bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Single Cell Analysis of Proteins in 2D Human Gastruloids Using Iterative Immunofluorescence
Authors: Freeburne Emily , Teague Seth , Khan Hina , Li Bolin , Ding Siyuan , Chen Bohan , Helms Adam , Heemskerk Idse
Published: October 2023

During development, cell signaling instructs tissue patterning, the process by which initially identical cells give rise to spatially organized structures consisting of different cell types. How multiple signals combinatorially instruct fate in space and time remains poorly understood. Simultaneous measurement of signaling activity through multiple signaling pathways and of the cell fates they control is critical to addressing this problem. Here we describe an iterative immunofluorescence protocol and computational pipeline to interrogate pattern formation in a 2D model of human gastrulation with far greater multiplexing than is possible with standard immunofluorescence techniques. This protocol and computational pipeline together enable imaging followed by spatial and co‐localization analysis of over 27 proteins in the same gastruloids. We demonstrate this by clustering single cell protein expression, using techniques familiar from scRNA‐seq, and linking this to spatial position to calculate spatial distributions and cell signaling activity of different cell types. These methods are not limited to patterning in 2D gastruloids and can be easily extended to other contexts. In addition to the iterative immunofluorescence protocol and analysis pipeline, Support Protocols for 2D gastruloid differentiation and producing micropatterned multi‐well slides are included. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.

Basic Protocol 1: Iterative immunofluorescence

Basic Protocol 2: Computational analysis pipeline

Support Protocol 1: Generating micropatterned multi‐well slides

Support Protocol 2: Differentiation of 2D gastruloids
Synthetic polyploidy in spice crops: A review
Authors: Neenu Maria George , Aswathi Akkaraparambil , Prasath Duraisamy
Published: October 2023

Spice crops comprise diverse, economically valuable crops with numerous applications ranging from culinary to pharmaceutical industries. Spices are an integral part of cuisines worldwide, imparting characteristic flavor, aroma, and pungency to food. Breeding and crop improvement efforts in spices have focused on enhancing yield and quality parameters (essential oil, oleoresin, fiber, etc.) along with bioactive chemical constituents. The prominent breeding strategies followed are selection, hybridization, mutation, in vitro approaches, and transgenics. Polyploidy is one of the drivers of speciation and evolution, increasing the biological diversity in many crops, including spices. Polyploidy, either through natural means or artificial induction, broadens the scope of crop improvement. The artificial induction of polyploidy is usually done via antimitotic chemicals, duplicating the complete chromosomal set and allowing for genetic alterations and rearrangements that result in phenotypic changes across the board. As a result, increasing ploidy in crops often results in improved yield, biomass, vigor, biotic and abiotic stress tolerance, and secondary metabolite production, all of which can contribute to the economic success of these crops. This review provides an overview of research on artificial polyploidization in spice crops, including the polyploidy induction system, polyploidy generation, and screening methods to select the polyploids of interest. Thus, we have summarized the significant applications of artificial polyploidy in crop improvement that can serve as a potent reference for future research works in the same direction in the under‐explored spice crops.
A novel MIMO SMC for comprehensive unified control of the cascaded DC‐DC and DC‐AC converters in grid connected photovoltaic systems
Authors: Radmand Fereshteh , Hosseini Firouz Mansour , Salimi Mahdi , Babaei Ebrahim
Published: October 2023

It is well known that DC‐DC boost converters are cascaded with DC‐AC inverters for grid connection of the photovoltaic (PV) systems. In the traditional control approaches, the mentioned DC‐DC and DC‐AC converters are controlled separately to facilitate the controller design problem. However, from the controller design viewpoint, the overall structure of the grid connected PV generator is a multi‐input multi‐output (MIMO) system. The duty cycle of the DC‐DC converter and inverter modulation index are the control inputs and, on the other hand, generated photovoltaic DC power and exported power to the grid are control outputs. Moreover, the inverter DC link voltage should be stabilized by the closed‐loop controller as well as an internal control output. If controllers are designed separately, it means that the interaction between DC‐DC and DC‐AC controllers isn't considered accurately, and since the isolated models of DC‐DC converter and DC‐AC inverter are extracted based on some approximated assumptions, separate controller design cannot guarantee stability and robustness of the whole system in a wide range of operation. To cope with these problems, in this paper, a novel MIMO sliding mode controller (SMC) is developed for comprehensive closed‐loop control of the DC‐DC boost converter cascaded with a single‐phase DC‐AC grid connected photovoltaic inverter. In the proposed approach, the dynamic model of whole system is developed comprehensively at first, and then, a unique MIMO controller is designed to control both DC‐to‐AC and DC‐to‐DC converters together. To cope with the nonlinear characteristic of the system and uncertainty of model parameters in a wide range, a fixed‐frequency SMC is developed using the comprehensive state space model of the closed loop system. In the proposed MIMO‐SMC controller, the AC power (which is exported to the grid) and operating point of the PV source are controlled via inverter modulation index and duty cycle of the DC‐DC boost converter, respectively. Another major advantage of the proposed system is mitigating the non‐minimum phase characteristic of the boost converter through the indirect control of inverter DC link capacitor. To evaluate the performance of the designed control system, simulation results are compared with a standard linear PI controller. It is shown that the developed system has zero steady‐state error and enjoys faster dynamic response during the start‐up and step changes of AC and DC current references. Moreover, it can maintain the stability of closed‐loop systems in a wide range of operations.
Insights from a Web‐based survey into the psychosocial experiences of adults with dyslexia: Findings from a final comment question
Authors: Nalavany Blace A. , Kennedy Reeve , Lee Mi Hwa , Carawan Lena W. , Knight Sharon M.
Published: October 2023

Not seemingly measuring up to Western societies' educational and occupational expectations for success, adults with dyslexia are at risk for discrimination, humiliation, low self‐esteem, low self‐efficacy, depression, and anxiety. We analysed 113 responses to the final comment question that was incorporated at the end of a quantitative survey on the socioemotional experiences of adults with dyslexia. The final comment question was not intended for conveying personal experiences, yet the final comment responses were personal, in‐depth, and substantive – indicators of quality recommended in survey research. Thematic analysis was used to analyse the data and develop themes. One overarching theme was yearnings for understanding and acceptance. Its associated subthemes included (1) “This stuff is torture”, (2) “Thank God I'm not normal, (3) educational experience, (4) coping strategies, (5) family support, and (6) generational dyslexia. This study contributes to the small but growing body of literature on the socioemotional experiences of adults with dyslexia. Among the implications for practice, policy and research, a larger challenge at the broader society level that embraces diversity, equity, and inclusion for individuals with dyslexia is forefront.
PCA‐based fast point feature histogram simplification algorithm for point clouds
Authors: Gan Zhong , Ma Boyu , Ling Zihao
Published: October 2023

In order to realize efficient and lightweight digital inspection technology, we propose an improved method to simplification large volumes of scanned point cloud data of aircraft integral panels and facilitate subsequent processing. Fast Point Feature Histogram (FPFH) method is utilized to extract feature information and optimize the Principal Component Analysis (PCA) algorithm to calculate the contribution degree to transform into principal components, yielding PCA‐based FPFH features. Next, based on PCA‐based FPFH features, we classify the point cloud data into non‐feature and feature point clouds and extract the feature point clouds through random downsampling to obtain simplified non‐feature point clouds, extract the feature point clouds to retain their boundary integrity, and downsample the remaining feature point clouds by curvature to obtain the simplified feature point clouds. Finally, we combine the two to obtain the final simplified panel point cloud data within 30 s. To evaluate the simplification effect, we adopt a standardized information entropy‐based point cloud simplification accuracy evaluation method based on the simplification rate. Our method achieves an information entropy of more than 0.95, indicating its effectiveness in simplification point cloud data for efficient and lightweight digital inspection technology.
Metabolic connectivity as a predictor of surgical outcome in mesial temporal lobe epilepsy
Authors: Strýček Ondřej , Říha Pavel , Kojan Martin , Řehák Zdeněk , Brázdil Milan
Published: October 2023

Objective

The study investigated metabolic connectivity (MC) differences between patients with unilateral drug‐resistant mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) and healthy controls (HCs), based on [18 F]‐fluorodeoxyglucose (FDG)–PET data. We focused on the MC changes dependent on the lateralization of the epileptogenic lobe and on correlations with postoperative outcomes.

Methods

FDG–PET scans of 47 patients with unilateral MTLE with histopathologically proven HS and 25 HC were included in the study. All the patients underwent a standard anterior temporal lobectomy and were more than 2 years after the surgery. MC changes were compared between the two HS groups (left HS, right HS) and HC. Differences between the metabolic network of seizure‐free and non‐seizure‐free patients after surgery were depicted afterward. Network changes were correlated with clinical characteristics.

Results

The study showed widespread metabolic network changes in the HS patients as compared to HC. The changes were more extensive in the right HS than in the left HS. Unfavorable surgical outcomes were found in patients with decreased MC within the network including both the lesional and contralesional hippocampus, ipsilesional frontal operculum, and contralesional insula. Favorable outcomes correlated with decreased MC within the network involving both orbitofrontal cortices and the ipsilesional temporal lobe.

Significance

There are major differences in the metabolic networks of left and right HS, with more extensive changes in right HS. The changes within the metabolic network could help predict surgical outcomes in patients with HS. MC may identify patients with potentially unfavorable outcomes and direct them to a more detailed presurgical evaluation.

Plain Language Summary

Metabolic connectivity is a promising method for metabolic network mapping. Metabolic networks in mesial temporal lobe epilepsy are dependent on lateralization of the epileptogenic lobe and could predict surgical outcomes.
Cyperus pangorei porous carbon electrodes for the sustainable symmetric supercapacitor application
Authors: Priya D. Siva , Kennedy L. John , Anand G. Theophil
Published: October 2023

Efficiently addressing natural biowaste has the potential to effectively mitigate pressing environmental concerns. Given the growing demand for energy, it is imperative to identify a safe and environmentally friendly method for producing biowaste‐based porous carbon (PC). Biowaste serves valuable carbon sources for the cost‐effective production of efficient PC materials. In this study, we focus on ongoing research aimed at converting a small‐scale industrial waste of Cyperus pangorei, into PC. To achieve this, we employed a simple and eco‐friendly approach, optimizing the process at four different temperatures to enhance its suitability for supercapacitor applications. By subjecting the Cyperus pangorei waste to a two‐step chemical activation process using potassium hydroxide (KOH) at 800°C (referred to as CPC8), we obtained a PCs with a well‐defined pore matrix, exhibiting a surface area of 711.2 m2g−1. The resulting PC exhibited 194.6 Fg−1 (0.5 Ag−1) of specific capacitance when tested in a 1 M Na2SO4 aqueous electrolyte. The galvanostatic study demonstrated remarkable 88.5 Whkg−1 of energy density at 1.7 kWkg−1 power density, along with a capacitance retention rate of 97.9% at 5000th cycle (8 Ag−1). Furthermore, electrochemical impedance study revealed 0.053 Ω of internal resistance, indicating enhanced ionic diffusion. Based on the excellent performance characteristics exhibited by CPC8, its practical application in supercapacitors holds great promise.
Beamforming and data detection in intelligent reflecting surfaces‐assisted communication using deep learning
Authors: Raghavendra Ashwini H. , Gurugopinath Sanjeev
Published: October 2023

In this article, we propose two deep neural network (DNN) architectures for an intelligent reflecting surface (IRS)‐assisted network with a single transmitter and multiple receivers. The first DNN is designed to obtain an optimal beamforming weight vector that maximizes the achievable sum rate over the IRS‐aided network. The beamforming vector is designed based on a pilot‐based channel estimation procedure, which requires only a small fraction of the available number of reflecting surfaces on the IRS to be active. The obtained vector is fed to the second DNN, which is designed for detecting information symbols from the transmitter. Our simulation study shows that the achievable rate obtained using the designed beamforming vector approaches the maximum achievable rate quickly, as the number of active elements increases. The impact of the number of active elements and the beamforming vector on the performance of the detector is also studied, in terms of the bit error rate (BER). We show that the BER performance of the second DNN is close to that of the optimal maximum likelihood detector. Further, we study the effect of the channel estimation errors on the performance of the DNNs. Moreover, we study the effect of the hyperparameters of the architectures on the training time and performance, in terms of root mean squared error and accuracy.
Physicochemical properties and survival assessment of potential probiotics in a novel dairy drink during storage
Authors: Gedik Oğuzhan , Karahan Aynur Gül
Published: October 2023

A novel fermented dairy drink utilizing microbial strains displaying potential probiotic attributes was formulated. The study constituted several experimental cohorts, including Lactiplantibacillus plantarum AB6‐25, isolated from a human stool sample; Lacticaseibacillus casei K2, sourced from a koumiss sample; Lacticaseibacillus rhamnosus 3B7, derived from a traditional yogurt sample; and identical lactic acid bacteria (LAB) in combination with yeast (Saccharomyces boulardii T8‐3C from chicken feces) strains. Two distinct iterations of probiotic‐fermented dairy drinks were generated by introducing subcultured microorganism cultures: LAB strains at a concentration of 1% each (designated as combination A) and a blend of LAB strains at 1% each along with T8‐3C at 0.5% (designated as combination B) into both whole and semi‐skimmed milk matrices. The fermentation process persisted until the pH reached 4.6 under constant conditions of 37 ± 1°C. Subsequently, the samples were held at 4 ± 1°C for 15 days. The groups' physicochemical, microbiological, and sensory characteristics were determined on days 1, 8, and 15 of storage, and the protein profile was determined. Standardized regression analysis and principal component analysis evaluated the results. Fat content affected the changes in dry matter. pH decreased in all samples during storage, particularly in the yeast group. The microorganism group positively affected syneresis, whereas fat content and the interaction of fat content and the microorganism group had a negative effect. The most critical factor in the decrease in syneresis was the increase in fat content. LAB and yeasts maintained their probiotic effects during storage, with a viability level of approximately 109 and 108 cfu/mL, respectively.
Sedimentary sequence and evolutionary characteristics of the rift system of Neoproterozoic Nanhua System and Doushantuo Formation: A case study from the northeastern margin of Sichuan Basin
Authors: Bian Congsheng , Sun Zheng , Chen Xuan , Li Chuanxin , Chai Shunqi , Deng Yuhao , Gao Tian
Published: October 2023

Neoproterozoic strata are widely developed in the Upper Yangtze region of South China, among which the Sinian Dengying Formation has been discovered with numerous large gas fields in the Sichuan Basin, and hence they have become an essential domain for natural gas exploration and development. The early‐to‐middle Neoproterozoic Nanhua System and Doushantuo Formation are characterized by rifting deposits in the northeastern margin of Sichuan Basin, but their depositional succession and sequence architectures are still unclear, which has largely restricted our understanding of the resource potential of these strata. In this paper, based on the outcrops of the Neoproterozoic Nanhua System and Doushantuo Formation in the northeastern margin of Sichuan Basin, we describe the stratigraphic distribution and sedimentary evolutionary characteristics, and establish the regional stratigraphic framework, sedimentary cycle and evolutionary sequence of the Nanhua System and Doushantuo Formation. The results show that the lithology of the Nanhua System and Doushantuo Formation is primarily composed of conglomerate, conglomeratic sandstone, medium‐fine sandstone, siltstone, mudstone, shale and tillite; a variety of sedimentary facies including alluvial fan, river, delta, coastal shore, shelf, basin and tillite were developed; five third‐order sequences could be identified, representing multiple cycles of marine transgression and regression. The climate during the deposition of the Nanhua System and Doushantuo Formation underwent from a warm and humid pre‐glacial period through cold and arid multiple glacial periods to a warm and humid interglacial period, which consequently formed a sedimentary sequence of alluvial fan and fluvial delta to tillite during the early period, shelf basin to tillite during the middle period and slope basin to delta facies during the late period. In terms of a plan view, the depositional pattern is composed of alluvial fans and deltas at the proximal part of the rift, deep‐water shelf to slope at the middle part of the rift and slope to basin facies at the central part of the rift. Finally, we propose that large‐scale distribution of high‐quality source rocks developed in the interglacial Datangpo and Doushantuo formations, while fluvial‐deltaic reservoirs occurred in the Gucheng, Nantuo and Doushantuo formations, thus showing favourable resource potential and exploration prospects within the Sichuan Basin.
Rebuttal to comment on “Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer”
Authors: Han James E. , Zakeri Kaveh , Michel Loren , Sherman Eric J. , Lee Nancy Y.
Published: October 2023

see pages 228‐229
Investigating salivary concentration of calcium ion in hypothyroidism
Authors: Borzuei Shiva , Amjad Samaneh Vaziri , Badiei Mohammadreza , Farmany Abbas , Cheraghi Zahra
Published: October 2023

Background and Aims

Hypothyroidism is the most common disease of the thyroid gland. Thyroid hormone plays a crucial role in regulating tissue growth and metabolism. Additionally, patients with thyroid dysfunction have a higher incidence of caries and periodontal problems. The presence of calcium and phosphate ions seems to be effective in remineralizing teeth and reducing caries. The aim of this study was to evaluate the salivary level of calcium in patients with hypothyroidism.

Results

The results of this study showed that saliva calcium concentration in patients with hypothyroidism is significantly lower than healthy subjects. Also, no significant association was found between salivary calcium levels and TSH and T4 hormones level of blood.

Conclusion

The increased prevalence of dental caries in patients with hypothyroidism may be related to a decrease in their calcium levels.
The role of the multidisciplinary team in surgical management of intractable tubo‐ovarian abscess as a late sequelae of challenging Crohn's disease in the modern era: A case report and review of current literature
Authors: Loganathan Shanghavie , Smyth Sarah Louise , Mykula Roman , Soleymani Majd Hooman
Published: October 2023

Chronic, severe Crohn's disease in a young female patient can result in surgical complexity. The rarity of the presentation of intractable pelvic abscesses within this etiology with additional considerations given to fertility concerns and hence requirement for input from a multi‐disciplinary team makes this a vital case in building a consensus for evidence‐based surgical management. A 29‐year‐old nulliparous woman was referred to our tertiary centre for surgical management of Crohn's disease with known tubo‐ovarian abscess and abdominoperineal and abdominal wall sinuses. Her previous surgical history included 4 midline laparotomies, subtotal colectomy and proctectomy with stoma formation. The patient underwent egg collection to preserve fertility. This was followed by midline laparotomy and abdominoperineal resection, which involved a retrograde radical modified hysterectomy using the Hudson technique, alongside excision of the perineal sinus, with reconstruction of the perineal defect using an internal pudendal artery perforator gluteal fold flap, and in addition to excision and drainage of the abdominal wall abscess. Involvement was sought from gynecological oncology, colorectal, urology, plastics, stoma, fertility, microbiology, and gastroenterology teams, which enabled successful preservation of end organ function and improvement in patient psychological well‐being. This case is a paradigm of surgical challenge, requiring expert gynecological oncology techniques including a retroperitoneal approach, nerve and vessel sparing considerations alongside colorectal and urological procedures. Moreover, we believe that our blueprint for effective multi‐disciplinary practice will inform the future management of gynecological surgery. Therefore this report aims to contribute towards the optimum management of the gynecological sequelae of Crohn's disease.
Sinus Arrest Associated With Continuous‐Infusion Cimetidine
Authors: Hulisz Darrell T. , Welko Jeffrey R. , Heiselman Darell E.
Published: October 2023

The administration of intermittent intravenous infusions of cimetidine is infrequently associated with the development of bradyarrhythmias. A 40‐year‐old man with leukemia and no history of cardiac disease developed recurrent, brief episodes of apparent sinus arrest while receiving continuous‐infusion cimetidine 50 mg/hour. The arrhythmias were temporally related to cimetidine administration, disappeared after dechallenge, and did not recur during ranitidine treatment. This is the first reported case of sinus arrest associated with continuous‐infusion cimetidine.
Variations in Prothrombin Time and International Normalized Ratio over 24 Hours in Warfarin‐Treated Patients
Authors: Bleske Barry E. , Welage Lynda S. , Warren Eric W. , Brown Morton B. , Shea Michael J.
Published: October 2023

Study Objective. To determine the variation of prothrombin times and international normalized ratio (INR) over 24 hours in humans.

Design. Prospective, parallel study.

Setting. University‐affiliated general clinical research center.

Patients. Six patients receiving long‐term warfarin therapy and six sex‐matched controls.

Interventions. Warfarin was administered to the patients at 6:00 P.M.

Measurements and Main Results. Prothrombin times and INR were determined every 2 hours over 24 hours. Time of study entry, meals, and sleep cycles were controlled. A significant cosinor rhythm for prothrombin times and INR (p≤0.03) occurred in warfarin‐treated patients, suggesting that diurnal variation occurs. The mean difference between the peak and trough prothrombin times was 1.8 ± 0.9 seconds (range 0.8‐3 sec) with a mean change of 9.3% ± 3.7%. The peak prothrombin time and INR values occurred between 4:00 A.M. and 8:00 A.M. in five patients, and trough values between 6:00 P.M. and midnight in five. No significant cosinor rhythm was noted for controls (p>0.5).

Conclusion. Significant variations in prothrombin time and INR occurred in patients receiving warfarin therapy, with the highest values occurring in the morning and the lowest in the evening. These results may have clinical implications for patients receiving either high‐ or low‐intensity warfarin therapy.
Acute Renal Failure After Administration of Intravenous Immunoglobulin: Review of the Literature and Case Report
Authors: Winward Doreen Bianchi , Brophy Mary T.
Published: October 2023

Within in last 7 years the literature has published several reports of acute renal failure after the administration of intravenous immunoglobulin. Review of these cases finds that all occurrences in the United States except one involved a sucrose‐containing immunoglobulin preparation, leading to the suspicion that sucrose may be the cause of the renal failure. Further investigation found that approximately 50 years ago, when sucrose was used as an osmotic diuretic, investigators reported acute renal failure in humans after intravenous infusions of 50 g or more. A patient at our institution developed acute renal failure similar to that described in published case reports after being administered a sucrose‐containing immunoglobulin.
Falsely Decreased Total Serum Calcium Concentration Associated With Iron Dextran Injection
Authors: Newsom Leslie , Erstad Brian L. , Nakazato Paul Z. , Daller John A.
Published: October 2023

We cared for a patient in whom iron dextran administration interfered with the determination of total serum calcium concentration. An unexpected elevation in serum phosphorus concentration also occurred after the iron dextran infusion. A MEDLINE search from 1966 to present was conducted, and the manufacturer of the iron dextran was contacted for information related to these findings. Several drugs and diseases were found that may decrease serum calcium and increase phosphorus concentrations. We found one anecdotal citation of iron dextran interfering with serum calcium concentrations, but no reports of interference with serum phosphorus concentrations. Doses of iron dextran in excess of 250 mg may cause a false decrease in total calcium concentration more than 4 hours after the infusion is completed. A false increase in serum phosphorus concentrations after the infusion requires further investigation.
Pharmacokinetics of Fluconazole in Immune‐Compromised Children With Leukemia or Other Hematologic Disease
Authors: Seay Russell E. , Larson Tom A. , Toscano John P. , Bostrom Bruce C. , O'Leary Maura C. , Uden Donald L.
Published: October 2023

Study Objective. To describe the pharmacokinetics of fluconazole in immune‐compromised children with leukemia or other hematologic disease.

Design. Prospective.

Setting. Children's Health Care‐Minneapolis hematology/oncology inpatient ward and outpatient clinic.

Patients. Ten immune‐compromised children (mean ± SD age 7.4 ± 4.0 yrs, weight 31.6 ± 25.9 kg) with leukemia or other hematologic disease.

Interventions. Serum was sampled before and after a single 6‐mg/kg intravenous dose and after seven oral 3‐mg/kg doses of fluconazole.

Measurements and Main Results. Mean (SD) pharmacokinetics were distribution half‐life 1.67 (1.25) hours, elimination half‐life 15.62 (3.21) hours, total body clearance 0.63 (0.19) ml/min/kg, volume of distribution for the central compartment 0.56 (0.10) L/kg, volume of distribution at steady state 0.77 (0.12) L/kg, absorption half‐life 0.41 (0.26) hour, and oral bioavailability 0.92 (0.09). Volume of distribution for the central compartment was highly correlated with body surface area (r2=0.891) and weight (r2=0.949). Volume of distribution at steady state correlated with body surface area (r2=0.986), and total body clearance correlated with body surface area (r2=0.867).

Conclusions. Fluconazole elimination was well described using a two‐compartment model. Oral absorption was rapid and nearly complete. Children have a larger volume of distribution for the central compartment and faster elimination rate than adults. Body surface area and weight are important factors in determining pharmacokinetics in these patients.
Lamotrigine
Authors: Burstein Aaron H.
Published: October 2023

Lamotrigine is a novel antiepileptic that, although its mechanism is not completely understood, appears to affect voltage‐activated sodium channels, resulting in inhibition of the presynaptic release of the excitatory neurotransmitter glutamate. It is well absorbed after oral administration. Its route of elimination is hepatic glucuronidation, which is susceptible to both hepatic microsomal enzyme‐inducing and ‐inhibiting agents. In clinical trials lamotrigine was effective as add‐on therapy for refractory partial seizures in adults. Small trials suggest the feasibility of monotherapy, but further controlled trials are warranted to support this practice. Additional data indicate the utility of lamotrigine for generalized seizures. Reported side effects are rash, nausea, vomiting, blurred vision, diplopia, and vision abnormalities. Lamotrigine appears to be an attractive alternative to currently available antiepileptics.
Renal Function and Methotrexate Clearance in Children With Newly Diagnosed Leukemia
Authors: Murry Daryl J. , Synold Timothy W. , Pui Ching‐Hon , Rodman John H.
Published: October 2023

Study Objectives. To determine whether glomerular filtration rate (GFR) changes during induction chemotherapy in children with leukemia, and to examine GFR as a determinant of pharmacokinetic variability of methotrexate clearance.

Design. Prospective, unblinded observational study in consecutive patients.

Setting. A research hospital.

Patients. Thirty‐eight children newly diagnosed with acute lymphoblastic leukemia.

Interventions. The patients received either high‐dose methotrexate 1 g/m2 intravenously over 24 hours or low‐dose methotrexate 30 mg/m2 orally every 6 hours for six doses; both regimens were followed by an intensive six‐drug chemotherapy regimen given over 6 weeks. Glomerular filtration rate was determined in each subject before and at the conclusion of induction therapy.

Measurements and Main Results. The GFR was determined from 99mTc‐DTPA serum clearance in all patients, and methotrexate clearance was estimated from serial serum concentrations in 18 of these children who received high‐dose methotrexate. Median values for GFR at diagnosis (131 ml/min/1.73 m2) and after induction therapy (120 ml/min/1.73 m2) were not significantly different (p=0.26) but were highly variable (range 49–274 ml/min/1.73 m2). Body size, age, and serum creatinine were correlated significantly with GFR at diagnosis. Amphotericin B therapy (6 patients) significantly decreased GFR (p=0.046) without a corresponding increase in serum creatinine. Methotrexate clearance (58–155 ml/min/m2) was significantly (p=0.007) correlated with GFR, but GFR accounted for only 37% of the variability of methotrexate clearance.

Conclusions. The GFR was normal but highly variable in these children with leukemia and was significantly altered by amphotericin. Our results explain little of the intersubject variability in methotrexate clearance.
Prolonged Neuromuscular Blockade in Two Critically Ill Patients Treated With Atracurium
Authors: Hoey Lori L. , Joslin Suzanne M. , Nahum Avi , Vance‐Bryan Kyle
Published: October 2023

Recent literature suggests that the risk of prolonged neuromuscular blockade associated with atracurium compared with other nondepolarizing neuromuscular blocking agents may be minimal. Two patients experienced prolonged weakness associated with the administration of atracurium. Both received atracurium 0.5–0.7 mg/kg/hour in combination with methylprednisolone 500–600 mg/day. Electromyographic results and creatine kinase levels were suggestive of muscular weakness in both patients. Despite high‐dose corticosteroid therapy, the electromyographic evidence supporting prolonged weakness did not suggest typical corticosteroid myopathy. Although some clinicians advocate routine administration of atracurium in critically ill patients due to the relative lack of reports of prolonged weakness, this may be premature. Although there are fewer reports of atracurium‐associated prolonged weakness compared with pancuronium and vecuronium, the patients we describe suggest that it may occur.
Drug Interactions and Antipsychotic Therapy
Authors: DeVane C. Lindsay
Published: October 2023

Various combinations of drugs may be used to treat psychotic disorders, but pharmacodynamic and pharmacokinetic interactions can result in adverse effects. In most cases, interactions are of clinical significance only when drug therapy is initiated or discontinued, or when major changes in dosage are made. A number of patient‐related variables also affect the clinical significance of a drug‐drug interaction. To help predict the occurrence of interactions, and therefore minimize or prevent them, the clinician should be familiar with each agent's pharmacokinetics, the enzymes involved in its metabolism, and the expected pharmacologic effects. With this knowledge, the clinician may consider decreasing the dosage of previous therapy or reducing the dosage of a coadministered drug to prevent or minimize the potential of an adverse interaction.
Decreased Responsiveness to Progesterone of Spermatozoa in Oligozoospermic Patients
Authors: FALSETTI COSTANZA , BALDI ELISABETTA , KRAUSZ CSILLA , CASANO ROSARIA , FAILLI PAOLA , FORTI GIANNI
Published: October 2023

ABSTRACT: Spermatozoa from oligozoospermic subjects are characterized by a reduced in vitro ability to penetrate hamster oocytes and by a decreased responsiveness to physiological stimuli that trigger the acrosome reaction. One of the first steps in the induction of the acrosome reaction is an increase of intracellular free calcium concentrations ([Ca2+],). It has been recently shown that progesterone (P) is able to increase [Ca2+], in capacitated human sperm at concentrations similar to those found in follicular fluid. We evaluated sperm [Ca2+], increase in response to P (0.1 μg/ml) in 19 normo‐ and 17 oligozoospermic subjects. The average percentage of [Ca2+], increase over the basal level was significantly lower in spermatozoa from oligozoospermic subjects when compared to normozoospermic subjects (138.7 ± 8.22% increase in oligo‐ versus 263.3 ± 39.7% increase in normozoospermic subjects; P < 0.001). Progesterone‐stimulated [Ca2+], increase was significantly correlated with sperm motility (r = 0.54), sperm concentration (r = 0.96), and sperm morphology (% of normal forms) (r = 0.49). In addition, P induced a significant increase of acrosome‐reacted spermatozoa in normospermic patients (n = 10), whereas no significant effect was observed in spermatozoa from oligozoospermic men (n = 7). Taken together, these results indicate that spermatozoa from oligozoospermic men have a reduced ability to initiate the cascade of events that lead to the acrosome reaction in response to a physiological stimulus, such as P, and might contribute to explaining the reduced fertilizing capacity of these patients.
Effect of Catheter Composition on Sperm Quality
Authors: DAVIS NINA S. , ROTHMANN SUSAN A. , TAN MING , THOMAS ANTHONY J.
Published: October 2023

ABSTRACT: Bladder catheterization for collection of retrograde ejaculates is commonly practiced, although previous studies have shown that materials used in the manufacture of the catheters may be toxic to sperm. Potential toxicity is particularly relevant to electroejaculation, as sperm from anejaculatory individuals undergoing this procedure characteristically exhibit poor motility and viability. To determine the effect of short‐term exposure to various catheter materials on sperm quality, donor semen was diluted with BWW medium and aliquots incubated for 1 and 5 minutes with segments of four different catheters. The catheters were composed of latex, silicone rubber, polytetrafluoroethytene (Teflon), and radio‐opaque Teflon, respectively. Following incubation, eosin‐nigrosin staining for viability was performed and sperm motility assessed using computer‐assisted sperm analysis (Cellsoft, Cryo Resources, Ltd). In the second phase of the study, donor semen was incubated with catheter segments coated with 0.3 ml of a water‐soluble, nontoxic lubricant (Cellulosagel, Lederle) to evaluate whether the combination adversely affects sperm. Percent motility and viability for the semen specimens incubated with the four catheters alone did not differ significantly from control values either at 1 or at 5 minutes (P = 0.3, motility; P = 0.6, viability). The addition of lubricant did not change the catheter data significantly, indicating the absence of independent or synergistic toxicity (P = 0.5, motility; P = 0.4, viability). This study provides substantial evidence that brief exposure to conventional catheters, with or without a nontoxic lubricant, does not adversely affect sperm motility or viability. In the setting of electroejaculation, then, use of catheters of varying composition with a sperm‐compatible lubricant would not be expected to have a detrimental effect on sperm function.
Recovery of Pituitary‐Gonadal Function in Male Rats after Long‐Term Suppression Induced by a Single Injection of Microcapsules of LH‐RH Antagonist Cetrorelix (SB‐75)
Authors: PINSKI JACEK , YANO TETSU , SZEPESHAZI KAROLY , GROOT KATE , SCHALLY ANDREW V.
Published: October 2023

ABSTRACT: The clinical utility of luteinizing hormone‐releasing hormone (LH‐RH) analogs can be greatly enhanced by a sustained delivery system, which could maintain elevated peptide levels in the blood for prolonged periods of time, up to several weeks. Recently, we developed long‐acting microcapsules and microgranules of the LH‐RH antagonist SB‐75. In this study, we examined the suppressive effects of a single injection of microcapsules of antagonist SB‐75 on gonadotropin and testosterone secretion, as well as on fertility, in male rats and the reversibility of those effects. Serum SB‐75 levels were measured by RIA. A dose of 20 mg of microcapsules/rat containing 3.58 mg of antagonist in poly(D,L‐lactide‐co‐glycolide), administered intramuscularly produced SB‐75 levels higher than 20 ng/ml for approximately 24 days, and a significant elevation was maintained until day 90. Serum testosterone was decreased to castration values for 164 days and LH levels were suppressed below the detection limit of the RIA for a period of 102 days. Serum FSH was suppressed by more than 90%, as compared to control animals, for a period of 58 days and remained significantly decreased until day 164 after the injection. This treatment also caused a significant decrease in the weights of the testes, seminal vesicles, and ventral prostate 30 days after peptide administration. The histology of the testes from the treated rats showed that spermatogenesis was totally depressed. No mature elongated or round spermatids were found in the seminiferous tubules, spermatocytes being the most advanced germ cell form in 99.5% of the testicular tubules. Ten months after injection, a complete recovery in organ weights, hormonal levels, and fertility was observed. Histological studies revealed a complete recovery of spermatogenesis, with 100% of seminiferous tubules containing mature elongated spermatids. All treated rats proved to be able to impregnate normal female rats. The offspring were normal, with no evidence of genetic abnormalities. The overall results demonstrate the efficacy of SB‐75 microcapsules in suppressing the pituitary‐gonadal axis for a prolonged period of time and show that the long‐term suppression of gonadal function induced by chronic treatment with antagonist SB‐75 is completely reversible.
Motile Sperm in Human Testis Biopsy Specimens
Authors: JOW WILLIAM W. , STECKEL JOPH , SCHLEGEL PETER N. , MAGID MARGRET S. , GOLDSTEIN MARC
Published: October 2023

ABSTRACT: We prospectively studied 62 consecutive infertile men who underwent 100 intraoperative wet prep cytological examinations of testis biopsy material obtained simultaneously with permanently fixed specimens. Wet preps were performed by placing a small sample of fresh testicular tissue on a slide, adding a drop of Ringer's lactate, and compressing the specimen under a glass coverslip. Among these 100 wet preps, complete sperm with tails were identified in 62 specimens, of which 44 contained nonmotile sperm and 18 contained motile sperm.

Reproductive tract obstruction was documented in 65 testes (65%) on subsequent reconstructive surgery and/or inferred from histological evaluation, including mean mature spermatid counts on the permanent sections fixed in Bouin's solution. Obstruction was absent in the remaining testes (35%).

All 18 testes with motile sperm found on wet prep were obstructed. These testes were also found to have complete spermatogenesis, a category selected to include normal spermatogenesis and slight hypospermatogenesis, determined by examination of the permanently fixed sections. The finding of motile vs. nonmotile sperm on a wet prep has positive predictive values of 100% vs. 81% for the presence of reproductive tract obstruction and 94% vs. 86% for complete spermatogenesis, respectively.

The presence of motile sperm in human testis biopsy specimens is a novel finding. When any complete sperm with tail is found in a testis biopsy wet prep, obstruction is likely. When motile sperm are present, obstruction is almost certain, and immediate exploration and reconstructive surgery can be justified. Furthermore, the finding of motile sperm on wet prep suggests that testicular sperm might be used for in vitro fertilization in cases where the entire epididymis and efferent ductules have been ablated or destroyed.
Sampling Factors Influencing Accuracy of Sperm Kinematic Analysis
Authors: OWEN DEREK H. , KATZ DAVID F.
Published: October 2023

ABSTRACT: Sampling conditions that influence the accuracy of experimental measurement of sperm head kinematics were studied by computer simulation methods. Several archetypal sperm trajectories were studied. First, mathematical models of typical flagellar beats were input to hydrodynamic equations of sperm motion. The instantaneous swimming velocities of such sperm were computed over sequences of flagellar beat cycles, from which the resulting trajectories were determined. In a second, idealized approach, direct mathematical models of trajectories were utilized, based upon similarities to the previous hydrodynamic constructs. In general, it was found that analyses of sampling factors produced similar results for the hydrodynamic and idealized trajectories. A number of experimental sampling factors were studied, including the number of sperm head positions measured per flagellar beat, and the time interval over which these measurements are taken. It was found that when one flagellar beat is sampled, values of amplitude of lateral head displacement (ALH) and linearity (LIN) approached their actual values when five or more sample points per beat were taken. Mean angular displacement (MAD) values, however, remained sensitive to sampling rate even when large sampling rates were used. Values of MAD were also much more sensitive to the initial starting point of the sampling procedure than were ALH or LIN. On the basis of these analyses of measurement accuracy for individual sperm, simulations were then performed of cumulative effects when studying entire populations of motile cells. It was found that substantial (double digit) errors occurred in the mean values of curvilinear velocity (VCL), LIN, and MAD under the conditions of 30 video frames per second and 0.5 seconds of analysis time. Increasing the analysis interval to 1 second did not appreciably improve the results. However, increasing the analysis rate to 60 frames per second significantly reduced the errors. These findings thus suggest that computer‐aided sperm analysis (CASA) application at 60 frames per second will significantly improve the accuracy of kinematic analysis in most applications to human and other mammalian sperm.
Expression of Inducible Nitric Oxide Synthase in Smooth Muscle Cells From Rat Penile Corpora Cavernosa
Authors: HUNG ALIDA , VERNET DOLORES , XIE YINING , RAJAVASHISTH TRIPATHI , RODRÍGUEZ JOSÉ ANTONIO , RAJFER JACOB , GONZÁLEZ‐CADAVID NÉSTOR F.
Published: October 2023

ABSTRACT: Nitric oxide (NO), the main mediator of penile erection, is assumed to be synthesized in the penis by the neuronal constitutive nitric oxide synthase (nNOS). However, nNOS has not been identified in the penile smooth muscle, the target of NO action. The other NOS isozymes, the inducible NOS (iNOS) and the endothelial NOS (eNOS) have not been reported in any penile tissue. The smooth muscle vascular and trabecular tissue from rat corpora cavernosa is represented in vitro by cell cultures designated RPSMC. To determine whether iNOS can be expressed in penile smooth muscle, RPSMC were treated with different lymphokines and/or bacterial lipopolysaccharide (LPS). The selected inducer, LPS/interferon, elicited at 48 hours up to a 50‐fold increase in nitrites in the medium; the increase continued by 72 hours. The induction was inhibited by L‐Nω‐nitroarginine methyl ester (L‐NAME), aminoguanidine, actinomycin D, cycloheximide, transforming growth factor‐β1 (TGF‐β1), and dexamethasone, but was resistant to nifedipine and platelet‐derived growth factor‐AB (PDGF‐AB). iNOS induction increased with cell passage. The [3H] L‐arginine/citrulline measurement of NO synthesis with intact cells confirmed these results. Incubations of soluble and particulate fractions showed that the cytosol contained most of the activity (Km = 43 μM), which was partially inhibited by ethyleneglycal‐bistetraacetic acid (EGTA). The 4.4‐kb iNOS mRNA peaked at a late period (24–30 hours) and remained high for up to 72 hours. iNOS mRNA induction was strongly inhibited by actinomycin D and dexamethasone, partially inhibited by TGF‐β1, inhibited slightly by PDGFAB, and unaffected by nifedipine. These results show that iNOS can be expressed in RPSMC in a cell passage‐dependent fashion that has so far not been reported for other cell lines, and that the induction reaches much higher levels than in rat or human vascular smooth muscle cells. The expression pattern is also distinctive for the penile cells in time course of induction, Ca2+ dependence, response to certain agents, and mRNA stability.