bluuebunny/crossref_metadata_2025 huggingface dataset:
A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue
Authors: Wadsworth Brennan J , Leiwe Marina , Minogue Eleanor A , Cunha Pedro P , Engman Viktor , Brombach Carolin , Asvestis Christos , Sah-Teli Shiv K , Marklund Emilia , Koivunen Peppi , Ruas Jorge L , Rundqvist Helene , Lanner Johanna T , Johnson Randall S
Published: September 2024

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.
An antimicrobial drug recommender system using MALDI-TOF MS and dual-branch neural networks
Authors: De Waele Gaetan , Menschaert Gerben , Waegeman Willem
Published: September 2024

Timely and effective use of antimicrobial drugs can improve patient outcomes, as well as help safeguard against resistance development. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is currently routinely used in clinical diagnostics for rapid species identification. Mining additional data from said spectra in the form of antimicrobial resistance (AMR) profiles is, therefore, highly promising. Such AMR profiles could serve as a drop-in solution for drastically improving treatment efficiency, effectiveness, and costs.This study endeavours to develop the first machine learning models capable of predicting AMR profiles for the whole repertoire of species and drugs encountered in clinical microbiology. The resulting models can be interpreted as drug recommender systems for infectious diseases. We find that our dual-branch method delivers considerably higher performance compared to previous approaches. In addition, experiments show that the models can be efficiently fine-tuned to data from other clinical laboratories. MALDI-TOF-based AMR recommender systems can, hence, greatly extend the value of MALDI-TOF MS for clinical diagnostics.All code supporting this study is distributed on PyPI and is packaged under: https://github.com/gdewael/maldi-nn
Artesunate, EDTA and colistin work synergistically against MCR-negative and -positive colistin-resistant Salmonella
Authors: Zhai Yajun , Liu Peiyi , Hu Xueqin , Fan Changjian , Cui Xiaodie , He Qibiao , He Dandan , Ma Xiaoyuan , Hu Gongzheng , Zhai Yajun
Published: September 2024

Discovering new strategies to combat the multi-drug resistance bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics, via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this paper, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against
mcr
-
1
−
and
mcr
-
1
+
Salmonella
strains either
in vitro
or
in vivo
, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD or MCR using the natural compound artesunate could be further investigated as an attractive strategy for treatment of
Salmonella
infection. Collectively, our work opens up avenues towards the potentiation of colistin and revealed an alternative drug combination strategy to overcome COL resistant bacterial infections.
Bam complex associated proteins in Escherichia coli are functionally linked to peptidoglycan biosynthesis, membrane fluidity and DNA replication
Authors: Bryant Jack A , Staunton Kara A , Doherty Hannah M , Alao Micheal B , Ma Xuyu , Morcinek-Orłowska Joanna , Goodall Emily CA , Gray Jessica , Milner Mathew , Cole Jeffrey A , de Cogan Felicity , Knowles Timothy J , Glinkowska Monika , Moradigaravand Danesh , Henderson Ian R , Banzhaf Manuel
Published: September 2024

Biogenesis of the bacterial outer membrane is key to bacterial survival and antibiotic resistance. Central to this is the β-barrel assembly machine (Bam) complex and its associated chaperones, which are responsible for transport, folding and insertion of outer membrane proteins (OMPs). The
Escherichia coli
Bam complex is composed of two essential subunits, BamA and BamD, and three non-essential accessory lipoproteins, BamB, BamC and BamE. Optimal Bam function is further dependent on the non-essential periplasmic chaperones DegP, Skp and SurA. Despite intensive study, the specific function of these non-essential Bam-associated proteins remains unknown. Here, we analysed Δ
bamB
, Δ
bamC
, Δ
bamE
, Δ
surA
, Δ
skp
and Δ
degP
knockout strains by phenotypic screening, conservation analysis and high-throughput genetics. We reveal that Bam complex activity is impacted by changes in outer membrane lipid composition and that enterobacterial common antigen is essential in the absence of the chaperone SurA. We also show components of peptidoglycan are conditionally essential with Bam accessory lipoproteins and that DNA replication control is perturbed in the absence of specific OMP assembly components. Together, our data indicates potential mechanisms for coordination of OMP biogenesis with other cellular growth processes such as LPS and peptidoglycan biogenesis, and DNA replication control.
Ten quick tips for electrocardiogram (ECG) signal processing
Authors: Chicco Davide , Karaiskou Angeliki-Ilektra , De Vos Maarten
Published: September 2024

The electrocardiogram (ECG) is a powerful tool to measure the electrical activity of the heart, and the analysis of its data can be useful to assess the patient’s health. In particular, the computational analysis of electrocardiogram data, also called ECG signal processing, can reveal specific patterns or heart cycle trends which otherwise would be unnoticeable by medical experts. When performing ECG signal processing, however, it is easy to make mistakes and generate inflated, overoptimistic, or misleading results, which can lead to wrong diagnoses or prognoses and, in turn, could even contribute to bad medical decisions, damaging the health of the patient. Therefore, to avoid common mistakes and bad practices, we present here ten easy guidelines to follow when analyzing electrocardiogram data computationally. Our ten recommendations, written in a simple way, can be useful to anyone performing a computational study based on ECG data and eventually lead to better, more robust medical results.
Disrupciones conceptuales en las interpretaciones de función lineal y función afín por parte de egresados de un programa de licenciatura en matemáticas del Caribe Colombiano
Authors: Rojas-Sandoval Yesika , Gregorio-Solorzano Jose , Tovar-Ortega Teremy , Cañate-Montie Janer De Jesús , Mercado-Martinez Luis Carlos
Published: September 2024

Analizar la interpretación y conceptualización de las funciones lineales y afines por parte de los egresados del programa Licenciatura en Matemáticas. El estudio destaca la necesidad de que los egresados integren la tecnología de manera efectiva en las prácticas docentes, enfatizando la importancia del conocimiento pedagógico y el uso de las herramientas apropiadas para mejorar la experiencia de aprendizaje de los estudiantes. La investigación se basa en el campo de la educación matemática y la teoría de las representaciones semióticas, centrándose en las representaciones mentales evocadas al contemplar conceptos matemáticos. El estudio metodológicamente se implementó un enfoque de tipo cualitativo para facilitar la reflexión desde una perspectiva tanto subjetiva como objetiva. La técnica seleccionada es la triangulación de datos, la cual se utiliza para analizar la información recopilada, examinando categorías como la conceptualización de las funciones lineales y afines y la teoría de las representaciones semióticas. Los hallazgos indican que los egresados tienen dificultades para pasar del lenguaje natural a la representación algebraica, lo que provoca deficiencias en el manejo de los datos y afecta a las actividades cognitivas relacionadas con la formación y el tratamiento matemáticos. La investigación enfatiza la importancia de mejorar la comprensión conceptual en la educación matemática, particularmente en áreas como las funciones lineales y afines, para mejorar la capacidad de los estudiantes de interpretar y trabajar con conceptos matemáticos de manera efectiva.
Assessment of Genetic Diversity in Garden Pea (Pisum sativum L.) and Identification of Promising Lines for Hybridization
Authors: Singh Gautam Pratap , Singh Vijay Kumar , Kumar Anand , Bhardwaj Ajay , Rai Ankur Kumar
Published: September 2024

The current study is being conducted to understand the degree of genetic divergence in order to discover more diversified parents for pea genetic advancement. The creation of high yielding varieties with stable productivity, resistance to diseases and unfavorable environmental conditions, various maturing types, a high rate of organic matter accumulation during the early stages of growth, a sufficiently high intensity of photosynthesis, increases in protein content, essential amino acids, and favorable ratios among them are the most important tasks for pea breeding. The present investigation was carried out at vegetable research farm and laboratory works in the department of Horticulture (Vegetable and Floriculture), BAU, Sabour, Bhagalpur, Bihar during the Rabi season 2020-21. The genotype Kashi Mukti, Kashi Uday, Kashi Nandini and VM-11 of cluster II exhibited superiority for earliness in first flower, days to 50% flowering and days to first picking and significantly better performance as measured by the lowest cluster mean and a substantial improvement in performance while the  genotype Haze-02  of cluster IV exhibited superiority for inter-nodal length , plant height , seeds per pod and total sugars (%) based on maximum cluster mean with significantly better performance. It is anticipated that progenies from such diversified crossings will exhibit a broad range of genetic diversity and more potential for transgressive segregant isolation in the later generations. Therefore, a multiple crossing program using these genotypes may be used to retrieve transgressive segregants.
A new spiral model for Saturn's magnetosphere
Authors: Carbary J. F.
Published: January 2016

Rather than a clock‐like strobe, a rotating spiral may underlie the ~10.7 h periodicities observed in many phenomena in Saturn's magnetosphere. This spiral is a density or flux wave propagating outward from the planet, and the periodicity is generated when a spacecraft encounters the wave. The wave moves outward with the Alfvén speed, which can be computed from the magnetic field strength and plasma mass density. Using data from the first 200 days of 2010, the observed field strength and plasma density are used to compute this speed and construct the spiral. When the Cassini spacecraft “flies through” this model on a real trajectory, the model produces a strong main period at 10.7 h with weaker secondary periods at 10.4 h and 11.0 h resulting from Doppler effects. Periodograms of observed phenomena from the same interval show a main peak at 10.7 h but with spurious secondary peaks due to noise.
Morphology of midlatitude electron density enhancement using total electron content measurements
Authors: Rajesh P. K. , Liu J. Y. , Balan N. , Lin C. H. , Sun Y. Y. , Pulinets S. A.
Published: January 2016

Using the global ionospheric map of total electron content in 2002–2009, this paper investigates anomalous, midlatitude electron density enhancement (MEDE) bounded by a tropical electron density trough and the usual midlatitude electron density trough at all times (24 h) of the day for the first time. The diurnal, seasonal, and longitudinal variations in the occurrence and strength of MEDE are studied at solar maximum (2002) and long deep solar minimum (2009), and latitude‐longitude dependence is examined using the data in 2002–2009. The results show that the MEDE occurs at all times of the day though pronounced at night (2200–0400 LT), and in some cases the daytime occurrence could be more frequent than the corresponding nighttime occurrence. The strength maximizes at around 0400 LT and is weak during daytime. Both the occurrence and strength are, in general, predominant in winter at low solar activity and exhibit significant longitudinal dependence. The E × B drift, strength, and direction of neutral wind and ionosphere‐plasmasphere plasma flow and their day‐to‐day variations are suggested to account for the existence of MEDE at all times of the day.
Rupture complexity and the supershear transition on rough faults
Authors: Bruhat Lucile , Fang Zijun , Dunham Eric M.
Published: January 2016

Field investigations suggest that supershear earthquakes occur on geometrically simple, smooth fault segments. In contrast, dynamic rupture simulations show how heterogeneity of stress, strength, and fault geometry can trigger supershear transitions, as well as other complex rupture styles. Here we examine the Fang and Dunham (2013) ensemble of 2‐D plane strain dynamic ruptures on fractally rough faults subject to strongly rate weakening friction laws to document the effect of fault roughness and prestress on rupture behavior. Roughness gives rise to extremely diverse rupture styles, such as rupture arrests, secondary slip pulses that rerupture previously slipped fault sections, and supershear transitions. Even when the prestress is below the Burridge‐Andrews threshold for supershear on planar faults with uniform stress and strength conditions, supershear transitions are observed. A statistical analysis of the rupture velocity distribution reveals that supershear transients become increasingly likely at higher stress levels and on rougher faults. We examine individual ruptures and identify recurrent patterns for the supershear transition. While some transitions occur on fault segments that are favorably oriented in the background stress field, other transitions happen at the initiation of or after propagation through an unfavorable bend. We conclude that supershear transients are indeed favored by geometric complexity. In contrast, sustained supershear propagation is most common on segments that are locally smoother than average. Because rupture style is so sensitive to both background stress and small‐scale details of the fault geometry, it seems unlikely that field maps of fault traces will provide reliable deterministic predictions of supershear propagation on specific fault segments.
The Future of Using Earth‐Abundant Elements in Counter Electrodes for Dye‐Sensitized Solar Cells
Authors: Briscoe Joe , Dunn Steve
Published: January 2016

With limited global resources for many of the elements that are found in some of the most common renewable energy technologies, there is a growing need to use “Earth‐abundant” elements as a long‐term solution to growing energy demands. The dye‐sensitized solar cell has the potential to produce low‐cost renewable energy, with inexpensive production and most components using Earth‐abundant elements. However, the most commonly used material for the cell counter electrode (CE) is platinum, an extremely expensive and rare element. A selection of the materials investigated as alternative CEs are discussed, including metal sulfides, oxides, carbides, and nitrides and carbon‐based materials such as carbon nanotubes, graphene, and conductive polymers. As well as having the potential for lower cost, these materials can also produce more‐efficient devices due to their high surface area and catalytic activity. Therefore, once issues such as stability have been studied in more detail and scale‐up of production methods are considered, there is a very promising future for the replacement of Pt in DSSCs with lower‐cost, Earth‐abundant alternatives.
Stable and Reusable Binaphthyl‐Supported Palladium Catalyst for Aminocarbonylation of Aryl Iodides
Authors: Sharma Nidhi , Sekar Govindasamy
Published: January 2016

A binaphthyl‐supported Pd nanoparticles (Pd‐BNP)‐catalyzed aminocarbonylation of aryl iodides in the presence of carbon monoxide and amines for the synthesis of amides has been developed. This methodology provides an efficient route for the synthesis of a COX‐2 enzyme inhibitor having anti‐inflammatory activity.

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An Efficient Synthesis of Polysubstituted Pyridines via CH Oxidation and CS Cleavage of Dimethyl Sulfoxide
Authors: Wu Xia , Zhang Jingjing , Liu Shan , Gao Qinghe , Wu Anxin
Published: January 2016

An expedient cleavage of the CS bond of dimethyl sulfoxide (DMSO) has been developed for the preparation of substituted pyridines from ketones. In this transformation, the co‐product formic acid was formed from ammonium formate, which acted as an important catalyst for the reaction. Notably, this transformation exhibited a broad substrate scope towards a wide variety of different ketones to give the corresponding substituted pyridines in high yields. Mechanistic studies suggested that dimethyl sulfoxide delivered a methylene fragment, which was subsequently captured in situ to give a pyridine.

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Chemoselective Addition of Halomethyllithiums to Functionalized Isatins:A Straightforward Access to Spiro‐Epoxyoxindoles
Authors: Pace Vittorio , Castoldi Laura , Mamuye Ashenafi Damtew , Langer Thierry , Holzer Wolfgang
Published: January 2016

An efficient, chemoselective approach to spiro‐epoxyoxindolesviathe addition of chloromethyllithium followed by ring‐closure of the intermediate alkoxide is reported. Chemoselectivity is fully preserved in the presence of different electrophilic sites. The synthetic potential of selected spiro‐epoxyindoles has been exploited in the copper(I)‐catalyzed intramolecular oxyarylation of an alkyne and in the formation ofN,N‐dimethylisoindigoviathe addition of dihalocarbenoids.

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Asymmetric Diels–Alder and Cascade Reaction of Quinone Imine Ketals and 2,4‐Dienals: Construction of Chiral Benzo[de]quinolone Derivatives
Authors: Gu Jing , Xiao Ben‐Xian , Chen Yu‐Rong , Du Wei , Chen Ying‐Chun
Published: January 2016

An asymmetric Diels–Alder cycloaddition reaction of quinone imine ketals and 2,4‐dienals has been investigated via trienamine catalysis of a secondary chiral amine. A series of chiral tricyclic benzo[de]quinolone derivatives were efficiently constructed in moderate to good yields and with high to excellent enantioselectivity after a cascade aromatization/intramolecular hemiaminal formation sequence (up to 98% ee, >19:1 dr). The methodology and the useful product scaffolds could be further utilized in both synthetic and medicinal fields.

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Copper(I)‐Catalyzed Synthesis of Chlorinated Tetrahydropyridazin‐3‐ones and 1,2‐Diazepan‐3‐ones from N‐Allyl‐N′‐trichloroacetylhydrazines
Authors: Ram Ram N. , Soni Vineet Kumar
Published: January 2016

The synthesis of chlorinated tetrahydropyridazin‐3‐ones and 1,2‐diazepan‐3‐ones has been developed. The present paper describes the application of Cu(I)‐catalyzed ATRC for the synthesis of heterocyclic molecules containing two heteroatoms (i.e., nitrogen) in the ring for the first time. An easy separation of the individual compounds from the product mixture could be achieved by considering their solubility/insolubility in n‐hexane. The presence of three chlorine atoms provides possibilities for further derivatization.

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Trisomy 18: A single‐center evaluation of management trends and experience with aggressive obstetric or neonatal intervention
Authors: Subramaniam Akila , Jacobs Adam P. , Tang Ying , Neely Cherry , Philips Joseph B. , Biggio Joseph R. , Robin Nathaniel H. , Edwards Rodney K.
Published: January 2016

We conducted a retrospective cohort study including all prenatal and postnatal diagnoses of trisomy 18 (T18) from 2004 to 2014 at a single tertiary referral center in the southern United States to evaluate the natural history and perinatal outcomes associated with T18 over the past decade. We analyzed pregnancy outcome, mode of delivery, and for live‐births, the number and types of neonatal interventions, and characterized interventions as aggressive or non‐aggressive. Survival analyses were conducted based on mode of delivery and aggressive compared to non‐aggressive interventions. A total of 167 cases of T18 were identified, 150 with available records. There were 141 (94.0%) with full T18; the remainder had mosaicism (1.3%), a translocation (0.7%), or an isochromosome 18 (4.0%). Most diagnoses were prenatal (73.3%, n = 110). Of the 150 patients, there were 54 live births: 21 (38.9%) delivered vaginally, 32 (59.3%) delivered by cesarean, and mode of delivery could not be ascertained for one. Median duration of survival was 12 days (interquartile range 3–90 days). Over time, there were no changes toward increased intervention (obstetric or neonatal). For the 49 neonates who received some intervention, there was no significant difference in survival time between neonates receiving aggressive (n = 36, median survival 24 days, interquartile range 6–247) and non‐aggressive (n = 13, median survival 30 days, interquartile range 8–148) intervention (P = 0.90). There was similarly no difference in neonatal survival based on mode of delivery (P = 0.79). Survival of infants with T18 is not improved with aggressive obstetric or neonatal care. © 2016 Wiley Periodicals, Inc.
Assay of fluoride by a novel organic–inorganic mesoporous nano‐sized sensor
Authors: Ma Qianmin , Lai Yuming , Gao Jinwei , Wang Qianming
Published: January 2016

In this report, we prepared a novel mesoporous silica nanostructure for selective detection of fluoride through ultraviolet absorption and emission changes. In the sensing system, a silica coupling reagent (3‐(triethoxysilyl)propyl isocyanate) linked 1‐naphthylamine has been covalently grafted onto the mesopores of inorganic network. These specially designed nanospheres can recognize fluoride from other anions based on hydrogen bond interactions. This approach may provide new opportunities for designing related sensing systems with enhanced physical or chemical properties. Copyright © 2016 John Wiley & Sons, Ltd.
Funktionserweiterung durch Porosität: Herstellung und Eigenschaften eines porösen Silikonschwamms
Authors: Wilke Timm , Haffer Stefanie , Waitz Thomas
Published: January 2016

Im Beitrag wird am Beispiel der Herstellung eines Silikons gezeigt, wie durch Veränderung der Struktur eines Materials neue Stoffeigenschaften erzeugt werden können. Durch Abbildung der Struktur einer Mikroemulsion wird ein Material mit Poren im Nanometerbereich hergestellt, welches im Vergleich zum unporösen Analogon eine höhere Gasspeicherfähigkeit und eine größere mechanische Flexibilität besitzt. Die Herstellung sowie die Eigenschaften des Materials werden im Beitrag in verschiedenen Experimenten beschrieben. In diesem Zusammenhang wird aufgezeigt, dass sich verschiedene klassische Inhalte des Chemieunterrichts wie etwa Hydrolyse‐ und Kondensationsreaktionen, Eigenschaften von Tensiden sowie Adsorption und Stofftrennung vernetzen und in verschiedenen Kontexten aufgreifen lassen.
Modern treatment of the systemic fungus diseases
Authors: Harrell E. Richard , Bocobo Florante C.
Published: January 2016

For many years the systemic fungus diseases received little attention from the members of the medical profession and in the curriculum of the medical schools in the United States. Recently there has been a gradual awakening to their importance. The introduction of increasing numbers of antifungal chemotherapeutic agents attest this new interest in the mycotic diseases. Beneficial or curative specific therapy is now possible for many of these diseases which previously were without effective means of treatment.
The uptake of thiopental by body tissues and its relation to the duration of narcosis
Authors: Price H. L. , Kovnat P. J. , Safer J. N. , Conner E. H. , Price M. L.
Published: January 2016

A mathematical analysis of the factors affecting thiopental redistribution in the human body after a single intravenous injection of the drug has been devised and presented. Concentration ratios of thiopental predicted mathematically were compared with those obtained by the direct measurement of concentrations in human blood and fat. Real and theoretical results agreed closely. According to the mathematical analysis, and also according to measurements made in man, the central nervous system attained a peak concentration of thiopental slightly less than 1 minute after intravenous injection of the drug. Five minutes later only half this concentration was present, and 10 to 20 minutes after this, only one tenth remained. The rate at which fat concentrated thiopental was too slow to explain the rate at which the central nervous system was depleted. Instead, the lean body tissues rapidly took up most of the thiopental which the brain lost. The lean tissues thus appeared primarily responsible for depleting the central nervous system of the anesthetic. These findings suggest that fat plays a smaller role in limiting the duration of thiopental narcosis than has been supposed; conversely, the mass of the body and the rate at which its tissues are perfused with blood appear more important than has been recognized.
Effects in man of single and combined oral doses of reserpine, iproniazid, and D‐lysergic acid diethylamide
Authors: DeMaar Edmund W. J. , Williams Harry L. , Miller A. I. , Pfeiffer C. C.
Published: January 2016

The use of d‐lysergic acid diethylamide, LSD, as a reference standard for the evaluation of psychopathologic symptoms was tested. A group of healthy male volunteers took weekly doses of LSD in order to become familiar with the temporary mental changes induced by the drug.

The subjects were able to identify three dose levels of LSD and to differentiate LSD from placebo and other drugs. A standard curve of the responses to LSD could be constructed for these subjects.

A combination of reserpine plus iproniazid was found not to produce LSD‐like psychopathologic symptoms. The addition of reserpine and iproniazid to LSD did not change the degree or intensity of LSD‐induced psychopathologic symptoms in man.
The nature of the antirheumatic action of salicylates
Authors: Done Alan K.
Published: January 2016

The problem of the mode of antirheumatic action of salicylates is approached through a consideration of structure‐activity relationships. Experimental properties of salicylates and structurally related compounds which parallel antirheumatic properties include the ability to produce elevated circulating corticoid levels, acidic strength (dissociability), chelating potential, and the ability to suppress experimental arthritis. Effects which do not parallel antirheumatic properties include uncoupling of oxidative phosphorylation, stimulation of oxygen consumption, effects on carbohydrate metabolism, and inhibitory effects on immunologic processes. The possible interrelationships of the various experimental effects and the application of studies on structure‐activity relationships to the problem of the mode of acton of salicylates are discussed.
Evaluation of 3‐benzylthiomethyl chlorothiazide A new oral diuretic
Authors: Hauman Robert L. , Weller John M.
Published: January 2016

A clinical evaluation is presented of the relative diuretic effectiveness of benzylthiomethyl chlorothiazide and hydrochlorothiazide in 17 edematous patients. Comparing single 100 mg. doses of each drug, benzylthiomethyl chlorothiazide is about 85 per cent as effective as hydrochlorothiazide.
Role of antihistamine therapy in diphenylhydantoin‐induced gingival hyperplasia: A clinical and histopathologic evaluation
Authors: Paddison Richard M. , Anthony Samuel , Ferriss Gregory S. , Welsh Ronald A.
Published: January 2016

Stimulated by the original report of Gaillard upon the favorable influence of chlorprophenpyridamine maleate on diphenylhydantoin‐induced gum hyperplasia, and the reports of Breg and Sturmer indicating that chlorprophenpyridamine maleate and other antihistamine drugs were of no effect on diphenylhydantoin‐induced gum hyperplasia, the authors have studied 35 patients with this condition to a marked degree.

In spite of the work of the previous investigators, our evaluation was felt warranted because of our use of a carefully controlled double‐blind experimental technique.

Our patients were given either chlorprophenpyridamine maleate or an identical‐appearing placebo. Placebo or antihistamine drugs were administered for a 17 week period, and clinical grading, photographic grading, and gum biopsies were performed upon each patient before and after the administration of the drugs.

In a well‐controlled experiment we demonstrated that chlorprophenpyridamine maleatet produced no evident visual or histopathologic change in diphenylhydantoin‐induced gum hyperplasia.
Drug therapy in hypertension
Authors: Smirk F. H.
Published: January 2016

The methods available for the reduction of the blood pressure level in arterial hypertension are outlined.

Effective blood pressure reduction decreases considerably the mortality of patients with grades 4, 3, and 2 retinopathy.

In 1961, very few hypertensive patients should continue to complain of potentially reversible hypertensive symptoms or of distressing side effects, although it may be necessary to try several drugs or combinations of drugs.
Clinical pharmacology of the tetracycline antibiotics
Authors: Kunin Calvin M. , Finland Maxwell
Published: January 2016

Some of the relevant features of the clinical pharmacology of the tetracycline antibiotics are reviewed, and, in particular, the absorption, excretion, and disposition in the body of the four homologues that are currently available for clinical use are compared. The relatively minor differences in the chemical structure of these drugs are accompanied by significant differences in some of their physical properties and by some quantitative differences in their absorption, excretion, and distribution in the body, their activity against different bacteria, and their clinical toxicity.
The hypotensive effect of imipramine hydrochloride in patients with cardiovascular disease
Authors: Muller Otto F. , Goodman Nelson , Bellet Samuel
Published: January 2016

The untoward effects of imipramine hydrochloride were studied in a group of 41 patients under 60 years of age who were without demonstrable cardiovascular disease and compared with those in a group of 50 patients with various degrees of generalized or coronary atherosclerosis. Effects on the following were investigated: recumbent and standing blood pressures, pulse, electrocardiograms, blood coagulation (bleeding time, clotting time, prothrombin time), liver function (SGOT, alkaline phosphatase, cephalin flocculation, thymol turbidity), and formed elements in the blood (hemoglobin, white blood cells with differential count, platelets).

Among the patients with cardiovascular disease, 4 developed congestive heart failure during imipramine administration, while severe postural hypotension was observed in 10 of 41 (24.4 per cent). Two developed myocardial infarction during a hypotensive period. Moderate hypotension was present in 7 patients (14 per cent). Few significant untoward effects were encountered in the patients without cardiac disease. Severe postural hypotension was not observed; rrwderate degrees occurred in only 3 of the 41 patients (7.3 per cent).

It is suggested that extreme caution be practiced in the treatment of depressive states in patients with known cardiovascular disease, especially in the older age group. Imipramine should be given in small doses and discontinued if postural hypotension occurs.
Clinical pharmacology of antiarrhythmic drugs
Authors: Bellet Samuel
Published: January 2016

Important advances in the pharmacology and clinical use of antiarrhythmic drugs have resulted recently from improved methods Of diagnosis, from increased knowledge of alterations of cardiac metabolism and the effect of electrolyte disturbance on arrhythmias, and from increased knowledge of the pharmacology of old and new antiarrhythmic drugs. These are discussed in detail.
The use of postpartum patients in evaluating analgesic drugs
Authors: Gruber Charles M. , Doss Jerome , Baptisti Arthur , Chernish Stanley M.
Published: January 2016

Patients were given capsules of identical appearance containing 32 mg. of codeine, meperidine, dextropropoxyphene, or a blank in combination with acetylsalicylic acid compound and alone. One or two capsules were administered four times daily for the duration of the postpartum hospitalization period. Analysis of the data suggested that correlation between estimates of pain intensity and estimates of pain relief is poor. In the doses used, none produced analgesia reliably different from that of a comparable blank. The intensity of all postpartum symptoms subsided so rapidly that this method of evaluation of analgesics proved ineffective.
Clinical and experimental observations with methiodal, an absorbable myelographic contrast agent
Authors: Harvey J. Paul , Freiberger Robert F. , Werner Gerhard
Published: January 2016

The intrathecal iniectuni of methiodal in myelography is associated with spinal anesthesia, pain, and autonomic dysfunction. Experiments carried out in cats revealed that methiodal blocked conduction in the ventral and dorsal route fibers, an action which did not develop in peripheral nerves. Other experiments in cats indicated that the duration of the effects on conduction is a consequence of slow removal of the drug rather than of delayed recovery. The results of these experiments are taken to indicate that the effects of methiodal may be ascribed to an action on the spinal cord or nerve roots.
Circulation time: Sodium dehydrocholate versus sodium succinate: With a case report of a systemic allergic reaction to sodium dehydrocholate
Authors: Schoenfeld Myron R. , Messeloff Charles R.
Published: January 2016

Circulation times were compared in 50 patients taking sodium dehydrocholate and sodium succinate. Sodium dehydrocholate was found to produce a shorter mean circulation time and less variable results from patient to patient as well as in the same patient. Sodium succinate was found to be safer and somewhat more acceptable to the patient, but its end point was not as sharp as that of sodium dehydrocholate and an end point could not be elicited in some cases.
Evaluation of therapeutic agents on the human skin: Method of simultaneous symmetrical paired comparisons
Authors: Sulzberger Marion B.
Published: January 2016

If chaos in therapy is to be avoided, it is plain that new and more accurate methods of evaluation, less costly of time but also of money, must be found.
Clinical pharmacology of chlorothiazide compounds
Authors: Kessler Richard H.
Published: January 2016

The chlorothiazide compounds are effective, safe diuretics. They are as potent when administered by mouth as when given parenterally. They augment the excretion of water, salt, and to a lesser extent K+ and HCO3‐ ions. They combine the saluretic action of the organic mercurials with the carbonic anhydrase inhibitory action of sulfonamyl compounds. In the former activity, they might like the mercurials cause alkalosis and refractoriness to diuretic therapy. Because of their latter activity, they minimize alkalosis by limiting H+ ion excretion. Alkalinization of the urine by chlorothiazide is accompanied by K+ ion loss which in itself may cause disease. With recognition of this danger, K+ loss can be minimized by dietary supplementation. Another danger inherent in chlorothiazide is elevation of plasma urate concentration. Depending on dosage, urinary urate excretion may be increased or decreased. In either event, the plasma concentration of urate increases and can be neither prevented nor corrected during chlorothiazide therapy. The chlorothiazide compounds are secreted by the cells of the prOXimal segment of the nephron. They share this transport system with p‐aminohippuric acid, phenol red, penicillin, and analogous compounds. By this route, they are rapidly removed from body fluids, chemically unchanged.
Local anesthetics
Authors: Vandam Leroy D.
Published: January 2016

Few drugs are more widely used than local anesthetics, and few have more predictable effects. Their wide usage stems from the apparent ease of administration, their therapeutic effect in relieving pain, and their consequent ready acceptance by the patient. Yet it is probable that no other class of drug is used so ineptly and results in so many immediate adverse reactions. Both failures and complications are brought about by lack of understanding of a few simple pharmacologic facts and technical principles. It is the aim of this article to review these so that local anesthesia may be more safely and successfully utilized.
Drug therapy in depressions: Controlled evaluation of imipramine, isocarboxazide, dextroamphetamine‐amobarbital, and placebo
Authors: Overall John E. , Hollister Leo E. , Pokorny Alex D. , Casey J. F. , Katz George
Published: January 2016

An evaluation of imipramine, isocarboxazide, dextroamphetamine‐amobarbital, and placebo was carried out in 204 patients with depressive syndromes in thirty‐two Veterans Administration Hospitals. Treatment with a fixed dosage schedule was followed for 3 weeks, the dosage becoming flexible during an ensuing 9 week period. Evaluation of responses was made by three rating scales specially derived for depressed patients.

After 3 weeks of treatment, imipramine was significantly more effective than the other three treatments as measured only by a thirty‐one item expert clinician's scale derived from the Inpatient Multidimensional Psychiatric Scale. Favorable responses to imipramine were often prompt, leading to loss of such patients from the study before the full 12 week treatment period had been completed. After 12 weeks of treatment, the patients who remained in all four treatment groups were significantly improved when each group was compared with its pretreatment level, but there were no statistically reliable differences between treatments at the end of the study. These results emphasize the need for controlled studies in depressive syndromes subject to spontaneous improvement.
A model for the appraisal of glucose metabolism
Authors: Seed John C. , Acton Forman S. , Stunkard Albert J.
Published: January 2016

A model for the appraisal of glucose metabolism is proposed in which glucose homeostasis is divided into three parts: a rate of glucose dispersion into its volume of distribution, a utilization rate, and a production rate. The interrelationships between these processes are formulated as differential equations and are numerically integrated for typical cases. An attempt is made to find the best numerical values for the parameters from a critical analysis of the literature in which data from man have been used as far as possible.

The principal results include the demonstration of the efficacy of mathematical models for the quantitative appraisal of glucose metabolism. Specifically, our model suggests the properties of a metabolite which can serve as a feedback control mechanism for the production of glucose, it shows the need for nonlinear mathematics to represent threshold phenomena, and it pOints to gaps in our understanding of glucose homeostasis. The approach used in this model should be useful in the analysis of the effects of drugs on glucose metabolism as well as in the study of normal glucose homeostasis.
Part II. Control and exploration of animal variables in drug research
Authors: Ingle Dwight J.
Published: January 2016

Some aspects of this symposium relate to a subject of primary importance in education—methods of testing claims to knowledge. Almost all procedures of education are concerned with the mastery of information, but relatively few teachers and students are interested in methods of discriminating between what information is fact and what is fancy. Perhaps some day the science of education will be able to teach young men and women to be creative. There are ways to destroy creativity, but the art of engendering it has not yet been developed.
Part III. A modification of the standard sequential test for the relative effectiveness of two therapies
Authors: Street Elisabeth
Published: January 2016

Bross7 in 1952 and Armitage2, 3 in 1954 and 1957 described in detail sequential test procedures that can be used in analysis of the results of controlled clinical trials in which two treatment regimens are being compared. Subsequent articles4, 6 have extended the method somewhat, but the first two remain recommended reading for those interested in the application of sequential tests to the results of clinical trials.
Diseases of medical progress: Present status
Authors: Modell Walter
Published: January 2016

Readers of this journal will recall the review by Col. Robert Harlan Moser, “Diseases of Medical Progress. Progress Report” (2:446‐522, 1961) which served to bring up to date the subject opened by him in an earlier review (New England J. Med. 255:606‐614, 1956) and in his book (Springfield, Ill., 1959, Charles C Thomas, Publisher). Colonel Moser plans, starting with this issue, to keep the subject current by publishing abstracts of papers on drug reactions as they appear. For the most part, these will be of reactions to new drugs or new reactions to old ones. To a lesser extent, better known reactions will also be included. The implications should be clear enough and the abstracts will be published without comment. It is to be understood that these are not critical abstracts and that there is the possibility that some of the reactions ascribed to drugs may prove to be fortuitous. The abstracts are published here so that the association of the effects with particular drugs may be watched for as the drugs continued to be used, since this will lead to conclusive evidence, one way or the other, as well as to fewer disasters.
A diuretic assay utilizing normal subiects Several
Authors: Martz B. L. , Syester Toledo , Sheedy Kathryn , Cokinos George C. , Schmid Lawrence D.
Published: January 2016

Several diuretics have been evaluated in an assay utilizing normal subjects given sodium chloride solution orally. This method provides a satisfactory means of testing for possible natriuretic activity and of exploring dose response. Natriuretic activity of 250 and 500 mg. of chlorothiazide, 0.25, 0.5, 1, and 2.5 mg. of cyclothiazide, and 50, 100, and 200 mg. of triamterene was demonstrated by this procedure.
Part XI. Exploratory trials of new drugs in man
Authors: Pfeiffer Carl C.
Published: January 2016

A necessary function of many laboratories in clinical pharmacology is the exploratory trial of chemicals in man. Studies can be initiated in man after minimal toxicity studies have been performed in animals, such as the LD50 in one or two species, subacute toxicity, autopsies on growing rats after 4 week trials, and pharmacodynamic trials in dogs. Adequate exploratory trials in man avoid double blind tests of drugs at ineffective dose levels such as occurred in a test of driver impairment with meprobamate and whisky in normal volunteers. The published answer of this study was "no impairment of driving skill," whereas the data obviously desired were to determine the mean oral dose level of either or both that will impair driving skill! It is not my purpose to discuss quantitative or statistically reliable pharmacologic experiments in man but rather to elaborate on our experiences with exploratory studies in normal subjects and patients.
Effect of an anionic polyelectrolyte (polyethylene sulfonate) in patients with cancer Clinical pharmacology of a macromolecule
Authors: Regelson William , Holland James F.
Published: January 2016

Polyethylene sulfonate, an anionic polymer of average molecular weight (13,000) with anticoagulant and lipolytic activity, was given by intramuscular and intravenous routes to 49 patients with cancer. Three patients of 35 who received an adequate trial of drug showed objective tumor regression, but clinical improvement was seen in only 1. Acute toxicity produced by polyethylene sulfonate after intravenous injection was characterized by hypotension, pain, abdominal cramping, diarrhea, cyanosis, paresthesia, convulsive seizures, confusion, and amnesia. Chronic toxicity occurred after both intramuscular and intravenous injection and was characterized by diarrhea, nausea, vomiting, thrombocytopenia, and elevation of acid phosphatase. Thrombocytopenia was seen in all patients who were studied adequately and was not associated with changes in other marrow elements. Factor V, the labile prothrombin accelerator, was reduced by drug administration.

Polyethylene sulfonate proved to have minimal tumor‐inhibiting activity, and its use was limited by serious toxicity. Further clinical studies of its action as a tumor inhibitor in man are not warranted.
Direct measurement of monoamine oxidase inhibition in humans
Authors: Levine Robert J. , Sioerdsma Albert
Published: January 2016

Monoamine oxidase (MAO) activity was measured in specimens of human jejunal mucosa obtained by peroral biopsy. Oral administration of isocarboxazid and oral and intravenaus administration of pargyline (MO‐911) were found to produce marked inhibition of MAO in this tissue. That these results are probably indicative of MAO inhibition in other tissues as well was suggested by correlative studies with MO‐911 in rats, and by concomitant alterations in urinary tryptamine. It appears that man is much more sensitive to MAO‐inhibiting drugs than are several other mammalian species. The usefulness of direct assays of tissue MAO in man is discussed.
Medical management of ascites in cirrhosis of the liver
Authors: Díes Federico , Molina Valentín , Santos María Elena , Rivera Alfonso
Published: January 2016

Diuretics were given alone or in combination to normal subjects and cirrhotic patients with ascites. Patients unable to excrete sodium and water under basal conditions (Stage I), were found to be systematically resistant to all drugs tested. Patients with ascites and essentially normal sodium and water excretion made good diuretic responses to all drugs. Resistance of patients was overcome by the combination of thiazides and meralluride. Potassium output increased in all cases, even in the absence of satisfactory diuretic responses. Potassium supplements should therefore be given. Maintenance of relatively low water intake was of value in preventing hyponatremia. Strict low sodium intake was found essential for good over‐all results.