The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells.

Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants.

Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women.

A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(∼)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination.

Botulinum toxin: a potential alternative to current treatment of neurogenic and idiopathic urinary incontinence due to detrusor overactivity.

OBJECTIVE: To analyze and report the current data on the treatment of both neurogenic and idiopathic detrusor overactivity with Botulinum toxin. METHODS: Literature review using Pub-Med and Medline from 1990 until June 30, 2006. RESULTS: Case series of patients with neurogenic detrusor dysfunction (NDD) and idiopathic detrusor overactivity (IDO) range from 15 to 200 patients with follow up from 12 to 36 weeks post-treatment. Significant improvements in cystometric bladder capacity, reflex volume at first urge to void, and bladder compliance are seen in nearly all patients. Approximately 50% of NDD patients achieved urinary continence and almost all had improvement in bladder control up to 36 weeks following treatment. Patients with IDO with urgency alone or with incontinence also had urodynamic as well as symptom improvement. Approximately 75% of patients with IDO and incontinence are dry at 12 weeks post-treatment. Urgency disappears on average in two thirds of patients. Quality of life scores also shows significant improvement for all groups. CONCLUSION: Botulinum toxin-A has emerged as a promising option for the treatment of neurogenic and refractory idiopathic detrusor overactivity. Studies to date have shown that not only is this treatment effective at decreasing urinary symptoms and incontinence, as well as improving potentially dangerous urodynamic measures, but it is also minimally invasive, reversible and safe. Questions over proper dosing and dilution, number of injection sites, and re-injection rates remain to be answered.

A brief history of testosterone.

PURPOSE: We explore the history of testosterone in the context of medical and scientific developments. MATERIALS AND METHODS: A review of the scientific and historical literature was conducted. RESULTS: The origins and effects of testosterone have been recognized throughout the history of humankind. Hunter performed testicular transplantation experiments in 1767 while studying tissue transplantation techniques, and almost a century later Berthold linked the physiological and behavioral changes of castration to a substance secreted by the testes. Brown-Séquard gave birth to the field of organotherapy in 1889 when he announced that his auto-injection of testicular extracts resulted in rejuvenated physical and mental abilities. Steinach and Niehans expanded upon Brown-Séquard's work with rejuvenation treatments involving vasoligation, tissue grafts and cellular injections. In 1935 David et al isolated the critical ingredient in organotherapeutic treatments, testosterone. CONCLUSIONS: The effects of the powerful hormone testosterone continue to inspire research and controversy 65 years later.

Preclinical toxicology studies with the angiotensin-converting enzyme inhibitor quinapril hydrochloride (Accupril).

Acute, subacute, and chronic toxicity studies, carcinogenicity bioassays, and reproductive and genetic toxicology studies were performed with quinapril, an ACE inhibitor used in the treatment of hypertension. Acute toxicity is minimal in rodents, and repeated dosing elicits gastric irritation, juxtaglomerular apparatus (JGA) hypertrophy and hyperplasia and tubular degenerative changes in the kidney, and reduced red cell parameters and heart weights in rodents and/or dogs. Other manifestations of toxicity, including hepatic lesions in dogs, reduced offspring weights in rats, marked sensitivity of the rabbit, and clastogenic effects at cytotoxic doses in the in vitro V79 chromosome aberration assay, have been reported with other drugs of this class.

Treatment of anejaculation with electroejaculation.

Male infertility caused by anejaculation is common after spinal cord injury (SCI) and following retroperitoneal lymph node dissection (RPLND) for testicular cancer. Other conditions sometimes associated with neurogenic ejaculation loss are diabetes mellitus, multiple sclerosis, extensive pelvic surgery and adult myelodysplasia. Primary absence of ejaculation also has been described. Few treatment options exist for these patients, if they wish to father a child. With electroejaculation (EEJ), or the low-current stimulation of the ejaculatory organs via a rectal probe, emission of semen can be initiated in these men. In non-SCI-patients EEJ requires general anaesthesia. The collected semen is washed and the motile sperm fraction isolated before artificial insemination (AI) of the partner. At the University of Michigan 198 men have been treated between 1986 and December 1991. An ejaculate could be obtained from nearly all patients. A major obstacle to success is the severe asthenozoospermia and the poor functional quality of the obtained sperm samples. This can be caused by the EEJ-technique itself, as well as by the long anejaculatory status. A semen sample with at least 10 million progressively motile sperm cells, useful for AI, was obtained in 75% of the SCI men and in 87% of the men following RPLND. In the couples wishing insemination, 49 pregnancies were induced, accounting for an overall pregnancy rate of 35% per couple. Thirty five healthy babies have been born. Only three complications were encountered. At Hannover Medical School only few patients have been stimulated to date. We could obtain an adequate sperm sample for AI from all of them. No complications were seen. As the first couple has just entered the phase of AI with husband sperm, an analysis of these results would be premature. Electroejaculation combined with artificial insemination is an efficient and safe treatment of male infertility due to neurogenic anejaculation.

Creation of a feline model of obstructive uropathy.

The aim of this project was to create a reproducible, quantifiable feline model of obstructive uropathy. Seventy-three adult female cats of comparable age were evaluated to obtain the normal control urodynamic data base. Twenty-four cats had a silastic cuff installed around the urethra to induce bladder outlet obstruction, and eight underwent a sham operation. Repeated urodynamic evaluations were performed at predetermined postoperative intervals. The obstructed and normal cats inhibited detrusor contractility by reflex striated urethral sphincter activity. Measurements of voiding pressure to verify the presence, and to assess the degree of induced outlet obstruction, required paralysis of the sphincter by curare. Following cuff implantation, voiding pressure increased from a mean normal of 17.2 cm./H2O to 31.6 to 42.5 cm./H2O in animals designated as moderately obstructed, and to 101.7-125.0 cm./H2O in animals designated as severely obstructed. 84.6% of the high pressure bladders developed vesicoureteral reflux. Analysis of resting, low bladder volume, urethral pressure profile (UPP) data and voiding pressures indicate a compensatory sphincteric response to filling in non-curarized animals, and a lack of that response in curarized animals. It appears that implantation of a silastic cuff to prevent full opening of the urethra during voiding, without actually compressing it, is a reasonable model of obstructive uropathy. The observation that the relationship between striated urethral sphincter activity and inhibition of detrusor contractility is influenced by administration of curare was unexpected, and may have clinical implications.

Predictors of success in electroejaculation of spinal cord injured men.

Rectal probe electroejaculation was attempted in 48 spinal cord injury men and greater than 10 million sperm were obtained in 71%. Patient age and interval since injury had no effect on outcome. The best performance was seen in thoracic paraplegics and in those using intermittent catheterization for bladder management. Indwelling urethral catheters and high pressure reflex voiding had a negative impact on electroejaculation results.

A human milk galactosyltransferase is specific for secreted, but not plasma, IgA.

IgA from human milk and colostrum is a substrate for a galactosyltransferase also present in milk and colostrum. The secreted IgA that serves as the best acceptor for the transferase activity is the IgA that fails to bind readily to jacalin lectin. Upon becoming galactosylated by the transferase, however, the IgA shows an increased affinity for jacalin. Glycosidase and electrophoretic results indicate that the transferred galactose is beta-linked to the alpha-chain of the IgA. The IgA:transferase activity can be purified by gel filtration and cation exchange chromatographies, as well as by affinity chromatography on Sepharose derivatized with UDP or IgM. The enzyme has an apparent Mr of about 64 kDa, is prevalent in both milk and colostrum, but has a sixfold higher sp act in colostrum.

Electroejaculation for recovery of semen after retroperitoneal lymph node dissection: case report.

Electroejaculation with a rectal probe was used successfully for semen recovery 8 years after bilateral suprarenal hilar lymph node dissection for stage IIB embryonal cell cancer. An adequate ejaculate was obtained in relation to total sperm count, motility and normal morphology. Prior use of sympathomimetic drugs, including imipramine and ephedrine, was unsuccessful in producing an ejaculation. Electrostimulation via a rectal probe seems to be a useful technique for semen recovery in the patient with anejaculation after retroperitoneal lymph node dissection.

The innervation and function of the lower urinary tract.

Vesical and urethral function are closely controlled by neural activity, both reflex and volitional. Relatively subtle abnormalities have serious consequences. Understanding of the natural history of neurogenic vesical dysfunction has improved over the past few years and is summarized in this review article.

Evaluation of chronic toxicity and carcinogenesis in rodents with the synthetic analgesic, tilidine fumarate.

The carcinogenic potential of tilidine fumarate, a synthetic analgesic, was studied for 80 and 104 weeks in mice and rats, respectively. Groups of 50 albino CF1 mice and 65 albino Wistar rats of each sex received tilidine fumarate-lactose blend (1:1) at doses of 100, 40 and 16 mg/kg. The control groups consisted of 100 mice and 115 rats of each sex and received the lactose vehicle only. Treatment-related non-neoplastic changes consisted of reversible, increased cytoplasmic eosinophilia of hepatocytes in high and mid dose rats corresponding to areas of proliferating smooth endoplasmic reticulum; and an increased incidence in high dose rats of proliferative or cystic lesions of the biliary epithelium. Adequate survival rates allowed stringent statistical analysis of neoplasia. Tilidine did not evoke increased tumor incidences or changes in the average latency or onset of tumors in either species. The most frequent tumors represented spontaneous neoplasia characteristic of historical background incidence in these strains. In mice, the only statistically significant (P less than 0.01) variation in tumor incidence was an increased rate of lung alveologenic adenocarcinomas in females at 100 mg/kg (24%), compared with the concurrent untreated controls (10%), but without a statistically significant difference from historical control data (27%). Female rats given 100 mg/kg showed statistically significant (P less than 0.01) decreased incidences of mammary fibroadenoma and pituitary adenoma. From these data, it was concluded that the synthetic analgesic tilidine does not possess tumorigenic potential in rodents.

Preclinical toxicology studies with the lipid-regulating agent gemcadiol.

Gemcadiol is a medium-length diol moiety with lipid-regulating properties in animals and man. The compound was not toxic when single doses were administered to rodents with the lethal dose greater than 7000 mg/kg in rats and mice. Rats treated for 13 or 52 weeks with 30 to 300 mg/kg had reversible food intake suppression and weight gain inhibition, decreased blood cholesterol, slight anemia, and generally dose-related but reversible decreases in glucose, and increases in alkaline phosphatase and blood urea nitrogen. Liver weights were increased, and there was accompanying hypertrophy and increased cytoplasmic eosinophilia of hepatocytes with associated peroxisome proliferation. Rats treated for 52 weeks also had mild renal tubular dilatation. Dogs given 25 to 300 mg/kg of gemcadiol for up to 52 weeks tolerated the compound better than rats. Effects related to compound administration were elevated serum alanine aminotransferase activity in female animals only, and microscopic cytoplasmic vacuolation and hyaline body formation in both sexes. Monkeys given 25 to 300 mg/kg gemcadiol for 13 weeks had slightly decreased serum cholesterol and slightly increased serum creatine phosphokinase. Teratology studies in rats or rabbits indicated no teratogenic response. Gemcadiol affects principally the liver, and the hepatic alterations seen in rats and dogs may reflect compensatory manifestations of altered metabolism related to the lipid-regulating activity of the compound.

Treatment of motor and sensory detrusor instability by electrical stimulation.

A new application of electrical stimulation to inhibit detrusor activity has been used in 15 patients with a variety of neural lesions. The results were astonishingly good and the device was well tolerated. In patients treated successfully for detrusor instability an absence of urgency occurred as a by-product of electrical stimulation. Therefore, stimulation was used to treat uncomfortable bladder urgency without detrusor instability and was successful in the majority of patients.

The influence of urethral position on urinary continence.

Bladder and urethral pressure responses to increasing intraabdominal pressure were studied in anesthetized cats. The results indicate that urethral responses are entirely passive and dependent on the intraabdominal position of the urethra. Urethral resistence to urine flow was not influenced by curare administration or complete sacral rhizotomy but was markedly decreased by phentolamine administration or the application of pressure directly to the bladder.