bluuebunny/crossref_metadata_2025 huggingface dataset:
Grouping groupers in the Mediterranean: Ecological baselines revealed by ancient proteins
Authors: Winter Rachel M. , de Kock Willemien , Mackie Meaghan , Ramsøe Max , Desiderà Elena , Collins Matthew , Guidetti Paolo , Presslee Samantha , Alegre Marta Munoz , Oueslati Tarek , Muniz Arturo Morales , Michailidis Dimitris , van den Hurk Youri , Taurozzi Alberto J. , Çakirlar Canan
Published: October 2023

Marine historical ecology provides a means to establish baselines to inform current fisheries management. Groupers (Epinephelidae) are key species for fisheries in the Mediterranean, which have been heavily overfished. Species abundance and distribution prior to the 20th century in the Mediterranean remains poorly known. To reconstruct the past biogeography of Mediterranean groupers, we investigated whether Zooarchaeology by Mass Spectrometry (ZooMS) can be used for identifying intra‐genus grouper bones to species level. We discovered 22 novel, species‐specific ZooMS biomarkers for groupers. Applying these biomarkers to Kinet Höyük, a Mediterranean archaeological site, demonstrated 4000 years of regional Epinephelus aeneus dominance and resiliency through millennia of fishing pressures, habitat degradation and climatic changes. Combining ZooMS identifications with catch size reconstructions revealed the Epinephelus aeneus capacity for growing 30 cm larger than hitherto documented, revising the maximum Total Length from 120 to 150 cm. Our results provide ecological baselines for a key Mediterranean fishery which could be leveraged to define and assess conservation targets.
DNAbarcoding of reef‐associated fishes of Saint Martin's Island, Northern Bay of Bengal, Bangladesh
Authors: Habib Kazi Ahsan , Islam Md. Jayedul , Sakib Md. Nazmus , Brishti Parsha Shanjana , Neogi Amit Kumer
Published: October 2023

This study employs the DNA barcoding approach to make a molecular taxonomic catalog of reef fishes of Saint Martin's Island (SMI), an ecologically critical area (ECA), and Marine Protected Area (MPA) in Bangladesh. DNA barcoding, along with morphological analysis, confirmed 84 reef‐associated fish species in SMI belonging to 16 orders, 39 families, and 67 genera. A total of 184 sequences were obtained in this study where 151 sequences (534–604 bp) of 81 species were identified from the COI barcode gene and 33 sequences (609 bp) of 19 species from the 16S rRNA gene region which were submitted to the GenBank and Barcode of Life Data System (BOLD). Among these sequences, 70 sequences of the COI gene and 16 sequences of 16S rRNA gene region from 41 species were submitted for the first time into the GenBank from Bangladesh. For molecular characterization analysis, another 37 sequences of 15 reef fish species of SMI were added from previous studies, making a total of 221 DNA sequences which comprised 179 sequences of 96 species for the COI gene and 42 sequences of 26 species for the 16S rRNA gene region. The COI sequences contain 145 haplotypes with 337 polymorphic sites, and the mean genetic distances within species, genera, and families were calculated as 0.34%, 12.26%, and 19.03%, respectively. On the contrary, 16S rRNA sequences comprised 31 haplotypes with 241 polymorphic sites, and the mean genetic divergences within species, genera, and families were 0.94%, 4.72%, and 12.43%, respectively. This study is a significant contribution to the marine biodiversity of Bangladesh which would facilitate the assessment of species diversity for strategizing management action. It is also an important input to the DNA barcode library of reef fishes of the northern Bay of Bengal.
Habits and attitudes toward writing affect the publication output of environmental biology trainees
Authors: Alshwairikh Yara A. , Fanton Ana Clara , Prats Kyra A. , Burak Mary K. , Duguid Marlyse C. , Rowland Freya E.
Published: October 2023

Publications are the mainstay of academic success, yet scientific writing requires consistent feedback and practice to build and maintain skills. In this study, we surveyed 342 environmental biology trainees (i.e., graduate students and postdoctoral scholars) about their writing habits. Our objective was to explore whether trainee writing habits align with suggestions from scientific writing guide books and articles, and how individual habits and attitudes may impact writing output. We found that the majority of respondents (>65%) felt negatively about writing and publishing, and few adhered to established advice such as scheduling writing time, setting attainable goals, or joining a writing accountability group. Our results show that trainees who dedicated more hours to writing each week and individually tracked their writing progress had more first‐author publications. In particular, graduate students who regularly scheduled writing time during the week and participated in writing groups also had more first‐author publications. Conversely, trainees who felt negatively about writing, wrote mainly before deadlines, and relied on “check‐ins” with advisors or writing groups to monitor writing progress had fewer first‐author publications. We describe ways that individuals, advisors, and institutions could improve trainee writing habits and assist them in developing more positive attitudes toward writing to ultimately help trainees achieve their writing goals.
Subnanomolar electrochemical sensing of mangiferin using a polycationic organohalloysite as electrode modifier
Authors: Melataguia Tchieno Francis Merlin , Dmitrieva Evgenia , Pengou Martin
Published: October 2023

A polycationic organohalloysite (H‐polyQ22) prepared by the sequential grafting of methylamine and 1,4‐butanediol diglycidyl ether in the interlayer space of (3‐aminopropyl)trimethoxysilane grafted halloysite is herein employed as a carbon paste electrode (CPE) modifier for the electrochemical determination of mangiferin, a bioactive molecule. When H‐polyQ22 was used as CPE modifier, the cyclic voltammetric response of mangiferin increased by ca. 8‐fold. This electrochemical response enhancement was shown to be the result of the great preconcentration capacity of H‐polyQ22. Since the H‐polyQ22 modified CPE proved to be a good signal enhancer, a new methodology for the sensitive determination of mangiferin was developed using square wave voltammetry. Under optimised conditions, a linear correlation between peak current and mangiferin concentration was obtained in the range from 0 to 2775.67 nM. A detection limit of 5.47×10−10 M was obtained based on a signal to noise ratio of 3, with a sensitivity of 193.58 μA/μM. The ability of some possible interferents such as human serum albumin, L‐cystine, ascorbic acid, glucose, dopamine and phenol to perturb the electrochemical signal of mangiferin in real sample analysis was alsoinvestigated.
Effect of water on the damage and energy dissipation feature of coal under uniaxial cyclic loading–unloading condition
Authors: Song Honghua , Zhao Yixin , Wu Yang , Li Xuehao , Gong Zhixin , Sun Zhuang , Jiang Yaodong , Guo Zihan
Published: October 2023

To gain insight into the reduction mechanism of water on the dynamic destabilization failure character of coal under mining disturbance conditions, the effect of water on the damage and energy dissipation feature of coal was investigated via cyclic uniaxial compressive loading–unloading test, acoustic emission (AE) monitoring technology, and theoretical analysis. It manifests that the softening effect of water on the mechanical properties of coal is still remarkable, lower uniaxial compressive strength and elastic modulus, while greater axial strain and higher Poisson's ratio are observed under the cyclic loading–unloading condition. Water‐saturated specimens dissipate more energy during the cyclic loading–unloading process, which reduces the proportion of input energy accumulated in the coal mass, thus lowering the burst proneness of coal. A greater amount of damage generates in air‐dried specimens than that in water‐saturated specimens at the first cyclic loading–unloading cycle, while lower damage increments are observed in the following cycles. This may be the reason for the minimal energy dissipation of air‐dried specimens in the following cycles. The elastic modulus behaves logarithmically versus the increasing cyclic loading–unloading cycle counts. The energy dissipated due to the damage evolution and plastic deformation of coal specimens positively correlates with the energy released by AE activities, the AE energy in air‐dried specimens has a greater concentration around the peak axial stress and a stronger correlation with the dissipated energy. The cumulative AE energy and energy dissipation density are linearly correlated during the cyclic loading–unloading process, which indicates a possibility in estimating the damage evolution and the dynamic failure risk of coal via cumulative AE energy, under the cyclic loading–unloading condition.
Towards secure IoT system from a smart city perspective: An optimized algorithm and implementation
Authors: Sharma Vishal , Beniwal Rohit , Kumar Vinod
Published: October 2023

Securing Internet of Things (IoT) systems is crucial for maintaining the resilience and trustworthiness of smart cities. In this context, the routing protocol's efficiency is pivotal for large‐scale IoT applications. However, achieving dependable and energy‐efficient routing in wireless sensor networks (WSNs) poses significant challenges due to limited and non‐rechargeable node energy resources. Also, traditional approaches often fell short of ensuring robust security and efficient data transmission. Hence, the purpose of this research was to address these shortcomings by introducing the Blowfish Honey‐Improved Spotted Hyena Optimization (BONY‐ISHO) protocol aimed at bolstering the security and efficiency of clustering and data routing in WSNs. Firstly, it introduces blockchain technology to establish secure and authenticated clustering, ensuring that only legitimate cluster heads and member nodes can participate. This innovation significantly enhances network security. Secondly, our protocol incorporates a hybrid Blowfish‐Honey cryptographic technique for data protection within the Area of Interest (AOI). This dual‐layer security approach, comprising Blowfish encryption and Honey encryption for key management, guarantees robust privacy and security. Thirdly, we have optimized data routing through the Improved Spotted Hyena Optimization (ISHO) algorithm, extending the network's lifetime and conserving energy resources. Performance evaluations confirm the superiority of the BONY‐ISHO protocol and existing solutions. It achieves a higher packet delivery ratio (99.8%), increased throughput (45 000 kbps), reduced energy consumption (1.68 joules), and minimized latency (0.068 sec) when compared to traditional methods. These performance enhancements make the BONY‐ISHO protocol a compelling choice for securing and optimizing IoT‐based WSNs. Our study concludes that the BONY‐ISHO protocol is a highly effective solution for addressing security and efficiency challenges in IoT‐based WSNs. By combining blockchain‐based authentication, hybrid cryptography, and intelligent routing algorithms, we have achieved a comprehensive enhancement of network security and data transmission efficiency. The protocol's ability to thwart malicious nodes and optimize routing pathways ensures the integrity and reliability of IoT‐based WSNs.
The use of Qigong and Tai Chi in the management of temporomandibular joint dysfunction: A systematic review
Authors: Salami Afeez A. , Kanmodi Kehinde K. , Leuke Bandara Dhanushka , Aladelusi Timothy O. , Amzat Jimoh , Lin Dan , Ojo Temitope O. , Jayasinghe Ruwan D.
Published: October 2023

Background and Aims

Qigong and Tai Chi (QTC) are mind‐body exercises involving a sequence of graceful movements, which promote self‐healing, meditation, and self‐cultivation. There is growing evidence that Qigong and/or Tai Chi therapy may improve the physical and psychological health among adults with multiple health conditions including joint movement. This systematic review aims to synthesize the available evidence on the type and effectiveness of QTC therapies used in the management of temporomandibular joint (TMJ) dysfunction.

Methods

This systematic review followed the AMSTAR‐2 guideline, and it was reported based on guidelines in the PRISMA checklist. The review involved a systematic search of nine electronic databases. After deduplication and screening of the literature retrieved from the search, only one article was included based on the review's inclusion criteria. Data was extracted from this article and synthesized.

Results

The only included article was on a non‐randomized control trial which investigated the role of Tai Chi Qigong (a form of Qigong) therapy in improving joint mobility and alleviating trismus among 52 survivors of nasopharyngeal carcinoma who had TMJ disorders. The study reported, at different time intervals (at pretest; at mid‐intervention; at posttest; and at follow‐up posttest), that no significant difference (p > 0.05) was observed concerning mouth opening capacity between the intervention group and the control group. However, over time, less severe deterioration in mouth‐opening was noted among the participants in the intervention group (p = 0.181) as compared to the control group (p < 0.001).

Conclusion

The role of QTC therapies in improving joint mobility and alleviating trismus is not yet fully understood, but it seems promising. The available evidence is inadequate to categorically conclude on the efficacy of these therapies. Further studies will be required to fully assess the effectiveness of QTC therapies in the management of TMJ dysfunction.
Anemia prevalence and its predictors among children under‐five years in Ghana. A multilevel analysis of the cross‐sectional 2019 Ghana Malaria Indicator Survey
Authors: Aheto Justice M. K. , Alhassan Yakubu , Puplampu Adikwor E. , Boglo Julius K. , Sedzro Kojo M.
Published: October 2023

Background and Aims

Despite the implementation of anemia control interventions in Ghana, anemia prevalence is still high in children under‐fives. Reducing the prevalence of anemia requires identifying and targeting associated critical risk factors. This study seeks to identify predictors of anemia among children under‐fives in Ghana.

Methods

Nationally representative data from the 2019 Ghana Malaria Indicator Survey was used in this study. Both fixed and random effects (multilevel) logistic regression models were applied to 2434 children to identify critical factors associated with anemia.

Results

In this study, 54% (95% confidence interval [CI] 52.0–57.0) of children under‐5 years were anemic. Infants were more likely to be anemic (66.7%) compared with other children below 5 years. In the multivariable multilevel model, the risk of anemia was found to be higher in younger children especially 6–11 months old (adjusted odds ratio [aOR] = 3.59, CI: 2.54–5.08) and 12–23 months old (aOR = 2.97, CI: 2.08–4.23), children who had malaria (aOR = 1.53, CI: 1.13–2.06), children whose mothers were not registered but not covered with health insurance (aOR = 1.45, CI: 1.21–1.74) or were not even registered for insurance (aOR = 1.49, CI: 1.15–1.93), children born to adolescent mothers (aOR = 2.21, CI: 1.36–3.57), children born to non‐Christian mothers (Islam [aOR = 1.53, CI: 1.17–2.00]), children born to families of poorer households (poorest [aOR = 3.01, CI: 1.64–5.51]; poorer [aOR = 2.56, CI: 1.65–3.98]); middle (aOR = 2.03, CI: 1.32–3.11) and richer (aOR = 1.78, CI: 1.19–2.64), and children who lived in either Upper East (aOR = 2.03, CI: 1.26–3.26) or Central (aOR = 2.52, CI: 1.42–4.47) regions. Significant unobserved community‐level differences in anemia prevalence were observed.

Conclusion

The probability of anemia in children under‐fives differs substantially from one community to another, and the prevalence remains high. The identified critical risk factors should be addressed. Multifaceted and targeted approaches are needed to help reduce the anemia prevalence in this setting to achieve the multiple United Nation's Sustainable Development Goals, which are related to risk and prevalence of anemia by 2030.
Analgesic Efficacy of Acetaminophen 1000 mg, Acetaminophen 2000 mg, and the Combination of Acetaminophen 1000 mg and Codeine Phosphate 60 mg versus Placebo in Acute Postoperative Pain
Authors: Skoglund Lasse A. , Skjelbred Per , Fyllingen Gunnar
Published: October 2023

Acetaminophen (APAP) 1000 mg, APAP 2000 mg, the combination of APAP 1000 mg plus codeine phosphate 60 mg (APAPCOD), and placebo (PBO) were compared in a 6‐hour, randomized, single‐dose, double‐blind, parallel‐group analgesic trial. All active treatments were statistically superior (p<0.05) to placebo for 4 hours after medication with respect to pain intensity (PI) and pain intensity difference (PID), and up to 3 hours regarding pain relief (PAR). The combination scored better than all other treatments on the summary analgesic efficacy measures sum PI (SUMPI), sum PID (SPID), and total PAR (TOTPAR). The combination was statistically superior to APAP 1000 mg on SUMPI, TOTPAR and maximum PAR (MAXPAR). Acetaminophen 2000 mg showed marginal numerical superiority over 1000 mg for SUMPI, but was not statistically superior for any summary efficacy measure. The 2000‐mg dose was numerically inferior to APAPCOD for every summary efficacy measure and statistically inferior regarding SPID and MAXPAR. We concluded that codeine 60 mg added to acetaminophen 1000 mg offers analgesic advantages, and acetaminophen reaches an analgesic ceiling effect at 1000 mg using the dental pain model.
Effects Of Acetaminophen After Bilateral Oral Surgery: Double Dose Twice Daily Versus Standard Dose Four Times Daily
Authors: Skoglund Lasse A. , Pettersen Nina
Published: October 2023

We compared acetaminophen (APAP) double dose 2000 mg twice a day on the day of oral surgery, decreasing to 1000 mg twice a day for the next 2 days, to a standard dose 1000 mg 4 times a day then 500 mg 4 times a day for 2 days. Compared to the double dose, there was 19% (p=0.03) less edema after the standard regimen on the third postoperative day. No statistical difference was seen between the two treatments with respect to ability to open the mouth, temperature on the nonoperated versus operated side, or summary analgesic efficacy measures. However, pain intensity scores indicate that APAP double dose gave less analgesia toward the end of the dosing interval than the standard regimen. It is proposed that double‐dose APAP twice daily does not have any analgesic and antiedematous advantages over the standard dose 4 times a day. The analgesic and antiphlogistic efficacies of APAP apparently do not coincide.
Dosage Forms of Cyclosporine
Authors: Yee Gary C.
Published: October 2023

Cyclosporine can be given intravenously or orally, as a solution or soft gelatin capsule. Because of the drug's poor water solubility, ethoxylated plant fats and ethanol are added to the commercially available dosage forms.
Antimicrobial Formulary Management: Meeting the Challenge in the Community Hospital
Authors: Rush David R.
Published: October 2023

We established a casework approach to develop an antibiotic formulary for a large community hospital. The program consists of a combination of comprehensive clinical and administrative strategies designed to reduce antimicrobial expenditures and improve the quality of antibiotic prescribing. Strategies included a background document summarizing each pharmacologic group of antimicrobial drugs and formulary preferences, presentations to medical and surgical departments, development of drug use evaluation strategies that complement the development of the formulary, and a monitoring program for nonformulary antibiotic use. The development of a customized microbiologic/antibiotic susceptibility report card specific to the institution's inpatient and outpatient microflora was an integral part of the program. This tool also allowed for the continuous compilation of comparison data and development of prescribing tips. Predetermined criteria were established providing physicians with microorganism susceptibility reports and preferred treatment alternatives linked to pharmacoeconomic concerns. These strategies can be implemented with or without direct clinical pharmacotherapy specialist involvement at the individual patient care level. (Pharmacotherapy 1991;11(1 Pt 2):19S‐26S)
Therapeutic Drug Monitoring of Cyclosporine‐Lipoprotein Levels
Authors: Yau Jonathan C. , Brunner Lane J. , Lopez‐Berestein Gabriel , LeMaistre C. Frederick , Luke David R.
Published: October 2023

Cyclosporine therapy is complicated by nephrotoxicity that is not predicted by drug levels. In this study serial trough blood samples were obtained from 11 allogeneic marrow transplant recipients after initiation of intravenous cyclosporine 2 mg/kg every 12 hours for a period extending 4 weeks after transplantation. Renal dysfunction, assessed by an increase in serum creatinine levels to twice baseline values or when greater than 175 μmol/L, was found in four patients. No associations between renal dysfunction and cyclosporine levels in whole blood, total plasma, or lipoprotein fractions were found. The ratios of maximum and mean high‐density low‐density lipoprotein cyclosporine concentrations were greatest in patients with renal dysfunction (p < 0.001). The data suggest therapeutic drug monitoring of cyclosporine in various biologic fluids does not predict onset of drug‐associated renal dysfunction. However, the relative role of high‐density to low‐density lipoprotein transport of cyclosporine may provide an index of renal functional changes associated with the agent.
Elevated phenytoin Concentration Caused by Sampling Through the Drug‐Administration Catheter
Authors: Murphy John E. , Ward Earl S.
Published: October 2023

Elevated phenytoin concentrations are a problem due to the toxic effects that can result. When an elevated concentration is reported, it is important to determine the validity of the report because therapeutic action may include withholding further doses. If the concentration is falsely elevated, the potential for seizure activity as it falls is inherent. Assessing validity involves considering laboratory error and assays of blood samples drawn from the wrong patient. The capacity‐limited biotransformation of phenytoin complicates the estimation of concentrations, making it more difficult to establish the accuracy of reported values. Our patient had a phenytoin concentration of 80.7 mg/L. It had been 13.4 mg/L the day before, and the patient received only an additional 400 mg prior to the reported high value. The pharmacokinetic team determined that the dose was administered through a triple‐lumen catheter from which blood may have been withdrawn for phenytoin analysis the next day. Venous sampling 7 hours after the 80.7‐mg/L value yielded a phenytoin concentration of 12.4 mg/L. Clinicians should consider this error potential in the differential evaluation of elevated concentration in apparently nontoxic patients.
Neurotoxicity Associated with Ceftazidime Therapy in Geriatric Patients with Renal Dysfunction
Authors: Slaker Ralph A. , Danielson Byron
Published: October 2023

Ceftazidime, a β‐lactamase‐stable, third‐generation cephalosporin, is widely used for the treatment of serious gram‐negative infections. Neurotoxicity has rarely been associated with the drug; however, two of our patients developed ceftazidime‐induced neurotoxicity that produced confusion, disorientation, agitation, generalized weakness, and myoclonus. In both patients these symptoms cleared with either discontinuation or reduction of the dosage of ceftazidime. This emphasizes the importance of adjusting the dosage of ceftazidime in patients with renal insufficiency.
Toxic Shock‐Like Syndrome
Authors: Erstad Brian L. , Witte Charles L. , Talkington Deborah F.
Published: October 2023

Invasive group A streptococcal infection has important diagnostic and therapeutic implications in patients with necrotizing fasciitis. We cared for a man with the full‐blown syndrome in whom many features of toxic shock syndrome were present, including profound hypotension and renal failure. The diagnostic similarities of toxic shock syndrome and the toxic shock‐like syndrome caused by group A Streptococcus could have led to inappropriate treatment. Successful therapy in our patient included high doses initially of broad‐spectrum antibiotics, repeated operative debridement of the lower leg (the affected limb), and ultimately, reconstructive surgery consisting primarily of split‐thickness skin grafts. The reemergence of invasive streptococcal infections may relate to changes either in virulence factors of the causative streptococcus or in exotoxins elaborated by this microorganism. A causative relationship between an exotoxin produced by group A Streptococcus and the toxic shock‐like syndrome has not yet been established.
Comparison of the Pharmacokinetics and Electrocardiographic Effects of Sublingual and Intravenous Verapamil
Authors: Berk Steven I. , Beckman Karen , Hoon Timothy J. , Hariman Robert J. , Hu Dayi , Siegel Frederick P. , Bauman Jerry L.
Published: October 2023

Using a dog model, a sublingual form of the free base of verapamil (SLV) was developed with the intent of avoiding stereoselective first‐pass metabolism and the necessity of intravenous administration. Intravenous verapamil (IVV) 5 mg and SLV 40 mg or 60 mg were sequentially administered to seven healthy human volunteers. Electrocardiograms and serum concentrations were obtained before and periodically from 5 to 480 minutes after each dose. The time to peak serum concentration (mean ± SD) was 77.6 ± 38.1 minutes after SLV. Bioavailability of SLV was 58.2 ± 36.9% compared to IVV. Verapamil half‐lives after IVV and SLV were 2.83 ± 0.93 and 2.28 ± 0.45 hours (NS), respectively. In one subject, the time to peak effect was delayed and overall change in PR interval was minimum. In the remaining six subjects, the maximum percentage increases in PR interval after IVV and SLV were 20.6 ± 6.4% and 14.8 ± 5.5% (p<0.05), respectively. Times to peak increase in PR interval were 28.3 ± 15.7 and 57.0 ± 17.5 minutes after IVV and SLV (p<0.05), respectively. Analysis of plots of percentage change in PR interval versus serum concentration revealed a shift to the right and therefore, lesser effect of SLV than of IVV in six subjects. All seven subjects complained of oral numbness and bitter taste. In conclusion, SLV is inferior to IVV in terms of rate and extent of absorption and pharmacologic effect in delaying atrioventricular nodal conduction. Probably SLV has little clinical utility because of its slow onset and poor tolerance.
Colony‐Stimulating Factors: Clinical Applications
Authors: Blackwell Susan , Crawford Jeffrey
Published: October 2023

Recombinant human colony‐stimulating factors (CSFs) have potential for wide use in the areas of oncology and infectious disease. Granulocyte CSF and granulocyte‐macrophage CSF currently are approved for use in the treatment of neutropenia associated with standard‐dose cancer chemotherapy and bone marrow transplantation, respectively. Other settings in which these agents have shown promise are dose‐intensive chemotherapy, enhancement of progenitor cell support, primary and acquired neutropenias, myelodysplasia, aplastic anemia, and cytopenias associated with human immunodeficiency virus infection or myelosuppressive therapies for such infection or related conditions. Clinical findings in these areas are encouraging, and potential exists for additional applications of the CSFs.
Pharmacokinetics and Administration of Colony‐Stimulating Factors
Authors: Petros William P.
Published: October 2023

Granulocyte colony‐stimulating factor (G‐CSF) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) generally are rapidly eliminated from the blood after intermittent intravenous infusion. Subcutaneous administration of these agents results in lower peak concentrations but is associated with prolonged systemic exposure. Elimination of the factors appears to occur by several mechanisms, including white blood cell receptor‐mediated endocytosis, metabolism by proteases, and urinary excretion by glomerular filtration with subsequent reabsorption and catabolism. The pattern and route of elimination are affected by type of factor and dosage, degree of glycosylation, renal function, and number of white blood cell receptors for the particular CSF. Granulocyte CSF and GM‐CSF are approved for use in patients with nonmyeloid malignancy who are receiving myelosuppressive chemotherapy, and those undergoing highdose chemotherapy and bone marrow transplantation, respectively. In these indications, treatment generally is initiated no earlier than 24 hours after chemotherapy and continued beyond the expected chemotherapy‐associated neutrophil count nadir. Limited information suggests that subcutaneous administration is more effective than intermittent intravenous infusion. The latter may require the addition of albumin to ensure stability. Storage and handling guidelines include preventing exposure to extreme temperatures and avoiding excessive agitation of the solution.
Variability in Teniposide Plasma Protein Binding Is Correlated With Serum Albumin Concentrations
Authors: Petros William P. , Rodman John H. , Relling Mary V. , Christensen Michael , Pui Ching‐Hon , Rivera Gaston K. , Evans William E.
Published: October 2023

Teniposide is a widely used anticancer drug that is extensively bound to plasma proteins (> 95%). We evaluated the drug's plasma protein binding in nine patients with acute lymphocytic leukemia who were in their first complete remission, and in a second group of nine patients at the time of relapse and subsequently after achieving another complete remission. Plasma protein binding was assessed by equilibrium dialysis, with direct high‐performance liquid chromatographic measurement of total and free teniposide. The mean unbound fraction was 0.44% (0.21–0.88%) in the plasma of patients in first remission. It was significantly higher in patients at the time of relapse (mean = 0.86%; range 0.68–1.08%) and after achieving another complete remission (mean = 1.25%; range 0.51–2.11%). Serum albumin values were significantly lower at the time of relapse (mean = 4.6 vs 4.0 mg/dl; p<0.014), and decreased further during intensive postremission therapy containing l‐asparaginase (mean = 3.2; p<0.05). For all 18 patients, a significant negative correlation (r2=0.667; p<0.001) was found between serum albumin and unbound teniposide, with low albumin being associated with higher unbound fraction. Such patients have higher systemic exposure to unbound (presumably active) teniposide at any given total plasma concentration of the agent.
Comparative Evaluation of the Neuromuscular and Cardiovascular Effects of Pipecuronium, Pancuronium, Atracurium, and Vecuronium Under Isoflurane Anesthesia
Authors: Larijani Ghassem E. , Gratz Irwin , Minassian Shahab S. , Hughes Deurward L. , Afshar Mary , Karayannis Basil N.
Published: October 2023

The neuromuscular and cardiovascular effects of intubating doses of pipecuronium 80 μg/kg, pancuronium 100 μg/kg, atracurium 500 μg/kg, and vecuronium 100 μg/kg were compared in 62 patients under isoflurane (end‐tidal concentration = 0.5–1%) anesthesia. Pipecuronium, pancuronium, and vecuronium had no significant effect on systolic or diastolic blood pressure. In one patient the administration of atracurium resulted in significant hypotension. Heart rate was significantly increased only after the administration of pancuronium. The neuromuscular‐blocking effect of pipecuronium and pancuronium appears to be twice as long as that of vecuronium and atracurium. Administration of neostigmine resulted in significantly faster recovery of muscle function in patients receiving vecuronium or atracurium. Although pipecuronium's neuromuscular‐blocking effect is similar to that of pancuronium, its lack of cardiovascular effects more closely resembles that of vecuronium.
Prospective Evaluation of Risk Factors for Antibiotic‐Associated Bleeding in Critically III Patients
Authors: Goss Thomas F. , Walawander Cynthia A. , Grasela Thaddeus H. , Meisel Steven , Katona Brian , Jaynes Karen
Published: October 2023

A prospective surveillance program was initiated to determine the relative role of antibiotics containing N‐methylthiotetrazole (NMTT) versus patient risk factors in producing antibiotic‐associated bleeding. Five hundred forty‐six critically ill patients with serum albumin 30 g/L or below were evaluated for evidence of a bleeding event as documented by clinical observation, hemoglobin changes, and transfusions. Bleeding events occurred in 16% of patients receiving an aminoglycoside combination, 10% receiving antibiotics with the NMTT side chain, and 14.5% receiving antibiotics not containing NMTT (p>0.05). The bleeding rate was highest in febrile patients with cancer (14.5%) and lowest in those with a suspected or documented abdominal infection (10%) (p=0.04), but within each patient group there was no difference among the antibiotics. We conclude that the use of NMTT‐containing antibiotics is not an independent risk factor for bleeding, but the role of severity of illness may be underappreciated.
Chronic Cough Responsive to Ibuprofen
Authors: Dales Robert E. , Lunau Mary A. , Tierney Michael G. , Schweitzer Irwin
Published: October 2023

A 57‐year‐old woman believed that ibuprofen, prescribed for back pain, improved her idiopathic chronic cough that had been resistant to inhaled and oral corticosteroids. To confirm this observation, we performed an n‐of‐1 clinical trial with four treatment periods, each separated by a 4‐day washout. Ibuprofen 1800 mg/day for 6 days or placebo was randomly allocated in a double‐blind fashion with a block size of 4. The number of coughs during the first 30 minutes after awakening were counted daily throughout the study using a tape recorder. Sixty‐two coughs/hour occurred while taking ibuprofen, compared with 164 with placebo. We conclude that ibuprofen may be effective in idiopathic chronic cough, and suggest that prostaglandins may be pathogenic factors in some patients.
Seizures Associated With Ganciclovir Therapy
Authors: Barton Terri L. , Roush Maura K. , Dever Lisa L.
Published: October 2023

A 32‐year‐old man diagnosed with acquired immunodeficiency syndrome and a disseminated cytomegalovirus infection experienced seizures associated with the administration of ganciclovir. Seizures began 1 month after initiation of therapy and worsened with increasing dosages. Despite phenytoin administration, the seizure‐like activity subsided only after discontinuing ganciclovir. After rechallenge with ganciclovir the seizures recurred. Although this case was confounded by numerous patient and disease factors, the Naranjo algorithm produced a score of 7, indicating a probable association between ganciclovir and seizure activity.
Evaluation and Comparison of the Adverse Effects of Streptokinase and Alteplase
Authors: Tisdale James E. , Colucci Robert D. , Ujhelyi Michael R. , Kluger Jeffrey , Fieldman Arnold , Chow Moses S. S.
Published: October 2023

The frequency and severity of adverse effects resulting from the administration of streptokinase and alteplase were determined in 126 consecutive patients who received standard dosages of these agents for the treatment of acute myocardial infarction. Evaluation was based on patient assessment by nursing staff, physicians, and the investigators before, during, and after thrombolytic administration. Overall, adverse effects occurred in 15 (41.7%) of 36 patients receiving streptokinase and 12 (13.3%) of 90 receiving alteplase (p=0.001). No major bleeding or neurologic events were documented. Minor bleeding occurred in 13.9% and 7.8% of streptokinase and alteplase recipients, respectively (p=0.47), and hypotension in 8 (22.2%) and 5 (5.6%), respectively (p=0.01). The frequency of hypotension associated with streptokinase was significantly higher than that with alteplase. Thrombolytic‐induced hypotension was easily managed and was not associated with sequelae.
Population Pharmacokinetics of Gentamicin in Neonates Using a Nonlinear, Mixed‐Effects Model
Authors: Jensen Paul D. , Edgren Bruce E. , Brundage Richard C.
Published: October 2023

The population pharmacokinetics of gentamicin in neonates was determined using a nonlinear, mixed‐effects model (NONMEM). The final regression equations derived to estimate clearance (Cl) and volume of distribution (Vd) were Cl = 0.120 * (WT/2.4)1,36 L/hr and Vd = 0.429 * (WT) L. The interindividual variability (% CV) for clearance was 26.2% and for volume of distribution 15.9%. Intraindividual variability was 11.0%. In a separate group of 30 neonates, the predictive ability of the NONMEM‐generated population variables was compared to the predictions from a standard two‐stage population analysis. The trough concentrations predicted using NONMEM‐generated parameters were significantly less biased and more precise; there were no significant differences between the methods in predicting peaks. NONMEM is a useful tool for determining population pharmacokinetics and appears to be consistent across populations using routine clinical data and limited observation.
Does Ranitidine Affect Blood Alcohol Concentrations?
Authors: Pipkin Graham A. , Mills Jane G. , Wood John R.
Published: October 2023

No interaction occurs between ranitidine and alcohol when alcohol 0.3 g/kg or more is taken by either fed or fasted subjects. Ranitidine is associated with small increases (2–4 mg/dl) in blood alcohol concentrations in subjects given alcohol 0.15 g/kg under specific experimental conditions. Mean peak blood alcohol concentrations nevertheless remain low (<20 mg/dl) after that amount, which is equivalent to about 3 oz of wine or 1 oz of 80‐proof liquor. Such changes also occur when alcohol is ingested after different types of foods, and are smaller than the increases when it is drunk on an empty compared with a full stomach. The pharmacokinetic effect seen with ranitidine is without apparent clinical or social significance.
Evaluation of Bromfenac and Ibuprofen for Pain After Orthopedic Surgery
Authors: Boström Åke A.S. , Forbes James A. , Adolfsson Christina , Beaver William T. , Bell Walter E.
Published: October 2023

Study Objectives. To determine the relative analgesic potency and adverse effect liability of bromfenac 25, 50, and 100 mg, and ibuprofen 200 and 400 mg in the treatment of postoperative pain after orthopedic surgery.

Design. Randomized, double‐blind, single‐dose, parallel‐group relative potency assay with evaluations at 30 minutes and then at hourly intervals for up to 6 hours.

Setting. Two wards of the orthopedic surgery department at the Centralsjukhuset (Central Hospital) in Karlstad, Sweden.

Patients. Two hundred inpatients with steady, moderate or severe pain within 72 hours after orthopedic surgery.

Interventions. Patients received a single oral dose of bromfenac 25, 50, or 100 mg, or ibuprofen 200 or 400 mg, when they experienced steady, moderate or severe pain that, in their opinion, required an analgesic. Using a self‐rating record, subjects rated their pain and its relief for 6 hours after medicating.

Measurements and Main Results. The study was a valid relative potency assay with estimates of bromfenac's potency relative to ibuprofen ranging from 10.9 (nurse's global evaluation) to 16.7 (sum of hourly analog pain intensity difference scores). That is, 11–16 times the dose of ibuprofen must be administered to equal the analgesic effect of bromfenac. Patients who had eaten breakfast or lunch within 60 minutes before or 30 minutes after receiving the study medication (“fed” patients) had lower efficacy scores than those who had not ingested food within these time constraints before or after receiving the study medication (“fasted” patients). Furthermore, patients who had eaten before receiving the study medication had significantly lower efficacy scores than those who had eaten after receiving the study medication.

Conclusions. The relative potency of the analgesic effect of bromfenac to ibuprofen is 11–16.7 in patients with pain after orthopedic surgery. Fed patients may have lower analgesic efficacy than fasted patients. Adverse effects for both bromfenac and ibuprofen were transient and consistent with the pharmacologic profiles of the drugs.
Pneumocystis carinii Pneumonia Prophylaxis During Pregnancy
Authors: Connelly Rita T. , Lourwood David L.
Published: October 2023

The frequency of human immunodeficiency virus (HIV) infection among pregnant womenis increasing. Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection in HIV‐infected patients, and prophylaxis is an important part of decreasing morbidity. Trimethoprim‐sulfamethoxazole (TMP‐SMX), pentamidine, and dapsone, alone or in combination with pyrimethamine, are the most commonly used drugs for PCP prophylaxis in the nonpregnant HIV‐infected population. Trimethoprim‐sulfamethoxazole, however, has the potential for adverse effects in the fetus. Limited data are available for the other agents administered as prophylaxis of PCP.
Does Gonadotropin Receptor Complex Have an Amplifying Role in cAMP/Testosterone Production in Leydig Cells?
Authors: BROWNE ELIZABETH S. , BHALLA VINOD K.
Published: October 2023

ABSTRACT: The dose—response relationship between luteinizing hormone/human chorionic gonadotropin (LH/hCG)‐stimulated biological response and 125I‐labeled hCG binding was studied in purified Leydig cells from adult rat testes. The concentration of hCG needed for one‐half maximal stimulation of cyclic adenosine monophosphate (cAMP) and testosterone production (ED50) was 2.16 × 10−11mol/L and 5.6 × 10−13mol/L, respectively. This suggests that extremely low levels of hormone in the range of 10−13mol/L hCG are sufficient to generate enough cAMP (5.66 pmol; 2.83 × 10−9mol/L) for steroidogenesis, thereby preserving the catalytic potential of the receptor‐cyclase system. Most of the cAMP formed at 10−13mol/L hCG was released into the medium, and the intracellular cAMP was much less and barely detectable (0.98 × 10−9mol/L; 1.96 pmol/2 × 106 cells). The specific binding of 125I‐labeled hCG to purified Leydig cells at a correspondingly higher hCG concentration (3 × 10−10mol/L) was extremely low and did not display a dose‐dependent increase in binding. Assuming the specific binding to represent 100% occupancy of high affinity receptors (14.2 fmol/ 2 × 106 cells per 2 ml), each mole of bound hCG generated 15,423 mol cAMP and 12,817 mol testosterone. The results show that the hormone interacts with cellular receptors as a catalyst to generate the biological response. Moreover, the true affinity of hormone‐receptor interaction responsible for the physiologic action is possibly much greater than previously reported for this system. This information should prove useful for reconstitution studies using the hormone receptor/G‐protein/adenylate cyclase system in vitro in soluble form.
Stage‐specific Expression of a Protein of the Acrosome of Baboon Sperm during Spermiogenesis Detected with a Monoclonal Antibody
Authors: ISAHAKIA MOHAMED A.
Published: October 2023

ABSTRACT: A single monoclonal antibody, BSA4, raised against baboon epididymal sperm was used to study the ontogeny of the baboon sperm acrosome region during testicular spermiogenesis. This antibody is not species‐specific but is restricted to the acrosome region in all other sperm examined (human, rat, and mouse). In the baboon, treatment of epididymal sperm with 0.05% Triton‐X results in complete loss of anterior acrosome staining. Such treated sperm display a distinct equatorial staining. Antibody BSA4 reacts with a determinant (molecular weight, 43,000 d) that first appears in postmeiotic round spermatids during spermiogenesis. When tested for an effect on the fertilization process in vitro, the antibody BSA4 displayed significant inhibition, indicating a possible functional role for the determinant on mouse sperm. Using the avidin‐biotin immunoperoxidase method, several stages of acrosome development were recognized: ie, cap, acrosome, and maturation stages of spermiogenesis. The antibody staining was restricted to the developing acrosome at all stages, indicating that the equatorial region is part of the acrosome and is expressed with temporal specificity during spermatogenesis in the baboon.
The Effects of Normal Aging on the Response of the Pituitary‐Gonadal Axis to Chronic Clomiphene Administration in Men
Authors: TENOVER JOYCE S. , BREMNER WILLIAM J.
Published: October 2023

ABSTRACT: Serum androgens decline with age in normal men, despite normal or elevated bioactive serum gonadotropins, suggesting that primary testicular dysfunction occurs with aging. The authors further assessed the question of age‐related testicular dysfunction by evaluating whether raising serum gonadotropins above the normal serum range for an extended time in healthy elderly men might result in bringing their gonadal function to a level similar to that found in young adult men. Five elderly (65 to 85 years old) and five young adult men (26 to 33 years old) were given 50 mg of clomiphene citrate (CC) twice a day for 8 weeks to stimulate gonadotropin production. During that time, testosterone (T), non‐sex hormone‐binding globulin bound T, and estradiol increased significantly in both age groups, while serum inhibin increased significantly only in the young adult men. The increases in serum androgens with CC administration were significantly greater in the young adult men than in the elderly men. These hormone changes occurred in the setting of serum gonadotropins that increased significantly in both age groups, although there was a tendency for the elderly men to have a smaller increase in luteinizing hormone. Despite 8 weeks of stimulation of the pituitary‐gonadal axis by CC administration, the elderly men demonstrated significantly diminished testicular responses compared with the young adult men. Sertoli cell function, as determined by inhibin production, was more diminished in the elderly men than was Leydig cell function. These data strengthen the hypothesis that normal aging in men is accompanied by a decline in testicular function.
The Emerging Role of Alpha Antagonists in the Therapy of Benign Prostatic Hyperplasia
Authors: LEPOR HERBERT
Published: October 2023

The rationale for using alpha blockade to treat benign prostatic hyperplasia (BPH) is based on the physiology and pharmacology of prostate smooth muscle. Approximately 20% of the area density of the prostate adenoma is smooth muscle. In vitro isometric tension studies have demonstrated that the contractile properties of the human prostate adenoma are mediated primarily by alpha1 adrenoceptors. Alpha blockers presumably decrease the resistance along the prostatic urethra by relaxing the smooth muscle component of the prostate. Over the past 14 years, at least 16 clinical trials have confirmed the efficacy of alpha blockade in the treatment of BPH. The primary advantage of terazosin over all other commercially available alpha blockers is that its longer half‐life allows for a once‐daily dosage regimen. Two Phase II studies conducted in the United States, a multi‐center dose titration randomized withdrawal study and the author's personal experience with terazosin, are summarized in this report. Overall, the peak urinary flow rate increased 50% and the mean urinary flow rate increased 46% following terazosin therapy. The mean obstructive and irritative scores improved 67% and 35%, respectively. The adverse reactions occurring with an incidence greater than 5% included headache (10%), asthenia (7%), and dizziness (14%). All adverse events were reversible on termination of therapy. The preliminary experiences with alpha blockers for the treatment of BPH has been very encouraging. Yet, the definitive role of alpha blockade in BPH awaits the reporting of multicenter, randomized placebo‐controlled studies