bluuebunny/crossref_metadata_2025 huggingface dataset:
Complications Associated with Immunosuppressive Therapy and Their Management
Authors: Min David I. , Monaco Anthony P.
Published: October 2023

Besides general complications of immunosuppression such as increased susceptibility to opportunistic infections or malignancy, individual immunosuppressive agents are associated with specific side effects. Nephrotoxicity is the major side effect of cyclosporine (CsA). Various attempts have been made to minimize this toxicity, such as monitoring drug blood levels, modifying the protocol, and coadministering other agents. Other side effects caused by CsA are hepatotoxicity, hyperkalemia, hypertension, tremor, gum overgrowth, and hirsutism. Azathioprine (AZA) causes dose‐related bone marrow suppression, commonly leading to leukopenia. Careful monitoring of complete blood cell count and dosage adjustment according to white blood cell count are usually adequate to prevent serious leukopenia. The side effects of corticosteroids are numerous and include slow wound healing and de novo insulin‐dependent diabetes mellitus. Many complications are dose related, and with low dosage or discontinuation of steroids, their frequency rapidly decreases. Antilymphoblast and antithymocyte globulins (P‐ALG) are foreign antibodies and may cause allergic‐type reactions such as fever, chill, and hypotension. The initial side effect of monoclonal antibody (muromonab‐CD3, OKT3) is similar to that of P‐ALG. It includes high fever, shaking chills, headache, rigors, and hypotension. To prevent it, acetaminophen, an antihistamine, and a steroid usually are administered before injection. Because this agent is also associated with high frequency of pulmonary edema, it should not be given to any patient who has more than 3% body weight gain during the week prior to therapy. In rare case, it causes aseptic meningitis or encephalopathy, which is manifested by fever, severe headache, and seizure.
Fixed‐Rate Reimbursement Fails to Cover Costs for Patients with Delayed Graft Function
Authors: Almond P. Stephen , Matas Arthur J. , Canafax Daniel M.
Published: October 2023

Medicare uses a fixed reimbursement schedule to pay the initial hospital costs for renal transplantation. This creates the potential to underpay for patients who develop the common complication of delayed graft function. We undertook a pilot study to determine if delayed graft function resulted in higher hospital charges and thus a loss in revenue when caring for these patients. Of 34 patients who experienced delayed graft function between October 12, 1987 and July 7, 1989, 9 (group 1) were randomly selected for study. During this same period 136 patients had immediate graft function; from them, another 9 (group 2) were selected by matching age, sex, and date of transplantation. The average (±SD) hospital stays for groups 1 and 2 were 17 ± 8 and 10 ± 2 days, respectively (p < 0.001). The average time on dialysis for group 1 was 10.3 ± 6.3 days (range 2–22 days). All dollars values were adjusted to a 1989 level, and we excluded kidney acquisition costs and professional fees. The average per patient charges for group 1 were $41,474 ± 15,211 (range $21,926–$66,311), compared with $23,774 ± 3245 (range $19,317‐$29,702) for group 2 (p< 0.001). We adjusted the charge values to estimate actual costs by using our hospital's average cost:charge ratio of 0.90 for 1987 and 1988, and 0.85 for 1989; the group 1 and group 2 average patient costs were $37,157 ± 13,836 and $21,397 ± 2921, respectively. The difference between Medicare reimbursement (1987=$24,997, 1988=$20,832, 1989=$20,879) and estimated costs for group 1 patients was an average loss of $13,544, with two patients exceeding the reimbursement amount, and for group 2 patients, a gain of $1749, with five patients exceeding the reimbursement amount. We conclude that delayed graft function prolonged initial hospital stay, creating costs that exceeded the Medicare fixed reimbursement rate for these patients, resulting in loss of revenue.
Antimicrobial Formulary Management: Meeting the Challenge in a Health Maintenance Organization
Authors: Carlson James A.
Published: October 2023

Group Health Cooperative of Puget Sound is a consumer‐governed health maintenance organization with approximately 380,000 enrollees. The enrollees are provided pharmacy services at 3 hospital locations, 28 primary care clinics, and 4 specialty care clinics. A Pharmacy and Therapeutics Committee (P&T) oversees cooperative–wide formulary management of all medications used for inpatients and outpatients, thus decreasing the stock of medications in all the pharmacy locations while providing representative drugs from all therapeutic classes. A subcommittee of the P&T committee, the Antibiotic Usage Review Group, manages the antimicrobial formulary. It consists of staff members from infectious disease, nursing, pulmonary medicine, family practice medicine, and pharmacy departments. The group provides recommendations based on seven specific areas: reviewing requests from prescribers for the addition of new antimicrobial agents to the formulary; evaluating antimicrobial agents by drug class; reviewing potential drugs for therapeutic interchange; developing use criteria for specific antimicrobial agents or classes; developing treatment algorithms for specific infectious diseases; performing drug use evaluations for antimicrobial agents; and approving the use of nonformulary antimicrobial agents. This approach has limited the inappropriate prescribing of antimicrobials and has increased the medical staff's knowledge on appropriate use of these agents. (Pharmacotherapy 1991;11(1 Pt 2):32S‐35S)
Ticlopidine: A New Antiplatelet Agent for Cerebrovascular Disease
Authors: Robert Sylvie , Miller Angela J. , Fagan Susan C.
Published: October 2023

Ticlopidine is a new prototype antiplatelet drug chemically unrelated to currently available agents. It causes an alteration in platelet membrane reactivity to a variety of aggregating stimuli and a marked prolongation of bleeding time, the mechanism of which remains unclear. Two major phase III multicenter trials, the ticlopidine‐aspirin stroke study (TASS) and the Canadian‐American ticlopidine study (CATS) reported that the agent may reduce the occurrence of stroke, myocardial infarction, or vascular death in patients of both sexes who have had recent cerebral ischemia. Ticlopidine has been well tolerated in preliminary studies, with the most commonly described adverse effects being rash and gastrointestinal complaints. The most important adverse effect is neutropenia, which was reported in both TASS and CATS, approximating a frequency of 0.9% and 0.8%, respectively. Ticlopidine holds considerable promise as adjunctive therapy in selected patients.
Cocaine: Its Effects on Maternal and Child Health
Authors: Young Sharon L. , Vosper Heather J. , Phillips Susan A.
Published: October 2023

Cocaine abuse has become one of America's leading public health problems. Its use throughout pregnancy is associated with an increased risk of abruptio placentae, stillbirth, and preterm labor. Cocaine‐associated neonatal complications include congenital malformations, decreased fetal growth, seizures, cerebral infarction and hemorrhage, auditory system deficits, sudden infant death syndrome, cardiac arrhythmias, necrotizing enterocolitis, and behavioral changes. Children followed throughout the first year of life continue to show developmental delay. Infants and children growing up in cocaine‐abusing families are at risk for drug‐related injuries. Accidental and intentional intoxication has occurred in infants and children from the smoke of freebase cocaine. The drug has also caused intoxication in breast‐feeding infants. Adolescents experimenting with cocaine are at risk, with an apparently high frequency of seizures and loss of consciousness, as well as behavioral changes and psychosocial dysfunction.
Combination Use of Sulfonylureas and Insulin in the Treatment of Noninsulin‐Dependent Diabetes Mellitus
Authors: Montgomery Patricia A.
Published: October 2023

Combination therapy with insulin and sulfonylureas for treatment of noninsulin‐dependent diabetes mellitus has been evaluated frequently. However, many of the trials either lacked proper control or were of inadequate duration, and none compared combination therapy to intensive insulin therapy using several daily injections. Such a combination decreases, but does not return to normal, glycosylated hemoglobin and fasting glucose concentrations in comparison to therapy with one or two daily injections of insulin in some subjects. Alternatively, adding a sulfonylurea to insulin therapy may allow a reduction in the insulin dosage without compromising glycemic control. When considering the use of the two agents, the possible advantage of a simplified insulin regimen must be weighed against the disadvantages of an increased potential for adverse effects and increased cost.
Pharmacokinetics of Low‐Dose Methotrexate in Adult Asthmatics
Authors: Glynn‐Barnhart Anne M. , Erzurum Serpil C. , Left Jonathan A. , Martin Richard J. , Cochran Judith Evans , Cott Gary R. , Szefler Stanley J.
Published: October 2023

Several reports have been published on the disposition of methotrexate (MTX) when given in low dosages, but none in asthmatic patients. To address this matter, pharmacokinetic studies were performed in nine patients with severe, steroid‐requiring asthma (ages 18–76 yrs) after the sixth weekly intramuscular dose of MTX. Theophylline pharmacokinetic studies were also performed at baseline prior to the start of MTX treatment and at the time of the MTX studies. Total systemic clearance of MTX, given as mean (SD), was 122.6 (25.1) ml/minute, volume of distribution at steady state 0.49 (0.2) L/kg, half‐life 3.1 (0.3) hours, mean residence time 5.0 (0.6) hours, and renal clearance 89.1 (36.3) ml/minute. These values are similar to those previously reported for other patient populations receiving low‐dose MTX. Eight of these patients were evaluated for changes in theophylline pharmacokinetics. Theophylline clearance at week 6 decreased an average of 19% from baseline and correlated inversely with total MTX clearance. Percentage change in theophylline clearance from baseline was inversely correlated with MTX nonrenal clearance, but was not statistically significant. This finding may indicate competition for clearance pathways between MTX and theophylline.
Nonprescription Ibuprofen: Side Effect Profile
Authors: Furey Sandy A. , Waksman Joel A. , Dash Barry H.
Published: October 2023

Single doses of nonprescription analgesics are commonly used to treat self‐diagnosed conditions. To evaluate the safety of single doses of nonprescriptionstrength ibuprofen, we examined reported side effects from 15 double‐blind, randomized, controlled trials we conducted of the drug to treat various common painful conditions (e.g., headache, sore throat). All studies included placebo and another nonprescription analgesic, acetaminophen. A total of 878 subjects received ibuprofen 200 or 400 mg, 849 acetaminophen 650 or 1000 mg, and 852 placebo. The overall frequency of side effects was comparable: ibuprofen 2.4%, acetaminophen 3.2%, and placebo 2.1%. The frequency of central nervous system symptoms was 0.8%, 2.1%, and 0.9%, respectively. Upper gastrointestinal upset ranged from 0.8–0.9% of subjects in all groups. We conclude that single doses of nonprescription ibuprofen are well tolerated and demonstrate a side effect profile indistinguishable from that of acetaminophen and placebo.
A Retrospective Review of the Use of Lipid‐Lowering Agents in Combination, Specifically, Gemfibrozil and Lovastatin
Authors: Wirebaugh Stewart R. , Shapiro Michael L. , McLntyre Thomas H. , Whitney Edwin J.
Published: October 2023

We conducted a retrospective review examining lipid profiles, creatine phosphokinase (CK) levels, and alanine aminotransferase levels (ALT) in patients receiving the combination of gemfibrozil and lovastatin. Serum lipid levels were significantly improved with therapy over those before therapy. Of the 70 patients receiving the combination, 5 experienced mild elevations in CK, 1 a mild elevation in ALT, and 1 mild elevations in both. No patient reported muscle weakness or muscle pain. The combination of these two medications appeared to be at least additive, highly effective, and well tolerated. The mean total cholesterol, triglyceride, and low‐density lipoprotein cholesterol levels decreased from 278, 306, and 180 mg% to 200, 151, and 129 mg%, respectively, and the mean high‐density lipoprotein cholesterol levels increased from 34 to 40 mg%. This retrospective data analysis suggests that the combination of gemfibrozil and lovastatin may be safe in patients with normal renal function when the dosage of lovastatin is limited and when CK and ALT levels are monitored carefully.
The Effect of Low‐Dose Phenytoin on High‐Density Lipoprotein Cholesterol
Authors: McKenney James M. , Petrizzi Kathleen S. , Briggs Geneva C. , Wright Jackson T.
Published: October 2023

We examined whether low doses of phenytoin, which should be associated with few dose‐related side effects, may increase the levels of high‐density lipoprotein (HDL) cholesterol. Of 35 healthy adult men who consented to participate, 31 completed the study. They took no medications and consumed no alcohol during the study. We used a three‐arm, parallel, prospective, randomized, double‐blind research design. Subjects took a single‐blind placebo capsule once daily at bedtime for 2 weeks and then were randomly assigned to receive identical‐appearing capsules containing 30 mg or 100 mg of phenytoin or placebo, once daily at bedtime for 4 weeks. The HDL cholesterol and HDL subtractions were determined from 12‐hour fasting blood samples obtained at the beginning and end of the single‐blind period and at the end of the third and fourth weeks of the double‐blind period. Mean differences between baseline and posttreatment HDL cholesterol levels with placebo, 30 mg phenytoin, and 100 mg phenytoin were 0.010 mmol/L (0.4 mg/dl), 0.005 mmol/L (0.2 mg/dl), and 0.096 mmol/L (3.7 mg/dl), respectively (p = 0.2947); baseline and posttreatment HDL2 and HDL3 levels were not different among the groups. Total cholesterol levels were significantly higher in subjects taking phenytoin 100 mg than in those taking phenytoin 30 mg or placebo. The results suggest that phenytoin in dosages of up to 100 mg daily for 4 weeks has no substantial effect on HDL cholesterol or HDL subtractions.
Prolonged Hemodialysis in Methanol Intoxication
Authors: Burgess Ellen
Published: October 2023

Methanol poisoning may be treated conservatively by inducing a diuresis and administering ethanol to halt the metabolism of methanol to more toxic metabolites. In severe intoxications, hemodialysis may be necessary to remove the toxins and limit the metabolic disturbances. The duration of dialysis needed to achieve this is unclear. A case report of a severe methanol poisoning is reported which required 21 hours of hemodialysis to bring the serum methanol levels down to a nontoxic level.
Risperidone
Authors: Cohen Lawrence J.
Published: October 2023

Risperidone, a benzisoxazole derivative, is a novel antipsychotic agent that has an extremely strong binding affinity for serotonin 5‐HT2 receptors, a strong binding affinity for dopamine D2 receptors, and a high affinity for α1‐ and α2‐adrenergic receptors and histamine H1 receptors. Its affinity for serotonin receptors is approximately 200 times greater than that of haloperidol, and its dopamine antagonistic potency is comparable to that of haloperidol. Its major metabolite, 9‐hydroxyrisperidone, has similar pharmacologic activity, and thus the parent compound and metabolite form the active antipsychotic moiety. Clinical trials demonstrate that risperidone is an effective antipsychotic agent that improves negative as well as positive symptoms of schizophrenia. At recommended dosages, the frequency of extrapyramidal side effects is no greater than that seen with placebo. The drug appears to be an advance in the treatment of psychoses.
Use of In Vitro and In Vivo Data in the Design, Development, and Quality Control of Sustained‐Release Decongestant Dosage Forms
Authors: Brock Michael H. , Dansereau Richard J. , Patel Vikram S.
Published: October 2023

Study Objectives. To investigate the use of in vitro and in vivo data in the development of a sustained‐release, carbomer‐based dosage form (Entex LA tablets); and to compare the in vitro dissolution of pseudoephedrine from a sustained‐release, hydroxypropylcellulose‐based dosage form (Entex PSE tablets) and four branded competitors with different sustained‐release matrixes.

Design. Entex LA: In vitro testing by rotating bottle method and in vivo testing as double‐blind, randomized, crossover, 24‐hour study. Entex PSE and four competitors: in vitro testing by paddle method.

Setting. A pharmaceutical research and development facility.

Patients. Fifteen healthy, adult, volunteer Caucasian men between ages 18 and 40 years.

Main Results. Three formulations of Entex LA, varying in carbomer content by 3–5%, were studied. As carbomer content increased, in vitro dissolution rate directionally decreased. Plasma concentrations of active ingredients guaifenesin and phenylpropanolamine were also slightly although directionally decreased. The in vitro method was sensitive to small changes in carbomer content. Larger changes in carbomer content would be required to establish an in vitro‐in vivo correlation. The in vitro comparison of Entex PSE and four similar branded products showed important differences in dissolution profiles. The mean cumulative release of pseudoephedrine from Entex PSE was 39% at 1.5 hours, 62% at 4.0 hours, and 80% at 8.0 hours. The other products released pseudoephedrine more rapidly, with the two fastest‐dissolving products releasing 61–62% in the first 1.5 hours.

Conclusions. Sustained‐release, polymer‐based dosage forms such as Entex LA and Entex PSE can be complex and pose special challenges in design, development, and reformulation. For Entex LA, changes in polymer concentration and dye system influenced the in vitro (dissolution) performance. In vivo (plasma) data helped establish a defined range in which carbomer concentration could be varied to achieve the best manufacturing performance without affecting product performance. For Entex PSE and four branded competitor products, the cumulative in vitro release (dissolution) of pseudoephedrine varied widely. Release from Entex PSE was more consistent and more gradual than that from some of the comparison products. Because the absorption rate of the active ingredients pseudoephedrine and guaifenesin is governed by the dissolution rate, the observed differences suggest that the products tested may differ in biologic performance. Although in vitro dissolution data may not necessarily correlate with in vivo differences in clinical safety or efficacy, the potential for unexpected product performance may be signaled by inconsistent in vitro dissolution characteristics, especially for sustained‐release dosage forms.
Cefuroxime‐Induced Acute Renal Failure
Authors: Goddard Julie K. , Janning Stephen W. , Gass Jennifer S. , Wilson Robert F.
Published: October 2023

Although drug‐induced allergic nephritis (DIAN) is one of the most common problems seen by nephrologists, its true frequency is probably underestimated. Diagnosis is often difficult and is typically only made in patients without another explanation for deteriorating renal function, and is often based solely on improvement after drug withdrawal. The diagnosis may be made more difficult due to lack of typical allergic symptoms, presence of other drugs, or confounding factors and equivocal noninvasive laboratory studies. The gold standard for diagnosis is renal biopsy but it is only rarely performed during the acute phase of the reaction and is not without risk. It is important to keep a high index of suspicion with regard to DIAN since it is usually rapidly reversible. Failure to recognize it and discontinue the offending agents may result in unnecessary morbidity and occasionally irreversible renal failure. In our patient, DIAN possibly was related to cefuroxime, but the patient did not experience associated allergic symptoms. The diagnosis was supported by the temporal course of renal deterioration during exposure to cefuroxime and improvement on its discontinuation; the pattern repeated with rechallenge. This is the first reported case of suspected DIAN due to cefuroxime.
A Test of the Human Sperm Acrosome Reaction Following Ionophore Challenge
Authors: CUMMINS JAMES M. , PEMBER SANDRA M. , JEQUIER ANNE M. , YOVICH JOHN L. , HARTMANN PETER E.
Published: October 2023

ABSTRACT: Acrosome reaction capacity was tested on semen samples from 53 fertile and 26 subfertile men. Preparations were divided into two aliquots after 3 or 24 hours of culture. One aliquot received 10 μmol/L calcium ionophore A23187 in dimethyl sulfoxide (DMSO) and the other received DMSO alone. Acrosome reactions were scored on ethanol‐permeabilized smears using fluorescein isothiocyanate (FITC)‐conjugated Pisum sativum lectin. The following factors were analyzed: the spontaneous reation rates (control); induced reaction rates (ionophore‐challenged); and the difference between the two, being the proportion of spermatozoa in the population capable of reacting in response to calcium influx (acrosome reaction to ionophore challenge [ARIC]). While spontaneous reactions bore no relation to fertility, induced reactions and ARICs were significantly reduced or absent in subfertile men, indicating acrosomal dysfunction as a likely cause of fertilization failure. The test was shown to have a predictive value for fertility comparable to that of the hamster ovum sperm penetration assay and to be a simple and cost‐effective addition to existing semenology.
Longitudinal Study of Semen Quality of Unexposed Workers Sperm Motility Characteristics
Authors: SCHRADER STEVEN M. , TURNER TERRY W. , SIMON STEPHEN D.
Published: October 2023

ABSTRACT: As part of a longitudinal study of human semen characteristics of unexposed workers, sperm motility measurements were made using computer‐assisted sperm analysis. Motility analyses were conducted on monthly samples from 46 men for 9 months. Measurements of curvilinear velocity, straight‐line velocity (VSL), linearity, amplitude of lateral head displacement (ALH), and beat‐cross frequency were collected in eight microscope fields for each semen sample. The variability within a sample, between samples from the same individual (between monthly samples), and between individuals were calculated using a nested analysis of variance. For all sperm motility measurements, at least 90% of the variation was observed between cells within a semen sample. For all variables, the component of variation between subjects was the smallest percentage (ranging from 1.3% for ALH to 4.0% for VSL). When sample means were used in the nested analysis of variation, at least 75% of the variation was observed between samples from the same individual. These results will be useful in power calculations for future studies.
Relationship between the Human Sperm Hypo‐osmotic Swelling Test and Sperm Penetration Assay
Authors: ROGERS B. JANE , PARKER ROBERT A.
Published: October 2023

ABSTRACT: The hypo‐osmotic swelling (HOS) test has been proposed as a useful assay in the diagnosis of the infertile male. A good correlation between the HOS test and the sperm penetration assay (SPA) in fertile and normal semen samples was initially found, but subsequently, no significant correlation was demonstrated with fertile and infertile patients. To validate the potential clinical usefulness of the HOS test, we evaluated 92 ejaculates using the HOS test, SPA, and traditional semen parameters. The methodology originally described by Jeyendran et al (1984) was used for the HOS test. The SPA was performed by the original procedure using an 18‐hour preincubation period, and for 28 ejaculates, a modified procedure using TEST‐yolk buffer was performed. Values of 60% or more for the HOS and 1% or more for the SPA were considered positive, and less than 60% for HOS and 0% for SPA were considered negative when the standard SPA was performed. For the TEST‐yolk buffered SPA, values of 20% or more were considered positive. The sensitivity of the HOS test was 87%, but the specificity was 36%. The association of the two tests over and above that expected by chance (Kappa) was only 0.23. Using logistic regression, both sperm count (P < 0.001) and morphology (P < 0.025) were significant predictors of the SPA classification, but the HOS test did not improve the predictive results (P > 0.50). Analysis of distribution of HOS test scores for “fertile” (SPA > 0%) and “infertile” (SPA = 0) samples showed such a wide overlap that it was impossible to designate a threshold value for a HOS test score that is predictive of a positive SPA result. The HOS test by itself has a modest ability to predict SPA. This was indicated by the modest correlation (r = 0.32) that, although highly significant (P = 0.0017), accounts for only about 10% of the total variation in SPA. The correlation between HOS and SPA results was related to SPA methodology since TEST‐yolk buffer‐enhanced SPA results provided a slightly higher correlation coefficient (r = 0.42). The HOS test does not appear to be a significant predictor of SPA results after considering other measurements.
The Pathophysiology of Benign Prostatic Hyperplasia
Authors: McCONNELL JOHN D.
Published: October 2023

Although benign prostatic hyperplasia (BPH) is one of the most common disease processes affecting the aging male, surprisingly little is known about its pathophysiology. Cause‐and‐effect relationships have not been established, despite intense research efforts in the last four or five decades aimed at elucidating the underlying etiology of prostatic growth in older men. Previously held notions that the clinical symptoms of BPH (prostatism) are due simply to a mass‐related increase in urethral resistance are too simplistic. It is now clear that a significant portion of the symptoms are due to obstruction‐induced detrusor dysfunction. Moreover, obstruction may induce a variety of neural alterations in the bladder and prostate that contribute to symptomatology. Undoubtedly, the constellation of cellular pathologies that give rise to the symptoms of BPH will be far more complex than we currently realize. Only by unraveling these complexities, however, will we be able successfully to design alternative strategies to treat, and possibly prevent BPH.
Response of Prostate Volume, Prostate‐Specific Antigen, and Testosterone to Flutamide in Men with Benign Prostatic Hyperplasia
Authors: STONE NELSON N. , CLEJAN SANDA J.
Published: October 2023

Patients diagnosed as having benign prostatic hyperplasia (BPH) had determination of prostate volume (PV), prostate‐specific antigen (PSA), and serum testosterone before consideration for entry into a double‐blind, randomized trial of flutamide (750 mg/day for 6 months). The mean PSA level for these patients (N = 43) was 7.6 ng/ml (range: 1.0 to 45.7), and the mean PV was 76.8 cm3 (range: 24 to 198). Linear regression analysis demonstrated a strong correlation between the two (r = 0.876, P < 0.05). Every 10 cm3 of prostate volume accounted for 1.02 ng/ml of PSA in the serum. Twenty‐two patients (11 treated with flutamide, 11 with a placebo) agreed to enter the study. Prostate volume decreased by 35% and PSA by 65% (P < 0.001) within 6 months. These changes occurred despite a 58.3% increase in serum testosterone levels (P < 0.01). Patients treated with a placebo experienced no significant changes. Side effects were minimal, and flutamide was well tolerated. These data suggest that androgen deprivation therapy with flutamide may be an effective and safe treatment for BPH.
Rationale for Using Aromatase Inhibitors to Manage Benign Prostatic Hyperplasia Experimental Studies
Authors: HABENICHT URSULA‐F. , ETREBY M. FATHY EL
Published: October 2023

Today, human benign prostatic hyperplasia (BPH) is considered primarily to be a disease of the stroma, in which estrogens are thought to play a considerable causative or permissive role. The growing incidence of BPH with increasing age coincides with a shift in the androgen:estrogen ratio in favor of estrogens, not only in terms of serum hormone values, but also in the prostate itself. Furthermore, evidence has been provided for a preferential accumulation of estrogens in the stroma of human hyperplastic tissue, and the presence of an estrogen receptor satisfying the classical criteria of high affinity and low capacity has been demonstrated. Also, animal studies have emphasized the potential role of estrogens in the pathogenesis of BPH. Experimentally, stimulation of the stroma, particularly of smooth muscle, can be induced by aromatizable substrates, such as androstenedione, in the prostates of beagles and cynomolgus monkeys. These effects can be antagonized by aromatase inhibitors, such as atamestane. In addition, the increase in intraprostatic estrogen concentrations and immunohistochemically detectable estrogen receptor content induced by androstenedione in intact dogs is completely reversed by simultaneous treatment with atamestane. In conclusion, clinical data, as well as that from animal models, emphasize an important role for estrogens in the development of BPH. Estrogen deprivation might, therefore, represent a useful treatment for human BPH.
A Permanent, Epithelializing Stent for the Treatment of Benign Prostatic Hyperplasia Preliminary Results
Authors: OESTERLING JOSEPH E.
Published: October 2023

Currently, there is much enthusiasm in the urologic community for the development of alternative treatments to transurethral prostatectomy for management of benign prostatic hyperplasia (BPH). At the Mayo Clinic, the role of a permanently implanted intraurethral stent (UroLume Wallstent) is being examined. It is a biocompatible prosthesis made from a “super” alloy that is woven into a tubular mesh. It is both flexible and self‐expanding with no elastic recoil; when fully expanded, it has a large internal diameter of 42 Fr (1.4 cm). Twelve patients (mean age = 67 years; range = 62 to 77 years) with obstructive BPH have been treated with this stent. After 3 months, the decrease in the total symptom score was 65% (mean preoperative score, 13.9 ± 5.2; mean postoperative score, 4.8 ± 3.7, P < 0.001), whereas the increase in peak urinary flow rate was 99% (mean preoperative value, 10.1 ± 3.3 ml/second; mean postoperative value, 20.1 ± 6.2 ml/second; P < 0.001). The postvoid residual urine volume decreased by 76% (mean preoperative value, 133 ± 68 ml; mean postoperative value, 32 ± 38 ml, P < 0.001). There has been no difficulty with infection, encrustation, stent erosion, stent migration, incontinence, or potency. Eight patients (67%), however, did have irritative voiding symptoms after stent placement. These untoward effects subsided markedly during the follow‐up period. No patient has required either pain or antispasmodic medications, and as of this time, it has not been necessary to remove any stent because of side effects. These results suggest that the intraurethral stent may be a viable treatment option for patients with BPH. Additional studies with more patients and long‐term follow‐up are warranted.
Is an Immunoassay Available for the Measurement of Bioactive LH in Serum?
Authors: ROSENFIELD ROBERT L. , HELKE JAMES
Published: October 2023

ABSTRACT: An in vitro bioassay for luteinizing hormone (LH) is in our opinion the “gold standard” bioassay. The rodent interstitial cell testosterone assay (RICT) is specific for bioactive LH and very sensitive, accurate, and reproducible. Diverse LH standards consistently display parallel dose‐response characteristics. Sera also manifest parallel dose‐response characteristics throughout reproductive life, with the exception of basal samples from prepubertal children. This indicates that all known hormones with LH bioactivity have a similar bioactive site. The in vivo bioassays for LH used for calibration of World Health Organization standards are more cumbersome and less precise and accurate than the in vitro bioassay. The ovarian ascorbic acid depletion assay corresponds better than the seminal vesicle weight assay with in vitro bioassay. Variation in the ratio of bioactive to immunoreactive LH (B/I) principally reflects variation in LH immunoassay dose‐response characteristics, rather than a change in the bioactive moiety of LH. The varying B/I ratio is due to molecular heterogeneity at multiple levels. Different LH standards contain different proportions of nonbioactive but immunoreactive material. The immunoreactive LH isoforms in serum contain different proportions of bioactive material and the isoform distribution differs with reproductive status. Furthermore, the antibodies comprising the various immunoassay systems detect heterogeneous epitopes on LH, which are not necessarily bioactive. B/I ratio disparities indicate lack of specificity of immunoassays for bioactive LH. Polyclonal antibody‐based radioimmunoassay requires the use of purified reagents, including a bioactive tracer, in order to achieve high specificity for bioactive LH. The new generation of monoclonal antibody‐based immunometric assays yields results that are lower than, but correlate with, LH measured by the in vitro bioassay. The purest of standards, even a recombinant standard, yields results that differ up to 50% or more from one immunoassay to another. Serum LH levels also differ up to two‐fold among assays. The immunometric assays have the advantage of being more sensitive and more specific for low levels of LH in serum than radio‐immunoassays, but B/I ratio discrepancies remain great. An immunoassay specific for the bioactive “docking site” of human LH isoforms is still needed.
Sperm Surface Fibronectin Expression Following Capacitation
Authors: FUSI F. M. , BRONSON R. A.
Published: October 2023

ABSTRACT: The Arg‐Gly‐Asp (RGD) amino acid sequence plays a role in many cell‐to‐cell and cell‐to‐matrix adhesion systems, as a recognition sequence for cell membrane receptors termed integrins. Receptors of the VLA subfamily of integrins recognize fibronectin, laminin, and collagen. Given the authors' findings that fibronectin‐derived, RGD‐containing peptides competitively inhibit sperm‐oolemmal adhesion and penetration in both heterologous (human‐hamster) and homologous (hamster‐hamster) gamete interactions, the expression of fibronectin on the surface of fresh, capacitated, and acrosome‐reacted human spermatozoa was studied. The majority of fresh spermatozoa did not display fibronectin on their plasma membrane (0 to 16% positive), as demonstrated by the lack of binding of both monoclonal and polyclonal anti‐fibronectin antibodies. In contrast, a significantly greater proportion of spermatozoa (varying between 18% to 100% for different donors) incubated overnight under capacitating conditions reacted with anti‐fibronectin antibodies. The induction of an acrosome reaction with progesterone did not alter the proportion of sperm displaying fibronectin or its distribution on the sperm surface. A physiologic role of fibronectin in sperm‐oolemmal interaction was suggested by the effects of anti‐fibronectin antibodies on sperm oolemmal adhesion and penetration of hamster eggs by human spermatozoa, which were both significantly reduced (P < 0.001).
Biochemical Alterations in the Proacrosin‐Acrosin System During Epididymal Maturation of the Rat Spermatozoa
Authors: NAGDAS S. K. , SKUDLAREK M. D. , ORGEBIN‐CRIST M.‐C. , TULSIANI D. R. P.
Published: October 2023

ABSTRACT: Acrosin, an acrosomal serine protease, is believed to have a role in fertilization. The enzyme is synthesized in an enzymatically inactive precursor form, proacrosin, and is processed to enzymatically active form(s). In the studies presented here, maturation‐associated changes in the proacrosin‐acrosin system of rat spermatozoa are reported. Acid‐solubilized components of spermatozoa from caput, corpus, and cauda epididymidis were resolved on gelatin‐sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) and the proteolytic bands visualized by enzymography. These studies reveal the presence of one form (52 kDa), two forms (52 and 41 kDa), and four forms (52, 41, 34, and 31 kDa) in the spermatozoa from caput, corpus, and cauda, respectively. The findings suggest that the enzymatically inactive high molecular weight component (proacrosin) present in the caput spermatozoa is partially converted to the low molecular weight components (acrosin) during epididymal transit. The sensitivity of these molecular forms to an inhibitor of acrosin, p‐nitrophenyl p'‐guanidino benzoate (NPGB), and the fact that all four forms cross‐reacted with the antibody against guinea pig testis proacrosin, suggest that these molecular forms are proacrosin‐acrosin components. To understand the mechanism of the changes in molecular forms, spermatozoa from caput, corpus, and cauda regions were subjected to in vitro activation, and the acid‐solubilized components resolved on gelatin‐SDS‐polyacrylamide gel. A smaller component of 34 kDa was generated from both the caput and corpus spermatozoa. No changes in the molecular form(s) of cauda spermatozoa were observed, even after in vitro activation for 4 hours. Inclusion of NPGB during in vitro activation blocked generation of the new molecular form from the caput spermatozoa. These studies indicate that intra‐acrosomal events during epididymal transit may be important in the production of functionally mature spermatozoa.
Testicular Function in Hyperthyroidism
Authors: HUDSON ROBERT W. , EDWARDS ALUN L.
Published: October 2023

ABSTRACT: Testicular function was assessed in nine men aged 17 to 35 years and seven men aged 36 to 46 years with Graves' disease. Levels of total testosterone, estradiol, sex hormone binding globulin, luteinizing hormone, and follicle stimulating hormone, and gonadotropin responses to gonadotropin releasing hormone were significantly greater than these levels and responses in age‐matched controls. Although the percentage of free testosterone was lower than control values in the hyperthyroid men, calculated levels of free testosterone were not different from normal. Lower than normal percentages of free estradiol values resulted in higher than normal calculated free estradiol levels. As a result, the free testosterone/free estradiol ratio in the men with Graves' disease was lower than normal. Although mean sperm densities in the hyperthyroid men were not different from control values, the percent forward progressive motility of sperm from these men was significantly lower than control values. The hormonal and seminal abnormalities corrected when the patients became euthyroid after radioiodine therapy. The results of this study indicate that hyperthyroid men may have abnormalities in their hypothalamic‐pituitary‐testicular axes.
A Comparison of Critical Osmolality and Hydraulic Conductivity and Its Activation Energy in Fowl and Bull Spermatozoa
Authors: WATSON P. F. , KUNZE E. , CRAMER P. , HAMMERSTEDT R. H.
Published: October 2023

ABSTRACT: Measurements were made of critical osmolality, the osmolality at which 50% of the cells are lysed, and of the permeation time, the time taken to lyse 50% of the cells in an osmotic solution lower than the critical osmolality, for fowl and bull spermatozoa. Cell lysis was determined by means of fluorescent viability stains (carboxyfluorescein diacetate and propidium iodide) using a flow cytometer. The advantages and pitfalls of this approach are addressed. The values obtained have been used to compute the water permeability, or hydraulic conductivity, of the plasma membrane and its activation energy for each species. Fowl spermatozoa were found to have a lower critical osmolality (17 mOsm) than bull spermatozoa (36 mOsm), and this is discussed in relation to the differences in cell shape and size. The hydraulic conductivities of fowl and bull spermatozoa were 2.1 and 10.8 μm × atmosphere × minute, respectively, and the respective activation energies were 4.4 and 3.0 kcal/mol. The relevance of these findings to cryopreservation of spermatozoa is considered.
β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD+/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis
Authors: Kalantary‐Charvadeh Ashkan , Nazari Soltan Ahmad Saeed , Aslani Somayeh , Beyrami Mehdi , Mesgari‐Abbasi Mehran
Published: October 2023

Doxorubicin (DOX) is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of β‐lapachone (β‐LAP), a natural quinone‐containing compound, in a mouse model of DOX‐induced hepatotoxicity. β‐LAP was orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed. β‐LAP ameliorated liver injury and liver function markers evoked by DOX. β‐LAP also downregulated the mRNA expression of nuclear factor‐kB‐corresponding genes including interleukin‐6, interleukin‐1β, and tumor necrosis factor‐α. Moreover, β‐LAP increased the nuclear factor erythroid 2‐related factor 2 target genes heme oxygenase‐1 and NAD(P)H: quinone oxidoreductase 1, along with antioxidant enzymes including reduced glutathione, catalase, and superoxide dismutase with simultaneous reduction in the lipid peroxidation product malondialdehyde. Meanwhile, it recovered NAD+/NADH ratios and subsequently elevated the protein levels of sirtuin‐1 (SIRT‐1), farnesoid X receptor (FXR), and phosphorylated AMP‐activated protein kinase (p‐AMPK). Collectively, these findings suggest a protective role of β‐LAP against DOX‐induced hepatotoxicity by partly regulating the NAD+/SIRT‐1/FXR/p‐AMPK axis.
Canola meal‐derived biochar for highly efficient dye removal and the impact of compression treatment on porous structure
Authors: Li Sheng , Zhang Sitian , Xu Chengzhi , Zhu Lian , Wei Benmei , Chen Lingyun , Wang Haibo
Published: October 2023

BACKGROUND

This study reported a canola meal‐based biochar adsorbent for highly efficient organic dyes removal. SEM, BET, Zeta‐potential and XPS etc. were employed to characterize the micro‐structure and chemical composition of the biochar, demonstrating the impact of compression treatment on its inner pore structure.

RESULTS

KOH‐activated carbonized canola meal‐compressed (KCCM‐C) showed a high specific surface area of up to 2135 m2 g−1 with an average pore size of 2.65 nm, which exhibited excellent adsorption capacity for both positively and negatively charged dyes with maximum values of 985 mg g−1 and 813 mg g−1 for methylene blue (MB) and methyl orange (MO) respectively, exceeding majority of the biochar adsorbents reported so far. The dye adsorption behavior was dominated by monolayer coverage with both physical adsorption and chemisorption. Langmuir isotherm model fitted well with the adsorption data, and the adsorption kinetic followed the pseudo‐second‐order model. Negative Gibbs free energy and positive enthalpy change indicated that the adsorption was a spontaneous endothermic process. XPS analysis indicated that the amino groups of proteins inside the canola meal as the active sites were oxidated by KOH prior to other components, while the compact structure of compressed canola meal was more conducive to the formation of uniform meso‐pores inside canola meal‐derived biochar improving its adsorption performance.

CONCLUSIONS

This high‐quality porous biochar, directly synthesized from the compressed canola meal, simplifies the grinding process and presents a valuable opportunity for the value‐added application of canola meal. © 2023 Society of Chemical Industry (SCI).
Dental students’ perceptions of instructor storytelling for clinical learning: A qualitative description study
Authors: Atiah Nafisa , Dahlseide Paulette , Sharmin Nazlee , Ganatra Seema , Perez Arnaldo
Published: October 2023

Objective

Storytelling has been infrequently used in dental education to link clinical knowledge and practice. Our study aimed to explore dental students’ views of instructor storytelling with an emphasis on clinical reasoning within a case‐based oral pathology seminar.

Methods

Qualitative description guided the study design. Participants were third‐ and fourth‐year undergraduate dental students who participated in the seminar. Data were collected through semi‐structured, one‐on‐one interviews. Data analysis was approached using inductive, manifest thematic analysis. Verification strategies were employed to ensure methodological rigor throughout the analysis.

Results

In total, 21 students participated in the study ranging in age from 22 to 29 years. Three interrelated themes were identified, which were related to storytelling authenticity, benefits, and recommendations for improvement. Specifically, students reported that instructor stories effectively conveyed genuine cases and clinical reasoning; were beneficial in terms of engagement, awareness, knowledge acquisition, and skill development; and needed to be educationally and clinically relevant to bridge the knowledge‐practice gap.

Conclusions

Instructor storytelling was regarded by dental students as both positive and beneficial. Research is needed to further demonstrate the effectiveness of instructor storytelling in fostering clinical learning and reasoning using indirect and direct outcome measures.
Synthesis and preclinical evaluation of a selective MET kinase positron emission tomography tracer
Authors: Lien Vegard Torp , Hauge Emily , Nuruddin Syed , Klaveness Jo , Olberg Dag Erlend
Published: October 2023

The tyrosine kinase MET (hepatocyte growth factor receptor) is activated or mutated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (1) formed the basis for a bioisosteric replacement, leading to the deoxyfluorinated analog [18F]2. [18F]2 could be synthesized with a “hydrous fluoroethylation” protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/μmol. In vitro autoradiography indicated that [18F]2 selectively binds to MET in PC3 tumor tissue, and in vivo biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs.
A case of hyperlysinemia identified by urine newborn screening
Authors: Yeganeh Mehdi , Auray‐Blais Christiane , Maranda Bruno , Sabovic Amanda , DeVita Robert J. , Lazarus Michael B. , Houten Sander M.
Published: October 2023

Hyperlysinemia is a rare autosomal recessive deficiency of 2‐aminoadipic semialdehyde synthase (AASS) affecting the initial step in lysine degradation. It is thought to be a benign biochemical abnormality, but reports on cases remain scarce. The description of additional cases, in particular, those identified without ascertainment bias, may help counseling of new cases in the future. It may also help to establish the risks associated with pharmacological inhibition of AASS, a potential therapeutic strategy that is under investigation for other inborn errors of lysine degradation. We describe the identification of a hyperlysinemia case identified in the Provincial Neonatal Urine Screening Program in Sherbrooke, Quebec. This case presented with a profile of cystinuria but with a very high increase in urinary lysine. A diagnosis of hyperlysinemia was confirmed through biochemical testing and the identification of biallelic variants in AASS. The p.R146W and p.T371I variants are novel and affect the folding of the lysine‐2‐oxoglutarate domain of AASS. The 11‐month‐old boy is currently doing well without any therapeutic interventions. The identification of this case through newborn urine screening further establishes that hyperlysinemia is a biochemical abnormality with limited clinical consequences and may not require any intervention.