bluuebunny/crossref_metadata_2025 huggingface dataset:
Dramatic Increase of Amoxicillin-Induced Crystal Nephropathy Found in a Cohort Study of French Pharmacovigilance Centers
Authors: Vodovar Dominique , Thomas Laure , Mongardon Nicolas , Lepeule Raphaël , Lebrun-Vignes Bénédicte , Biour Michel , Netzer Florence , Haouache Hakim , Le Beller Christine , Dhonneur Gilles
Published: December 2017

An increase in amoxicillin-induced crystal nephropathy (AICN) incidence has been recently suggested. The aims of this study were to investigate the trend of AICN incidence through Paris' regional centers of pharmacovigilance (Paris RCPVs) and better describe this rare adverse drug reaction. Forty-five AICN cases were identified between 1985 and 2016. All cases, except one, were reported since 2010. Amoxicillin (AMX) was administered intravenously (65 [interquartile range {IQR}, 43 to 110] mg/kg of body weight/day) in all patients, either for treating infection (
n
= 15) or as surgical prophylaxis (
n
= 30). Delay between AMX administration and AICN onset was 1 (IQR, 1 to 3) day; 30, 4, and 11 patients developed KDIGO stage 1, 2, and 3 acute kidney injury, respectively. Delay between AICN onset and kidney function recovery was 4 (IQR, 2 to 6) days. Precipitating factors were identified in only one-third of cases. Twelve patients required intensive care unit admission, and 8 needed renal replacement therapy. Neither chronic kidney disease nor death was observed. We confirmed the recent and dramatic increase of AICN in the Paris RCPVs since 2010. The absence of precipitating factors in the majority of cases and the onset of AICN in apparent routine indications, such as surgical prophylaxis, are alarming and justify a high vigilance from all AMX prescribers.
Impact of Real-Time Therapeutic Drug Monitoring on the Prescription of Antibiotics in Burn Patients Requiring Admission to the Intensive Care Unit
Authors: Fournier A. , Eggimann P. , Pantet O. , Pagani J. L. , Dupuis-Lozeron E. , Pannatier A. , Sadeghipour F. , Voirol P. , Que Y.-A.
Published: December 2017

As pharmacokinetics after burn trauma are difficult to predict, we conducted a 3-year prospective, monocentric, randomized, controlled trial to determine the extent of under- and overdosing of antibiotics and further evaluate the impact of systematic therapeutic drug monitoring (TDM) with same-day real-time dose adaptation to reach and maintain antibiotic concentrations within the therapeutic range. Forty-five consecutive burn patients treated with antibiotics were prospectively screened. Forty fulfilled the inclusion criteria; after one patient refused to participate and one withdrew consent, 19 were randomly assigned to an intervention group (patients with real-time antibiotic concentration determination and subsequent adaptations) and 19 were randomly assigned to a standard-of-care group (patients with antibiotic administration at the physician's discretion without real-time TDM). Seventy-three infection episodes were analyzed. Before the intervention, only 46/82 (56%) initial trough concentrations fell within the range. There was no difference between groups in the initial trough concentrations (adjusted hazard ratio = 1.39 [95% confidence interval {CI}, 0.81 to 2.39],
P
= 0.227) or the time to reach the target. However, thanks to real-time dose adjustments, the trough concentrations of the intervention group remained more within the predefined range (57/77 [74.0%] versus 48/85 [56.5%]; adjusted odd ratio [OR] = 2.34 [95% CI, 1.17 to 4.81],
P
= 0.018), more days were spent within the target range (193 days/297 days on antibiotics [65.0%] versus 171 days/311 days in antibiotics [55.0%]; adjusted OR = 1.64 [95% CI, 1.16 to 2.32],
P
= 0.005), and fewer results were below the target trough concentrations (25/118 [21.2%] versus 44/126 [34.9%]; adjusted OR = 0.47 [95% CI, 0.26 to 0.87],
P
= 0.015). No difference in infection outcomes was observed between the study groups. Systematic TDM with same-day real-time dose adaptation was effective in reaching and maintaining therapeutic antibiotic concentrations in infected burn patients, which prevented both over- and underdosing. A larger multicentric study is needed to further evaluate the impact of this strategy on infection outcomes and the emergence of antibiotic resistance during long-term burn treatment. (This study was registered with the ClinicalTrials.gov platform under registration no. NCT01965340 on 27 September 2013.)
Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis
Authors: Wijnant Gert-Jan , Van Bocxlaer Katrien , Yardley Vanessa , Harris Andy , Murdan Sudaxshina , Croft Simon L.
Published: December 2017

AmBisome (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with those of the deoxycholate form of AmB (DAmB; trade name Fungizone) in murine models of
Leishmania major
CL. Drug levels at the target site (the localized lesion) 48 h after single intravenous (i.v.) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6, and 8). After single and multiple dosing, intralesional concentrations were 5- and 20-fold, respectively, higher than those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25, or 12.5 mg/kg (i.v.), there was a clear correlation between dose level, intralesional AmB concentration, and relative reduction in parasite load and lesion size (
R
2
values of >0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation.
Transcriptional Response to Lactic Acid Stress in the Hybrid Yeast Zygosaccharomyces parabailii
Authors: Ortiz-Merino Raúl A. , Kuanyshev Nurzhan , Byrne Kevin P. , Varela Javier A. , Morrissey John P. , Porro Danilo , Wolfe Kenneth H. , Branduardi Paola
Published: December 2017

Lactic acid has a wide range of applications starting from its undissociated form, and its production using cell factories requires stress-tolerant microbial hosts. The interspecies hybrid yeast
Zygosaccharomyces parabailii
has great potential to be exploited as a novel host for lactic acid production, due to high organic acid tolerance at low pH and a fermentative metabolism with a high growth rate. Here we used mRNA sequencing (RNA-seq) to analyze
Z. parabailii
's transcriptional response to lactic acid added exogenously, and we explore the biological mechanisms involved in tolerance.
Z. parabailii
contains two homeologous copies of most genes. Under lactic acid stress, the two genes in each homeolog pair tend to diverge in expression to a significantly greater extent than under control conditions, indicating that stress tolerance is facilitated by interactions between the two gene sets in the hybrid. Lactic acid induces downregulation of genes related to cell wall and plasma membrane functions, possibly altering the rate of diffusion of lactic acid into cells. Genes related to iron transport and redox processes were upregulated, suggesting an important role for respiratory functions and oxidative stress defense. We found differences in the expression profiles of genes putatively regulated by Haa1 and Aft1/Aft2, previously described as lactic acid responsive in
Saccharomyces cerevisiae
. Furthermore, formate dehydrogenase (
FDH
) genes form a lactic acid-responsive gene family that has been specifically amplified in
Z. parabailii
in comparison to other closely related species. Our study provides a useful starting point for the engineering of
Z. parabailii
as a host for lactic acid production.

IMPORTANCE
Hybrid yeasts are important in biotechnology because of their tolerance to harsh industrial conditions. The molecular mechanisms of tolerance can be studied by analyzing differential gene expression under conditions of interest and relating gene expression patterns to protein functions. However, hybrid organisms present a challenge to the standard use of mRNA sequencing (RNA-seq) to study transcriptional responses to stress, because their genomes contain two similar copies of almost every gene. Here we used stringent mapping methods and a high-quality genome sequence to study the transcriptional response to lactic acid stress in
Zygosaccharomyces parabailii
ATCC 60483, a natural interspecies hybrid yeast that contains two complete subgenomes that are approximately 7% divergent in sequence. Beyond the insights we gained into lactic acid tolerance in this study, the methods we developed will be broadly applicable to other yeast hybrid strains.
Multicenter Clinical Evaluation of the Alere i Respiratory Syncytial Virus Isothermal Nucleic Acid Amplification Assay
Authors: Hassan Ferdaus , Hays Lindsay M. , Bonner Aleta , Bradford Bradley J. , Franklin Ruffin , Hendry Phyllis , Kaminetsky Jed , Vaughn Michael , Cieslak Kristin , Moffatt Mary E. , Selvarangan Rangaraj
Published: December 2017

The Alere i respiratory syncytial virus (RSV) assay is an isothermal nucleic acid amplification test capable of detecting RSV directly from respiratory specimens, with results being available in ≤13 min after test initiation. The objective of this study was to evaluate the performance characteristics of the Alere i RSV assay in a point-of-care setting by using direct nasopharyngeal (NP) swab specimens (direct NP) and nasopharyngeal swab specimens eluted and transported in viral transport medium (VTM NP). The study was a prospective, multicenter, clinical trial conducted at 9 sites across the United States to evaluate the clinical performance of the Alere i RSV assay with respiratory specimens obtained from both children (age, <18 years) and older adults (age, >60 years). The performance of the Alere i RSV assay was compared with that of the reference method, the Prodesse ProFlu+ real-time reverse transcriptase PCR (RT-PCR) assay. All specimens with discrepant test results were tested further by a second FDA-cleared PCR assay (the Verigene respiratory virus plus nucleic acid test; Luminex Inc., TX). A total of 554 subjects with signs and symptoms of respiratory infections were enrolled, and respiratory samples were collected in this study. In comparison with the ProFlu+ real-time RT-PCR, the overall sensitivity and specificity of Alere i RSV assay for the detection of RSV were 98.6% (95% confidence interval [CI], 94.4 to 99.7%) and 98.0% (95% CI, 95.8 to 99.1%), respectively, for direct NP and 98.6% (95% CI, 94.4 to 99.7%) and 97.8% (95% CI, 95.5 to 98.9%), respectively, for VTM NP. The Alere i RSV is a highly sensitive and specific molecular assay ideal for rapid RSV detection in patients in the point-of-care setting due to its minimal hands-on time and rapid result availability.
RSAD2 and AIM2 Modulate Coxsackievirus A16 and Enterovirus A71 Replication in Neuronal Cells in Different Ways That May Be Associated with Their 5′ Nontranslated Regions
Authors: Yogarajah Thinesshwary , Ong Kien Chai , Perera David , Wong Kum Thong
Published: December 2017

Coxsackievirus A16 (CV-A16) and enterovirus A71 (EV-A71) are closely related enteroviruses that cause the same hand, foot, and mouth disease (HFMD), but neurological complications occur only very rarely in CV-A16 compared to EV-A71 infections. To elucidate host responses that may be able to explain these differences, we performed transcriptomic analysis and real-time quantitative PCR (RT-qPCR) in CV-A16-infected neuroblastoma cells (SK-N-SH), and the results showed that the radical
S
-adenosylmethionine domain containing 2 (RSAD2) was the highest upregulated gene in the antimicrobial pathway. Increased RSAD2 expression was correlated with reduced viral replication, while RSAD2 knockdown cells were correlated with increased replication. EV-A71 replication showed no apparent correlation to RSAD2 expressions. Absent in melanoma 2 (AIM2), which is associated with pyroptotic cell death, was upregulated in EV-A71-infected neurons but not in CV-A16 infection, suggesting that the AIM2 inflammasome played a significant role in suppressing EV-A71 replication. Chimeric viruses derived from CV-A16 and EV-A71 but containing swapped 5′ nontranslated regions (5′ NTRs) showed that RSAD2 expression/viral replication and AIM2 expression/viral replication patterns may be linked to the 5′ NTRs of parental viruses. Differences in secondary structure of internal ribosomal entry sites within the 5′ NTR may be responsible for these findings. Overall, our results suggest that CV-A16 and EV-A71 elicit different host responses to infection, which may help explain the apparent lower incidence of CV-A16-associated neurovirulence in HFMD outbreaks compared to EV-A71 infection.

IMPORTANCE
Although coxsackievirus A16 (CV-A16) and enterovirus A17 (EV-A71) both cause hand, foot, and mouth disease, EV-A71 has emerged as a leading cause of nonpolio, enteroviral fatal encephalomyelitis among young children. The significance of our research is in the identification of the possible differing and novel mechanisms of CV-A16 and EV-A71 inhibition in neuronal cells that may impact viral neuropathogenesis. We further showed that viral 5′ NTRs may play significant roles in eliciting different host response mechanisms.
Epidemiology and return to play following isolated syndesmotic injuries of the ankle: a prospective cohort study of 3677 male professional footballers in the UEFA Elite Club Injury Study
Authors: Lubberts Bart , D’Hooghe Pieter , Bengtsson Håkan , DiGiovanni Christopher W , Calder James , Ekstrand Jan
Published: December 2017

Aim

To determine the epidemiology of isolated syndesmotic injuries in professional football players.

Methods

Data from 15 consecutive seasons of European professional football between 2001 and 2016 contributed to the dataset of this study. Match play and training data from a total of 3677 players from 61 teams across 17 countries have been included. Team medical staff recorded player exposure and time loss injuries. Injury incidence was defined as the number of injuries per 1000 player-hours. Injury burden was defined as number of days absence per 1000 player-hours. Seasonal trends for isolated syndesmotic injury incidence, isolated syndesmotic injury proportion of ankle ligament injuries and isolated syndesmotic injury burden were analysed via linear regression.

Results

The isolated syndesmotic injury incidence was 0.05 injuries per 1000 hours of exposure (95% CI 0.04 to 0.06) or one injury per team every three seasons. The injury incidence during match play was 13 times higher compared with during training, 0.21 (95% CI 0.16 to 0.26) and 0.02 (95% CI 0.01 to 0.02), respectively. Out of the 1320 ankle ligament injuries registered during the 15 seasons, 94 (7%) were diagnosed as isolated syndesmotic injuries. An annual increase in injury incidence was observed (R2=0.495, b=0.003, 95% CI 0.001 to 0.004, P=0.003). However, no significant annual change of injury burden was observed (R2=0.033, b=0.032, 95% CI −0.073 to 0.138, P=0.520). Seventy-four per cent of the injuries were contact related, and the mean (±SD) absence following an isolated syndesmotic injury was 39 (±28) days.

Conclusions

The incidence of isolated syndesmotic injuries in elite professional European football annually increased between 2001 and 2016.
Functional lesional neurosurgery for tremor: back to the future?
Authors: Schreglmann Sebastian R , Krauss Joachim K , Chang Jin Woo , Martin Ernst , Werner Beat , Bauer Ronald , Hägele-Link Stefan , Bhatia Kailash P , Kägi Georg
Published: December 2017

For nearly a century, functional neurosurgery has been applied in the treatment of tremor. While deep brain stimulation has been in the focus of academic interest in recent years, the establishment of incisionless technology, such as MRI-guided high-intensity focused ultrasound, has again stirred interest in lesional approaches.

In this article, we will discuss the historical development of surgical technique and targets, as well as the technological state-of-the-art of conventional and incisionless interventions for tremor due to Parkinson’s disease, essential and dystonic tremor and tremor related to multiple sclerosis (MS) and midbrain lesions. We will also summarise technique-inherent advantages of each technology and compare their lesion characteristics. From this, we identify gaps in the current literature and derive future directions for functional lesional neurosurgery, in particularly potential trial designs, alternative targets and the unsolved problem of bilateral lesional treatment. The results of a systematic review and meta-analysis of the consistency, efficacy and side effect rate of lesional treatments for tremor are presented separately alongside this article.
Modified sprint interval training protocols: physiological and psychological responses to 4 weeks of training
Authors: McKie Greg L. , Islam Hashim , Townsend Logan K. , Robertson-Wilson Jennifer , Eys Mark , Hazell Tom J.
Published: December 2017

Sprint interval training (SIT) protocols involving brief (≤15 s) work bouts improve aerobic and anaerobic performance, highlighting peak speed generation as a potentially important adaptive stimulus. To determine the physiological and psychological effects of reducing the SIT work bout duration, while maintaining total exercise and recovery time, 43 healthy males (n = 27) and females (n = 16) trained for 4 weeks (3 times/week) using one of the following running SIT protocols: (i) 30:240 (n = 11; 4–6 × 30-s bouts, 4 min rest); (ii) 15:120 (n = 11; 8–12 × 15-s bouts, 2 min rest); (iii) 5:40 (n = 12; 24–36 × 5-s bouts, 40 s rest); or (iv) served as a nonexercising control (n = 9). Protocols were matched for total work (2–3 min) and rest (16–24 min) durations, as well as the work-to-rest ratio (1:8 s). Pre- and post-training measures included a graded maximal oxygen consumption test, a 5-km time trial, and a 30-s maximal sprint test. Self-efficacy, enjoyment, and intentions were assessed following the last training session. Training improved maximal oxygen consumption (5.5%; P = 0.006) and time-trial performance (5.2%; P = 0.039), with a main effect of time for peak speed (1.7%; P = 0.042), time to peak speed (25%; P < 0.001), and body fat percentage (1.4%; P < 0.001) that appeared to be driven by the training. There were no group effects for self-efficacy (P = 0.926), enjoyment (P = 0.249), or intentions to perform SIT 3 (P = 0.533) or 5 (P = 0.951) times/week. This study effectively demonstrated that the repeated generation of peak speed during brief SIT work bouts sufficiently stimulates adaptive mechanisms promoting increases in aerobic and anaerobic capacity.
Effect of the addition of a fungicide to glyphosate applied postemergence on crop injury, disease control, and corn yield
Authors: Soltani Nader , Hooker David C. , Brinkman Jonathan , Sikkema Peter H.
Published: December 2017

The addition of pyraclostrobin, pyraclostrobin/fluxapyroxad, pyraclostrobin/metconazole, trifloxystrobin/propiconazole, azoxystrobin/propiconazole, and trifloxystrobin/prothioconazole fungicides to glyphosate reduced disease incidence up to 19% and disease severity up to 4% compared with glyphosate alone. Fungicides evaluated can be safely mixed with glyphosate for corn production, but fungicide use was not associated with increased corn yield.
Resource partitioning between kit foxes (Vulpes macrotis) and coyotes (Canis latrans): a comparison of historical and contemporary dietary overlap
Authors: Byerly P.A. , Lonsinger R.C. , Gese E.M. , Kozlowski A.J. , Waits L.P.
Published: December 2017

Range expansions by generalists can alter communities and introduce competitive pressures on native species. In the Great Basin Desert, USA, coyotes (Canis latrans Say, 1823) have colonized and are now sympatric with native kit foxes (Vulpes macrotis Merriam, 1888). Since both species have similar diets, dietary partitioning may facilitate coexistence. We analyzed coyote and kit fox diets, then compared our results to an earlier study. Because populations are dynamic, we expected that decreases in prey or increases in predator abundance could alter dietary patterns. We found no significant changes in population-level prey diversity for kit foxes or coyotes, but found high levels of dietary overlap between species. We did detect a significant decrease in the relative importance of leporids (family Leporidae) in the diets of both canids, but they remained important for coyotes. The relative importance of small mammals was greater for kit foxes than coyotes, but their importance had not changed significantly over time. We detected significant declines in prey diversity per sample (scat-level dietary diversity) for both canids, suggesting that during a foraging event, individuals may encounter less diverse prey now than historically. These findings suggested that kit foxes and coyotes were not limited by prey, despite high dietary overlap.
Plane branches with Newton non-degenerate polars
Authors: Hefez A. , Hernandes M. E. , Iglesias M. F. H.
Published: December 2017

To an equisingularity class of complex plane branches, described by its multiplicity [Formula: see text] and characteristic exponents [Formula: see text], [Formula: see text], there is a naturally associated family [Formula: see text] of equations containing a complete set of analytic representatives for all branches of the class. We show in this paper that the general polar curve of any member of [Formula: see text] is Newton degenerate, except when [Formula: see text], in which case the general member of [Formula: see text] corresponds to a curve which has a Newton non-degenerate general polar curve with a fixed Newton polygon, or when [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], with [Formula: see text] and [Formula: see text] is odd, in which case [Formula: see text] has a subset containing a complete set of analytic representatives for all branches of the class whose general member has also a Newton non-degenerate general polar curve with a fixed Newton polygon. In both cases, we give explicit Zariski open sets the points of which represent branches with Newton non-degenerate polars and describe the topology of their general polars.
Half conformally flat generalized quasi-Einstein manifolds of metric signature (2,2)
Authors: Brozos-Vázquez Miguel , García-Río Eduardo , Gilkey Peter , Valle-Regueiro Xabier
Published: December 2017

We provide classification results for and examples of half conformally flat generalized quasi-Einstein manifolds of signature [Formula: see text]. This analysis leads to a natural equation in affine geometry called the affine quasi-Einstein equation that we explore in further detail.
A Disturbance-Free Built-In Self-Test and Diagnosis Technique for DC-DC Converters
Authors: Shafiee M. , Beohar N. , Bakliwal P. , Roy S. , Mandal D. , Bakkaloglu B. , Ozev S.
Published: December 2017

Complex electronic systems include multiple power domains and drastically varying dynamic power consumption patterns, requiring the use of multiple power conversion and regulation units. High-frequency switching converters have been gaining prominence in the DC-DC converter market due to their high efficiency and smaller form factor. Unfortunately, they are also subject to higher process variations, and faster in-field degradation, jeopardizing stable operation of the power supply. This article presents a technique to track changes in the dynamic loop characteristics of DC-DC converters without disturbing the normal mode of operation using a white noise–based excitation and correlation. Using multiple points for injection and analysis, we show that the degraded part can be diagnosed to take remedial action. White noise excitation is generated via a pseudo-random disturbance at reference, load current, and pulse-width modulation (PWM) nodes of the converter with the test signal energy being spread over a wide bandwidth, without significantly affecting the converter noise and ripple floor. The impulse response is extracted by correlating the random input sequence with the disturbed output generated. Test signal analysis is achieved by correlating the pseudo-random input sequence with the output response and thereby accumulating the desired behavior over time and pulling it above the noise floor of the measurement set-up. An off-the-shelf power converter, LM27402, is used as the device-under-test (DUT) for experimental verification. Experimental results show that the proposed technique can estimate converter natural frequency and quality factor (
Q
-factor) within ±2.5% and ±0.7% error margin respectively, over changes in load inductance and capacitance. For the diagnosis purpose, a measure of inductor's DC resistance (DCR) value, which is the inductor's series resistance and indicative of the degradation in inductor's
Q
-factor, is estimated within less than ±1.6% error margin.
Effect of cholecystokinin on myoelectric activity of small bowel of the dog.
Authors: Mukhopadhyay A K , Thor P J , Copeland E M , Johnson L R , Weisbrodt N W
Published: December 2017

The effect of cholecystokinin on the myoelectric activity of the small intestine was determined in conscious dogs. Six animals were implanted with electrodes along the small intestine, and a cannula was placed in the stomach. A second cannula was inserted into the duodenum in three animals, and a pancreatic fistula was prepared in three animals. Recordings were made in the fasted state, during the intravenous infusion of either saline or cholecystokinin-octapeptide (CCK-OP), during the intraduodenal infusion of either saline or L-tryptophan, and during the fed state. CCK-OP disrupted the fasted pattern of myoelectric activity, caused a dose-dependent increase in spike potentials, and caused a dose-dependent increases in pancreatic protein secretion. Stimulation of myoelectric activity occurred at doses that produced submaximal protein secretion; however, the stimulation was not identical to that seen with feeding. Intraduodenal infusion of L-tryptophan increased pancreatic protein secretion, interrupted the fasted pattern of motility, and induced a pattern similar to that seen with feeding. We conclude that CCK alters small intestinal motility and may play a role in the changes in small-bowel motility caused by the ingestion of food.
Glucose and lactate kinetics after endotoxin administration in dogs.
Authors: Wolfe R R , Elahi D , Spitzer J J
Published: December 2017

We studied the effects of E. coli endotoxin on the glucose and lactate kinetics in dogs by means of the primed constant infusion of [6(-3)H] glucose and Na-L-(+)-[U-14C] lactate. The infusion of endotoxin induced a transient hyperglycemic level, followed by a steady fall in plasma glucose to hypoglycemic levels. The rate of appearance (Ra) and the rate of disappearance (Rd) of glucose were both significantly elevated (P less than .05) for 150 min after endotoxin, after which neither differed from the preinfusion value. The metabolic clearance rate of glucose was significantly elevated at all times 30 min postendotoxin. By 30 min postendotoxin, Ra and Rd of lactate, plasma lactate concentration, and the percent of glucose turnover originating from lactate were significantly elevated and remained so for the duration of the experiment. We concluded that after endotoxin hypoglycemia developed because of an enhanced peripheral uptake of glucose and a failure of the liver to maintain an increased Ra of glucose. We also concluded that lactate became an important precursor for gluconeogenesis and an important metabolic substrate.
Structure-function relationships of peptide fragments of gastrin and cholecystokinin.
Authors: Kaminski D L , Ruwart M J , Jellinek M
Published: December 2017

This study evaluates the structure-function relationships of the C-terminal peptide fragments of gastrin and cholecystokinin (CCK) in the biliary system and the stomach. Dogs with chronic biliary and gastric fistulas were used. Administration of the common fragments of CCK and gastrin with four and five amino acids and the active fragments of CCK with six through eight amino acids without sulfation of tyrosine in position 7 failed to alter hepatic bile flow from control values while significantly stimulating gastric hydrogen ion output. Administration of the seven and eight amino acid peptide fragments of CCK with sulfation of tyrosine in position 7 significantly increased hepatic bile flow. Administration of the sulfated octapeptide with 4 microgram/kg per h of nonsulfated octapeptide did not result in the inhibition of the choleresis produced by the sulfated peptide. The gastric hydrogen ion response produced by the administration of the nonsulfated and sulfated peptide was equal to that of the nonsulfated peptide alone. These results suggest that in the biliary system the receptor is highly specific as sulfation of the peptide fragment of CCK is essential for combining with the receptor, whereas in the stomach the receptor has little specificity and combines with all of the peptide fragments evaluated.
Effect of a bovine hypothalamic extract on glucose utilization by rat adipocytes.
Authors: Grimes L J , Mok C , Martin J M
Published: December 2017

This study was undertaken to assess whether a hypothalamic extract has any direct metabolic action on adipose and muscle tissues. An acid bovine hypothalamic extract (HE) was tested for its effect on the utilization of D[U-14C]glucose by isolated rat adipocytes and rat hemidiaphragms. The HE was ineffective in stimulating the conversion of labeled glucose into CO2 and glycogen by rat hemidiaphragm. However, in isolated adipocytes, the HE had significant lipogenic activity. This lipogenic effect was independent of insulin and nonsuppressible by insulin antibodies. The dose-response curve was linear and saturable. That insulin and the HE were not additive at maximal concentrations suggests that they act through a common rate-limiting step, possibly a receptor site. Other hypothalamic substances tested (thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, and substance P) showed no lipogenic activity. Somatostatin (6 microgram/ml) was an insulin potentiator but only when preincubated with the fat cells. It is concluded that the hypothalamic regulation of body weight may be mediated by a neurohumoral mechanism affecting adipose tissue stores.
Epinephrine and dopamine beta-hydroxylase secretion from bovine adrenal.
Authors: Jacobs T P , Henry D P , Johnson D G , Williams R H
Published: December 2017

The perfusate of the isolated, acetylcholine-stimulated bovine adrenal was studied for epinephrine (E) concentration and dopamine beta-hydroxylase (DBH) activity. Analysis of single stimuli showed that DBH disappeared from the perfusate with a t1/2 of 19.1-29.0 min. whereas E disappeared with a t1/2 of 0.78-1.0 min. Stimulation every 5 min over 105 min caused a gradual decline in E concentration to 36% of its initial value, whereas DBH activity reached a plateau after the second stimulus and thereafter remained unchanged. The decline in E was not influenced by addition of catecholamine precursors and biosynthetic cofactors to the medium and was not accompanied by a shift in the ratios of E and norepinephrine (NE) in the perfusate. Inhibitors of DBH activity were not detected in the perfusate and nonexocytotic leakage of DBH into the perfusate did not occur. These results document the temporal dissociation of the appearance and disappearance of DBH and E after a single stimulus and the progressive dissociation of DBH and E secretion under conditions of prolonged perfusion with rapid and repetitive stimulation. Possible explanations of these observations are offered.
Bile acid structure and biliary lipid secretion. II. A comparison of three hydroxy and two keto bile acids.
Authors: Hoffman N E , Sewell R B , Smallwood R A
Published: December 2017

The effect of five bile acids on biliary lipid secretion was studied in the pentobarbital-anesthetized cat. The dihydroxy acid, taurohyodeoxycholic acid, was indistinguishable from another dihydroxy acid, taurochenodeoxycholic acid, but secretion of both phospholipid and cholesterol was considerably reduced with two mono-keto dihydroxy acids, tauro-3alpha,12alpha-dihydroxy-7-keto-5beta-cholanoic acid and tauro-3alpha,7alpha-dihydroxy-12-keto-5beta-cholanoic acid. The effect of a trihydroxy bile acid, taurocholic acid was as previously described. The effect of the keto bile acids may be explained by the ability of these bile acids to solubilize lipid, but such an explanation is inadequate for the difference between di- and trihydroxy bile acids. An intracellular effect of bile acid is postulated.
Alterations of glucose metabolism during perfusion of rat lung with paraquat.
Authors: Bassett D J , Fisher A B
Published: December 2017

Isolated perfused rat lungs were used to investigate effects of paraquat on lung glucose metabolism. Lungs were ventilated with 5% CO2 in air and perfused with Krebs-Ringer bicarbonate buffer, pH 7.4, containing albumin and 5.5 mM radiolabeled D-glucose. Control lung glucose utilization, estimated from rate of 3H2O production from [5-3H]glucose, was 44 mumol/h-g dry wt. Pentose cycle activity, based on 14CO2 specific yields at the end of perfusions with [1-14C]- and [6-14C]glucose, was 14% of glucose utilization. During perfusion with 1.5 mM paraquat, glucose utilization increased 28%, 14CO2 production via the pentose cycle increased 182% (P less than 0.005), CO2 production via mitochondrial metabolism increased 39% (P less than 0.02), and the rate of lactate production increased 28% (P less than 0.05). Pyruvate production and the lactate-to-pyruvate ratio were not significantly altered. The data indicate that interaction of paraquat with the lung results in increased turnover of cytoplasmic NADPH and increased mitochondrial metabolism, but no significant change in cytoplasmic redox state. The findings are compatible with intracellular enzymatic reduction of paraquat by an NADPH-requiring reductase.
Amino acid stimulation of oxygen and substrate utilization by cardiac myocytes.
Authors: Burns A H , Reddy W J
Published: December 2017

The inclusion of plasma levels of the natural amino acids plus 2.5 mM glutamate and 2.5 mM malate (PAAGM) raised the oxygen consumption and glucose oxidation of isolated cardiac myocytes in phosphate buffered saline. The addition of calcium (1.25 mM) and magnesium (0.66 mM) potentiated the stimulatory effect of PAAGM on glucose oxidation and oxygen consumption, PAAGM did not alter the shape of the dose-response curve for glucose oxidation by the isolated cardiac myocyte preparation. It did increase the amount of glucose oxidation at any given media glucose concentration up to 20 mM. PAAGM also increased the rate of lactate oxidation by the isolated cardiac myocyte preparation. PAAGM did not stimulate the oxidation of octanoate unless there was glucose present in the incubation media as well. Measurements of the concentrations of free amino acids indicated higher levels in myocytes incubated in PAAGM than in myocytes incubated in phosphate buffered saline. The data suggest that substrate metabolism by the isolated cardiac myocyte preparation can be influenced by the presence of plasma constituents that would be available to the myocardium in vivo.
Synthesis of chromogranins and dopamine beta-hydroxylase by perfused bovine adrenal glands.
Authors: Ledbetter F H , Kilpatrick D , Sage H L , Kirshner N
Published: December 2017

The incorporation of [3H]leucine into chromogranins and into soluble and membrane-bound dopamine beta-hydroxylase (DBH) was studied in isolated perfused adrenal glands. [3H]chromogranins and [3H]DBH were quantitatively determined by immunoprecipitation. The amounts of soluble [3H]DBH formed were about equal to the amounts of membrane-bound [3H]DBH whereas the amounts of [3H]chromogranin were 5- to 20-fold greater than that of soluble [3H]DBH. On continuous sucrose density gradients, [3H]chromogranin was unimodally distributed after 2- to 20-h chase periods and accumulated in a vesicle having a lower buoyant density than mature chromaffin vesicles. At 2 h both membrane and soluble [3H]DBH were both bimodally distributed whereas after a 20-h chase period the distribution of soluble and membrane [3H]DBH was essentially unimodal and paralleled the distribution of [3H]chromogranin. These studies indicate that [3H]chromogranin, soluble [3H]DBH, and membrane [3H]DBH are synthesized concomitantly, but that each is transported into chromaffin vesicles at different rates.
Synthesis of taurocholate by rat fetal liver in organ culture: effects of cortisol in vitro.
Authors: Graham T O , Van Thiel D H , Little J M , Lester R
Published: December 2017

Taurocholate production by fetal hepatic organ cultures was measured by radioimmunoassay. Taurocholate production was maximal on day 1 of in vitro incubation, but was demonstrable in organ cultures maintained for periods up to 15 days. Explants obtained from fetuses of 18 gestational days of age produced only 82 pmol taurocholate per milligram dry weight of tissue during the first 24 h of incubation. Explants obtained from fetuses 21 gestational days of age produced 1,043 pmol taurocholate per milligram dry weight. The presence of cortisol (2.0 X 10(-6) M) in the incubation medium increased synthesis of taurocholate by rat fetal liver in which total taurocholate rose 50-fold above control after 120 h of incubation. In increasing concentrations from 2.0 X 10(-9) M to 2.0 X 10(-7) M, cortisol produced an incremental rise in taurocholate. However, additional increases in cortisol dose failed to provide further stimulation, and taurocholate production was inhibited by cortisol concentrations of 2.0 X 10(-5) M. The results provide further validation for the technique of fetal hepatic organ culture. They demonstrate that taurocholate synthesis is increasing rapidly during the final stages of gestation and show that cortisol augments taurocholate synthesis in a dose-response pattern.
Alkaline phosphatase in adaptation to low dietary phosphate intake.
Authors: Kempson S A , Kim J K , Northrup T E , Knox F G , Dousa T P
Published: December 2017

Previous findings suggest that alkaline phosphatase (Alk Pase) may be involved in phosphate transport. Since phosphate reabsorption is enhanced in the kidney and duodenum of animals stabilized on a low-phosphorus diet (LPD), Alk Pase was measured in the kidney, small intestine, and other tissues in LPD rats. In particulate fractions from the renal cortex, intestine, renal medulla, liver, and heart ventricle from LPD rats the activity of Alk Pase was significantly increased but the activities of other plasma membrane enzymes were not different between control and LPD groups. The increased Alk Pase in the renal cortex was localized to the brush border of the proximal tubule histochemically and by measurement of Alk Pase in brush-border preparations. Also in the renal cortex, typical enzymes associated with mitochondria, lysosomes, and cytosol were unchanged with the exception of cytosolic adenosine 3',5' cyclic-monophosphate phosphodiesterase, which was increased in LPD rats. Alk Pase in the renal cortex and intestine may play a role in the enhanced phosphate reabsorption in LPD animals.
Glucocorticoid and estrogen regulation of corticosteroid-binding globulin production by rat liver.
Authors: Feldman D , Mondon C E , Horner J A , Weiser J N
Published: December 2017

We have recently demonstrated that rat liver can synthesize and secrete corticosteroid-binding globulin (CBG). The present study extends these observations and examines the hormonal regulation of hepatic CBG production. Male rats were pretreated by adrenalectomy and/or glucocorticoid or estrogen administration and the rate of CBG production was measured in vitro. The production rates were assessed by the generation of specific corticosterone binding sites in both a liver-slice preparation and in an isolated perfused liver. The two techniques showed qualitatively similar results. Adrenalectomy enhanced and glucorticoid administration inhibited the rate of CBG production and secretion. Pretreatment of male rats with estradiol stimulated the rate of CBG production. The production rates were 20- to 40-fold higher in the perfused liver demonstrating its superiority over the liver-slice system. The livers from intact rats secreted CBG binding sites at a rate of approximately 18 pmol/g liver per hours, generating an estimated 20% of the total CBG content of a rat each day. The possible clinical implications of the therapeutic use of glucocorticoids that bind to CBG, yet inhibit CBG production, are discussed.
Circadian rhythm of liver glycogen metabolism in rats: effects of hypothalamic lesions
Authors: Ishikawa K. , Shimazu T.
Published: December 2017

The effects of electrolytic lesions of the suprachiasmatic nucleus (SCN) and ventromedial nucleus (VMH) of the hypothalamus on the circadian rhythm of liver glycogen metabolism were studied in rats fed during the dark period (2000–0800 h). Bilateral lesions of the SCN did not affect appreciably the circadian rhythmicity in three parameters of liver glycogen metabolism, i.e., glycogen content and glycogen synthetase I and phosphorylase a activities. In contrast, bilateral lesions of the VMH resulted in almost complete loss of circadian rhythmicity in phosphorylase a activity by lowering the high activity normally observed in late evening. VMH lesions also reduced the amplitudes of the rhythms of synthetase I activity and glycogen content, but did not abolish their rhythmicities. These results suggest that the integrity of the VMH, rather than the SCN, is important for regulation or expression of the food-triggered circadian rhythm of liver phosphorylase a activity. The implication of the lateral hypothalamic nucleus in regulation of the circadian rhythm of liver synthetase I is also discussed.
Nitrogen handling in adult hypothalamic obese rats
Authors: Karakash C. , Rohner-Jeanrenaud F. , Hustvedt B. E. , Jeanrenaud B.
Published: December 2017

Several aspects of nitrogen metabolism have been studied in adult nonhyperphagic, hyperinsulinemic, ventromedial hypothalamus (VMH)-lesioned rats. Ten days postoperatively, VMH-lesioned rats had high plasma levels of urea and low plasma tyrosine, while plasma alanine, glutamine, total amino acid, and protein levels were unaltered. Urea production and excretion were increased in VMH-lesioned rats. Increased urea synthesis could not be attributed to enhanced peripheral release of amino acids. In vitro, measurements of hepatic amino acid uptake and liver protein synthesis did not reveal any disturbances of these processes in VMH-lesioned rats. However, hepatic transamination and lipogenesis from amino acids were increased following VMH-lesions. In addition to the hyperinsulinemia previously reported to occur in nonhyperphagic VMH-lesioned rats, this study showed an increased glucagon secretion from perfused pancreases of these animals. These data together suggest that the excess of the two hormones at the portal vein of VMH-lesioned rats would favor uptake and deamination of amino acids, their diversion to lipid synthesis and possibly other pathways, with consequent increase in urea production and reduced supply of amino acids to peripheral tissues available for nitrogen retention.
Sleep-promoting material from human urine and its relation to factor S from brain
Authors: Krueger J. M. , Bacsik J. , Garcia-Arraras J.
Published: December 2017

A sleep-promoting factor was extracted from human urine. Intraventricular infusion of the purified material induced excess slow-wave sleep in rats and rabbits for 5--10 h after the infusion. Chemical properties of the urinary factor were similar to those of factor S derived from whole brains of sleep-deprived goats, sheep, and rabbits. The behavior of the urinary factor in two ion exchange chromatographic steps, high voltage electrophoresis, gel-filtration, and ultrafiltration was similar to that of factor S. Effects of the purified urinary factor on slow-wave sleep of rats and rabbits were similar in time-course and duration to those of factor S from brain. However, the factor obtained from human urine did not increase the amplitude of cortical slow waves to the same extent as did factor S from brains of sleep-deprived animals.
Effects of glucocorticoid treatment and food restriction on rat hindlimb muscles
Authors: Gardiner P. F. , Montanaro G. , Simpson D. R. , Edgerton V. R.
Published: December 2017

Various metabolic, histochemical, and contractile measurements were made on soleus and gastrocnemius muscles of adult rats treated with triamcinolone acetonide (1 mg . kg-1 . day-1 for 6 wk), and compared to similar measurements in pair-fed and control animals. Contractile measurements were performed in situ under pentobarbital anesthesia. Gastrocnemius muscles from steroid-treated rats showed higher twitch and tetanic tensions when expressed in grams/gram of muscle, compared to control rats. Similar, although less marked, trends occurred in the less atrophied gastrocnemius muscles from pair-fed rats. Soleus muscles from steroid-treated rats exhibited significantly higher (139% of control) twitch tension (grams/gram of muscle), and elevated twitch/tetanus ratios, compared to control and pair-fed groups. No alterations occurred in muscle contractile speed in either muscle. The greater atrophy of fast compared to slow fiber types in gastrocnemius muscles under both experimental conditions did not occur in the soleus, a predominantly slow-twitch muscle. The atrophic and contractile responses of fast and slow muscles to these two conditions were quantitatively as well as qualitatively different.
Role of prostaglandins in contractile activity of the ampulla of the rabbit oviduct
Authors: Harper M. J. , Coons L. W. , Radicke D. A. , Hodgson B. J. , Valenzuela G.
Published: December 2017

Contractile activity of the ampulla of rabbit oviducts removed 24 h after an ovulating injection was studied in vitro. Spontaneous activity, field-stimulated activity, and response to phenylephrine were studied in normal, reversed, and scraped (endosalpinx removed) sections of tissues in the presence or absence of inhibitors of prostaglandin synthetase (8 or 51 micrograms/ml indomethacin or 10 or 100 micrograms/ml 5,8,11,14-eicosatetraynoic acid (ETA)). The effects of in vivo treatment with 10 mg/kg of indomethacin on the same responses were examined. Scraped tissues produced more prostaglandin E and F (measured by radioimmunoassay) than did normal tissues, and this production was suppressed by 10 micrograms/ml of indomethacin or 100 micrograms/ml of ETA. Production of prostaglandin by normal tissues was not depressed by these compounds in vitro, but was significantly reduced by pretreatment of the animals with indomethacin in vivo. In the absence of the endosalpinx, the myosalpinx exhibited spontaneous activity and responded to field stimulation and phenylephrine. Scraped and reversed tissues, however, showed a faster decline in response to field stimulation than normal tissues, and this was due to the traumatization. By contrast, traumatization increased the sensitivity of the tissue to respond to phenylephrine. Inhibition of prostaglandin synthetase by low doses of indomethacin or ETA prevented desensitization of the tissue to field stimulation, but this desensitization was little affected by the higher doses of indomethacin in vitro or in vivo. ETA did not affect the phenylephrine dose-response curves and nor did 8 micrograms/ml of indomethacin, whereas the high dose was inhibitory. Spontaneous activity was only affected by the in vivo pretreatment with indomethacin, which prevented the decline in activity of scraped tissue with time.