bluuebunny/crossref_metadata_2025 huggingface dataset:
Perspectives on the Improvement of Quality of Life with Epoetin Alfa Therapy
Authors: Lundin A. Peter , Delano Barbara G. , Quinn‐Cefaro Rosemary
Published: October 2023

Epoetin alfa (recombinant human erythropoietin) effectively diminishes the anemia associated with end‐stage renal disease (ESRD). Although many clinical manifestations of ESRD have been attributed to uremic toxins, the ability of epoetin alfa therapy to improve several of these conditions, such as diminished energy levels, appetite, cold tolerance, sexual function, and cognitive abilities, suggests that anemia may be an important factor in uremia‐associated symptoms. Correction of this anemia results in improvements in the patient's quality of life. These improvements can be measured by objective criteria such as exercise tolerance tests, or by subjective standards such as patient response to questionnaires. In studies to date, both subjective and objective data show that epoetin alfa therapy significantly improves the quality of life of patients with ESRD.
Antidepressants in the Management of Chronic Pain Syndromes
Authors: Egbunike Ifeanyi G. , Chaffee Betty J.
Published: October 2023

Conditions in which antidepressants have been used include diabetic neuropathy, postherpetic neuralgia, headaches, arthritis, chronic back pain, cancer, thalamic pain, facial pain, and phantom limb pain. Although much of the available information is derived from inadequately controlled trials, it seems that antidepressants provide analgesia in many of these disorders. The analgesic effects tend to be independent of antidepressant effects, and doses of heterocyclic antidepressants used for analgesia seem to be lower than those considered effective in the treatment of depression. Doses should be started low and gradually increased until the patient reaches the highest tolerable dose. Onset of analgesia is variable, ranging from 1 day to 10 weeks. Common side effects include dry mouth, drowsiness, urinary retention, orthostatic hypotension, and constipation. Optimum dosages and schedules have not been established.
Transdermal Timolol: β Blockade and Plasma Concentrations After Application for 48 Hours and 7 Days
Authors: McCrea Jacqueline B. , Vlasses Peter H. , Franz Thomas J. , Zeoli Laura
Published: October 2023

An effective and well‐tolerated transdermal β‐adrenergic blocker that could be applied once weekly would facilitate compliance. The pharmacokinetics and pharmacodynamics of a once‐weekly formulation of transdermal timolol, a β‐blocker, were evaluated in healthy males. One (n = 6), two (n = 5), and three (n = 5) patches (97.5 mg base/12.58‐cm2 patch) were applied at weekly intervals to the subjects' inner arm for 48 hours (part A) and two patches were applied for 7 days (part B). In part A, mean exercise (bicycle ergometry) heart rate (beats/min, bpm) was suppressed from baseline at 48 hours after the patch (p < 0.05) in each case (1 patch 167 vs 131 bpm; 2 patches 165 vs 120 bpm; 3 patches 159 vs 120 bpm). Mean plasma timolol concentrations at 48 hours after the patch for one, two, and three patches were 5, 11, and 14 ng/ml, respectively. For part B, mean exercise heart rate at baseline, 24, and 168 hours was 161, 113, and 130 bpm (p < 0.05), and mean plasma timolol concentrations at these times were 0, 23, and 4 ng/ml. The relationship between suppression of exercise heart rate and plasma timolol concentrations within subjects was well described by an inhibitory EMAX model, where EMAX ranged from a suppression of 42–65 bpm associated with a 50% inhibitory (IC50) concentration that ranged from 2–4 ng/ml. Transdermal timolol was associated with significant B blockade for up to 7 days, and caused only minimal skin irritation.
Pharmacodynamics of Trimethoprim‐Sulfamethoxazole in Listeria Meningitis: A Case Report
Authors: Friedrich Lawrence V. , White Roger L. , Reboli Annette C.
Published: October 2023

Infections in the cerebrospinal fluid (CSF) occur in an area of impaired host defenses; therefore, bactericidal antibiotics that reach adequate concentrations in the CSF are necessary for treatment. Measurements of antibiotic penetration into the CSF include CSF inhibitory and bactericidal titers, the absolute antibiotic concentration in the CSF, and the CSF: serum concentration ratio. We present the case of a patient with Listeria monocytogenes meningitis who failed to respond clinically to standard therapy, and whose organism demonstrated tolerance to Ampicillin (MBC: MIC = 258: 1) that successfully responded to trimethoprim‐sulfamethoxazole (TMP‐SMX). The CSF peak bactericidal titer to TMP‐SMX was 1:8, corresponding to that reported as necessary for successful outcome in patients with meningitis. The CSF peak: MBC ratios for TMP and SMX were less than 3:1 and equal to 3:1, respectively. These individual ratios are lower than those suggested for successful treatment of meningitis; however, the recommended ratios were established using single agents and did not account for synergistic activity with a drug combination such as TMP‐SMX. The failure of standard therapy in this patient underscores the importance of MIC/MBC testing when tolerance is suspected or when CSF penetration of antibiotics is relatively poor. In addition, measurements of CSF inhibitory and bactericidal titers, which incorporate the antibiotic concentration in the CSF, susceptibility of the infecting microorganism, and host defense factors, may be useful in monitoring patients with meningitis.
Aldose Reductase Inhibitors
Authors: Kirchain William R. , Rendell Marc S.
Published: October 2023

The present management of diabetes consists of attempting to control blood sugar tightly in the normal range and to treat individual complications such as neuropathy and retinopathy as they appear. Whereas these measures are perhaps effective in slowing the progress of diabetic complications, they do not cure the underlying process. The aldose reductase inhibitors have been investigated as possible remedies for various diabetic complications. Aldose reductase is an enzyme present in several human tissues that reduces glucose to sorbitol. In animal models there is evidence that the production of sorbitol is associated with the development of diabetic complications. Animal and human studies have tested the ability of aldose reductase inhibitors to halt or reverse diabetic complications. The weight of evidence leads to two conclusions: first, that aldose reductase inhibitors may bring significant relief to patients with certain diabetic complications; and second, that the current approach to proving clinical efficacy may not be adequate for these drugs.
Renal Dysfunction Associated with Ciprofloxacin
Authors: Hatton Jimmi , Haagensen Darrow
Published: October 2023

We cared for a 64‐year‐old woman who experienced increased serum creatinine levels after 8 days of ciprofloxacin therapy. She had previously received a course of several antibiotics, including gentamicin. Renal function returned to normal 18 days after the ciprofloxacin was discontinued. This is the eighth reported case of nephrotoxicity associated with this agent. The mechanism and predisposing factors have not been defined.
The Influence of Enteral Feedings on Sustained‐Release Theophylline Absorption
Authors: Plezia Patricia M. , Thornley Susanne M. , Kramer Thomas H. , Armstrong Edward P.
Published: October 2023

In a randomized, crossover study the influence of enteral feedings (Ensure) on the absorption of theophylline from a sustained‐release preparation (Theo‐24) was evaluated. Six healthy, male subjects, age 22 to 37 years, participated. In phase 1 the subjects received a single oral dose of Theo‐24 6 mg/kg with 100 ml of water at 8:00 a.m. In phase 2, they received 100 ml boluses of Ensure hourly, beginning 3 hours prior to the oral dose and continuing for a total of 1000 ml. In phase 3, subjects received a single 30‐minute intravenous infusion of an equivalent dose of aminophylline. After each dose, serial blood samples were collected for 72 hours. No statistically significant differences in area under the curve (AUC∞0) (126.0 vs 127.3 μg hr/ml), maximum concentration (3.80 vs 4.08 μg/ml), or time to peak plasma level (13 vs 11 hrs) were found between phases 1 and 2. Mean AUC∞0 for the intravenous phase (161.4 μg hr/ml) was significantly higher than the AUC for either oral study (p < 0.05). The mean bioavailability was 81 % for phase 1 and 80% for phase 2. Percent absorbed versus time plots revealed no difference in rate of absorption between treatments. We conclude that short‐term administration of the enteral feeding Ensure does not influence the absorption of theophylline when administered as the sustained‐release product Theo‐24.
Evaluation of a Rapid Monitoring System to Study Heparin Pharmacokinetics and Pharmacodynamics
Authors: Cipolle Robert J. , Uden Donald L. , Gruber Scott A. , Jossart Gregg H. , Taylor Cindy A. , Erdmann Gary R. , Canafax Daniel M.
Published: October 2023

The pharmacokinetic and pharmacodynamic characteristics of heparin were studied in 10 healthy volunteers using the Hepcon/System B‐10. This coagulation‐monitoring system uses each patient's body weight, height, baseline activated clotting time (ACT), and heparin dose response values to determine initial heparin doses. We administered a calculated mean ± SD heparin dose of 85 ± 14 U/kg to 10 subjects to achieve a mean ± SD target ACT of 364 ± 29 seconds. This dose produced a mean ± SD measured peak ACT of 337 ± 53 seconds from a mean ± SD baseline of 121 ± 10 seconds. The measured peak ACT values resulting from the individualized heparin doses were within 20% of the desired peak in 9 (90%) of the subjects. Using the ACT values, the average mean residence time for heparin effect was 1.2 hours and half‐life was 0.8 ± 0.2 hours, with all the subjects' values returning to within 10% of baseline by 4 hours after the dose. Using the protamine‐derived heparin concentrations, heparin total‐body clearance ranged from 43 to 99 ml/hr/kg (mean ± SD 73.3 ± 14.5 ml/hr/kg). A linear relationship was found between heparin concentration and change in ACT that was described by ΔACT = 16.85 + 136.7 (heparin concentration). We conclude that this method is easy to perform and accurate for determining initial heparin dosage requirements, and could be an important improvement over existing approaches. In addition, it is a valuable research tool for studying heparin pharmacodynamics and pharmacokinetics.
Risk of Nephrotoxicity with Combination Vancomycin‐Aminoglycoside Antibiotic Therapy
Authors: Pauly David J. , Musa David M. , Lestico Mitchell R. , Lindstrom Mary J. , Hetsko Cyril M.
Published: October 2023

One hundred five patients receiving concurrent aminoglycoside and vancomycin therapy of at least 5 days' duration were retrospectively reviewed for development of nephrotoxicity. All had their vancomycin and aminoglycoside serum concentrations controlled by a clinical pharmacokinetics service. Nephrotoxicity occurred in 28 (27%) of the patients. Twenty‐two of the 28 had other factors that are known to contribute to renal failure (amphotericin B therapy, sepsis, liver disease, obstructive uropathy, pancreatitis, anesthesia). The remaining six developed nephrotoxicity without other known contributing factors. Logistic regression analysis revealed associations between nephrotoxicity and age, sex, aminoglycoside trough and vancomycin peak and trough serum concentrations, length of aminoglycoside and vancomycin therapy, concurrent amphotericin B therapy, liver disease, neutropenia, and peritonitis (p < 0.05). In addition to factors previously reported, this study found that neutropenia and peritonitis are associated with an increased risk of nephrotoxicity. Patients with one or more risk factors warrant close monitoring of renal function as well as vancomycin and aminoglycoside serum concentrations.
Influence of Pentoxifylline on Steady‐State Theophylline Serum Concentrations from Sustained‐Release Formulations
Authors: Ellison Mark J. , Horner Ronnie D. , Willis Stephen E. , Cummings Doyle M.
Published: October 2023

This clinical study assessed the influence of pentoxifylline and its metabolites on steady‐state serum theophylline concentrations. Nine healthy volunteers took sustained‐release formulations of pentoxifylline, theophylline, and a combination of both agents each for 7 days at standard therapeutic doses in a randomized order. Serum theophylline concentrations were analyzed using fluorescence‐polarization immunoassay (TDx) technique. During the pentoxifylline treatment phase, serum theophylline concentrations were undetectable, demonstrating the lack of assay interference from pentoxifylline and its metabolites. Mean trough steady‐state serum theophylline concentrations were 30% higher (p < 0.05) during the combination treatment phase compared to theophylline administration alone, and varied considerably. Although side effects were more frequent during the combination phase, differences in the number of adverse reactions did not achieve statistical significance. This study demonstrates an interaction between theophylline and pentoxifylline, and indicates that close monitoring of serum theophylline concentrations during combination therapy is warranted.
Hospitalizations Because of Hypoglycemia in Users of Animal and Human Insulins. 2. Experience in the United States
Authors: Jick Ms. Susan S. , Derby Ms. Laura E. , Gross Kenneth M. , Jick Hershel
Published: October 2023

In a 10‐year (1979–1988) follow‐up study of young insulin‐dependent diabetics carried out at Group Health Cooperative of Puget Sound, the frequency of hospitalization for hypoglycemia remained constant. During the early years only animal insulins were available; during the latter years, human insulins were used in a majority of patients. The adjusted relative risk estimate for hospitalizations for hypoglycemia comparing users of human with users of animal insulins was 0.6 (95% confidence interval 0.2, 2.3). We conclude that the use of human insulins is not associated with an increased risk of hospitalization for hypoglycemia as compared with animal insulins in this population.
Trimethoprim‐Sulfamethoxazole Anaphylactoid Reactions in Patients with AIDS: Case Reports and Literature Review
Authors: Johnson Michael P. , Goodwin S. Diane , Shands Joseph W.
Published: October 2023

Adverse effects are common in patients with acquired immunodeficiency syndrome (AIDS) who receive trimethoprim‐sulfamethoxazole (TMP‐SMX). Two patients experienced a rare anaphylactoid syndrome. Within hours of receiving a double‐strength TMP‐SMX tablet, a 28‐year‐old human immunodeficiency virus (HIV)‐positive man developed fever, hypotension, and bilateral pulmonary infiltrates. Broad‐spectrum antimicrobial therapy was begun but discontinued 2 days later when signs and symptoms resolved and specimens for Pneumocystis carinii were negative. A 38‐year‐old man developed rash, fever, hypotension, hyperbilirubinemia, renal dysfunction, and bilateral pulmonary infiltrates after taking two doses of oral TMP‐SMX. Several antimicrobial agents, including parenteral pentamidine, were administered despite lack of evidence for P. carinii or other infection. Four case reports of similar reactions in patients with AIDS have been published. Notable differences exist between the syndrome described and anaphylaxis. The TMP‐SMX anaphylactoid reactions in patients with AIDS mimic sepsis or opportunistic infection, thus making diagnosis difficult.
Comparison of Repeat Doses of Intramuscular Ketorolac Tromethamine and Morphine Sulfate for Analgesia after Major Surgery
Authors: Brown Colin R. , Mazzulla James P. , Mok Martin S. , Nussdorf R. Theodore , Rubin Paul D. , Schwesinger Wayne H.
Published: October 2023

A multicenter, randomized, double‐blind, parallel study in 542 patients with moderate or severe postoperative pain compared the analgesic efficacy and safety of intramuscular ketorolac 30 mg (324 patients), morphine 6 mg (110 patients), and morphine 12 mg (108 patients) administered as needed as often as every 2 hours for a maximum of 20 doses or 5 days. The efficacy of ketorolac 30 mg was comparable to that of morphine 12 mg on every efficacy measure (average pain intensity, average pain relief, mean overall medication rating, and percentage of patients withdrawing because of inadequate relief). Ketorolac was statistically superior to morphine 6 mg for average pain intensity and mean overall rating. Ketorolac‐treated patients had fewer adverse events than those who received either morphine dose.
Effects of Ketorolac Tromethamine on Hemostasis
Authors: Greer Ian A.
Published: October 2023

Ketorolac tromethamine is a potent prostaglandin synthetase inhibitor useful in the treatment of postoperative pain. Since it is also known to have antiplatelet properties, we determined the effect of ketorolac, alone and in combination with low‐dose heparin, on hemostasis. Each of 12 healthy male volunteers received the following drug combinations on a double‐blind, crossover basis: ketorolac dummy/heparin dummy, ketorolac active/heparin dummy, ketorolac active/heparin active, and ketorolac dummy/heparin active. Ketorolac significantly prolonged bleeding time, and inhibited platelet aggregation and platelet thromboxane production. Heparin had no effect on bleeding time or platelet function, but significantly prolonged the kaolin‐cephalin clotting time and increased anti‐Xa levels. Ketorolac had no effect on the kaolin‐cephalin clotting time or anti‐Xa levels, and no interaction was found between ketorolac and heparin. The modest prolongation of bleeding time with ketorolac is unlikely to be of any major clinical significance, as the value remained within the normal range in almost all subjects. However, because of its antiplatelet properties, the drug should be used with caution in persons with hemostatic disorders.
Evaluation of Ketorolac, Aspirin, and an Acetaminophen‐Codeine Combination in Postoperative Oral Surgery Pain
Authors: Forbes James A. , Butterworth Geraldine A. , Burchfield William H. , Beaver William T.
Published: October 2023

One‐hundred twenty‐eight outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double‐blind basis, to receive oral doses of ketorolac tromethamine 10 mg, aspirin 650 mg, a combination of acetaminophen 600 mg plus codeine 60 mg, or placebo. Using a self‐rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. All active medications were significantly superior to placebo. The acetaminophen‐codeine combination was significantly superior to aspirin for peak analgesia. Ketorolac was significantly superior to aspirin for every measure of total and peak analgesia, and significantly superior to acetaminophen‐codeine for measures of total effect. The analgesic effect of ketorolac was significant by hour 1 and persisted for 6 hours. Repeat‐dose data also suggested that ketorolac 10 mg was superior to aspirin 650 mg and acetaminophen‐codeine on the day of surgery. Differences among the active medications were trivial for the postoperative days 1–6 analyses. The frequency of adverse effects was over 4 times greater for acetaminophen‐codeine than for ketorolac or aspirin.
Comparison of Intravenous Ketorolac Tromethamine and Morphine Sulfate in the Treatment of Postoperative Pain
Authors: Brown Colin R. , Moodie John E. , Wild Vicki M. , Bynum Lincoln J.
Published: October 2023

This study compared the efficacy and safety of ketorolac tromethamine and morphine sulfate in alleviating moderate or severe pain immediately after major surgery. One hundred twenty‐two patients were randomly assigned to receive single intravenous injections of ketorolac 10 mg, ketorolac 30 mg, morphine 2 mg, or morphine 4 mg; patients could receive a second dose 15 minutes thereafter, upon request, and most received both available doses. Analgesic efficacy was measured by interviewing patients and assessing pain intensity and pain relief for 6 hours after the first medication administration. The two drugs showed a similar onset of action, peaking 1 hour after administration. When placed in order of descending efficacy, the mean scores for most efficacy measures fell into the following sequence: ketorolac 30 mg, ketorolac 10 mg, morphine 4 mg, and morphine 2 mg. There were no statistically significant differences among the two ketorolac doses and the high dose of morphine, but all three of these treatments were significantly superior to the low morphine dose. One patient who took morphine 4 mg withdrew because of drowsiness; other common adverse events reported included nausea, vomiting, somnolence, and dyspepsia. There were no statistically significant differences in the frequency of adverse events among the treatment groups. Intravenous ketorolac is effective for the treatment of postoperative pain.
Effects of ß‐Lactamase‐Mediated Antimicrobial Resistance: The Role of ß‐Lactamase Inhibitors
Authors: Maddux Michael S.
Published: October 2023

Production of ß‐lactamase is the most common mechanism of bacterial resistance to ß‐lactam antibiotics. Virtually all bacteria have the capability of synthesizing the enzyme. Microorganisms may already possess the native genetic information necessary for ß‐lactamase production (i.e., chromosomal), or may acquire the capacity by transfer of DNA from another organism (i.e., plasmid‐mediated). The level of ß‐lactamase production may be stable and noninducible (constitutive enzyme production), or may be stimulated on exposure to selected ß‐lactam antibiotics (inducible enzyme production). Inhibitors such as clavulanic acid and sulbactam prevent antibiotic degradation by the ß‐lactamases of many clinically significant pathogens. Therefore, currently available ß‐lactam‐ß‐lactamase‐inhibitor combinations exhibit broad spectra of in vitro activity. Ticarcillin‐clavulanate possesses clinically significant activity against many bacteria, including streptococci, Staphylococcus aureus, Bacteroides fragilis, and numerous Enterobacteriaceae. Amoxicillin‐clavulanate and ampicillin‐sulbactam demonstrate clinically significant activity against streptococci (including enterococci), S. aureus, B. fragilis, and some Enterobacteriaceae. Ticarcillin‐clavulanate is indicated for treatment of serious infections, including septicemia. Amoxicillin‐clavulanate is useful in the treatment of upper respiratory, urinary tract, and skin and soft tissue infections. Ampicillin‐sulbactam may be used for treatment of intraabdominal, gynecologic, urinary tract, and skin and soft tissue infections.
Hot Tubs, Sex, Sushi, and Infectious Diseases
Authors: Lorber Bennett
Published: October 2023

Over the past 20 years, striking and interesting changes in patterns of diseases have occurred due to transmissible agents. Among them are the recognition of new diseases, new clinical manifestations of old diseases, new ecologic niches for traditional pathogens, and new modes of disease transmission. Implicated causes for these changing patterns include alterations in lifestyle with respect to sexual behavior, leisure activity, and dietary trends, together with the impact of immigration and the effects of medical progress. A review of these changes demonstrates the dynamic nature of medicine, and the impact that societal change can have on disease patterns.
Monotherapy versus Combination Antimicrobial Therapy: A Review
Authors: Barriere Steven L.
Published: October 2023

In view of the newer antibiotics that can cover the spectrum of organisms in mixed infections, single agents are now a viable option for antimicrobial therapy. In addition, monotherapy is relatively nontoxic and possibly less costly than combination therapy. Combinations may be more effective in preventing the emergence of resistance, however, and can also provide synergistic effects. They are a necessity in mycobacterial infections, enterococcal endocarditis, and deep‐seated pseudomonal infections, as well as in patients with gram‐negative bacillary infection with profound granulocytopenia.
Antimicrobial Therapy of Anaerobic Infections, 1991
Authors: Sanders Charles V. , Aldridge Kenneth E.
Published: October 2023

Most anaerobic infections are polymicrobial and must be treated with agents active against a variety of both aerobic and anaerobic bacteria. Antimicrobial therapy is used both to contain infections and to treat those that have not been contained (bacteremia). Bacterial resistance, especially to penicillins and tetracyclines, but also to newer agents of other classes, continues to increase and often requires treatment with more than one drug. Combination therapy is also frequently necessary in serious infections, and is indicated for empiric management before receiving results of in vitro microbiology laboratory tests. However, recent results suggest that monotherapy for anaerobic infections may dominate in the future, although combination therapy has been the mainstay of antimicrobial therapy. Selection of an agent must take into account the site of infection and thus the bacteria most likely to be found. It should be kept in mind that in vitro susceptibility is not the only determinant of antimicrobial effectiveness. The pharmacology of the drug—absorption, distribution, concentration in body fluids and tissues, and metabolism—also plays an important role. Finally, the nature and severity of the underlying illness, the toxicity of the agent, and costs must be considered.
Preparation and Characterization of Monoclonal Antibodies Against Sperm‐Specific Lactate Dehydrogenase C4
Authors: WANG SHI‐XIAN , LUO AN‐MING , LIANG ZHI‐GUO , SONG JI‐FAN , WANG HUAI‐AN , CHEN YAN‐XIANG
Published: October 2023

LDH‐C4, the testis‐specific isozymes of lactate dehydrogenase (LDH), is the predominant LDH isozyme in mammalian spermatozoa. Nine monoclonal antibodies against mouse LDH‐C4 have been developed. These antibodies were tested for cross reactivity with LDH‐C4 from human testis and with LDH‐1–5 from mouse and human testes by Immunoelectrophoresis, bio‐dot, and western blot assays. The results showed that all monoclonal antibodies were specific to LDH‐C4 only: they did not react with LDH‐1–5 from mice, nor from humans. The immunologic localization of the monoclonal antibodies on capacitated sperm was observed by indirect immunofluorescent assay. On mouse sperm the antibodies were bound to the tail only, but on human sperm eight antibodies were bound to the postacrosome, some to the neck and to the mid‐piece. Most of the antibodies belonged to the Ig G class.
Does Ethane 1,2‐Dimethanesulphonate (EDS) Have a Direct Cytotoxic Effect on the Seminiferous Epithelium of the Rat Testis?
Authors: SPRANDO ROBERT L. , SANTULLI ROSEMARY , AWONIYI CALEB A. , EWING LARRY L. , ZIRKIN BARRY R.
Published: October 2023

The authors examined the possibility that ethane 1,2‐dimethanesulphonate (EDS) has a cytotoxic effect on spermatogenesis that is not secondary to androgen withdrawal resulting from the well known cytotoxic effect of EDS on Leydig cells. Adult male rats were implanted with polydimethylsiloxane (PDS) capsules containing testosterone (T) and estradiol (E), and were simultaneously injected with EDS. The PDS‐TE implants, by inhibiting luteinizing hormone (LH) production, prevented Leydig cells from repopulating the testis and clamped testosterone within the seminiferous tubules at increasing concentrations relative to implant size. In rats that received EDS alone, the number of advanced spermatids per testis was significantly reduced by 2 weeks, but within 8 weeks returned to the numbers maintained in vehicle‐injected control rats or in vehicle‐injected rats that received testosterone‐ and estradiol‐filled capsules of 24 cm and 0.1 cm, respectively (PDS‐24TE). Surprisingly, in rats that received an EDS injection plus PDS‐24TE implants, the number of advanced spermatids per testis was significantly reduced at 8 weeks and severe seminiferous tubule atrophy occurred despite the fact that the testosterone concentration was sufficient to quantitatively maintain spermatogenesis in vehicle‐injected rats. In rats injected with EDS and implanted with 24 cm testosterone but not estradiol‐filled capsules (PDS‐24T), the advanced spermatid number per testis was significantly higher than that in the EDS plus PDS‐24TE rats, but significantly lower than that in control rats. These results suggest that EDS may have a cytotoxic effect on the seminiferous epithelium that is independent of the elimination of Leydig cells, and that EDS and estradiol act synergistically to exert a profound toxic effect on I spermatogenesis.
Absence of Antisperm Antibodies in Anejaculatory Men
Authors: MENGE ALAN C. , OHL DANA A. , DENIL JOHAN , KORTE M. KATE , KELLER LAURA , McCABE MARCIANNA
Published: October 2023

Antisperm antibodies were assessed in the serum samples of 73 men unable to ejaculate naturally and on the sperm cells of 13 of these men. None of the serum samples were found to be positive by sperm agglutination or sperm immobilization methods and antibodies were detected by an immunobead assay on the sperm cells of one of the 13 men examined.
Changing Relationships between Testis Size, Sertoli Cell Number and Spermatogenesis in Sprague‐Dawley Rats
Authors: BERNDTSON WILLIAM E. , THOMPSON TERRY L.
Published: October 2023

Relationships between several reproductive characteristics were investigated in 25 Sprague‐Dawley rats aged 60, 150, and 240 days (n = 75). Daily sperm production correlated with body weight (r = 0.63), paired testes weight (r = 0.68), testes weight as a percentage of body weight (r = −0.50), the number of spermatids supported per Sertoli cell (r = 0.51) and the number of Sertoli cells per gram (r = 0.89) or per testis (r = 0.95) among rats pooled across age groups. In general, the number and magnitude of significant coefficients of correlation were decreased when calculated within age groups. The latter often appeared to reflect a statistical consequence of relative homogeneity among rats rather than the absence of a biological relationship. However, the total number of Sertoli cells per testis correlated with daily sperm production within age groups, and could account for 85 to 94% of the variability in sperm production at 150 and 240 days, respectively.
Plasma Levels of Estradiol, Testosterone, and DHEAS Do Not Predict Risk of Coronary Artery Disease in Men
Authors: CONTOREGGI CARLO S. , BLACKMAN MARC R. , ANDRES REUBIN , MULLER DENNIS C. , LAKATTA EDWARD G. , FLEG JEROME L. , HARMAN S. MITCHELL
Published: October 2023

Prior studies have reported men with coronary artery disease (CAD) to have elevated plasma levels of estrogens and reduced concentrations of dehydroepiandrosterone (DHEA) or DHEA‐sulfate (DHEAS). We investigated whether gonadal steroids or DHEAS are risk factors for CAD in men, using a prospective design, in a well characterized population studied at regular intervals. We studied 46 men (Cardiac group) who developed CAD and 124 men (Control group) who remained free of CAD (mean follow‐up, 9.5 years). We measured testosterone (T), estradiol (E2), and DHEAS, as well as plasma binding of T and E2, in samples stored before the onset of CAD (Cardiac group) or at matched times (Control group). Body mass index, blood pressure, and total serum cholesterol were measured at each visit. Both systolic blood pressure (SBP; P < 0.001) and cholesterol (P < 0.001) were increased in the Cardiac group, but no significant differences were found in total or free T or E2, the ratio of E2/T, or DHEAS between the two groups. The difference in cholesterol was significant only in men ≤65 years old (P < 0.001), and SBP only in men >65 years old (P < 0.005). Cholesterol (P < 0.05) and E2 (P < 0.001) appeared to decrease with age in the Cardiac, but not the Control, group. Moreover, total (P < 0.01) and free E2 (P < 0.05) were lower only in Cardiac men ≤55 years old. Correlations of SBP and cholesterol with steroid levels revealed only a weak inverse association of free T level with SBP (P < 0.03). These data suggest that in men, adrenal and gonadal steroids do not strongly influence CAD risk and that cholesterol and SBP are more important CAD risk factors in young and in old men, respectively. Moreover, our findings are consistent with those that indicate a cardioprotective role for endogenous E2 in men, as well as in women.
Atrial Natriuretic Peptide Precursor Material in Rat Testis
Authors: VOLLMAR ANGELIKA M. , FRIEDRICH ANITA , SCHULZ RÜDIGER
Published: October 2023

Atrial natriuretic peptide (ANP) has recently been suggested to play a role in the regulation of male reproduction. Specifically, it has been shown to affect steroidogenesis in Leydig cells. The data presented here demonstrate that the rat testis also contains immunoreactive, ANP‐like material (IR‐ANP). Characterization of this material was conducted by high‐pressure liquid chromatography (HPLC) analysts employing two different antisera to recognize either the C‐ or the N‐terminals of the ANP prohormone (ANP 1–126). The IR‐ANP corresponded to the 15 kd ANP precursor molecule (ANP 1–126), indicating the synthesis of ANP within the testis. This was supported by the detection of ANP messenger RNA transcripts (Northern blot hybridization) in the testis. These data indicate that ANP is expressed in the rat testis and support the notion that it may function in a paracrine and/or autocrine fashion in this organ.
Spermatic Cord Torsion Contralateral Testicular Degeneration at Various Ages in the Rat
Authors: HEINDEL RACHEL M. , PAKYZ RUTH E. , COSENTINO M. JAMES
Published: October 2023

Unilateral spermatic cord torsion causes damage to the contralateral testis in humans and animal models. It is now known, however, at what age an animal's reproductive capacity is most susceptible to this type of trauma. To determine if the animal's age is a factor in its susceptibility to reproductive damage, rats at 30 to 70 days of age were subjected to unilateral spermatic cord torsion. Rats of the same ages underwent sham surgery and served as controls. The animals were allowed to recover from the surgery and to attain puberty before a period of fertility testing. Fertility, serum testosterone, organ weight, and testicular histologic data were obtained after the breeding period. Our data indicate that animals undergoing torsion at the youngest (30 days) and oldest (70 days) ages exhibited no change in the parameters studied. Animals between the ages of 35 and 50 days are highly susceptible to reproductive damage due to unilateral spermatic cord torsion, and the 35‐day‐old animals exhibit the most susceptibility. The stages of testicular development occurring during this period are such that damage to one testicle will result in degeneration of both organs. However, once the animal is older than 50 days, its reproductive capacity is not affected by spermatic cord torsion. The specific period of susceptibility in the development of human testes is yet to be defined.
Nuclear Androgen Receptor Dynamics in Testicular Peritubular and Sertoli Cells
Authors: BUZEK S. W. , SANBORN B. M.
Published: October 2023

Nuclear androgen receptor dynamics were analyzed in peritubular cells and compared with those in cultured Sertoli cells. Nuclear receptors with a high affinity for [3H]dimethylnortestosterone (DMNT; mibolerone) exhibited equilibrium constants of 0.8 and 0.7 nmol, in Sertoli and peritubular cells, respectively. Time‐ and dose‐dependent accumulation of nuclear bound receptors after exposure of whole cells to [3H]testosterone was similar for both cell types. Exogenously administered ligands demonstrated similar relative potencies as competitors with [3H]T for Sertoli and peritubular cell nuclear binding sites: DMNT > T > medroxyprogesterone acetate (MPA) > cyproterone acetate (CPA) τ hydroxyflutamide (OHF). Cells incubated with T or MPA showed increased nuclear androgen receptor concentrations compared to untreated controls, whereas those treated with CPA or OHF did not. These results demonstrate that the nuclear androgen receptor dynamics of peritubular cells are consistent with those of target cells. Since the dynamics are similar in Sertoli and peritubular cells, both cell types have the potential to respond to local androgen concentrations and may play important roles in androgen‐dependent effects on seminiferous tubule function.
The Effect of Duration of Exposure on the Expression of Lead Toxicity on the Male Reproductive Axis
Authors: SOKOL REBECCA Z.
Published: October 2023

This study assesses the significance of duration of exposure on the expression of lead toxicity on the male reproductive system. Male Wistar rats, 52 days old, were treated with 0.0% or 0.6% lead acetate in their water for 7, 14, 30, or 60 days prior to sacrifice. In all cases, the lead‐treated groups had blood lead and free erythrocyte protoporphyrin (FEP) levels significantly higher than control animals (P < 0.0001). Serum testosterone levels and spermatogenesis were suppressed in all lead‐treated groups compared to the corresponding controls (P < 0.05 and P < 0.001, respectively), except for the group treated for 7 days. The data presented verify that exposure to lead acetate is toxic to the reproductive axis in male rats, but that increased duration of exposure after 14 days does not further suppress serum testosterone levels or spermatogenesis.
Effect of Sperm‐Associated Antibodies on the Acrosomal Status of Human Sperm
Authors: LANSFORD BRYAN , HAAS GILBERT G. , DEBAULT LAWRENCE E. , WOLF DON P.
Published: October 2023

The acrosomal status of human sperm was assessed by the specific binding of Pisum sativum lectin to the acrosomal matrix. Immunoglobulin G (IgG) fractions of plasmas that were positive for IgG antisperm antibodies inhibited acrosomal loss, initiated acrosomal loss, or had no effect on acrosomal loss. Two of five sperm samples associated in vivo with only IgG, zero of one sample associated with only sperm‐associated immunoglobulin A (IgA), and six of eight samples associated with both IgA and IgG underwent acrosomal loss prior to exposure to calcium ionophore. Two sperm samples associated with IgG or IgA or both were inhibited from undergoing acrosome loss after exposure to calcium ionophore. None of the seven antibody‐negative sperm samples underwent an increased spontaneous acrosomal loss or were inhibited from undergoing acrosomal loss after exposure to calcium ionophore.
Characterization and Partial Purification of the 8–9S Androgen Receptor from Benign Prostatic Hyperplasia Tissues
Authors: KOUTSILIERIS MICHAEL , GRONDIN FRANCINE , BOUTHILLIER FRANCOIS , RADWAN FAROUK , CARMEL MICHEL , ELHILALI MOSTAFA , LEHOUX JEAN‐GUY
Published: October 2023

The present study reports a 3,800‐fold purification of the 8‐9S androgen‐receptor complex from benign prostate hyperplasia (BPH) tissues using differential chromatography. In addition, the BPH androgen receptor complexes have been characterized using sucrose density gradient (SDG) ultracentrifugation, gel permeation, and anion exchange high performance liquid chromatography (HPLC). Results indicate that a) under nontransforming conditions, BPH cytosols contained both 8‐9S (40–78%) and 4S (22–60%) androgen‐receptor forms, b) apparent molecular weights of these androgen‐receptor complexes, as analyzed by gel permeation HPLC, were estimated to correspond at 270 kDa, and 90 kDa respectively, c) 8‐9S androgen‐receptor complexes were retained on an anion exchange HPLC column and could be eluted at 0.22 M KCl at a linear gradient, whereas 4S complexes were not retained on anion exchange columns under identical experimental conditions, d) 10X dilution of BPH cytosols containing only the 4S (0.6 M KCl) form and subsequent chromatography on anion exchange HPLC system was indicative of fragmentation (these fragments were retained on anion exchange columns and could be eluted by 0.33 M KCl on a linear gradient HPLC), and e) increased temperature (22 C) was permissive of proteolytic fragmentation (fragments were estimated to correspond at 30, 15, and 5 kDa). The results are discussed in relationship with the composition of the nontransformed androgen‐receptor molecules.
Cyclosporine: Its Effects on Testicular Function and Fertility in the Prepubertal Rat
Authors: SEETHALAKSHMI L. , FLORES CARLOS , CARBONI A. A. , BALA RAM , DIAMOND DAVID A. , MENON MANI
Published: October 2023

The authors examined the effects of the immunosuppressive drug cyclosporine (CsA) on the male reproductive system in prepubertal rats. Twenty‐one‐day‐old rats were subcutaneously injected with either cremaphorsaline vehicle or CsA (1 and 2 mg/kg/d). The animals were treated until they were 66 days old. Cyclosporine did not affect the weights of the body or testis but decreased the weights of all sex accessory organs. Quantitative analysis of the tubules in stage VII of spermatogenesis revealed a decline in the cell counts of pachytene spermatocytes and step VII spermatids. Testicular and epididymal sperm counts and motility were decreased by 50% and fertility by 60%.

Cyclosporine lowered serum testosterone despite an elevation of LH, indicating that the drug directly inhibited testosterone synthesis. Serum creatinine levels were normal in the treated animals, precluding renal failure as the cause for this impairment. Intratesticular concentrations of pregnenolone and 17‐hydroxy progesterone were significantly elevated, while those of progesterone, androstenedione, and testosterone were markedly reduced. Determination of steroidogenic enzyme activities indicated that the administration of CsA inhibited the activity of Δ5‐3B‐hydroxy steroid dehydrogenase‐Δ5‐4 isomerase (3beta‐HSD). These results clearly indicate that CsA in the doses used is harmful to the male reproductive function in prepubertal rats.
In Vitro Interactions of Calmodulin with the Ovine Proacrosin‐Acrosin System
Authors: FRENETTE GILLES , CHAFOULEAS JAMES G. , TREMBLAY ROLAND R. , DUBÉ JEAN Y.
Published: October 2023

The authors studied the interaction of calmodulin (CaM) with proacrosin and acrosin from ram spermatozoa. CaM binding evaluated by the [125I]‐CaM overlay procedure was shown to occur preferentially with both proacrosin and acrosin in the presence of EGTA; in the presence of Ca2+, the interaction was less intense. Further studies with native proenzyme preparations showed that proacrosin activation at pH 7.1 or 8.0 was significantly accelerated in the presence of CaM and EGTA (t1/2 = 23 min vs. 55 min for EGTA alone at pH 7.1), but not in the presence of Ca2+ (t1/2 = 73 min). The enzymatic activity of acrosin towards benzoyl arginine paranitroanilide, however, was not significantly affected by CaM whether Ca2+ was absent or present. Finally, the authors demonstrated that acrosin hydrolyzed CaM rapidly and extensively in the presence of EGTA. These results indicate that CaM interacts in vitro with proacrosin and acrosin, and that acrosin can attenuate CaM activity through proteolysis. Whether these interactions also occur in vivo and are involved in some aspects of spermatozoa function remains to be determined.
Longitudinal Study of Semen Quality of Unexposed Workers: SPERM HEAD MORPHOMETRY
Authors: SCHRADER STEVEN M. , TURNER TERRY W. , SIMON STEPHEN D.
Published: October 2023

As part of a longitudinal study of human semen characteristics of unexposed workers, sperm head measurements were made using image analysis (Image Technologies Corp., Deer Park, NY). Morphometry was conducted on monthly samples from 45 men for 9 months. Measurements of area, perimeter, length, width, the width‐length ratio, and the oval factor (4 [pi] area/perimeter2) of 100 sperm heads per sample were obtained. The variability within a sample, between monthly samples from the same individual, and between individuals were calculated for each parameter. Tolerance intervals for each parameter were calculated, and are expected to contain 75% of all individual measurements. Similar intervals were calculated for the means and coefficients of variation of a semen sample. The largest source of variability was attributed to individual cell variation within a semen sample.
Human Sperm Motion Analysis By Automatic (Hamilton‐Thorn Motility Analyzer) and Manual (Image‐80) Digitization Systems
Authors: OLDS‐CLARKE PATRICIA , BAER HARRY M. , GERBER WALTER L.
Published: October 2023

Two systems allowing quantitative, objective analysis of sperm movement were compared: 1) the Hamilton‐Thorn Motility Analyzer (HTM), in which sperm images are digitized automatically, and 2) the Image‐80, a modified image‐analysis system in which sperm movement is digitized manually by hand tracing from videotape (Tessler and Olds‐Clarke, 1985). Videotapes were made of human spermatozoa obtained by a swim‐up procedure. The same videotape frames were analyzed by both systems. The mean percentage of motile spermatozoa was similar as judged by eye with either the HTM or Image‐80 monitors and as reported by the HTM. For every motile spermatozoon, two motility parameters were calculated: linearity (a measure of track shape) and curvilinear yelocity at 30 frames/second (a measure of track speed). When samples from five donors were averaged, there were no significant differences in mean linearity between automatic and manual systems. Also, linearity as reported by the HTM and Image‐80 systems for the same track was significantly correlated (r = 0.72; N = 80). Whereas the absolute values for curvilinear velocity were slightly but significantly higher for the Image‐80 system than for the HTM system, their correlation was also significant (r = 0.91). Since the two systems provide comparable data on percentage of motile sperm as well as speed and path shape parameters, this suggests that the HTM automatic digitization is accurate for images of human spermatozoa.
cAMP Response of Cultured Sertoli Cells from Immature and Adult Hamsters Effect of Hypophysectomy and Cryptorchidism
Authors: HEINDEL JERROLD J.
Published: October 2023

The ability of FSH to stimulate cAMP accumulation in Sertoli cells cultured from either hamsters or rats declines with the age of the animal. Hypophysectomy or bilateral cryptorchidism of immature rats prevents this normal age‐related decline in Sertoli cell response to FSH. However, neither hypophysectomy nor cryptorchidism of adult rats can restore the Sertoli cell response to that of the immature animal. In contrast, the Sertoli cell response to FSH in the adult golden hamster, a photoperiodic animal, can be restored to that of an immature animal during short photoperiod‐induced testicular regression. Thus, the purpose of these experiments was to determine if the Sertoli cell response to FSH would also be restored to that of an immature animal when testicular regression was induced by other means, namely, hypophysectomy or bilateral cryptorchidism. As in the rat, hypophysectomy or cryptorchidy of immature hamsters resulted in decreased testicular growth and a cAMP response to FSH in cultured Sertoli cells, which remained at the high level of an immature animal. However, in contrast to the rat, hypophysectomy or bilateral cryptorchidism of the adult hamster resulted in not only testicular regression, but also a restored ability of FSH to stimulate cAMP accumulation in Sertoli cells cultured from these animals. Indeed, the magnitude and specificity of the Sertoli cell cAMP response to agents was the same in Sertoli cells cultured from testes undergoing testicular regression induced by either short photoperiod (ie, natural means), hypophysectomy, or cryptorchidy. That is, the ability of FSH to stimulate Sertoli cell cAMP accumulation was “restored” to levels indicative of Sertoli cells from an immature animal, whereas the response to cholera toxin, forskolin, or isoproterenol was not changed from the adult response. Although the mechanism of this specific restoration of FSH responsiveness of Sertoli cells from hamsters with regressed testes is not clear, the fact that it occurs in testes regressed by seemingly independent mechanisms may ultimately provide us with a model necessary to understand this phenomenon.