Angiogenesis Therapy for the Treatment of Erectile Dysfunction

IntroductionOver the past 15 years, significant advances have been made in the treatment of erectile dysfunction (ED). The most significant of these advances has been pharmacological treatment of ED with phosphodiesterase type 5 (PDE5) inhibitors. This therapy greatly increased the awareness of ED and has helped stimulate research into the underlying causes of ED. While treatment with PDE5 inhibitors continues to be the current therapy of choice, approximately 40% of men treated with PDE5 inhibitors fail to have significant improvement in erectile function and PDE5 inhibitors do not reverse the vasculopathic processes associated with ED. With this in mind, new therapies must be developed. The treatment with angiogenic growth factors such as vascular endothelial cell growth factor (VEGF) may be one such therapy.AimThis review will focus on defining key terms in the angiogenic process, angiogenic growth factors, and different delivery methods, and summarize results from angiogenic therapies for the treatment of ED.MethodsA review of the literature was performed on all angiogenic therapies for the treatment of ED. A brief review on the angiogenic factors was also performedResultsAngiogenic therapies for the treatment of ED are possible and promising; however, further investigation is needed to advance clinically.ConclusionsAlthough numerous studies have now employed angiogenic factors for the possible treatment of ED in several animal models, we are still not at the point to begin human investigations. Future studies need to examine proper dosage of the angiogenic agent, route of delivery, time course for delivery, and combination therapies. Lysiak JJ, Kavoussi PK, Ellati RT, Steers WD, and Annex BH. Angiogenesis therapy for the treatment of erectile dysfunction.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

CD40 expression by gingival fibroblasts: correlation of phenotype with function

CD40, a member of the tumor necrosis factor-alpha receptor family, is constitutively expressed by cells of hematopoietic and non- hematopoietic origin, including fibroblasts. Signaling through this receptor molecule regulates inflammatory cytokine secretion by many cell types. Based on the recently described cytokine secretory heterogeneity of fibroblast cell subsets, we hypothesized that secretion of inflammatory cytokines by gingival fibroblast cultures may be dictated by the existence of differential proportions of cytokine- secreting subpopulations which express high levels of CD40. After examining a large number of gingival fibroblast (GF) cultures we find that the frequency of IL-6- and IL-8-secreting cells mirrors the frequency of cells expressing high levels of CD40 in these cultures. In addition, we demonstrate a direct functional relationship between CD40 expression and IL-6 or IL-8 secretion by showing that ligation of this molecule on GF, and CD40+ fibroblast subsets in particular, up- regulates secretion of these cytokines in vitro.      

Elderly Patients with Suppressed Serum TSH but Normal Free Thyroid Hormone Levels Usually Have Mild Thyroid Overactivity and are at Increased Risk of Developing Overt Hyperthyroidism

The clinical and biochemical characteristics of 15 elderly patientswith low levels of thyrotrophin (TSH) (<0.1 mU/L) but normalfree tri-iodothyronine, (T3) and free thyroxine (T4) (groupS) were compared with 10 euthyroid subjects (group E) and 10hyperthyroid patients (group T). Free T3 and free T4 were significantlyhigher (p<0.05) in group S(6.3±0.5 and 18.6±1.0pmol/l, respectively) than in group E(4.6±0.3, 12.6+0.6).In common with elderly hyperthyroid patients (group T)patientsin group S had few signs or symptoms of thyrotoxocosis, butthe Wayne score (clinical index of hyperthyroidism) was higherin group S than in euthyroid subjects (p<0.05). Thyroid microsomal,thyrogolobulin or thyrotrophin receptor antibodies were commonin group T (n=9)but not in groups S(n=2) or E(n=1). This suggestsa low prevalence of Graves' disease in group S compared to groupT. Combined thyrotrophin releasing hormone (TRH; 200 µgi.v.) and gonadotrophin releasing hormone GnRH; 100 µgi.v.) tests were performed; no cases of low TSH due to hypopituitarismwere identified in group S. During a mean of 7.9 (4–12)months of observation TSH reverted to the normal range (>0.2mU/L)in 7 of 15 patients in group S; thyroid hormone concentrationsrose above the normal range in four, however, only two patientsrequired treatment for hyperthyroidism. It is unlikely thatthe suppressed TSH of patients in group S was due to mild thyroidhormone excess; although this is often a transitory phenomenon,these patients are at increased risk of developing overt hyperthyroidism.     

Excitatory and inhibitory influences on bladder activity elicited by electrical stimulation in the pontine micturition center in the rat

Electrical stimulation at various sites in the dorsal pontine tegmentum in urethane anesthetized rats modulated activity of the urinary bladder as well as efferent firing on bladder postganglionic nerves. Electrical stimulation (0.2 ms 50 Hz, 5-20 V or 30-150 microA, 2-5 s train duration) using a microelectrode (tip diameter, 10-20 microns) in an excitatory area located rostral and medial to the locus coeruleus evoked short latency (less than 2 s) large amplitude (greater than 20 cm H2O) bladder contractions and increased firing on the bladder postganglionic nerves. Stimulation at sites adjacent to the excitatory area inhibited bladder postganglionic nerve firing and bladder activity. Inhibitory responses were evident as either a decrease in intravesical pressure, an increased interval between bladder contractions, or an interruption or elimination of bladder contractions. The threshold intensity for excitation using a large electrode (2-4 V) was slightly higher than that for inhibition (1.5-2 V). The optimum sites for evoking bladder contractions were located in and close to the laterodorsal tegmental nucleus (LDT) and in the periaqueductal gray just dorsal or dorsolateral to the LDT. The extent of the area that induced bladder contractions was 0.5-1.2 mm in diameter in each rat when a microelectrode was employed for electrical stimulation. Electrical stimulation in the optimum site for evoking bladder contractions induced relatively little striated muscle activity and produced no short-latency blood pressure changes. The longer latency blood pressure changes associated with a spontaneous bladder contraction were still present following a stimulation of the dorsolateral pons. These data are consistent with the view that neurons in the dorsal pontine tegmentum play an important role in the regulation of urine storage as well as urine release.     

汉族志愿者阿米替林代谢与异喹呱羟化代谢的关系

8名男性健康志愿者po阿米替林100 mg后,以阿米替林及其3种代谢物的血浓度曲线下面积(AUC₀^∞)计算阿米替林的脱甲基化代谢及羟基化代谢能力。结果提示个体间阿米替林及其3种代谢物的AUC差异很大。其中7名志愿者测定异喹呱羟化代谢表型,6例为异喹呱强代谢者,1例为弱代谢者。尿中异喹呱的羟化代谢率与阿米替林的羟基化代谢率、阿米替林和10-羟基阿米替林的AUC₀^∞呈显著相关。阿米替林总血浆清除率与异喹呱羟化代谢率呈弱相关。此结果表明阿米替林和异喹呱的羟化代谢可能由同一酶控制,阿米替林的羟基化代谢和脱甲基化代谢可能为两个独立的代谢途径。     

Review of 31 cases of morphologic hepatitis in liver transplant patients not related to disease recurrence

AIMS: We examined the clinical and pathologic features of morphologic hepatitis occurring after liver transplantation (LT) that is unrelated to disease recurrence. METHODS: Between February 1998 and December 2003, 704 primary LTs were performed at our center. Patients transplanted for diagnoses with low risk of disease recurrence were considered for our study (n = 282). Those with hepatitis C (HCV), hepatitis B (HBV), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) were excluded. Those with morphologic hepatitis comprised our case series and had medical records reviewed for clinical associations, duration, and outcome. RESULTS: Thirty-one cases were identified. They were transplanted for cryptogenic cirrhosis (n = 13), steatohepatitis (n = 12), alpha-1-antitrypsin deficiency (n = 3), tumor (n = 2), and acetaminophen toxicity (n = 1); 22 cases (67%) presented within the first 8 months post-LT (range, 0.5-72 months). Histological activity was mild in 19 and moderate in 12. Associated conditions were identified in 19 patients (57%) with 3 categories being identified: probable drug toxicity (n = 7), systemic infection (n = 4), and mechanical or hemodynamic abnormalities (n = 8). Of the 25 cases that underwent follow-up biopsy 2 to 32 months (mean, 15.5 months) after the index biopsy, 10 cases had resolution and 15 cases had persistence of the infiltrate. One patient had evidence of de novo HBV infection. CONCLUSIONS: Morphologic hepatitis occurred in 11% of patients at low risk for disease recurrence. Associated conditions could be grouped into three categories: drug toxicity, systemic infection, and mechanical or hemodynamic factors. Most cases did not appear to progress or improved over time, with no allograft loss occurring as a result of chronic hepatitis.