade 4, and 2/2 with grade 5. No correlation was found between renal parenchymal defects and clinical presentation of the pyelonephritis, type of the microorganism, presence of bacteremia, or the number of recurrent infections. In adequately treated infants, renal damage is probably due to a reflux-associated, preexisting, congenital renal parenchymal pathology and not to the inflammatory process. We suggest that DMSA scintigraphy should not be performed routinely in every infant with UTI and should be reserved primarily for children with VUR grade 3 and above.

A method for recursive training of neural networks for classification is proposed. It searches for the discriminant functions corresponding to several small local minima of the error function. The novelty of the proposed method lies in the transformation of the data into new training data with a deflated minimum of the error function and iteration to obtain the next solution. A simulation study and a character recognition application indicate that the proposed method has the potential to escape from local minima and to direct the local optimizer to new solutions.

Aim: To investigate sodium (NA(+)) potassium (K(+)) adenosine triphosphatase (ATPase) activity in newborn infants at different gestational ages, to elucidate the mechanism underlying poor renal sodium conservation in preterm infants., Methods: Fifty three healthy newborn infants, gestational age 30-42 weeks, were studied. Umbilical cord red blood cell Na(+) K(+)ATPase activity, plasma renin activity, and plasma aldosterone activities were measured in all of them. Red blood cell Na(+) K(+)ATPase activity was re-examined in eight preterm infants, one and two weeks after birth. Total and ouabain sensitive ATPase activity was measured spectrophotometrically using a method that couples ATP hydrolysis with NADH oxidation., Results: Red blood cell Na(+) K(+)ATPase activity was significantly lower (p<0.01) in preterm babies with a gestational age below 35 weeks, compared with those with aged 35 weeks and above: 2.3 (0.8) and 6.7 (1.3) nmol NADH/minute/mg protein, respectively. There was no correlation between gestational age, Na(+) K(+)ATPase, plasma renin activity and aldosterone values either in the preterm or term babies. Two weeks after birth, irrespective of gestational age, the enzyme activity of the preterm babies increased to values similar to those observed in the term neonates at birth., Conclusion: The differences in sodium homeostasis between term and preterm babies are modulated via changes in Na(+) K(+)ATPase activity.

Unlabelled: Following reports on adult patients with neutropenia as a result of administration of intravenous immunoglobulin (IVIG) we have investigated the incidence and consequences of neutropenia following IVIG treatment in children with immune thrombocytopenic purpura (ITP). The medical records of 14 children with ITP who received IVIG as inpatients were reviewed. Past and present history, age, previous medications, complete blood count and differential before and after treatment with IVIG were recorded for each patient. The patients, aged 5.5 +/- 3.5 (0.5-11.5) years [mean +/- SD; range] received one or more courses of IVIG. Neutropenia (total neutrophils < 2000/mm3) was observed within 24 h after the first course of IVIG in five children (36%). The pretreatment neutrophil count in this group was not significantly different from that observed in the patients without IVIG-induced neutropenia (p = 0.98). The condition resolved spontaneously and without complications in all patients within 48 h. In a preliminary experiment in which bone marrow derived mononuclear cells were assayed for the clonogenicity in methylcellulose, there was no suppressive effect of IVIG on the number of CFU-GM colonies., Conclusions: Since IVIG is currently administered in a vast number of medical indications, neutropenia following IVIG administration may not be an uncommon finding. It seems to be transient and self limited.

Digoxin and gentamicin are widely used in pediatric medicine, and therapeutic monitoring is mandatory because of their narrow margin of safety and wide interpatient and intrapatient pharmacokinetic variabilities. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is often difficult. In 11 children treated with digoxin for various cardiac conditions, and in 24 children treated with gentamicin (14 patients were administered gentamicin three times a day, and 10 once-daily), drugs levels were measured in plasma and saliva. There was no correlation between plasma total or free digoxin concentrations and saliva levels, precluding the clinical use of the saliva test for digoxin. No correlation was found between plasma gentamicin concentrations and saliva levels when the drug was administered three times a day; however, good correlation was found when the drug was administered once-daily (r2 = 0.89, p < 0.0001). Saliva may be used as a noninvasive method of measuring gentamicin serum concentrations to guide dosage adjustments in patients administered the drug once-daily.

The aim of this study was to determine whether using air enema for acute intussusception is related to a higher rate of recurrence than other methods of treatment. A 10-y (1986-95) retrospective study was performed in a university-affiliated paediatric division. The overall recurrence rate for 97 patients with acute intussusception was 7.8% (10% of whom were treated non-surgically). There were no recurrences following the surgical treatment. In matched groups of patients, no risk factors were found for recurrence following air vs barium enema.

Visual evoked potentials (VEPs) were performed in a blind fashion in 114 children aged 3 to 17 years with different types of headaches, in order to investigate whether this could be helpful in the diagnosis of migraine versus other types of headaches in children. The study showed that the amplitude between P100 and N2 was significantly larger in children with migraine headaches (mean 19.8 microvol, SD 7.75) compared with other types of headaches (mean 13.1 microvol, SD 7.45). These results suggest that the sensitivity of VEP P100 amplitude to distinguish migraine headaches in children is 67%, the specificity of VEP is 83%, and the predictive positive value is 83%. VEP study might be helpful in work-up of a child with headache, particularly a young child, when signs and symptoms may not be characteristic.

Circumcision seems to reduce the overall incidence of urinary tract infections (UTI), although a few studies have suggested that ritual circumcision may be a predisposing factor for UTI within the first 2 weeks following the procedure. The aim of this study was to investigate a possible causal relationship between ritual circumcision and UTI. The study comprised 82 infants with UTI, 55 females and 27 males under the age of 1 year. All males were circumcised on the eighth day of life. The median age of infection was 0.75 and 7.0 months for males and females, respectively. Fifty-two percent (14/27) of UTI episodes were diagnosed within the 2 weeks following circumcision. A significantly lower incidence in Escherichia coli-induced UTI was observed in males compared to females, 67% and 93%, respectively. Similarly, the incidence of E. coli-induced UTI was also significantly lower in males presenting within 2 weeks following circumcision (57%) compared to infants presenting prior or more than 2 weeks following the procedure (92%). Positive blood cultures of an identical microorganism were observed in 6/27 males compared to 2/55 females. The incidence of urinary tract malformations and their severity were similar in both sexes. We conclude that the high incidence of UTI following a ritual Jewish circumcision, as well as the relatively high preponderance of bacteria other than E. coli, may suggest a causal relationship between circumcision and UTI.

Screening of children and adolescents for hyperlipidemia is controversial. We performed a cholesterol surveillance study of 806 children aged between 6 and 14 years. The initial cholesterol screening test was done by finger stick in the non-fasting state. Children with cholesterol values exceeding 4.55 mmol/l ("borderline" risk) and their parents had their lipid profiles measured following a 12 h fast by venipuncture. The incidence of coronary risk factors in the families of children with hypercholesterolemia was estimated. Of the initial group, 71 children had total capillary cholesterol levels > or = 4.55 mmol/l, and in 65 of these children serum lipid profile was reexamined after an overnight fast. Fifty-five children were found to have total venous cholesterol (TVC) levels < 4.55 mmol/l, and 27 of the 55 had a low density lipoprotein (LDL) cholesterol level > 3.4 mmol/l ("borderline" risk). A positive correlation was found between TVC and LDL-cholesterol levels. Of the hypercholesterolemic children 49% had a parent with hyperlipidemia and 13% had a family history of premature myocardial infarction (before 55 years of age). We conclude that screening of children based on the presence of hypercholesterolemia or its possible complications in other family members may fail to identify many of the children with hypercholesterolemia. Thus, if thorough identification of young children with hypercholesterolemia is desired, inclusive population screening would be the most effective approach.

A pair of non-identical twins with severe pseudohypoaldosteronism (PHA) were followed over a period of 4 years. The diagnosis was based on dehydration, hyponatremia, hyperkalemia, high urine sodium/potassium ratios, and high serum concentrations of aldosterone and renin. Sweat and saliva electrolyte concentrations were high, suggesting multifocal target-organ unresponsiveness to mineralocorticoids. No hydramnios was observed during pregnancy. Despite continuous treatment with sodium chloride and sodium bicarbonate (< or = 20 g/day) and cation exchange resin (Kayexalate, sodium polystyrene sulfonate, < or = 4 g/kg per day), the children had repeated episodes of dehydration, hyponatremia, and hyperkalemia. Growth velocity was normal in both twins. Catch-up growth was observed following infancy in the first twin. Normalization of plasma aldosterone, electrolytes, and renin concentrations was achieved at the age of 9 months.

Background: In previous studies, the oral calcium loading and deprivation test has been used to distinguish between children with renal (fasting) hypercalciuria (RH) and absorptive hypercalciuria (AH)., Objective: We evaluated the long-term clinical course of 30 children with idiopathic hypercalciuria and investigated the influence of urinary sodium excretion, as a reflection of its intake, on urinary calcium excretion., Methods: Thirty normocalcemic, normophosphatemic children (21 boys and 9 girls) with urinary calcium to creatinine ratios greater than 0.57 mmol/L/mmol/L ( > 0.21 mg/dL/mg/dL on the three consecutive examinations participated in this study. They were divided according to their responses to calcium deprivation and loading into AH (16 patients) and RH (14 patients)., Results: When restudied 3 to 7 years later, 6 of the 16 children with AH were normocalciuric and three demonstrated characteristics compatible with RH. The remaining seven patients maintained their initial AH pattern. Of the 14 children with RH, four were normocalciuric and four demonstrated AH. The remaining six children maintained their initial RH pattern. A significant positive correlation was observed between urine sodium and calcium excretion in children with AH or RH. Children who were normocalciuric at the second study had significantly lower values of urine sodium excretion when compared with those in whom hypercalciuria persisted., Conclusions: We suggest that AH and RH constitute a continuum. The change in characteristics observed during the second study suggests that any attempt to divide these patients into two physiologically distinct subtypes may be artificial. The main factor influencing urinary excretion of calcium in our patients seemed to be sodium intake.

The amnion is a metabolically active tissue that has been identified as a site of synthesis of numerous products. We report that amnion tissue explants and amnion-derived epithelial cells synthesize and secrete six proteins of the complement system, C1r, C1s, C1 inhibitor, factor B, C3, and factor H. Synthesis of C2 was minimal and variable, and C5 was not detected. The six synthesized proteins had size and subunit composition characteristic of proteins synthesized in HEp2, a long term cell line derived from malignant epithelial cells. Constitutive and regulated synthesis of five of the six proteins was similar in amnion tissue and cells. However, synthesis of factor B was different in tissue and cells; constitutive synthesis was 12-fold higher in tissue than in cells, and interleukin-1 did not alter synthesis in tissue, but increased synthesis by 11.7-fold in cells. These results indicate that amnion may be a source of complement proteins present in the amnion fluid and may contribute to local host defense along with endometrial glandular epithelial cells, which synthesize C3. Furthermore, our results suggest that amnion tissue is stimulated in vivo to synthesize factor B and cannot respond to interleukin-1 with a further increase in the synthesis rate.

Serum lipids were measured in children and their parents from 40 families in which the father had a myocardial infarction or coronary heart disease (CHD) before age 40 years. The relationship between physical activity and serum lipid concentrations in the children was also evaluated. Twenty six men had one or more abnormal lipid value (in mmol/l): total venous cholesterol (TVC) > 6.24, triglycerides < 2.55, low density lipoprotein cholesterol (LDL-C) > 4.42, or high density lipoprotein cholesterol (HDL-C) < 0.91. There were 15 spouses with significant hyperlipidaemia (values above). In the 107 children examined, TVC mean (SD) was 4.68 (1.17), triglycerides 1.4 (0.8), LDL-C 3.0 (1.0), and HDL-C 1.18 (0.28). Altogether 42% of the children had significant hyperlipidaemia. No significant correlation was found between the degree of physical activity of the children and their LDL-C and TVC concentrations. However, a significant positive correlation was found between the degree of physical activity and HDL-C and a significant negative one with triglyceride concentrations. It is concluded that screening the progeny of young CHD patients is highly productive in identifying young people at excessive risk for future CHD. The data also suggest that promoting high degrees of activity among these children may have a positive influence on risk factors for adult onset CHD.

Brainstem auditory evoked potentials (BAEPs) were performed on 114 children with attention deficit disorder (ADD). Prolonged latencies of waves III and V and longer brainstem transmission time interval of waves I-III and I-V were observed in the study group compared with normal controls. A significant asymmetry of wave III latency between the ears was found in children with ADD, but not observed in the control group. The authors conclude that children with ADD have brainstem dysfunction. BAEPs, an objective electrophysiological test, may contribute to the diagnosis of ADD, distinguishing these children from the normal population.

Primary psoas abscess is a relatively rare disease with highest incidence in children and adolescents. It usually presents with fever, abdominal pain and limp. Limping tends to incriminate musculoskeletal problems below the pelvis, but movement of the hip involves the psoas muscle which is mostly retroperitoneal and intimately related to pelvic and intraperitoneal organs. Although the current tendency is to use abdominal sonography, rectal examination is still a valuable step in clinical examination, and may help to assess a pelvic mass or abscess. The following case report describes the elusive nature of psoas abscess and a rare occurrence of abscess rupture and peritonitis, immediately after rectal examination.

Pseudohypoaldosteronism is a hereditary salt-wasting syndrome usually seen in infancy with weight loss, dehydration, and failure to thrive. The pathophysiologic origin of pseudohypoaldosteronism is unknown. The defect could be related to the unresponsiveness of target organs to mineralocorticoids resulting in hyponatremia, hyperkalemia, and markedly elevated plasma aldosterone and renin levels. Red blood cell Na+, K(+)-ATPase activity was measured in a pair of twins with pseudohypoaldosteronism, in an unrelated child with hypoaldosteronism, and in an age-matched group of 50 healthy infants and young children. The enzyme was assayed by a method that couples ATP hydrolysis with NADH oxidation. Plasma renin and aldosterone levels were measured by RIA. Red blood cell Na+, K(+)-ATPase activity in the twins with pseudohypoaldosteronism was very low at the time of diagnosis (3 wk). In both twins a time-related gradual increase in enzyme activity was observed during the 1st mo of life, reaching control values between 6 and 8 mo of age. This increase was associated with both a reduction in salt requirement and clinical improvement. Plasma renin activity and aldosterone levels were very high at the time of diagnosis. Plasma renin activity reverted gradually to normal values, whereas aldosterone levels remained high throughout the follow-up period. The child with hypoaldosteronism had normal Na+, K(+)-ATPase activity at diagnosis and during follow-up.

A 16-year-old girl, presenting initially with pericarditis and life threatening pericardial tamponade, developed clinical episodes characteristic of FMF few months later. This case report and several others reported previously, suggest that FMF should be considered in patients from certain ethnic groups presenting with pericardial effusion.

A controlled clinical study compared the antipyretic effectiveness of acetaminophen administered at regular 4h intervals (group 1, n = 53) versus sporadic usage contingent upon a body temperature above 37.9 degrees C (group 2, n = 51) in 104 children presenting with simple febrile convulsions. The incidence of febrile episodes or temperature values were similar in spite of significantly larger amounts of acetaminophen administered to patients in group 1. Four and 4 children in groups 1 and 2, respectively, had a second episode of febrile seizures, in all of them within the first 24h of admission. We conclude that the prophylactic administration of acetaminophen in children with febrile seizures is not effective in the prevention of fever, the reduction of its degree, or in preventing the early recurrence of febrile seizures.

Sydenham chorea, a major manifestation of acute rheumatic fever, has been the most common form of acquired chorea during childhood. Despite the recent dramatic decline in both incidence and severity of rheumatic fever in our area, the frequency of carditis was unchanged. This study investigated retrospectively the incidence of chorea in the last three decades (1960-1990) in our area. During the 30 years of the survey, 28 patients with Sydenham chorea were treated in our centre of whom 10 were seen between 1960-1970, 17 between 1970-1980, and only one patient between 1980-1990.

The physical and the functional distribution of Torpedo nicotinic-cholinergic receptors expressed in Xenopus oocytes was assayed. Physical hemispheric receptor distribution was tested by binding of 125[I]-bungarotoxin. The density of the expressed nicotinic receptors was equal on both hemispheres (ratio animal/vegetal = 1.1 +/- 0.2). Functional distribution was tested either by whole hemispheric response assay or by monitoring responses from small areas on the two hemispheres. While the first method yielded results that suggested uniform receptor density distribution, the second method indicated two-fold higher responsiveness on the animal hemisphere, when compared with the vegetal hemisphere. Direct comparison on oocytes of the same donors did not reveal significant differences between the two assays. We did see, however, a high variability among the different donors (animal/vegetal activity ratio range 0.5-4.7). Overall, in 35 experiments in 18 donors, the animal/vegetal ratio of hemispheric responsiveness was 1.4. The possible source of this high variability may have been the large excess of bungarotoxin-binding sites over the number of active channels. We have also tested hemispheric responsiveness ratio with different concentrations of acetylcholine. When acetylcholine concentration was below 10 microM, the animal/ vegetal ratio was significantly lower than 1.0. Similar results were obtained with nicotinic receptors expressed after injection of RNA transcribed in vitro from cloned mouse nicotinic receptor subunits. These results imply that hemispheric membrane heterogeneity may affect receptor and/or channel activities to yield polarized channel activity despite nearly homogeneous receptor distribution.

The interaction of the acetylcholine receptor (AChR) binding site domain with specific antibodies and with alpha-bungarotoxin (alpha-BTX) has been compared. The cloned and expressed ligand binding domain of the mouse AChR alpha-subunit binds alpha-BTX, whereas the mongoose-expressed domain is not recognized by alpha-BTX. On the other hand, both the mouse and mongoose domains bind to the site-specific monoclonal antibody 5.5. These results demonstrate that the structural requirements for binding of alpha-BTX and mcAb 5.5, both of which interact with the AChR binding site, are distinct from each other.

The brainstem function of eight children with familial dysautonomia was investigated by brainstem auditory evoked potentials and compared with that of age-matched healthy control children. All median latencies of waves III and V in the study group were significantly higher than those of the control children. Brain transmission times of waves I-III and I-V were significantly prolonged in the study group compared with the control group. These results provide additional objective support for the assumption that the brainstem function of children with familial dysautonomia is affected by this disease.

Midazolam (Versed), the first water-soluble benzodiazepine, has had widespread acceptance as a parenteral anxiolitic agent. Its antiepileptic properties were studied in adult patients with good results. Midazolam was administered intramuscularly to 48 children, ages 4 months to 14 years, with 69 epileptic episodes of various types. In all but 5 epileptic episodes, seizures stopped 1-10 min after injection. These results suggest that midazolam administered intramuscularly may be useful in a variety of epileptic seizures during childhood, specifically when attempts to introduce an intravenous line in convulsing children are unsuccessful.