bluuebunny/crossref_metadata_2025 huggingface dataset:
Cefmetazole Sodium: Pharmacology, Pharmacokinetics, and Clinical Trials
Authors: Schentag Jerome J.
Published: September 2023

Cefmetazole sodium is a semisynthetic cephamycin antibiotic. It has a broad spectrum of activity comparable to that of the second‐generation cephalosporins, covering gram‐positive, gram‐negative, and anaerobic bacteria. Unlike the second‐generation cephalosporins, cephamycins such as cefmetazole are usually active against Bacteroides fragilis. Cefmetazole is also active against β‐lactamase‐producing organisms that are resistant to first‐generation cephalosporins or penicillins. The pharmacokinetics of cefmetazole allow parenteral administration (intravenous or intramuscular) 2–3 times daily for treatment of infection. The drug has been studied in gynecologic, intraabdominal, urinary tract, respiratory tract, and skin and soft tissue infections. Administered preoperatively, it may reduce the frequency of infection in certain clean‐contaminated or potentially contaminated procedures, including cesarean section, abdominal or vaginal hysterectomy, cholecystectomy (high‐risk patients), and colorectal surgery. On the basis of in vitro spectrum, pharmacokinetics, and data from a relatively small number of clinical trials, this agent may be considered when a second‐generation cephalosporin is indicated.
Muromonab CD‐3: A Review of Its Pharmacology, Pharmacokinetics, and Clinical Use in Transplantation
Authors: Hooks Michael A. , Wade Catherine S. , Millikan William J.
Published: September 2023

Muromonab CD‐3 (OKT‐3) is a monoclonal antibody that is highly effective in the treatment of acute rejection in solid organ transplants. Due to its monoclonal nature, each molecule is identical because it is derived from a single antibody‐producing clone. OKT‐3 is administered only by intravenous injection and has a harmonic half‐life of approximately 18 hours. It binds specifically to the CD‐3 complex, which is involved in antigen recognition and cell stimulation, on the surface of T lymphocytes. Immediately after administration CD‐3‐positive T lymphocytes are abruptly removed from the circulation. The route of metabolism for OKT‐3 is not clear; it may be removed by opsonization by the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production. The agent has been effective in reversing corticosteroid‐resistant acute rejection in renal, liver, and cardiac transplant recipients. Its use in pancreatic and bone marrow recipients is inconclusive. OKT‐3 has a considerable number of initial side effects, and some life‐threatening reactions may occur. This drug should not be administered to any patient who is greater than 3% usual body weight because of the potential for the development of severe pulmonary edema. OKT‐3 may also be associated with a high rate of infection, especially of the viral type. The usual dose is 5 mg administered as an intravenous bolus over 2–4 minutes daily for 10–14 days. Approximately 85% of patients treated with OKT‐3 develop reactive human antimurine antibodies that, over time, may lead to tachyphylaxis and neutralization of the murine antibody OKT‐3. OKT‐3 is potent immunosuppressive agent and is an important prototype of future monoclonal antibodies.
Rifampin and Ansamycin Interactions with Cyclosporine After Renal Transplantation
Authors: Vandevelde Chris , Chang Andria , Andrews Denis , Riggs Wayne , Jewesson Peter
Published: September 2023

Cyclosporine whole blood concentrations are routinely monitored to help ensure optimal therapy. Several drugs have been shown to alter cyclosporine disposition by altering hepatic metabolism. Rifampin, a potent enzyme inducer, has been demonstrated to increase cyclosporine clearance. The effects of ansamycin, a chemically related investigational antibiotic, on cyclosporine disposition, have not been previously published. We report a renal transplant patient receiving cyclosporine and consecutive therapy with rifampin and ansamycin. When compared to rifampin, ansamycin's effect on cyclosporine disposition appeared to be delayed and of less magnitude. Further characterization of this interaction is required. Until this issue is resolved, we would advise careful monitoring of cyclosporine blood levels in patients receiving either rifampin or ansamycin in concert with cyclosporine.
Acute and Long‐term Effects of a Single Dose of the Fungicide Carbendazim (Methyl 2‐Benzimidazole Carbamate) on the Male Reproductive System in the Rat
Authors: NAKAI MASAAKI , HESS REX A. , MOORE BILLY J. , GUTTROFF ROBERT F. , STRADER LILLIAN F. , LINDER RALPH E.
Published: September 2023

ABSTRACT: The effects of carbendazim (methyl 2‐benzimidazole carbamate) on the testis, efferent ductules, and sperm were determined in the adult rat after a single oral dose. Two experimental trials were performed: a time response between 2 hours and 32 days after exposure using 0 and 400 mg/kg, and a dose response at 2 and 70 days after exposure using 0 to 800 mg/kg doses. In experiment 1, effects were seen throughout the 32‐day period, beginning 8 hours after exposure; the effects included first an increase in testis weight, then decreases in testicular spermatid numbers and in the percentage of morphologically normal cauda sperm. In experiment 2, significant testicular and efferent ductal alterations occurred in animals treated with doses of 100 mg/kg or greater. A dose‐dependent increase in testicular weight 2 days after treatment was accompanied by increases in seminiferous tubular diameter and excessive loss of immature germ cells in a stage‐dependent manner. There was also a dose‐dependent increased incidence of occlusions in the efferent ductules. The occluded ductules were characterized by severe inflammation and exhibited disorganization of the epithelium. At 70 days, there were dose‐dependent decreases in mean testis weight and mean seminiferous tubular diameter; however, only minimal long‐term effects were seen at 50 mg/kg. In testes exhibiting seminiferous tubular atrophy of greater than 25% (100 mg/kg or greater doses), all of the testes were associated with efferent ductules containing occlusions. Caput sperm numbers were significantly reduced in these testes. Occlusions, abnormal ductules, fibrosis, spermatic granulomas, and mineralization were observed in the ductuli efferentes. Long‐term effects of carbendazim on the testis were induced primarily by ductal occlusions. Results show that carbendazim produces more severe short‐ and long‐term effects on the male reproductive system than the fungicide benomyl.
Leydig Cell Function after Experimental Testicular Torsion Despite Loss of Spermatogenesis
Authors: BAKER LINDA A. , TURNER TERRY T.
Published: September 2023

ABSTRACT: Little is known about specific testicular cell responses to periods of testicular torsion. In particular, the steroidogenic capacity of Leydig cells in the post‐torsion testis is unknown. Male Sprague‐Dawtey rats (450–550 g) underwent no torsion (control) or a 720° unilateral testicular torsion for either 0 (sham), or 1 or 2 hours. Such torsions have previously been shown to cause progressive damage to the rat testis. One, 15, or 30 days after torsion repair all animals (n = 5–10/group) were prepared for testicular venipuncture and intravenous infusion of ovine luteinizing hormone (LH) via the femoral vein. Testicular venous blood was collected directly from the surface of the testis both 5 minutes prior to and 90 minutes after infusion of predetermined ED50 (0.1 μg) or ED100 (0.5 μg) doses of LH. Testicular venous serum (TVS) was assayed for testosterone (T) by radioimmunoassay. Control animal TVS T concentrations before LH infusion and 90 minutes after ED50 and ED100 LH stimulation were 103 ± 25, 621 ± 103, and 1,055 ± 140 ng/ml, respectively. Testes having experienced a 1‐hour torsion did not have a significantly (P < 0.05) reduced capacity to respond to ED50 and ED100 stimulation at either 15 and 30 days after the torsion. Testes having experienced a 2‐hour torsion did have significantly reduced (P < 0.05) ED50 responses at both 1 hour and 30 days after torsion repair. More remarkably, significant steroidogenic reserve was still present in testes after torsion, which in previous studies had been shown to have permanent loss of spermatogenesis. The functional survival of Leydig cells bodes well for the potential to find medical treatments that will aid in the survival of the torsed testis.
CapacitationIn Vitroof Stallion Spermatozoa: Comparison of Progesterone‐Induced Acrosome Reactions in Fertile and Subfertile Males
Authors: Meyers Stuart A. , Overstreet James W. , Liu Irwin K. M. , Drobnis Erma Z.
Published: September 2023

ABSTRACT:Mammalian sperm that have completed capacitation are capable of undergoing the acrosome reaction in response to a number of biological and chemical stimuli. In the present report, we have investigated the ability of progesterone to stimulate acrosome reactions of stallion sperm capacitated in vitro. Motile sperm were selected by a two‐layer Percoll gradient centrifugation and were incubated in TALP medium modified by the 1:1 (v/v) addition of TEST‐yolk medium for 5 hours at 39°C, under 5% CO2in humidified air. Sperm incubatedin vitroin TALP‐TEST medium had a higher percentage of acrosome reactions following the addition of progesterone (3.18 μmol/L) compared to controls (P< 0.05). Furthermore, sperm from stallions classified as fertile on the basis of breeding history had higher percentages of progesterone‐induced acrosome reactions in comparison with stallions classified as subfertile (P< 0.05). Acrosome reactions were assessed routinely by fluoresceinated lectin binding, but the physiological appearance of induced acrosome reactions was confirmed at the ultrastructural level by transmission electron microscopy. We conclude that 1) TALP‐TEST medium supports stallion sperm capacitationin vitrot2) progesterone‐induced acrosome reactions are physiological, and 3) sperm from fertile stallions may be more responsive to progesterone‐induced acrosome reactions than those of subfertile stallions. This is the first report in a nonhuman species that differences exist between the sperm of fertile and subfertHe males in the ability to capacitate and acrosome reactin vitro. These data suggest that some cases of stallion sperm dysfunction may have a molecular etiology and that tests of sperm function, such as response toin vitrocapacitation and agonists of the acrosome reaction, may be useful in evaluation and therapy of stallion subfertility.
Expression of Mannose‐Binding Sites on Human Spermatozoa and Their Role in Sperm‐Zona Pellucida Binding
Authors: CHEN JITH‐SHYAN , DONCEL GUSTAVO F. , ALVAREZ CRISTINA , ACOSTA ANIBAL A.
Published: September 2023

ABSTRACT: A D‐mannosylated albumin (DMA) neoglycoprotein was assessed to validate experimentally a probe capable of detecting mannose‐binding sperm receptors involved in human sperm‐egg interaction. DMA specifically blocked zona binding of swim‐up human spermatozoa in a concentration‐dependent manner. While no considerable effect was observed on sperm‐zona initial contact, almost 50% of spermatozoa bound to the zona during a 2‐hour period detached from it when DMA was introduced in the incubation medium. DMA inhibition was evident when 10% fetal bovine serum, but not 3.5% human serum albumin (HSA), was used as Ham's F10 medium supplementation. This may be due to the amount of free calcium in the medium since addition of 40 mM CaCl2 to F10‐HSA restored DMA inhibition. Furthermore, the higher the calcium concentration in the incubation buffer, the greater the DMA blockage of sperm‐zona binding. Unfixed sperm presented fluorescent DMA label over the entire acrosomal area (cap pattern), or concentrated at the equatorial segment (bar pattern). These patterns increased during capacitation, appearing on an average of 20% of the sperm after overnight incubation. They also increased, especially the bar pattern, following calcium ionophore treatment. Nearly all of methanol‐fixed spermatozoa displayed the fluorescent label at the head level. Concomitant assessment of sperm membrane integrity and DMA fluorescent patterns revealed that DMA fluorescence coincided mostly with permeabilized or altered sperm plasma membrane. In conclusion, DMA is a suitable probe to identify human sperm mannose‐binding sites crucially involved in sperm‐zona interaction. These sites appear to require free calcium concentrations to operate, and their expression changes with capacitation and acrosome reaction. Precise location on human spermatozoa, however, warrants further investigation.
Mammalian Sperm DNA Susceptibility to In Situ Denaturation Associated with the Presence of DNA Strand Breaks as Measured by the Terminal Deoxynucleotidyl Transferase Assay
Authors: SAILER BRIAN L. , JOST LORNA K. , EVENSON DONALD P.
Published: September 2023

ABSTRACT: Sperm from four mammalian species were analyzed by the sperm chromatin structure assay (SCSA) and the terminal deoxynucleotidyl transferase assay (TdTA) using flow cytometry. The SCSA quantitates the susceptibility of sperm nuclear DNA to in situ acid denaturation, while the TdTA quantitates the presence of endogenous DNA strand breaks in sperm nuclear chromatin. Correlations were seen between the percentage of sperm cells showing susceptibility to in situ acid denaturation and the percentage of cells showing the presence of DNA strand breaks for humans (r = 0.56, P = 0.004), rams (r = 0.84, P < 0.001), bulls (r= 0.78, P < 0.001), and stallions (r = 0.65, P < 0.001). No significant differences were seen when using fresh or frozen samples for either assay. These results suggest that sperm cells that are more susceptible to in situ DNA denaturation may have a greater number of accessible endogenous DNA strand breaks. We hypothesize that the DNA strand breaks produced in the normal transition from a somatic cell histone complex to a protamine complex are not ligated properly, resulting in residual DNA strand breaks and altered chromatin structure. Alternatively, altered chromatin structure could lead to the accessibility of the endogenous DNA strand breaks.
Automated Sperm Morphometry Analysis (ASMA) in the Rabbit
Authors: GRAVANCE CURTIS G. , DAVIS RUSSELL O.
Published: September 2023

ABSTRACT:New methods of specimen preparation were developed and a new method of objective, automated sperm morphometry analysis (ASMA) was performed to reduce the technical variation in the rabbit sperm morphology assay. The optimal staining procedure was a modified GZIN stain, which allowed the ASMA instrument to accurately recognize the distal end of the sperm head and to achieve the highest sperm recognition rate (94%). Washing and resuspending sperm to a standard concentration increased the number of sperm per microscopic field in low‐concentration samples and reduced the field‐to‐field variation in all samples. Washing also decreased the number of sperm recognition errors by the ASMA instrument. Mean metric measurements for all sperm were: length, 7.38 μm; width, 3.91 μm; width/length, 0.53; area, 22.10 μm; and perimeter, 19.20 μm. Within‐specimen coefficients of variation (CVs) ranged from 0.8% to 5.5% and between‐animal CVs ranged from 2.7% to 7.5%. The use of standard specimen preparation techniques and ASMA technology can significantly reduce the technical variation in the rabbit sperm morphology assay.
Distribution of Mouse Sulfated Glycoprotein‐1 (Prosaposin) in the Testis and Other Tissues
Authors: MORALES CARLOS R. , HAY NINA , EL‐ALFY MOHAMED , ZHAO QING
Published: September 2023

ABSTRACT: Mouse sulfated glycoprotein‐1 (SGP‐1) is the homologue of rat SGP‐1 and human prosaposin. Rat SGP‐1 is one of the major secretory products of rat Sertoli cells in culture. Human prosaposin is the precursor of four lysosomal saposins, termed A, B, C, and D, that are generated by limited proteolysis. Saposins are sphingolipid‐binding proteins that function as activators for lysosomal enzymes involved in sphingolipid hydrolysis of the former. Recently, we have generated a cDNA encoding the mouse SGP‐1 by polymerase chain reaction amplification of a mouse testicular Uni‐Zap XR cDNA library with two synthetic oligonucleotide primers and have used it as a probe for examining the tissue distribution of SGP‐1 mRNA. We have also studied the distribution of the translation product of SGP‐1 mRNA in the same tissues. The analysis demonstrated that SGP‐1 is expressed ubiquitously in all tissues examined. This investigation showed that, in mouse testis, two forms of SGP‐1 exist: a 70‐kDa secreted protein and a 65‐kDa protein corresponding to the lysosomal form of SGP‐1, which may be involved in the generation of saposins. Light microscope immunocytochemistry with anti‐SGP‐1 antibody demonstrated that, in the mouse seminiferous tubules, the translation product of SGP‐1 mRNA is expressed in Sertoli cells but not in germinal cells. Electron microscope immunogold labeling with anti‐SGP‐1 antibody yielded a strong reaction on lysosomes and phagolysosomes containing residual bodies but not on endosomes or luminal residual bodies. These results demonstrate that SGP‐1 is not internalized from the lumen but is targeted directly to the lysosomes from the Golgi apparatus. Immunoblotting also confirmed the existence of a secreted form of testicular SGP‐1 delivered to the lumen of the seminiferous tubules. The production of a secreted and a lysosomal form of SGP‐1 by Sertoli cells indicates that this protein plays a multifunctional role. This study also suggests that the lysosomal form of SGP‐1 may be involved in the degradation of membrane glycolipids from residual bodies phagocytosed by Sertoli cells.
Detection of Alpha‐Fetoprotein mRNA in Seminoma
Authors: YUASA TAKESHI , YOSHIKI TATSUHIRO , OGAWA OSAMU , TANAKA TSUTOMU , ISONO TAKAHIRO , MISHINA MUTSUKI , HIGUCHI KAYOKO , OKADA YUSAKU , YOSHIDA OSAMU
Published: September 2023

ABSTRACT: The classic testicular tumor marker alpha‐fetoprotein (AFP) is associated with nonseminomatous germ cell tumors, including embryonal carcinoma, yolk sac tumor, and teratoma. AFP is not considered to be produced by pure seminoma. However, postmortem studies have demonstrated that 30 to 45% of patients who died of seminoma initially diagnosed harbored nonseminomatous metastases and had an elevated serum AFP. We analyzed AFP expression by immunohistochemistry and by nested reverse transcription–polymerase chain reaction (RT‐PCR) in 10 seminomas, 3 embryonal carcinomas, and 1 immature teratoma, diagnosed by traditional clinical methods. Positive immunohistochemical staining was observed in all embryonal carcinomas and in the teratoma but not in the seminomas. AFP mRNA, however, was found in 6 of 10 seminomas, in all embryonal carcinomas, and in the teratoma. The nucleotide sequence of PCR products was identical with that of the AFP gene. We conclude that the analysis of AFP gene expression by nested RT‐PCR would be useful for detecting minute quantities of nonseminomatous germ cell elements in classic seminoma. Moreover, the existence of AFP mRNA suggests the possibility that seminoma cells can differentiate into nonseminomatous germ cells.
Evidence for Catecholaminergic, Neuronlike Cells in the Adult Human Testis: Changes Associated with Testicular Pathologies
Authors: MAYERHOFER A. , FRUNGBERI M. B. , FRITZ S. , BULLING A. , JESSBERGER B. , VOGT H.‐J.
Published: September 2023

ABSTRACT: Neuronlike, catecholaminergic cells expressing tyrosine‐hydroxylase (TH) have recently been found in the testis of a nonhuman primate species, the rhesus monkey. We examined whether neuronlike cells are present in the human testis. To this end, we first determined if the genes for TH and for a voltage‐activated sodium channel (NaCh), a prerequisite for neuronal excitability, are expressed in normal adult testes. Using an RT‐PCR approach, cDNA clones, identical to the sequences of human TH and to the alpha subunit of a NaCh type, were isolated. Immuno‐histochemical methods localized the corresponding proteins in testicular biopsies from adult men (age range, 28–44 years) without testicular pathologies and from infertile patients with either Sertoli cell only (SCO) syndrome or severe hypospermatogenesis and germ cell arrest (GA). TH and NaCh antibodies, as well as antibodies recognizing dopamine‐transporter protein, identified immunoreactive cells of mainly bipolar or occasionally multipolar, elongated phenotype in most, but not all, biopsies of each group (12 out of 23). The results were corroborated by identification of TH gene expression by RTPCR approaches in biopsies. Immunore‐active cell bodies, as well as nerve fibers, were more readily detected in SCO and GA biopsies. This was quantified after immunohistochemically isualizing all testicular neuronal elements, cell bodies, and fibers, with a neurofilament 220 (NF‐220) monoclonal antibody in one set of randomly selected sections from all biopsies. We found significantly increased NF‐220‐immunoreactive cell bodies and fibers in SCO‐syndrome and GA biopsies. These results show the existence of an as yet unknown testicular catecholaminergic neuronlike cell type in the human testis. This cell type may complement and act in concert with the well‐known testicular sympathetic innervation. The increase of both “intrinsic” (neuronal cells) and “extrinsic” (nerve fibers) neuronal elements in pathological testicular biopsies suggests that the two parts of the human testicular nervous system may be involved in pathogenesis and/or maintenance of GA and SCO syndromes.
Measurement of Prostate‐Specific Antigen and Human Glandular Kallikrein 2 in Different Body Fluids
Authors: LÖVGREN JANITA , VALTONEN‐ANDRÉ CAMILLA , MARSAL KAREL , LIUA HANS , LUNDWALL ÅKE
Published: September 2023

ABSTRACT: It has been demonstrated that prostate‐specific antigen (PSA), in spite of its name, can be detected in body fluids and tumors from a variety of organs. Investigations have shown that human glandular kallikrein 2 (hK2), a related prostate‐secreted protease, can activate the zymogen form of PSA, suggesting that the two enzymes might work as a functional unit, with hK2 as the activator molecule and PSA as the effector molecule. If this is true, then hK2 should be found together with PSA in body fluids other than seminal plasma, as well. Recently, a sensitive and specific assay was devised for hK2, enabling its measurement in picogram quantities. With this assay, the concentration of hK2 was determined in samples of seminal plasma, amniotic fluid, breast milk, and saliva. Simultaneously, the samples were assayed for molecular forms of PSA. In seminal plasma, the mean PSA concentration was 0.82 mg/ml, while the hK2 level was around two orders of magnitude lower: mean value, 6.4 μg/ml. Approximately the same ratio of PSA to hK2 as in seminal plasma was found in amniotic fluid and breast milk, but in most samples, the hK2 values were too low for direct measurements and had to be concentrated prior to analysis. Measurable levels of PSA, all in the free form, were detected in amniotic fluid at the thirteenth week of gestation and then gradually increased to levels around and over 1 μg/L from the twentieth week. Significant levels of PSA were detected in amniotic fluid collected at delivery, also. Measurable levels of mammary PSA were primarily detected in colostrum, with a range from less than 0.03 μg/L to 2.1 mg/L. Around half of the molecules were in complex with protease inhibitor. Most surprisingly, determinations on saliva samples showed that none of them had detectable PSA levels but had measurable concentrations of hK2 with a mean value, 0.09 μg/L. The presence in saliva suggests that hK2 can be the human equivalent to one of the mouse salivary kallikreins with important biological function, like the epidermal growth factor–binding protein or the y subunit of nerve growth factor. However, this was ruled out, as a phylogenetic analysis showed that the human and mouse glandular kallikreins evolved independently from a common precursor after the separation of the primate and rodent lineages. In conclusion, the measurements show that in addition to the previously known secretion in seminal plasma, hK2 is secreted in amniotic fluid, breast milk, and saliva. Furthermore, the concerted expression of PSA and hK2 in seminal plasma, amniotic fluid, and breast milk suggests that the two proteases might form a functional unit but not always as demonstrated by the sole presence of hK2 in saliva.
TGF‐β Could Be Involved in Paracrine Actions in the Epididymis of the Marmoset Monkey (Callithrix jacchus)
Authors: BOMGARDNER DANBELA , WEHRENBERG UWE , RUNE GABRIELE M.
Published: September 2023

ABSTRACT: The transforming growth factor‐β1 (TGF‐β1) and the transforming growth factor‐β receptor type II (TGF‐βRII) were studied in the epididymis of sexually mature marmoset monkeys (Callithrix jacchus) by immunohistochemical localization of the protein and by polymerase chain reaction (PCR) analysis of the mRNA level. In order to specify reactive cell types, the morphology of all three segments (caput, corpus, and cauda epididymidis) was evaluated by light microscopy. Six different cell types could be distinguished: principal, basal, apical, and clear cells, as well as intraepithelial lymphocytes and macrophages. Using immunohistochemistry, specific staining for TGF‐β1 in the caput was found in 47% of the apical cells, whereas the TGF‐βRII was located in the apical portion of 91% of all principal cells. In the corpus epididymidis, 20% of the apical cells were immunopositive for TGF‐β, and binding of the receptor antibody occurred in 17% of the principal cells (all numbers based on counts of counterstained nuclei). All differences between percentages in the caput and corpus were significant as determined by chi‐square test. PCR analysis revealed detectable levels of TGF‐β1 mRNA in the marmoset epididymis. Our results indicate for the first time that TGF‐β1 is synthesized in the marmoset epididymis, possibly in a different subpopulation of epididymal cells than the TGF‐β receptor type II. Thus, TGF‐β might be of functional relevance in the primate epididymis.
INTEGRATED MODELING: AN AVIONICS CASE STUDY
Authors: Maier Mark W.
Published: September 2023

Integrated Modeling is a methodology that synthesizes the functional, physical, performance, and managerial designs of a system. It makes use of Quality Function Deployment, real time structured methods, and metrics to produce linked and checkable system designs. Integrated Modeling is an outgrowth of experience in applying structured methodologies to avionics systems. This paper describes the application of Integrated Modeling to a simplified radar warning receiver. This study grew out of a larger re‐engineering study of a major avionics system. This case study simplifies the system, but explicitly integrates the performance, functional, and physical projections of the system.
4.4.4 Adapting UML for an Object Oriented Systems Engineering Method (OOSEM)
Authors: Lykins Howard , Friedenthal Sanford , Meilich Abraham
Published: September 2023

Object‐oriented (OO) techniques have been used predominately by software engineers. Why would systems engineers want to add OO techniques to their existing practices? How should such techniques be adapted to be useful to systems engineers? This paper will show how an Object‐Oriented Systems Engineering Method (OOSEM) addresses these questions and how the use of the Unified Modeling Language (UML) at the systems engineering (SE) level can facilitate capture of system requirements and design information and ease communication between systems and software engineers. The techniques overviewed in this paper have been applied to information systems and have allowed engineers to model system needs, requirements, architectural design, and their allocation to hardware, software, databases, and manual procedures. The authors believe that OOSEM is applicable to engineering of other types of systems as well.
1.6.4 Systems Engineering is Not Just Engineering—Or is It? A Critical Look at the Scope of our Profession
Authors: Martin James N.
Published: September 2023

It is commonly perceived that systems engineering is merely another branch of engineering. Of course, in many ways this is true. But there are some unique aspects of systems engineering that are not relevant to “regular” engineering. This paper will describe these differences. By understanding these differences, it will help the practitioner of the systems discipline to perform the requisite tasks in a more effective manner. For systems engineering to develop into a more mature discipline, it is essential that all key attributes of the practice be understood. This paper will attempt to describe these key attributes.
Anti‐Siglec‐15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury‐Induced Immobilization in Rats
Authors: Peng Yuanzhen , Langermann Solomon , Kothari Priyanka , Liu Linda , Zhao Wei , Hu Yizhong , Chen Zihao , Moraes de Lima Perini Mariana , Li Jiliang , Cao Jay , Guo X. Edward , Chen Lieping , Bauman William A. , Qin Weiping
Published: September 2023

Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐15 is expressed on the cell surface of mature osteoclasts. Anti‐Siglec‐15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec‐15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4‐month‐old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, −18.7%), trabecular bone volume (−43.1%), trabecular connectivity (−59.7%), and bone stiffness (−76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec‐15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Experience conducting a community‐engaged student research project involving an underrepresented community: A reflective essay
Authors: Grieve LilyAnne M. , Murthy Vinaya S.
Published: September 2023

Recruiting racially and ethnically underrepresented participants into genetics research studies has been challenging. While many institutions have taken steps to address the inequity in genetics research, genetic counseling training programs have the chance to inspire students to engage with underrepresented communities through utilizing different research methodologies. These methodologies can help students focus on research projects that increase access to genetics services and improve clinical care. Community‐engaged research (CER) presents a pedagogical approach to enhance service‐learning opportunities for students. Furthermore, it allows students to develop practical research skills for doing research with the community, rather than on the community. CER is a collaborative community‐academic partnership that leads to mutual benefit and outcomes such as inclusion and engagement of the community in research, building trust and relationships, and increasing cultural awareness and exposure. In addition, CER can be used to address research and healthcare inequities by providing opportunities for genetics professionals and trainees to work closely with underrepresented populations. We aim to highlight the opportunities CER provides to students, mentors, and faculty within the context of graduate research in genetic counseling training from the experiences of a student and an educator. In addition, we hope to emphasize the necessity for projects like these to address the gaps in participation of underrepresented patient populations in research and identify areas that are mutually beneficial to improve health outcomes, patient care experiences, access, and service delivery. This reflective essay illustrates the completion of a CER project that was developed in collaboration with community members to address gaps in clinical genetics services in Indigenous healthcare.
Statement from the Asia Summit: Current state of arrhythmia care in Asia
Authors: Shimizu Wataru , Kusumoto Fred M. , Agbayani Michael‐Joseph F. , Apiyasawat Sirin , Chen Minglong , Ching Chi Keong , Choi Jong‐Il , Do Van Buu Dan , Hanafy Dicky A. , Hurwitz Jodie L. , Johar Sofian , Kalman Jonathan M. , Khan Aamir Hameed H. , Khmao Pichmanil , Krahn Andrew D. , Ngarmukos Tachapong , Nguyen Son Thai Binh , Nwe Nwe , Oh Seil , Soejima Kyoko , Stiles Martin K. , Tsao Hsuan‐Ming , Tseveendee Saruul
Published: September 2023

On May 27, 2022, the Asia Pacific Heart Rhythm Society and the Heart Rhythm Society convened a meeting of leaders from different professional societies of healthcare providers committed to arrhythmia care from the Asia Pacific region. The overriding goals of the meeting were to discuss clinical and health policy issues that face each country for providing care for patients with electrophysiologic issues, share experiences and best practices, and discuss potential future solutions. Participants were asked to address a series of questions in preparation for the meeting. The format of the meeting was a series of individual country reports presented by the leaders from each of the professional societies followed by open discussion. The recorded presentations from the Asia Summit can be accessed athttps://www.heartrhythm365.org/URL/asiasummit‐22. Three major themes arose from the discussion. First, the major clinical problems faced by different countries vary. Although atrial fibrillation is common throughout the region, the most important issues also include more general issues such as hypertension, rheumatic heart disease, tobacco abuse, and management of potentially life‐threatening problems such as sudden cardiac arrest or profound bradycardia. Second, there is significant variability in the access to advanced arrhythmia care throughout the region because of differences in workforce availability, resources, drug availability, and national health policies. Third, collaboration in the area already occurs between individual countries, but no systematic regional method for working together is present.
Custom three‐dimensional printed implants for reconstruction of oncologic pelvic defects
Authors: Oyem Precious C. , Burke Zachary D. , Mesko Nathan W. , Nystrom Lukas M.
Published: September 2023

The use of three‐dimensional printed implants in the field of orthopedic surgery has become increasingly popular and has potentiated hip reconstruction in the setting of oncologic resections of the pelvis and acetabulum. In this review, we examine and discuss the indications and technical considerations for custom implant reconstruction of pelvic defects.
Untangling the effects of climate variation and human interference on grassland dynamics in North China
Authors: Ren Hanyu , Liu Yangyang , Wen Zhongming , Shi Haijing , Zhou Ronglei , Wang Zhenqian , Kareem Hafiz Abdul , Zhang Wei
Published: September 2023

Climatic and anthropogenic disturbances play pivotal roles in shaping the dynamics of grassland. Quantifying their impacts on grassland variation is essential to ensure sustainable grassland management. In this study, we employed the Thornthwaite Memorial and Carnegie–Ames–Stanford‐approach (CASA) models to investigate the spatiotemporal effects of these two variables on grassland variation in northern China from 2000 to 2016, using the net primary productivity (NPP) as a measure. Our findings reveal that approximately 25.92% of the grassland in northern China experienced degradation, while restored grasslands occupied 45% of the total grassland area. The average grassland actual NPP (ANPP) and human‐induced NPP decreased at rates of −0.60 and −5.62 gC m−2 a−1, respectively. Conversely, potential NPP exhibited an upward trend with an average increase of 2.27 gC m−2 a−1. Furthermore, grassland ANPP showed a projected increase in most parts of northern China. Climate change emerged as the primary driver for grassland restoration in Xinjiang, Qinghai, and Inner Mongolia, leading to an increase of 21582.79 Gg C in grassland NPP. In contrast, human activities were the dominant catalysts for grassland degradation, resulting in a reduction of 51932.3 Gg C in grassland NPP. Human‐induced grassland degradation was ubiquitous in northwest and northeast China. With the exception of slope grassland, climate change primarily influenced the restoration of most grassland types, while human activities were the primary cause of degradation. Our analysis indicated a strong correlation between temperature and grassland degradation, while precipitation played a pivotal role in grassland restoration in northern China. Human interference demonstrated both positive and negative impacts on grassland changes. In conclusion, the increase in precipitation and the implementation of ecological restoration plans have effectively promoted the restoration of grasslands in northern China.
Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology
Authors: Jiang Mingjie , Yang Zhongyuan , Dai Juanjuan , Wu Tong , Jiao Zan , Yu Yongchao , Ning Kang , Chen Weichao , Yang Ankui
Published: September 2023

The polymorphic microbiome has been proposed as a new hallmark of cancer. Intratumor microbiome has been revealed to play vital roles in regulating tumor initiation and progression, but the regulatory mechanisms have not been fully uncovered. In this review, we illustrated that similar to other components in the tumor microenvironment, the reside and composition of intratumor microbiome are regulated by tumor cells and the surrounding microenvironment. The intratumor hypoxic, immune suppressive, and highly permeable microenvironment may select certain microbiomes, and tumor cells may directly interact with microbiome via molecular binding or secretions. Conversely, the intratumor microbiomes plays vital roles in regulating tumor initiation and progression via regulating the mutational landscape, the function of genes in tumor cells and modulating the tumor microenvironment, including immunity, inflammation, angiogenesis, stem cell niche, etc. Moreover, intratumor microbiome is regulated by anti‐cancer therapies and actively influences therapy response, which could be a therapeutic target or engineered to be a therapy weapon in the clinic. This review highlights the intratumor microbiome as a vital component in the tumor microenvironment, uncovers potential mutual regulatory mechanisms between the tumor microenvironment and intratumor microbiome, and points out the ongoing research directions and drawbacks of the research area, which should broaden our view of microbiome and enlighten further investigation directions.
Eddy current‐induced artifact correction in high b‐value ex vivo human brain diffusion MRI with dynamic field monitoring
Authors: Ramos‐Llordén Gabriel , Park Daniel J. , Kirsch John E. , Scholz Alina , Keil Boris , Maffei Chiara , Lee Hong‐Hsi , Bilgic Berkin , Edlow Brian L. , Mekkaoui Choukri , Yendiki Anastasia , Witzel Thomas , Huang Susie Y.
Published: September 2023

Purpose

To investigate whether spatiotemporal magnetic field monitoring can correct pronounced eddy current‐induced artifacts incurred by strong diffusion‐sensitizing gradients up to 300 mT/m used in high b‐value diffusion‐weighted (DW) EPI.

Methods

A dynamic field camera equipped with 16 1H NMR field probes was first used to characterize field perturbations caused by residual eddy currents from diffusion gradients waveforms in a 3D multi‐shot EPI sequence on a 3T Connectom scanner for different gradient strengths (up to 300 mT/m), diffusion directions, and shots. The efficacy of dynamic field monitoring‐based image reconstruction was demonstrated on high‐gradient strength, submillimeter resolution whole‐brain ex vivo diffusion MRI. A 3D multi‐shot image reconstruction framework was developed that incorporated the nonlinear phase evolution measured with the dynamic field camera.

Results

Phase perturbations in the readout induced by residual eddy currents from strong diffusion gradients are highly nonlinear in space and time, vary among diffusion directions, and interfere significantly with the image encoding gradients, changing the k‐space trajectory. During the readout, phase modulations between odd and even EPI echoes become non‐static and diffusion encoding direction‐dependent. Superior reduction of ghosting and geometric distortion was achieved with dynamic field monitoring compared to ghosting reduction approaches such as navigator‐ and structured low‐rank‐based methods or MUSE followed by image‐based distortion correction with the FSL tool “eddy.”

Conclusion

Strong eddy current artifacts characteristic of high‐gradient strength DW‐EPI can be well corrected with dynamic field monitoring‐based image reconstruction.
Genetic dissection of serum vaspin highlights its causal role in lipid metabolism
Authors: Breitfeld Jana , Horn Katrin , Le Duc Diana , Velluva Akhil , Marzi Carola , Grallert Harald , Friedrich Nele , Pietzner Maik , Völker Uwe , Völzke Henry , Ahlqvist Emma , Aly Dina Mansour , Tuomi Tiinamaija , Baber Ronny , Kratzsch Jürgen , Thiery Joachim , Isermann Berend , Loeffler Markus , Klöting Nora , Blüher Matthias , Stumvoll Michael , Heiker John T. , Tönjes Anke , Scholz Markus , Kovacs Peter
Published: September 2023

Objective

Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity‐related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated.

Methods

A meta‐analysis of genome‐wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype‐Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured.

Results

A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10−8, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low‐density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice.

Conclusions

The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.
Implementation of suitable optimal control strategy through introspection of different delay induced mathematical models for leprosy: A comparative study
Authors: Ghosh Salil , Roy Amit Kumar , Roy Priti Kumar
Published: September 2023

Involving intracellular delay into a mathematical model and investigating the delayed systems by incorporating optimal control is of great importance to study the cell‐to‐cell interactions of the disease leprosy. Keeping this in mind, we have proposed two different variants of delay‐induced mathematical models with time delay in the process of proliferation of Mycobacterium leprae bacteria from the infected cells and a similar delay to indicate the time‐lag both in the proliferation of M. leprae bacteria and the infection of healthy cells after getting attached with the bacterium. In this research article, we have performed a comparative study between these two delayed systems equipped with optimal control therapeutic approach to determine which one acts better to unravel the complexities of the transmission and dissemination of leprosy into a human body as far as scheduling a perfect drug dose regime depending on this analysis remains our main priority. Our investigations suggest that adopting optimal control strategy consisting of combined drug therapy eliminates the oscillatory behavior of the delayed systems completely. Existence of optimal control solutions are demonstrated in detail. To achieve the optimal control profiles of the drug therapies and to obtain the optimality systems, Pontryagin's Minimum principle with delay in state are employed for our controlled systems. Furthermore, the analytical as well as the numerical outcomes obtained in this research article indicate that the delayed bacterial proliferation and M. leprae‐induced infection model equipped with optimal control policy performs more realistically and accurately in the form of a safe and cost‐effective double‐drug therapeutic regimen. All the mathematical results are verified numerically and the numerical results are compared with some recent clinical data in our article as well.
The Bulk Trace FEM for the simultaneous solution of structural membranes on all level sets over a bulk domain
Authors: Fries Thomas‐Peter , Kaiser Michael W.
Published: September 2023

A finite element method for the simultaneous solution of boundary value problems (BVPs) posed on all level sets over some bulk domain is proposed. A level‐set function is used to define ‐dimensional curved manifolds which are bounded by the d‐dimensional bulk domain. The BVPs considered herein model structural ropes and membranes in a large displacement context, resulting in a geometrically non‐linear mechanical model. For the numerical analysis, the bulk domain is discretized using d‐dimensional finite elements which do not conform to the level sets implying the domains of interest. However, they conform to the boundary of the bulk domain. The proposed variant of the FEM is a hybrid between classical and non‐conforming FEMs and may be labeled Bulk Trace FEM. Numerical studies confirm optimal higher‐order convergence rates for the proposed method when simultaneously approximating BVPs on all level sets.